Amino acid derivatives

The invention provides amino acid derivatives of the formula ##STR1## wherein E represents CHO or B(OH).sub.2 ; PA0 R.sup.1 represents lower alkyl (optionally substituted by halo, cyano, lower alkylthio, aryl-lower alkylthio, aryl or heteroaryl), lower alkenyl or lower alkynyl; PA0 R.sup.2 represents lower alkyl optionally substituted by hydroxy, carboxy, aryl, aminocarbonyl or lower cycloalkyl; and PA0 R.sup.3 represents hydrogen or lower alkyl; or PA0 R.sup.2 and R.sup.3 together represent di- or trimethylene optionally substituted by hydroxy; PA0 R.sup.4 represents lower alkyl (optionally substituted by hydroxy, lower cycloalkyl, carboxy, aryl, lower alkylthio, cyano-lower alkylthio or aryl-lower alkylthio), lower alkenyl, aryl or lower cycloalkyl; PA0 R.sup.5 represents lower alkyl (optionally substituted by hydroxy, lower alkylthio, aryl, aryl-lower alkylthio or cyano-lower alkylthio) or lower cycloalkyl; PA0 R.sup.6 represents hydrogen or lower alkyl; PA0 R.sup.7 represent lower alkyl (optionally substituted by hydroxy, carboxy, aryl or lower cycloalkyl) or lower cycloalkyl; PA0 R.sup.8 represents lower alkyl optionally substituted by hydroxy, carboxy or aryl; and PA0 R.sup.9 represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl, and salts of acidic compounds of formula I with bases, which are viral proteinase inhibitors useful as antiviral agents, especially for the treatment or prophylaxis of infections caused by Hepatitis C, Hepatitis G and human GB viruses.

FIELD OF THE INVENTION 
The present invention is concerned with amino acid derivatives and a 
process for their manufacture. 
SUMMARY OF THE INVENTION 
The amino acid derivatives provided by the present invention are compounds 
of the formula 
##STR2## 
wherein E represents CHO or B(OH).sub.2 ; 
R.sup.1 represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 represents hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together represent di- or trimethylene optionally 
substituted by hydroxy; 
R.sup.4 represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower 
alkyl, carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower 
alkyl, aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 represents hydrogen or lower alkyl; 
R.sup.7 represent lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; and 
R.sup.9 represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, 
arylcarbonyl, lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or 
aryl-lower alkoxycarbonyl; 
and salts of acidic compounds of formula I with bases. 
The compounds of formula I and their aforementioned salts inhibit 
proteinases of viral origin and are useful in the treatment of viral 
infections, particularly viral infections caused by Hepatitis C, Hepatitis 
G and the human GB viruses. 
This invention also provides processes of producing compounds of formula I 
comprising: (a) when E is CHO, treating a corresponding acetal with a 
strong acid; or (b) when E is B(OH).sub.2, treating a corresponding 
dioxaborolane with a strong base or an alkali metal periodate.

DETAILED DESCRIPTION OF THE INVENTION 
This invention provides compounds of the formula 
##STR3## 
wherein E is CHO or B(OH).sub.2 ; 
R.sup.1 is lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 is hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together are di- or trimethylene optionally substituted 
by hydroxy; 
R.sup.4 is lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, 
carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 is lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, 
aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 is hydrogen or lower alkyl; 
R.sup.7 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; and 
R.sup.9 is lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, 
lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower 
alkoxycarbonyl, 
and salts of acidic compounds of formula I with bases. 
As used in this specification, the term "lower alkyl", alone or in 
combination, denotes a straight-chain or branched chain alkyl group 
containing 1-7, preferably 1-4, carbon atoms, e.g. methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl, sec.butyl, tert.butyl, n-pentyl, 
neopentyl and the like. "The terms "lower alkenyl" and "lower alkynyl" 
denote alkenyl groups preferably containing 2-7 carbon atoms, e.g. vinyl, 
allyl, n-propenyl, n-butenyl, and the like, and, respectively, alkynyl 
groups containing 2-7 carbon atoms, e.g. propargyl and the like. The term 
"lower cycloalkyl" denotes a cycloalkyl group containing 3-7 carbon atoms, 
e.g. cyclopropyl, cyclobutyl, cyclopentyl and the like. The lower alkoxy 
part of a "lower alkoxycarbonyl" group is a lower alkyl ether group in 
which the lower alkyl moiety has the aforementioned significance. The term 
"aryl" denotes a monocyclic or polycyclic aromatic hydrocarbon group, e.g. 
phenyl, naphthyl or the like which is unsubstituted or substituted by one 
or more substituents selected from e.g. lower alkyl, lower alkoxy, nitro, 
halo, halo-lower alkyl, hydroxy, acetamido and the like. The term 
"heteroaryl" denotes a 5- or 6-membered aromatic heterocyclic group which 
contains N, O and/or S as the hetero atom(s) and which is optionally 
benz-fused and/or substituted in the same manner as the aryl group defined 
above. Examples of heteroaryl groups are furyl, thienyl, pyridyl, 
pyrimidinyl, benzofuranyl, benzothienyl, quinolyl, isoquinolyl and the 
like. 
The compounds of formula I contain at least six asymmetric carbon atoms and 
can therefore exist in the form of optically pure diastereoisomers, 
mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of 
diastereoisomeric racemates. The present invention includes within its 
scope all of these possible forms. 
One class of preferred compounds of formula I comprises those in which 
R.sup.1 represents lower alkyl, halo-lower alkyl, lower alkylthio-lower 
alkyl, aryl-lower alkylthio-lower alkyl, heteroaryl-lower alkyl, lower 
alkenyl or lower alkynyl. Fluoro-lower alkyl is the preferred halo-lower 
alkyl group. Preferred heteroaryl-lower alkyl groups are thienyl-lower 
alkyl and furyl-lower alkyl. In a preferred embodiment of each of the 
embodiments of compounds of formula I described above, R.sup.2 represents 
lower alkyl, lower cycloalkyl-lower alkyl or aryl-lower alkyl. In a 
preferred embodiment of each of the embodiments of compounds of formula I 
described above, R.sup.3 represents hydrogen. In another preferred 
embodiment of each of the embodiments of compounds of formula I described 
above, R.sup.2 and R.sup.3 together represent trimethylene optionally 
substituted by hydroxy. In a preferred embodiment of each of the 
embodiments of compounds of formula I described above, R.sup.4 represents 
lower alkyl, lower cycloalkyl-lower alkyl, aryl-lower alkyl, aryl or lower 
cycloalkyl. In a preferred embodiment of each of the embodiments of 
compounds of formula I described above, R.sup.5 represents aryl-lower 
alkyl or lower cycloalkyl. In a preferred embodiment of each of the 
embodiments of compounds of formula I described above, R.sup.6 represents 
hydrogen. In a preferred embodiment of each of the embodiments of 
compounds of formula I described above, R.sup.7 represents lower alkyl, 
carboxy-lower alkyl aryl-lower alkyl or hydroxy-lower alkyl. In a 
preferred embodiment of each of the embodiments of compounds of formula I 
described above, R.sup.8 represents hydroxy-lower alkyl, carboxy-lower 
alkyl or aryl-lower alkyl. In a preferred embodiment of each of the 
embodiments of compounds of formula I described above, R.sup.9 represents 
lower alkyl-carbonyl or carboxy-lower alkylcarbonyl. 
Examples of these preferred compounds in which E represents CHO are: 
2(S)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butyraldeh 
yde; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4-diflu 
orovaleraldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-tr 
ifluorobutyraidehyde; 
2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.glut 
amyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(methylt 
hio)propionaldehyde; 
2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(butylt 
hio)propionaldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-penten 
aldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentyn 
al; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexynal 
; 
3-(benzylthio)-2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl 
]-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]a 
mino]propionaldehyde; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(2-thie 
nyl)propionaldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(3-thi 
enyl)propionaldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-3-(2-naphthy 
l)-D-alanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4 
,4-trifluorobutyraldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-seryl-D-valyl]-2-methyl-L-phen 
ylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]hexanal; 
(Z)-2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha. 
-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hex 
enal; 
2(RS)-[[N-[N-[N-[N-[N-(benzyloxycarbonyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalany]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trif 
luorobutyraldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-4-chloro-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-tr 
ifluorobutyraldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-valyl]-2-m 
ethyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobuty 
raldehyde; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5-methylh 
exanal; 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5-hexenal 
; 
2(RS)-[[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-norleucyl 
]-2-methyl-L-phenylalanyl-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluoro 
butyraldehyde; 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-2-cyclohex 
ylglycyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4- 
trifluorobutyraldehyde; and 
2(RS)-[[N-[N-[N-[N-[N-(4-acetamidobenzoyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-tr 
ifluorobutyraldehyde; 
and examples of these preferred compounds in which E represents B(OH).sub.2 
are: 
1(RS)-[[N-[N-[N-[N-[N-(3-Carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylbor 
onic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butylboro 
nic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-buteny 
lboronic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-4-chloro-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino] 
-3-butenylboronic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanyl]a 
mino]-3-butenylboronic acid; 
1(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]pentylboro 
nic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-L-2-cyclohexylglycyl]-L-leucyl]aminolpropy 
lboronic acid; 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-L-2-cyclohexylglycyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboroni 
c acid; and 
1(RS)-[[N-[N-[N-[N-[N-(benzyloxycarbonyl)-L-.alpha.-aspartyl]-D-valyl]-2-me 
thyl-L-phenylalanyl]-3-methyl-L-valyl-L-leucyl]amino]propylboronic acid. 
This invention provides a process for producing a compound of the formula: 
##STR4## 
wherein E is CHO; 
R.sup.1 is lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 is hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together are di- or trimethylene optionally substituted 
by hydroxy; 
R.sup.4 is lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, 
carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 is lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, 
aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 is hydrogen or lower alkyl; 
R.sup.7 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; and 
R.sup.9 is lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, 
lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower 
alkoxycarbonyl; 
which process comprises treating an acetal of the formula 
##STR5## 
wherein any carboxy, hydroxy or aminocarbonyl group present in the acetal 
is protected, and R.sup.10 and R.sup.11 are each independently a lower 
alkyl; with a strong acid, thereby producing the compound. A further 
embodiment of this process comprises treating the compound of formula I as 
produced by the above process, wherein the compound is acidic, with a 
base, thereby producing a salt of the compound. In an embodiment of the 
process described above, the acetal of formula II is bonded to a solid 
phase peptide synthesis resin. 
This invention provides process for producing a compound of the formula 
##STR6## 
wherein E is B(OH).sub.2 
R.sup.1 is lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 is hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together are di- or trimethylene optionally substituted 
by hydroxy; 
R.sup.4 is lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, 
carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 is lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, 
aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 is hydrogen or lower alkyl; 
R.sup.7 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 represents lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; and 
R.sup.9 is lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, 
lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower 
alkoxycarbonyl; 
which process comprises treating a substituted dioxaborolane of the formula 
##STR7## 
wherein any carboxy, hydroxy or aminocarbonyl group present in the 
dioxaborolane is or is not protected, and Q is 
##STR8## 
wherein R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each are hydrogen or 
lower alkyl and R.sup.16 and R.sup.17 each are hydrogen or lower alkyl, 
with a strong acid when Q is (a) and with an alkali metal periodate when Q 
is (b) thereby producing the compound. A further embodiment of this 
process comprises treating the compound of formula I as produced by the 
above process, wherein the compound is acidic, with a base, thereby 
producing a salt of the compound. In an embodiment of the process 
described above, the acetal of formula II is bonded to a solid phase 
peptide synthesis resin. 
More specifically, the compounds of formula I hereinbefore and salts of 
acidic compounds of formula I with bases are manufactured by 
a) for the manufacture of a compound of formula I in which E represents 
CHO, deacetalizing and, where required, deprotecting an acetal of the 
general formula 
##STR9## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, 
R.sup.8 and R.sup.9 have the significance given earlier, provided that any 
carboxy, hydroxy and/or aminocarbonyl group(s) present is/are in protected 
form, and R.sup.10 and R.sup.11 each represent lower alkyl, or 
b) for the manufacture of a compound of formula I in which E represents 
B(OH).sub.2, ring opening and, where required, deprotecting a substituted 
dioxaborolane of the general formula 
##STR10## 
wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, 
R.sup.8 and R.sup.9 have the significance given earlier, provided that any 
carboxy, hydroxy and/or aminocarbonyl group(s) present may be in protected 
form, and Q represents a group of the formula 
##STR11## 
wherein R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each represent hydrogen 
or lower alkyl and R.sup.16 and R.sup.17 each represent hydrogen or lower 
alkyl, 
and 
c) if desired, converting an acidic compound of formula I obtained into a 
salt with a base. 
Protected carboxy, hydroxy and aminocarbonyl groups which are present in 
the acetal starting materials of formula II and which may be present in 
the substituted dioxaborolane starting materials of formula III are 
carboxy, hydroxy and, respectively, aminocarbonyl groups protected with 
any conventional protecting group known from peptide chemistry. In 
particular, R.sup.2, R.sup.4, R.sup.7, R.sup.8 and/or R.sup.9 can 
preferably represent tert-butoxycarbonyl-lower alkyl as protected carboxy, 
R.sup.2, R.sup.4, R.sup.5, R.sup.7 R.sup.8 and/or R.sup.9 can preferably 
represent lower alkyl O-tert.butyl ether as protected hydroxy and R.sup.2 
can preferably represent tritylaminocarbonyl-lower alkyl as protected 
aminocarbonyl-lower alkyl. 
The deacetalization of an acetal of formula II, preferably one in which 
R.sup.10 and R.sup.11 each represent methyl, according to embodiment a) of 
the process according to the invention can be carried out using any 
conventional strong acid such as those described in T. W. Greene, P. G. M. 
Wuts, Protecting Groups in Organic Syntheses, 2nd edition, John Wiley & 
Sons 1991, in the presence of an inert organic solvent such as a 
halogenated aliphatic hydrocarbon, e.g. dichloromethane, and in the 
presence of water. Preferably the strong acid is trifluoroacetic acid or 
an equivalent strong acid Suitably, the deacetalization is carried out at 
about room temperature. When protected carboxy, hydroxy and/or 
aminocarbonyl groups are present in the acetal starting material, these 
are converted into free carboxy, hydroxy and/or aminocarbonyl groups under 
the conditions of the deacetalization. 
According to a variant of embodiment a) of the process according to the 
invention, an acetal starting material of formula II is bonded to a solid 
phase peptide synthesis resin. In one embodiment the starting material is 
bonded to a solid phase peptide synthesis resin as described in Example 4. 
In this case, cleavage from the resin takes place under the conditions 
used for the deacetalization. 
The ring opening of a substituted dioxaborolane of formula III in which Q 
represents a group of formula (a), preferably one in which R.sup.12, 
R.sup.13, R.sup.14 and R.sup.15 each represent methyl, according to 
embodiment b) of the process according to the invention can also be 
carried out using any conventional strong acid such as those described in 
T. W. Greene, P. G. M. Wuts, Protecting Groups in Organic Syntheses, 2nd 
edition, John Wiley & Sons 1991, in an inert organic solvent, e.g. a 
halogenated aliphatic hydrocarbon such as dichloromethane, and optionally 
in the presence of water. Preferably the strong acid is trifluoroacetic 
acid or an equivalent strong acid. Suitably, the ring opening is carried 
out at about room temperature. When protected carboxy, hydroxy and/or 
aminocarbonyl groups are present in the substituted dioxaborolane starting 
material, these are converted into free carboxy, hydroxy and/or 
aminocarbonyl groups under the conditions of the ring opening. 
The ring opening of a substituted dioxaborolane of formula III in which Q 
represents a group of formula (b), especially one in which one of R.sup.16 
and R.sup.17 represents hydrogen and the other represents methyl, 
according to embodiment b) of the process in accordance with the invention 
can be carried out in a conventional manner. Conveniently, the ring 
opening is carried out using any conventional periodate, especially an 
alkali metal periodate, especially sodium periodate in a buffered 
aqueous-organic medium, suitably at about room temperature. 
Advantageously, the medium consists of a mixture of an inert 
water-miscible organic solvent, e.g. acetone, and aqueous ammonium 
acetate. Any protected carboxy, hydroxy and/or aminocarbonyl group(s) 
present in the substituted dioxaborolane starting material are deprotected 
in a conventional manner known in tbe art e.g. by treatment with 
trifluoroacetic acid, prior to the ring opening. 
According to a variant of embodiment b) of the process according to the 
invention, a substituted dioxaborolane of formula III in which Q 
represents a group of formula (a) is bonded to a solid phase synthesis 
resin. The bonding is typically through an alkyl group R.sup.12, R.sup.13, 
R.sup.14 or R.sup.15 linked to the resin via an amide bridge. Cleavage 
from the resin takes place under the conditions used in embodiment b) of 
the process. 
In accordance with embodiment c) of the process acidic compounds of formula 
I can be converted into salts with bases, e.g. alkali metal salts such as 
sodium or potassium salts, alkaline earth metal salts such as calcium or 
magnesium salts, salts with organic bases, e.g. salts with amines such as 
N-ethylpiperidine, procaine or dibenzylamine, or salts with basic amino 
acids such as salts with arginine or lysine. The formation and isolation 
of such salts can be carried out according to conventional methods known 
in the art. 
This invention provides acetal compounds of the formula 
##STR12## 
wherein R.sup.1 is lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 is hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together are di- or trimethylene optionally substituted 
by hydroxy; 
R.sup.4 is lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, 
carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 is lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, 
aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 is hydrogen or lower alkyl; 
R.sup.7 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; 
R.sup.9 is lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, 
lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower 
alkoxycarbonyl; and 
R.sup.10 and R.sup.11 are each independently a lower alkyl. Preferred 
values of R.sup.1 through R.sup.9 for compounds of formula II are as 
described above in connection with the compounds of formula I. 
These acetal compounds can be prepared, for example, by firstly reducing a 
hydroxamate of the general formula 
##STR13## 
wherein R.sup.1, R.sup.10 and R.sup.11 have the significance given earlier 
and Q.sup.1 represents an amino protecting group, e.g. 
tert.butoxycarbonyl, 
with an alkali metal aluminium hydride, e.g. lithium aluminium hydride, 
treating the product with methanolic hydrochloric acid to give the 
hydrochloride salt of a compound of the formula 
##STR14## 
wherein R.sup.1, R.sup.10 and R.sup.11 have the significance given earlier, 
and subsequently either subjecting this to sequential coupling with 
respective amino acids or subjecting a fragment obtained during such a 
sequential coupling to further coupling with a peptide derivative of 
appropriate length. Alternatively, a compound of formula V can be coupled 
with a suitable pentapeptide. 
The aforementioned coupling reactions can be carried out in a manner known 
per se in peptide chemistry, conveniently using the respective amino acid 
or di, tri-, tetra- or pentapeptide appropriately protected as described 
above and also at any amino group present by Fmoc 
[(9-fluorenyl)methoxycarbonyl] in the presence of hydroxybenzotriazole, 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 
N-methylmorpholine and in an inert organic solvent, e.g. a halogenated 
hydrocarbon such as dichloromethane. 
The hydroxamates of formula IV required for the preparation of the acetal 
starting materials of formula II are known compounds or analogues of known 
compounds which can be prepared in an analogous manner to the known 
compounds. 
The acetal starting materials of formula II can also be synthesised from a 
compound of formula V on a solid phase peptide synthesis resin. This 
procedure is known and is described in detail in Handbook from Fourth 
International Symposium on Solid Phase Synthesis and Combinatorial 
Chemical Libraries, Edinburgh, 1995. 
This invention provides dioxaborolanes of formula 
##STR15## 
wherein R.sup.1 is lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower 
alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl, 
heteroaryl-lower alkyl, lower alkenyl or lower alkynyl; 
R.sup.2 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower 
alkyl; and 
R.sup.3 is hydrogen or lower alkyl; or 
R.sup.2 and R.sup.3 together are di- or trimethylene optionally substituted 
by hydroxy; 
R.sup.4 is lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl, 
carboxy-lower alkyl, aryl-lower alkyl, lower alkylthio-lower alkyl, 
cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower 
alkenyl, aryl or lower cycloalkyl; 
R.sup.5 is lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, 
aryl-lower alkyl, aryl-lower alkylthio-lower alkyl, cyano-lower 
alkylthio-lower alkyl or lower cycloalkyl; 
R.sup.6 is hydrogen or lower alkyl; 
R.sup.7 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl, 
aryl-lower alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl; 
R.sup.8 is lower alkyl, hydroxy-lower alkyl, carboxy-lower alkyl or 
aryl-lower alkyl; and 
R.sup.9 is lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, 
lower alkylsulphonyl, arylsulphonyl, lower alkoxycarbonyl or aryl-lower 
alkoxycarbonyl; and 
Q is 
##STR16## 
wherein R.sup.12, R.sup.13, R.sup.14 and R.sup.15 each are hydrogen or 
lower alkyl and R.sup.16 and R.sup.17 each are hydrogen or lower alkyl, 
and wherein any carboxy, hydroxy or aminocarbonyl group present in the 
dioxoborolane is or is not protected. Preferred values of R.sup.1 through 
R.sup.9 for the compounds of formula III are as described above for 
compounds of formula I. These dioxaborolanes, which include the 
substituted dioxaborolanes of formula III used as starting materials in 
embodiment b) of the process according to the invention can be prepared, 
for example, as illustrated in Scheme A hereinafter in which R.sup.1 and Q 
have the significance given earlier: 
##STR17## 
Having regard to Scheme A, in step a) a compound of formula VI is reacted 
with an alkali metal bis[tri(lower alkyl)silyl]amide, e.g. lithium 
bis(trimethylsilyl)amide, in an inert organic solvent such as an ether, 
e.g. diethyl ether or tetrahydrofuran, and then treated with a strong 
acid, e.g. trifluoroacetic acid, to give a compound of formula VII. 
In step b) a compound of formula VII is converted into a compound of 
formula III either by coupling with a pentapeptide, by sequential coupling 
with respective amino acids or by coupling a fragment obtained during the 
sequential coupling with a peptide derivative of the desired length, with 
the amino acid or peptide used being appropriately protected as described 
above and also at any amino group present by Fmoc. These coupling 
reactions can be carried out in a manner known per se in peptide 
chemistry, for example using the amino acid or peptide in the form of a 
mixed anhydride formed e.g. with a lower alkyl haloformate such as 
isobutyl chloroformate and carrying out the coupling in the presence of a 
suitable base, e.g. a tertiary organic base such as N-methylmorpholine. 
Substituted dioxoborolanes of formula III obtained by the foregoing 
coupling and which carry a protecting group on the substituent at R.sup.2, 
R.sup.4, R.sup.5, R.sup.7, R.sup.8 and/or R.sup.9 can be selectively 
deprotected in a conventional manner, e.g. using trifluoroacetic acid, to 
the corresponding compounds which carry a free carboxy, hydroxy and/or 
aminocarbonyl group on the respective substituent, while retaining the 
protected boronic acid moiety denoted by Q. These selectively deprotected 
compounds are also active as inhibitors of proteinases of viral origin and 
can be used in the treatment of viral infections in the same manner as the 
compounds of formula I 
Compounds of formula VI can be prepared, for example, from a compound of 
the general formula 
EQU Cl.sub.2 CH--Q (VIII) 
wherein Q has the significance given earlier, which is a known compound or 
an analogue of a known compound, by reaction with a compound of the 
formula R.sup.1a -MgHal, wherein R.sup.1a has the same significance as 
R.sup.1 hereinbefore, but contains one carbon atom less and Hal represents 
halogen, preferably bromine. The reaction is carried out under the 
conventional conditions of a Grignard reaction, for example in an inert 
organic solvent such as an ether, e.g. diethyl ether or tetrahydrofuran. 
When Q represents a group of formula (b), the reaction is carried out in 
the presence of zinc chloride. 
A compound of formula VI in which R.sup.1 represents bromo-lower alkyl or 
fluoro-lower alkyl and Q represents a group of formula (a) can be 
prepared, for example, by hydroborating a bromo- or fluoro-lower alkene, 
e.g. 3-bromopropene or 3-fluoropropene, reacting the hydroboration product 
with a diol of the formula R.sup.12 R.sup.13 C(OH)--C(OH)R.sup.14 
R.sup.15, wherein R.sup.12, R.sup.13, R.sup.14 and R.sup.15 have the 
significance given earlier, e.g. 2,3-dimethyl-2,3-butanediol, and reacting 
the resulting 2-(bromo- or fluoro-lower alkyl)-1,3,2-dioxaborolane with 
dichloromethane in the presence of lithium diisopropylamine. The 
hydroboration can be carried out in a conventional manner, for example 
using phenylboronic acid at an elevated temperature, e.g. about 
100.degree. C., in the absence of a solvent or using borane-dimethyl 
sulphide complex in the presence of cyclohexene in an inert organic 
solvent, e.g. dimethoxyethane, at about 0.degree. C. followed by treatment 
with trimethylamine N-oxide. 
A substituted dioxoborolane of formula III in which Q represents a group of 
formula (a) can also be synthesised on a solid phase peptide synthesis 
resin. For example, a 4-methylbenzhydryl resin can be reacted with a 
dioxoborolanyl-valeric acid of the general formula 
##STR18## 
wherein R.sup.1, R.sup.2, R.sup.12, R.sup.14, R.sup.15 and Q.sup.1 have the 
significance given earlier, 
and the product can be converted into the required resin-bonded starting 
material by successive deprotection and coupling with a protected amino 
acid. 
Compounds of formula IX can be conveniently prepared by reacting a 
tert-butyl 6,7-dihydroxy-3,6,7-tri(lower alkyl)-6-octenoate with 
dichloromethyl diisopropoxyborane, condensing the resulting compound of 
the general formula 
##STR19## 
wherein R.sup.12, R.sup.14 and R.sup.15 have the significance given 
earlier, 
with a compound of formula R.sup.1 MgHal, wherein R.sup.1 has the 
significance given earlier and Hal represents halogen, preferably bromine, 
under the conditions of a Grignard reaction, reacting the resulting 
compound of the general formula 
##STR20## 
wherein R.sup.1, R.sup.12, R.sup.14 and R.sup.15 have the significance 
given earlier, 
with an alkali metal bis[tri(lower alkyl)silyl]amide, condensing the 
resulting compound of the general formula 
##STR21## 
wherein R.sup.1, R.sup.12, R.sup.14 and R.sup.15 have the significance 
given earlier, 
with a protected amino acid of the general formula 
EQU Q.sup.2 HN--CH(R.sup.2)--COOH (XIII) 
wherein R.sup.2 has the significance given earlier and Q.sup.2 represents 
Fmoc, 
and de-esterifying the resulting compound of the general formula 
##STR22## 
wherein R.sup.1, R.sup.2, R.sup.12, R.sup.14, R.sup.15 and Q.sup.2 have the 
significance given earlier. 
As mentioned earlier, the compounds of formula I and salts of acidic 
compounds of formula I with bases are inhibitors of proteases of viral 
origin. The activity against one such protease, namely HCV protease, can 
be demonstrated using the following assay: 
Construction of plasmid for the expression of MBP-NS3"Gly .sub.12 -NS4A 
enzyme in E. coli 
The nucleotide sequence of this expression plasmid is given in FIG. 1 
appended hereto and the amino acid sequence of its expression product is 
given in FIG. 2 appended hereto. It is based on the pMAL.RTM.-c2 vector 
supplied by New England Biolabs, Inc. (32 Tozer Rd., Beverly, Mass., USA). 
The principle of the construction was to create an in-frame fusion of the 
maltose binding protein (MBP) gene supplied by the pMAL-c2 vector, and 
sequences of the HCV genome necessary for NS3 proteinase activity. These 
HCV sequences were inserted between the EcoRI and HindIII sites of the 
pMAL-c2 polylinker (positions 2695 and 3556 respectively of the sequence 
given in FIG. 1). 
HCV sequences were derived from plasmids pDS 3348-4045 and pBFK 3348-6062, 
described by Bartenschlager et al, 1993 (Journal of Virology, 67, 
3835-3844). Regions encompassing the NS3 proteinase domain (amino acids 
1007-1219) and the NS4A domain (amino acids 1658-1711) were isolated and 
inserted into the pMAL-c2 vector using standard recombinant DNA 
techniques, including the PCR amplification of required sequences. Between 
the NS3 and NS4A domains, a linker region was constructed using synthetic 
oligonucleotides (positions 3343-3390; amino acids 606-621). The resulting 
plasmid was used to transform E. coli (strain MC1061) cells and expression 
of the MBP-NS3"Gly .sub.12 -NS4A enzyme was induced as described below. 
Protein expression and purification 
E. coli (strain MC1061) cells transformed with the foregoing plasmid were 
grown in Luria broth containing ampicillin (100 .mu.g/ml) at 37.degree. C. 
The cells were grown until an optical density of 0.5 at 600 nm had been 
reached and enzyme expression was then induced by adding 1 mM 
isopropylthiogalactoside and incubating at 37.degree. C. for a further 3 
hours. The cells were harvested by centrifugation and stored at 
-80.degree. C. 
A pellet from 4 l of bacterial culture was resuspended in E. coli lysis 
buffer (20 mM Tris HCl, pH 7.5, containing 150 mM NaCl, 1 mM EDTA and 10 
mM dithiothreitol) and cell lysis was achieved by two passages through a 
French Pressure cell. The clear supernatant obtained by centrifugation 
(18000 g, 30 minutes) was then applied to an amylose resin column 
(4.times.1 cm) (New England Biolabs) which had been equilibrated with 
ice-cold 50 mM Tris HCl, pH 8.5, containing 200 mM NaCl, 1 mM 
dithiothreitol and 5% glycerol. The column was washed thoroughly with the 
equilibration buffer and bound protein was eluted using the equilibration 
buffer containing 10 mM maltose. Fractions of 1 ml were collected, with 
fractions containing the enzyme being pooled and stored at -80.degree. C. 
Enzyme concentration was assayed by the method of M. B. Bradford, 
Analytical Biochemistry, 1976, vol. 72, p. 248. 
Assay 
Compounds of formula I (routinely prepared as stock solutions in DMSO) were 
assayed for their ability to inhibit the cleavage of a quenched 
fluorescence substrate [NS4A/B.F peptide 
(N-[4-[4-(dimethylamino)phenylazo]benzoyl]-L-.alpha.-aspartyl-L-.alpha.-gl 
utamyl-L-methionyl-L-.alpha.-glutamyl-L-.alpha.-glutamyl-L-cysteinyl-L-alan 
yl-L-seryl-L-histidyl-N5-[2-(5-sulpho-1-naphthylamino)ethyl]-L-glutaminamid 
e); Wilkinson et al, Society for General Microbiology Meeting, University 
of Warwick, England, 28 March 1996] based on the NS4A/4B cleavage site by 
enzyme MBP-NS3"Gly .sub.12 -NS4A in microtitre plates as follows: 
The enzyme (1 .mu.g) was added to 200 .mu.l final volume of a mixture 
containing 50 mM Tris HCl, pH 8.5, with 1 mM dithiothreitol, 0.1% Triton 
X-100 and the test compound of formula 1. The resulting mixture was 
incubated at room temperature for 15 minutes prior to starting the 
reaction by the addition of NS4A/B.F peptide to a final concentration of 
10 .mu.M. The progress of the reaction was evaluated with a Perseptive 
Biosystems Cytofluor II using an excitation wavelength of 360 nm and an 
emission wavelength of 530 nm. After incubation for a further 10 minutes, 
the reduction in fluorescence in the presence of inhibitor was measured. 
This was plotted against inhibitor concentration and the inhibitor 
concentration which caused 50% reduction (IC.sub.50) was calculated by 
manual graphical analysis or by the use of the Perseptive Biosystems 
Cytocalc curve fitting program. 
The results obtained in the foregoing assay with representative compounds 
of formula I are compiled in the following Table: 
TABLE 
______________________________________ 
Compound of formula I 
HCV proteinase IC.sub.50 (.mu.mol/l) 
______________________________________ 
A 0.09 
B 0.07 
C 0.064 
D 0.034 
E 0.038 
F 0.16 
______________________________________ 
Compounds: 
A=2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pent 
enaldehyde. 
B=2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4-dif 
luorovaleraldehyde. 
C=2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4- 
trifluorobutyraldehyde. 
D=1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-bute 
nylboronic acid. 
E=1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylb 
oronic acid. 
F=1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butylbo 
ronic acid. 
The compounds of formula I and salts of acidic compounds of formula I with 
bases can be used as medicaments, e.g. in the form of pharmaceutical 
preparations. The pharmaceutical preparations can be administered 
enterally such as orally in the form of tablets, coated tablets, dragees, 
hard and soft gelatine capsules, solutions, emulsions or suspensions, 
nasally, e.g. in the form of nasal sprays, or rectally, e.g. in the form 
of suppositories. They may, however, also be administered parenterally, 
e.g. in the form of injection solutions. In one embodiment, this invention 
provides a pharmaceutical composition comprising from ten to five hundred 
milligrams of a compound of each of the embodiments of compounds of 
formula I described above, and a compatible pharmaceutical carrier. 
The compounds of formula I and their aforementioned salts can be processed 
with pharmaceutically inert, organic or inorganic carriers for the 
production of pharmaceutical preparations. Lactose, corn starch or 
derivatives thereof, talc, stearic acid or its salts and the like can be 
used, for example, as such carriers for tablets, coated tablets, dragees 
and hard gelatine capsules. Suitable carriers for soft gelatine capsules 
are, for example, vegetable oils, waxes, fats, semi-solid and liquid 
polyols and the like; depending on the nature of the active ingredient no 
carriers are, however, usually required in the case of soft gelatine 
capsules. Suitable carriers for the production of solutions and syrups 
are, for example, water, polyols, sucrose, invert sugar, glucose and the 
like. Suitable carriers for suppositories are, for example, natural or 
hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. 
The pharmaceutical preparations can also contain preservatives, 
solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, 
colorants, flavorants, salts for varying the osmotic pressure, buffers, 
masking agents or antioxidants. They can also contain still other 
therapeutically valuable substances. 
Medicaments containing a compound of formula I or a salt of an acidic 
compound of formula I with a base in association with a compatible 
pharmaceutical carrier are also an object of the present invention, as is 
a process for the production of such medicaments which comprises bringing 
one or more of these compounds or salts and, if desired, one or more other 
therapeutically valuable substances into a galenical administration form 
together with a compatible pharmaceutical carrier. 
As mentioned earlier, the compounds of formula I and salts of acidic 
compounds of formula I with bases can be used in accordance with the 
invention as therapeutically active substances, especially as antiviral 
agents. The dosage can vary within wide limits and will, of course, be 
fitted to the individual requirements in each particular case. In general, 
in the case of administration to adults a convenient daily dosage should 
be about 3 mg to about 3 g, preferably about 10 mg to 1 g. The daily 
dosage may be administered as a single dose or in divided doses and, in 
addition, the upper dosage limit referred to earlier may be exceeded when 
this is found to be indicated. 
Finally, the use of compounds of formula I and salts of acidic compounds of 
formula I with bases for the production of medicaments, especially of 
antiviral medicaments, is also an object of the invention. 
The invention is illustrated by the following Examples. In the Examples SSA 
denotes the solvent system 0.1% TFA in water and SSB denotes the solvent 
system 0.1% TFA in 70% acetonitrile 30% water. 
EXAMPLE 1 
0.1 g (0.1 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-N1-[1(S)-(dimethoxymethyl)propyl]-L-leucinamide was dissolved in 
3 ml of dichloromethane, 3 ml of trifluoroacetic acid and 90 mg of water 
and the mixture was stirred at room temperature for 30 minutes. The 
solution was diluted with 20 ml of toluene and the solvent was removed by 
evaporation. The resulting white solid was triturated with diethyl ether 
and filtered off. The solid was purified by RP-HPLC on a C18 Dynamax 
column (pore size 300 .ANG.; column size 21.4 mm.times.50 mm). The elution 
gradient comprised 90% SSA 10% SSB to 95% SSB 5% SSA over 8.5 minutes. 
After lyophilization overnight there were obtained 25 mg of 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butyralde 
hyde as a white foam. MS: m/e 819.5 [M+H].sup.+. 
The starting material was prepared as follows: 
i) A solution of 25 g (63.6 mmol) of L-leucine benzyl ester 
p-toluenesulphonic acid salt, 14.69 g (63.6 mmol) of 
N-(tert-butoxycarbonyl)-3-methyl-L-valine, 9.73 g (63.6 mmol) of 
1-hydroxybenzotriazole, 7.32 g (63.3 mmol) of N-ethylmorpholine and 12.21 
g (63.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride in 500 ml of dichloromethane was stirred at room temperature 
overnight. The solution was washed with water, sodium hydrogen carbonate 
solution, 2M hydrochloric acid and saturated sodium chloride solution and 
dried over anhydrous magnesium sulphate. Evaporation gave 21.65 g of 
N-[(N-tert-butoxycarbonyl)-3-methyl-L-valyl]-L-leucine benzyl ester as an 
oil which was used in the next step without further purification. MS: m/e 
435 [M+H].sup.+. 
ii) A solution of 9.74 g (22.4 mmol) of 
N-[(N-tert-butoxycarbonyl)-3-methyl-L-valyl]-L-leucine benzyl ester in 25 
ml of trifluoroacetic acid and 50 ml of dichloromethane was stirred at 
room temperature for 30 minutes. The solvent was removed by evaporation 
and 50 ml of toluene were added. Evaporation gave 
N-(3-methyl-L-valyl)-L-leucine benzyl ester as an oil which was used in 
the next step without further purification. 
iii) A solution of the foregoing oil, 9g (22.4 mmol) of 
N-(9-fluorenylmethoxycarbonyl)-2-methyl-L-phenylalanine, 3.43 g (22.4 
mmol) of 1-hydroxybenzotriazole, 3.87 g (33.66 mmol) of N-ethylmorpholine 
and 4.31 g (22.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride in 100 ml of dichloromethane was stirred at room temperature 
overnight. The solution was washed with water, sodium hydrogen carbonate 
solution, 2M hydrochloric acid and saturated sodium chloride solution and 
dried over anhydrous magnesium sulphate. Evaporation and chromatography on 
silica gel using 30% ethyl acetate in petroleum ether (b.p. 40-60.degree. 
C.) for the elution gave 12.32 g of N-[N-[N-[(9-fluorenyl) 
methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine 
benzyl ester as an oil. MS: m/e 718 [M+H].sup.+. 
iv) A solution of 10 g (13.95 mmol) of 
N-[N-[N-[(9-fluorenyl)-methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of 
dichloromethane was stirred for 30 minutes at room temperature. The 
solvent was removed by evaporation and the residue was chromatographed on 
silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol 
in dichloromethane for the elution. Evaporation gave 6.9 g of 
N-[N-[2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 
the form of an oil which was used in the next step without further 
purification. 
v) A solution of 6.9 g of the foregoing oil, 2.13 g (13.95 mmol) of 
1-hydroxybenzotriazole, 2.68 g (13.95 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.93 g 
(13.95 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert.-butyl-L-.alpha.-glutamic acid in 
150 ml of dichloromethane was stirred at room temperature overnight. The 
solution was washed with water, sodium hydrogen carbonate solution, 2M 
hydrochloric acid and saturated sodium chloride solution and dried over 
anhydrous magnesium sulphate. Evaporation and chromatography of the 
residue on silica gel using 30% ethyl acetate in petroleum ether (b.p. 
40-60.degree. C.) for the elution gave 10.89 g of 
N-[N-[N-[N-[(9-fluorenyl)-methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester as a 
thick oil. MS: m/e 903 [M+H].sup.+. 
vi) A solution of 10.89 g (12.07 mmol) of 
N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml 
of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at 
room temperature. The solvent was removed by evaporation and the residue 
was chromatographed on silica gel using firstly 20% ethyl acetate in 
hexane and then 10% methanol in dichloromethane for the elution. 
Evaporation gave 
N-[N-[N-[O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in 
the next step without further purification. 
vii) A solution of the foregoing oil, 4.96 g (12.07 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspartic acid, 
1.85 g (12.07 mmol) of 1-hydroxybenzotriazole and 2.32 g (12.07 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 100 ml of 
dichloromethane was stirred at room temperature overnight. The solution 
was washed with water, sodium hydrogen carbonate solution, 2M hydrochloric 
acid and saturated sodium chloride solution and dried over anhydrous 
magnesium sulphate. Evaporation and chromatography of the residue on 
silica gel using ethyl acetate for the elution gave 10.088 g of 
N-[N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-va 
lyl]-L-leucine benzyl ester as a white solid. MS: m/e 1074 [M+H].sup.+. 
viii) A solution of 10.088 g (9.4 mmol) of 
N-[N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl] 
O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl 
-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of 
piperidine and 120 ml of dichloromethane was stirred for 30 minutes at 
room temperature. The solvent was removed by evaporation and the residue 
was chromatographed on silica gel using firstly 20% ethyl acetate in 
hexane and then 10% methanol in dichloromethane for the elution. 
Evaporation gave 
N-[N-[N-[N-[O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.alpha.-glutam 
yl-2-methyl-L-phenylalanyl]-3-methyl-L-valyl-L-leucine benzyl ester in the 
form of an oil which was used in the next step without further 
purification. 
ix) A solution of 8 g of the foregoing oil, 1.64 g (9.4 mmol) of tert-butyl 
hydrogen succinate, 1.44 g (9.4 mmol) of 1-hydroxybenzotriazole and 1.805 
g (9.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride in dichloromethane was stirred at room temperature 
overnight. The solution was washed with water, sodium hydrogen carbonate 
solution, 2M hydrochloric acid and saturated sodium chloride solution and 
dried over anhydrous magnesium sulphate. Evaporation and trituration of 
the residue with acetone gave 6.87 g of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine benzyl ester as a white solid. MS: m/e 1008.6 
[M+H].sup.+, m/e 1030.3 [M+Na].sup.+. 
x) A solution of 6.8 g (6.75 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine benzyl ester in 200 ml of dimethylformamide was 
hydrogenated over 600 mg of 10% palladium/carbon for 1 hour. The catalyst 
was removed by filtration and the filtrate was evaporated to give 15 g of 
crude product which was chromatographed on silica gel using 10-15% 
methanol in dichloromethane for the elution to give 6 g of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine as a white solid of melting point 235-236.degree. C.; 
MS: m/e 918.4 [M+H].sup.+, m/e 940.3 [M+Na].sup.+. 
xi) 370 mg (2.5 mmol) of N,O-dimethyl 
2(S)-(tert-butoxyformamido)butyrohydroxamate were dissolved in 20 ml of 
anhydrous tetrahydrofuran under nitrogen and the solution was cooled to 
0.degree. C. in an ice-bath. 1.5 ml (1.5 mmol) of 1M lithium aluminium 
hydride in tetrahydrofuran were added and the mixture was stirred at 
0.degree. C. for 10 minutes. 20 ml of saturated aqueous potassium hydrogen 
sulphate were added and the mixture was stirred vigorously under nitrogen 
for 30 minutes at room temperature. The mixture was then diluted with 50 
ml of diethyl ether and the organic layer was separated, dried over 
anhydrous magnesium sulphate and the solvent was evaporated. The residue 
was dissolved in 10 ml of a saturated methanolic hydrogen chloride 
solution, stirred for 1 hour, then diluted with 50 ml of toluene and 
evaporated to dryness. The resulting oil was dissolved in 10 ml of 
dichloromethane and 184 mg (0.2 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl) 
propionyl]-O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.alpha.-glutamy 
l]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine, 58 mg (0.3 mmol) 
of 2-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride, 41 mg (0.3 
mmol) of 1-hydroxy-7-azabenzotriazole and 350 mg (3.0 mmol) of 
N-ethylmorpholine were added. The mixture was stirred for 30 minutes then 
washed in sequence with saturated sodium bicarbonate solution and 2M 
hydrochloric acid and dried over anhydrous magnesium sulphate. The 
solution was evaporated to dryness and the residue was chromatographed on 
silica gel using 4% methanol in dichloromethane for the elution. After 
trituration with diethyl ether there were obtained 110 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)propyl]-leucinamide as a white solid of 
melting point 242-244.degree. C. MS: m/e 1001.5 [M+H-MeOH].sup.+, m/e 1055 
[M+Na].sup.+. 
Analysis for C.sub.53 H.sub.88 O.sub.14 N.sub.6 [1033.315]. Calculated: C, 
61.61; H, 8.58; N, 8.13% Found: C, 61.52, H, 8.45; N, 8.19% 
EXAMPLE 2 
70 mg (0.067 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide were stirred 
in a mixture of 4 ml of trifluoroacetic acid, 4 ml of dichloromethane and 
30 mg of water at room temperature for 30 minutes. The solution was 
evaporated to dryness in a vacuum and the residue was chromatographed on 
silica gel using dichloromethane/methanol/acetic acid/water (60:13:2:2) 
for the elution. There were obtained 36 mg of 
2(RS)-[[N-[N-[N-[N-[N-[(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pent 
ynal (9:1 mixture of diastereoisomers) as a white solid. MS: m/e 829.6 
[M+H].sup.+. 
The starting material was prepared as follows: 
i) A solution of 12.17 g (57.14 mmol) of 
N-(tert-butoxycarbonyl)-1(S)-amino-4-pentynoic acid, 8.74 g (64.74 mmol) 
of hydroxybenzotriazole, 6.96 g (71.43 mmol) of N,O-dimethylhydroxylamine, 
8.21 g (71.43 mmol) of N-ethylmorpholine and 13.7 g (71.43 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 250 ml of 
dichloromethane was stirred for 18 hours, then washed with 2M hydrochloric 
acid and saturated sodium bicarbonate solution, dried and evaporated to 
give 14.2 g of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4-pentynohydroxamate as a viscous gum which 
slowly crystallized. 
Analysis for C.sub.12 H.sub.20 N.sub.2 O.sub.4 [256.3021. Calculated: C, 
56.24; H, 7.87; N, 10.93% Found: C, 56.01, H, 7.81; N, 10.92% 
ii) 10 ml (10 mmol) of 1M lithium aluminium hydride in tetrahydrofuran were 
added to a solution of 3.15 g (12.3 mmol) of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4-pentynohydroxamate in 50 ml of dry 
tetrahydrofuran at 0.degree. C. under a nitrogen atmosphere. The solution 
was stirred for 20 minutes and then 40 ml of saturated potassium hydrogen 
sulphate solution were added dropwise. The mixture was stirred for 15 
minutes and then diluted with diethyl ether. The organic layer was dried 
over magnesium sulphate and evaporated to give an oil which was dissolved 
in 50 ml of methanolic hydrogen chloride solution. The solution was left 
at room temperature for 1 hour and then evaporated to dryness to give a 
dark brown gum. 1.05 g of the gum were added to a solution of 2.06 g (5.84 
mmol) of N-[(9-fluorenyl)methoxycarbonyl]-L-leucine, 867 mg (6.42 mmol) of 
hydroxybenzotriazole, 1.233 g (6.42 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.216 g 
(19.27 mmol) of N-ethylmorpholine in 40 ml of dichloromethane. The 
solution was stirred at room temperature for 18 hours, washed with 2M 
hydrochloric acid and saturated sodium bicarbonate solution, dried over 
magnesium sulphate and evaporated to give a gum which was chromatographed 
on silica gel using ethyl acetate/petrol (2:3) for the elution. There were 
obtained 1.1 g of 
N2-[(9-fluorenyl)methoxycarbonyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L- 
leucinamide as an off-white solid. .sup.1 H NMR (400 MHz, DMSO-d.sub.6) 
.delta.: 0.86 (6H,dd), 1.35-1.65 (3H,m), 2.22-2.39 (2H,m), 2.75(1H,t), 
3.22 (3H,s), 3.27 (3H,s), 3.91 (1H,m), 4.08 (1H,m), 4.15-4.3 (4H,m), 7.29 
(2H,m), 7.4 (2H,t), 7.42 (1H,d), 7.71 (2H,d), 7.84 (1H,d), 7.88 (2H,d). 
iii) 525 mg (1.1 mmol) of 
N2-[(9-fluorenyl)methoxycarbonyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L- 
leucinamide were dissolved in 20 ml of dichloromethane and 5 ml of 
piperidine and the mixture was stirred at room temperature for 30 minutes. 
The mixture was evaporated to dryness and the residue was chromatographed 
on silica gel using firstly ethyl acetate/petrol (1:1) and then 
methanol/dichloromethane (1:9) for the elution. Evaporation of the 
dichloromethane solution gave a gum which was added to a solution of 363 
mg (1.03 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-leucine, 149 
mg (1.1 mmol) of hydroxybenzotriazole and 288 mg (1.5 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 ml of 
dichloromethane. The mixture was stirred for 18 hours, then washed with 2M 
hydrochloric acid and saturated sodium bicarbonate solution, dried over 
magnesium sulphate and evaporated to dryness. The residue was 
chromatographed on silica gel using ethyl acetate/petrol (1:2) for the 
elution to give 501 mg of 
N2-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxy 
methyl)-3-butynyl]-L-leucinamide as a white foam. MS: m/e 592.3 
[M+H].sup.+, 560.3 [M+H-MeOH].sup.+. 
iv) 490 mg (0.83 mmol) of 
N2-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxy 
methyl)-3-butynyl]-L-leucinamide were dissolved in 16 ml of dichloromethane 
and 4 ml of piperidine and the mixture was stirred at room temperature for 
30 minutes. The mixture was evaporated to dryness and the residue was 
chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and 
then methanol/dichloromethane (1:9) for the elution. Evaporation of the 
dichloromethane solution gave a gum which was added to a solution of 321 
mg (0.8 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanine, 122 mg (0.9 
mmol) of hydroxybenzotriazole and 192 mg (1 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 ml of 
dichloromethane. The mixture was stirred for 18 hours, then washed with 2M 
hydrochloric acid and saturated sodium bicarbonate solution, dried over 
magnesium sulphate and evaporated to dryness. The residue was 
chromatographed on silica gel using ethyl acetate/petrol (2:3) for the 
elution to give a white foam which was dissolved in 16 ml of 
dichloromethane and 4 ml of piperidine and left at room temperature for 30 
minutes. The mixture was evaporated to dryness and the residue was 
chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and 
then methanol/dichloromethane (1:9) for the elution. Evaporation of the 
dichloromethane solution gave a gum which was added to a solution of 213 
mg (0.5 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid, 74 
mg (0.55 mmol) of hydroxybenzotriazole and 115 mg (0.6 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of 
dichloromethane. The mixture was stirred for 18 hours, then washed with 2M 
hydrochloric acid and saturated sodium bicarbonate, dried over magnesium 
sulphate and evaporated to dryness. Trituration of the residue with 
diethyl ether gave 345 mg of 
N2-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N 
1-[1(S)-(dimethoxymethyl)-3-butynyl]-leucinamide as a white solid. MS: m/e 
938 [M+H].sup.+, 906 [M+H-MeOH].sup.+. 
v) 340 mg (0.36 mmol) of 
N2-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-b 
utynyl]-L-leucinamide were dissolved in 12 ml of dichloromethane and 3 ml 
of piperidine and the mixture was stirred at room temperature for 30 
minutes. The mixture was evaporated to dryness and the residue was 
chromatographed on silica gel using firstly ethyl acetate/petrol (1:1) and 
then methanol/ dichloromethane (1:9) for the elution. Evaporation of the 
dichloromethane solution gave a gum which was added to a solution of 144 
mg (0.35 mmol) of N-[(9-fluorenyl) 
methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspartic acid, 54 mg (0.4 mmol) of 
hydroxybenzotriazole and 96 mg (0.5 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 15 ml of 
dichloromethane. The mixture was stirred for 18 hours, then washed with 2M 
hydrochloric acid and saturated sodium bicarbonate solution, dried over 
magnesium sulphate and evaporated to dryness. Trituration of the residue 
with diethyl ether gave 360 mg of 
N2-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspar 
tyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-v 
alyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide as a white solid. 
MS: m/e 1077 [M+H-MeOH].sup.+. 
vi) 350 mg (0.32 mmol) of 
N2-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspar 
tyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-v 
alyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide were dissolved in 
12 ml of dichloromethane and 3 ml of piperidine and the mixture was 
stirred at room temperature for 30 minutes. The mixture was evaporated to 
dryness and the residue was chromatographed on silica gel using firstly 
ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the 
elution. Evaporation of the dichloromethane solution gave a foam which was 
added to a solution of 104 mg (0.6 mmol) of succinic acid monotert-butyl 
ester, 81 mg (0.6 mmol) of hydroxybenzotriazole and 192 mg (1 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of 
dichloromethane. The mixture was stirred for 18 hours, then washed with 2M 
hydrochloric acid and saturated sodium bicarbonate solution, dried over 
magnesium sulphate and evaporated to dryness. Chromatography of the 
residue on silica gel using 4% methanol in dichloromethane for the elution 
and trituration with ethyl acetate gave 145 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-butynyl]-L-leucinamide as a white 
solid. MS: m/e 1043 [M+H].sup.+, 1011 [M+H-MeOH].sup.+. 
EXAMPLE 3 
94 mg (0.86 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-N1-[3,3,3-trifluoro-1(S)-(dimethoxymethyl)propyl]-L-leucinamide 
were stirred in a mixture of 4 ml of trifluoroacetic acid, 4 ml of 
dichloromethane and 30 mg of water at room temperature for 30 minutes. The 
solution was evaporated to dryness in a vacuum and the residue was 
chromatographed on silica gel using dichloromethane/methanol/acetic 
acid/water (120:15:3:2) for the elution. There were obtained 41 mg of 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-t 
rifluorobutyraldehyde (7:1 mixture of diastereoisomers) as a white solid. 
MS: m/e 873 [M+H].sup.+. 
The starting material was prepared as follows: 
184 mg (0.2 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine were suspended in 6 ml of dichloromethane and treated 
with 34 mg (0.25 mmol) of hydroxybenzotriazole followed by 391 mg (1.75 
mmol) of 3,3,3-trifluoro-1(S)-dimethoxymethyl-propylamine hydrochloride 
and 690 mg (6 mmol) of N-ethylmorpholine. The mixture was stirred for 2 
hours, then washed in sequence with 2M hydrochloric acid and saturated 
sodium bicarbonate solution and dried over magnesium sulphate. The solvent 
was removed by evaporation and the resulting solid, after trituration with 
diethyl ether, was chromatographed on silica gel using 4% methanol in 
dichloromethane for the elution. There were obtained 101 mg of 
N2-[N-[N-[N-[N-[(3-tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl-O- 
tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N 
1 -[3,3,3-trifluoro-1(S)-(dimethoxymethyl)propyl]-L-leucinamide as a white 
solid. MS: m/e 1088 [M+H].sup.+. 
EXAMPLE 4 
0.02 g (0.006 mmol) of 
5-[4-[[N-[N-[N-[(9-fluorenyl)-methoxycarbonyl]-2-methyl-L-phenylalanyl]-3- 
methyl-L-valyl]-L-leucyl]-N-3,3,3-trifluoro-1 
(RS)-(dimethoxymethyl)propyl]-amino]methyl]-3,5-dimethoxyphenoxy]-N-(4-met 
hyl-.alpha.-(RS)-phenylbenzyl)valeramide-polystyrene conjugate was 
suspended and agitated in 0.7 ml of dimethylformamide/piperidine (4:1). 
After 5 minutes the resin was drained and then resuspended in and agitated 
with 0.7 ml of dimethylformamide/piperidine (4:1) for a further 5 minutes. 
The resin was then drained and washed five times with 1.5 ml of 
dimethylformamide. 
The resin was then suspended in a solution of 0.026 g (0.06 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine in 0.3 ml of 
dimethylformamide and then a mixture of 0.019 g (0.06 mmol) of 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoraborate and 
0.012 g (0.12 mmol) of N-methylmorpholine dissolved in 0.3 ml of 
dimethylformamide was added. After agitating for 2 hours the resin was 
drained and washed five times with 1.5 ml of dimethylformamide. 
The resin was resuspended in and agitated with 1.5 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and resuspended in and agitated with dimethylformamide/piperidine (4:1) 
for a further 5 minutes. Then, the resin was drained and washed five times 
with 1.5 ml of dimethylformamide. 
The resin was then suspended in a solution of 0.025 g (0.06 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspartic acid in 
0.3 ml of dimethylformamide and then a mixture of 0.019 g (0.06 mmol) of 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoraborate and 
0.012 g (0.12 mmol) of N-methylmorpholine dissolved in 0.3 ml of 
dimethylformamide was added. After agitating for 2 hours the resin was 
drained and washed five times with 1.5 ml of dimethylformamide. 
The resin was resuspended in and agitated with 1.5 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and resuspended in and agitated with dimethylformamide/piperidine (4:1) 
for a further 5 minutes. Then, the resin was drained and washed five times 
with 1.5 ml of dimethylformamide. 
The resin was then suspended in a solution of 0.01 g (0.06 mmol) tert-butyl 
hydrogen succinate in 0.3 ml of dimethylformamide and treated with a 
mixture of 0.019 g (0.06 mmol) 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium etrafluoroborate and 
0.012 g (0.12 mmol) of N-methylmorpholine dissolved in 0.3 ml of 
dimethylformamide. After agitating for 2 hours the resin was drained and 
washed 5 times with 1.5 ml of dimethylformamide and then twice with 1.5 ml 
of dichloromethane. 
The resin was treated with 0.8 ml of trifluoroacetic acid/water (19:1) and 
then agitated for 30 minutes. It was then filtered off and washed with 0.8 
ml of trifluoroacetic acid/water (19:1). The combined trifluoroacetic 
acid/water mixtures were then evaporated in a vacuum centrifuge and the 
residue was suspended in 0.8 ml of acetonitrile/water (1:1) and freeze 
dried. There were obtained 6.3 mg of 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-3-(2-naphth 
yl)-D-alanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4, 
4,4-trifluorobutyraldehyde as a white solid; MS: m/e 941.5 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 18 g (60.0 mmol) of N,O-dimethyl 
2(RS)-(tert-butoxyformamido)-4,4,4-trifluorobutyrohydroxamate were 
dissolved in 230 ml of anhydrous tetrahydrofuran and the solution was 
cooled to 0.degree. C. 48 ml (48 mmol) of a 1M solution of lithium 
aluminium hydride in tetrahydrofuran were then added dropwise while 
maintaining the temperature at 0.degree. C. The mixture was stirred for 10 
minutes at 0.degree. C. and then the reaction was quenched by the dropwise 
addition of saturated potassium hydrogen sulphate solution to pH 1 while 
maintaining the temperature at below 20.degree. C. The resulting white 
slurry was stirred vigorously for a further 30 minutes and was then 
partitioned in three equal aliquots of diethyl ether. The combined diethyl 
ether fractions were washed with saturated sodium chloride solution, dried 
over anhydrous magnesium sulphate, filtered and evaporated. The residue 
was then dissolved in 100 ml of anhydrous saturated methanolic hydrogen 
chloride solution and left overnight at 4.degree. C. The mixture was 
evaporated and the residue was triturated with dichloromethane. The 
filtrate was evaporated and the residue was chromatographed on silica gel 
using 5% methanol, 3% acetic acid and 1.5% water in dichloromethane for 
the elution. There were obtained 8.80 g of 
3,3,3-trifluoro-2(RS)-(dimethoxymethyl)-propylamine hydrochloride as a 
white solid. .sup.1 H NMR: (CDCl.sub.3).delta.: 2.60-2.96 (m,2H), 3.49 
(d,6H), 3.57-3.69 (q,1H), 4.66 (d,1H), 8.72 (br s,3H). 
ii) To a stirred mixture of 5.6 g (25.0 mmol) of 
3,3,3-trifluoro-2(RS)-(dimethoxymethyl)-propylamine hydrochloride 3.65 ml 
of triethylamine, 7.8 g (25.0 mmol) of 
4-[4-(ethoxycarbonyl)butoxy]2,6-dimethoxybenzaldehyde and 25 g of 3 .ANG. 
molecular sieves in dichloromethane were added 5.8 g (27.5 mmol) of sodium 
triacetoxyborohydride. After 3 hours the molecular sieves were removed by 
filtration. The filtrate was then washed with three equal aliquots of 
saturated sodium bicarbonate solution and dried over anhydrous magnesium 
sulphate and filtered. The solvent was removed by evaporation and the 
resulting orange oil was chromatographed on silica gel using 60% ethyl 
acetate in hexane for the elution. There were obtained 10.4 g of ethyl 
5-[4-[[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propylamino]methyl]-3,5-dime 
thoxyphenoxy]valerate as a pale orange oil; .sup.1 H NMR : 
(CDCl.sub.3).delta.: 1.25 (t,3H), 1.78-1.87 (m,4H), 2.18-2.52 (m,4H), 
2.86-2.92 (m,1H), 3.33 (d,6H), 3.77 (s,6H), 3.81 (d,2H), 3.96 (t,2H), 4.13 
(q,2H), 4.26 (d,1H), 6.18 (s,2H); MS: m/e 482.2 [M+H], 504.2 [M+Na]. 
iii) A solution of 6.6 g (18.7 mmol) of 
N-[(9-fluorenyl)-methoxycarbonyl]-L-leucine and 9.7 g (18.7 mmol) of 
7-azabenzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate 
in 50 ml of anhydrous dichloromethane was stirred at room temperature for 
15 minutes. To this mixture were then added 6.0 g (12.4 mmol) of ethyl 
5-[4-[[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propylamino]methyl]-3,5-dime 
thoxyphenoxy]valerate and 4.3 ml of (24.8 mmol) diisopropylethylamine. 
After stirring overnight at 25.degree. C. the mixture was diluted with 
dichloromethane and washed in sequence with water, 10% citric acid 
solution, saturated sodium hydrogen carbonate solution and saturated 
sodium chloride solution, then dried over anhydrous magnesium sulphate and 
filtered. The solvent was removed by evaporation and the residue was 
chromatographed on silica gel using 30% ethyl acetate in hexane for the 
elution. There were obtained 8.06 g of ethyl 
5-[4-[[N-[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]-N-[3,3,3-trifluoro-1( 
RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethoxyphenoxy]valerate; 
MS: m/e 839.4 [M+Na], 855.3 [M+K]. 
iv) 8.0 g (9.8 mmol) of 
5-[4-[[N-[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]-N-[3,3,3-trifluoro-1( 
RS)-(dimethoxymethyl)-propyl]amino]methyl]-3,5-dimethoxyphenoxy]valerate 
and 40 ml of piperidine were dissolved in 145 ml of dry dichloromethane 
and the solution was stirred at room temperature for 30 minutes. It was 
then evaporated in a vacuum and the residue was chromatographed on silica 
gel using 2% methanol, 49% dichloromethane and 49% hexane followed by 5% 
methanol, 47.5% dichloromethane and 47.5% hexane for the elution. There 
were obtained 4.09 g of ethyl 
5-[4-[[N-[3,3,3-trifluoro-1(RS)-dimethoxymethyl)propyl]-N-(L-leucyl)amino] 
-methyl]-3,5-dimethoxyphenoxy]valerate as a clear stiff oil; MS: m/e 595 
[M+H]. 
v) A solution of 2.76 g (7.8 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valine, 1.60 g (8.5 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.60 g 
(10.7 mmol) of N-hydroxybenzotriazole in 70 ml of dichloromethane was 
stirred at 0 C. for 15 minutes. There were then added 4.06 g (7.1 mmol) 
of ethyl 5-[4-[[N-[3,3,3-trifluoro-1 
(RS)-(dimethoxymethyl)propyl]-N-(L-leucyl)-amino]methyl]-3,5-dimethoxyphen 
oxy]valerate and 2.7 ml (21.3 mmol) of N-ethylmorpholine in 70 ml of 
dichloromethane. After stirring overnight at room temperature the mixture 
was washed in sequence with 10% citric acid solution, saturated sodium 
hydrogen carbonate solution and saturated sodium chloride solution, dried 
over anhydrous magnesium sulphate, filtered and evaporated. The residue 
was chromatographed on silica gel using 35% ethyl acetate in hexane for 
the elution. There were obtained 6.11 g of ethyl 
5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-L-leucyl]- 
N-[3,3,3-trifluoro-1(RS)-(dimethoxyethyl)propyl]amino]methyl]-3,5-dimethoxy 
-phenoxy]valerate as a white foam; MS: m/e 952.5 [M+Na], 968.5 [M+K]. 
vi) 5.8 g (6.3 mmol) of ethyl 
5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-L-leucyl]- 
N-[3,3,3-trifluoro-1(RS)-(dimethoxyethyl)propyl]amino]methyl]-3,5-dimethoxy 
phenoxy]valerate and 18 ml of piperidine were dissolved in 90 ml of 
dichloromethane and the solution was stirred at room temperature for 1 
hour. It was then evaporated and the residue was chromatographed on silica 
gel using 3% methanol, 48.5% dichloromethane and 48.5% hexane for the 
elution. There were obtained 4.1 g of ethyl 
5-[4-[[N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]-N-[N-(3-methyl-L- 
valyl)-L-leucyl]amino]methyl]-3,5-dimethoxyphenoxy]-valerate as a white 
foam; MS: m/e 708.6 [M+H], 730.5 [M+Na]. 
vii) 4.0 g (5.7 mmol) of ethyl 
5-[4-[[N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]-N-[N-(3-methyl-L- 
valyl)-L-leucyl]-amino]methyl]-3,5-dimethoxyphenoxy]-valerate were 
dissolved in 40 ml of methanol. 2.4 g (17.3 mmol) of potassium carbonate 
and 8.0 ml of water were then added and the mixture was stirred for 2 days 
at room temperature. The solvent was removed by evaporation and the 
residue was dissolved in 20 ml of water and 20 ml of dioxan. 2.9 g (8.6 
mmol) of N-[(9-fluorenyl)-methoxycarbonyloxy]-succinimide were then added 
and the mixture was stirred for 3 hours. The mixture was adjusted to pH 3 
with 10% citric acid and then washed with three equal aliquots of 
dichloromethane. The combined organic layers were washed with saturated 
sodium chloride solution, dried over anhydrous magnesium sulphate, 
filtered and the filtrate was evaporated. The residue was chromatographed 
on silica gel using 4% tert-butyl methyl ether in dichloromethane for the 
elution. There were obtained 5.12 g of 
5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-L-leucyl]- 
N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]amino]methyl]-3,5-dimethox 
yphenoxy]valeric acid as a white foam; MS: m/e 870.8 [M+H-MeOH], 888.7 
[M+H-CH.sub.3 ], 889.7 [M-CH.sub.3 ]902.7 [M+H], 924.7 [M+Na]. 
viii) 5.4 g (5.4 mmol) of 4-methylbenzhydrylamine resin were swollen in 30 
ml of dimethylformamide, excess solvent was drained from the resin and it 
was then washed twice with 20 ml dimethylformamide/N-methylmorpholine 
(9:1). The resin was then resuspended in 10 ml of dimethylformamide 
containing 4.98 g (5.4 mmol) of 
5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valyl]-L-leucyl]- 
N-[3,3,3-trifluoro-1(RS)-dimethoxymethyl)propyl]amino]methyl-3,5-dimethoxyp 
henoxy]-valeric acid and 1.74 g (5.4 mmol) of 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoraborate. 
Thereto there were added 1.18 ml (10.8 mmol) of N-methylmorpholine 
dissolved in 10 ml of dimethylformamide. The resulting mixture was 
agitated for 2 hours and the resin was then drained and washed five times 
with 30 ml of dimethylformamide. The resin was then resuspended in 30 ml 
of dimethylformamide containing 2.03 ml (21.6 mmol) of acetic anhydride 
and 2.96 ml (27 mmol) of N-methylmorpholine. This mixture was agitated for 
30 minutes and the resin was then drained and washed five times with 30 ml 
of dimethylformamide each time. The resin was resuspended in and agitated 
in 30 ml of dimethylformamide/piperidine (4:1). After 5 minutes the resin 
was drained, resuspended and again agitated in the foregoing 
dimethylformamide/piperidine mixture for a further 5 minutes. The resin 
was then drained and washed five times with 30 ml of dimethylformamide. 
ix) A solution of 3.2 g (8.1 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine and 2.17 g 
(6.75 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium 
tetrafluoroborate in 22 ml of dimethylformamide was added to the resin 
from paragraph viii) and subsequently 1.5 ml (13.5 mmol) of 
N-methylmorpholine were added. The mixture was agitated for 30 minutes and 
then the resin was drained and washed five times with 30 ml of 
dimethylformamide, twice with 30 ml of dichloromethane, twice with 30 ml 
of ethyl acetate and twice with 30 ml of diethyl ether. After drying there 
were obtained 8.95 g of 
5-[4-[[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanyl]-3-m 
ethyl-L-valyl]-L-leucyl]-N-[3,3,3-trifluoro-1(RS)-(dimethoxymethyl)propyl]a 
mino]methyl]-3,5-dimethoxyphenoxy]-N-(4-methyl-.alpha.-(RS)-phenylbenzyl)va 
leramide-polystyrene conjugate as a pale brown solid (0.31 mmol/g loading 
estimated by quantitation of dibenzofulvene at 301 nm). 
EXAMPLE 5 
0.236 g (0.215 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-butenyl 
]-L-leucinamide was dissolved in 1.5 ml of water, 13.5 ml of 
trifluoroacetic acid and 7 ml of dichloromethane and the solution was 
stirred at room temperature for 1 hour and then left to stand at 4.degree. 
C. for 18 hours. The solution was then diluted with toluene and 
evaporated. The residue was triturated with diethyl ether and the 
resulting solid was filtered off. The solid was purified by RP-HPLC on a 
Dynamax C18 column (5 micron, 300 .ANG., 21.4 mm.times.50 mm). The elution 
gradient comprised 95% SSA:5% SSB to 95%:SSB 5% SSA over 6 minutes and 
there were obtained, after lyophilization, 69 mg of 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-buten 
ylboronic acid as a foam; MS: m/e 847 [M+H]. 
The starting material was prepared as follows: 
i) 2 g (9.48 mmol) of 
2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved 
in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen 
atmosphere to -78.degree. C. 9.5 ml (9.5 mmol) of 1M allylmagnesium 
bromide were added dropwise and the solution was stirred at room 
temperature for 18 hours. The solution was partitioned between ethyl 
acetate, saturated sodium chloride solution and 2M hydrochloric acid 
solution. The aqueous layer was extracted with ethyl acetate and the 
organic layers were combined and dried over anhydrous sodium sulphate. 
After filtration and evaporation the oil obtained was distilled to give 
1.45 g of 2-(1 
(RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; b.p. 
53.degree. C./0.4 mm Hg. 
ii) 6.6 ml (6.6 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise to a solution of 1.43 g (6.6 mmol) of 
2-(1 (RS)-chloro-3-butenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 
ml of tetrahydrofuran under nitrogen at -78.degree. C. The solution was 
then stirred overnight at room temperature. The solvent was removed by 
evaporation and the residue was taken up in diethyl ether. Insoluble 
material was removed by filtration and the filtrate was cooled to 
0.degree. C. 1.5 ml (19.8 mmol) of trifluoroacetic acid were added and the 
solution was stirred at 0.degree. C. for 30 minutes. The resulting 
precipitate was filtered off and dried to give 0.5 g of 
.alpha.-(RS)-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate which was used in the next step without further 
purification. 
iii) 0.25 g (0.27 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine was dissolved in 4 ml of dimethylformamide and 4 ml of 
dichloromethane. 0.15 ml (1.6 mmol) of N-methylmorpholine was added and 
the solution was cooled to -15.degree. C. under a nitrogen atmosphere. 50 
mg (0.38 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 10 minutes at -15.degree. C. 0.1 g (0.32 mmol) of 
.alpha.-(RS)-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate was added and the mixture was stirred at room temperature 
for 18 hours. After evaporation the residue was partitioned between ethyl 
acetate and 2M hydrochloric acid. The organic layer was washed with 2M 
hydrochloric acid, water and saturated sodium chloride solution and then 
dried over anhydrous sodium sulphate. After evaporation there was obtained 
0.3 g of 
N2-N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha. 
-aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-meth 
yl-L-valyl]-N1 
-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-butenyl]-L-leucina 
mide in the form of a solid; MS: m/e 1097 [M+H]. 
EXAMPLE 6 
0.25 g (0.23 mmol) of 
N2-N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl-O-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-L 
-leucinamide was dissolved in 1.5 ml of water, 13.5 ml of trifluoroacetic 
acid and 7 ml of dichloromethane and the solution was stirred at room 
temperature for 1 hour and then left to stand at 4.degree. C. for 18 
hours. The solution was diluted with toluene and evaporated. The residue 
was triturated with diethyl ether and the resulting solid was filtered 
off. The solid was purified by RP-HPLC on an Aquapore octyl column (20 
micron, 100 mm.times.10 mm). The elution gradient comprised 95% SSA:5% SSB 
to 5% SSA:95% SSB over 6 minutes and there were obtained, after 
lyophilization, 92 mg of 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylbo 
ronic acid as a foam; MS: m/e 835 [M+H]. 
The starting material was prepared as follows: 
i) 2.64 g (12.5 mmol) of 
2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane were dissolved 
in 30 ml of tetrahydrofuran and the solution was cooled under a nitrogen 
atmosphere to -78.degree. C. 11.8 ml (12.5 mmol) of 1.06M ethylmagnesium 
bromide were added dropwise and the solution was stirred at room 
temperature for 18 hours. The solution was partitioned between ethyl 
acetate, saturated sodium chloride solution and 2M hydrochloric acid 
solution. The aqueous layer was extracted with ethyl acetate and the 
organic layers were combined and dried over anhydrous sodium sulphate. 
After filtration and evaporation the oil obtained was distilled to give 
2.04 g of 2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane; 
b.p. 53.degree. C./0.8 mm Hg. 
ii) 10 ml (10 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise to a solution of 2.03 g (9.9 mmol) of 
2-[1(RS)-chloropropyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml 
tetrahydrofuran under a nitrogen atmosphere at -78.degree. C. The solution 
was then stirred overnight at room temperature. The solvent was removed by 
evaporation and the residue was taken up in diethyl ether. Insoluble 
material was removed by filtration and the filtrate was cooled to 
0.degree. C. 2.3 ml (30 mmol) of trifluoroacetic acid were added and the 
solution was stirred at 0.degree. C. for 30 minutes. The resulting 
precipitate was filtered off and dried to give 0.5 g of 
a-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate as a white solid. 
Analysis for C.sub.11 H.sub.21 BNF.sub.3 O.sub.4 [299.15]. Calculated: C, 
44.17; H, 7.08; N, 4.68% Found: C, 44.06, H, 7.05, N, 4.71%. 
iii) 0.25 g (0.27 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine was dissolved in 2 ml of dimethylformamide and 5 ml of 
dichloromethane. 0.15 ml (1.6 mmol) of N-methylmorpholine was added and 
the solution was cooled to -15.degree. C. under a nitrogen atmosphere. 50 
mg (0.38 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 10 minutes at -15.degree. C. 0.1 g (0.33 mmol) of 
.alpha.-(RS)-ethyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate was added and the mixture was stirred at room temperature 
for 18 hours. After evaporation the residue was partitioned between ethyl 
acetate and 2M hydrochloric acid. The organic layer was washed with 2M 
hydrochloric acid, water and saturated sodium chloride solution and then 
dried over anhydrous sodium sulphate. After evaporation there was obtained 
0.26 g of 
N2-N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]-L-l 
eucinamide in the form of a solid; MS: m/e 1085 [M+H]. 
EXAMPLE 7 
0.16 g (14.6 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-l 
eucinamide was dissolved in 4 ml of trifluoroacetate acid and 4 ml of 
dichloromethane. 4 drops of water were added and the solution was stirred 
at room temperature for 3 hours. The residue was triturated with diethyl 
ether and the resulting solid was filtered off and dried to give, after 
lyophilization, 139 mg of 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]butylbor 
onic acid as a foam; MS: m/e 849 [M+H]. 
The starting material was prepared as follows: 
i) 0.5 g (2.37 mmol) of 
2-(dichloromethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was dissolved 
in 10 ml of tetra-hydrofuran and the solution was cooled under a nitrogen 
atmosphere to -78.degree. C. 2.4 ml (2.4 mmol) of 1M propylmagnesium 
bromide were added dropwise and the solution was stirred at room 
temperature for 18 hours. The solution was partitioned between ethyl 
acetate, saturated sodium chloride solution and 2M hydrochloric acid 
solution. The aqueous layer was extracted with ethyl acetate and the 
organic layers were combined and dried over anhydrous sodium sulphate. 
After evaporation there was obtained 0.38 g of 
2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as an oil 
which was used in the next step without further purification. 
ii) 1.7 ml (1.7 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise to a solution of 0.37 g (1.69 mmol) of 
2-[1(RS)-chlorobutyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 20 ml of 
tetrahydrofuran under nitrogen at -78.degree. C. The solution was then 
stirred overnight at room temperature. The solvent was removed by 
evaporation and the residue was taken up in diethyl ether. Insoluble 
material was removed by filtration and the filtrate was cooled to 
0.degree. C. 0.39 ml (5.1 mmol) of trifluoroacetic acid was added and the 
solution was stirred at 0.degree. C. for 30 minutes. The solution was 
evaporated and the residue was co-evaporated with toluene to give 0.62 g 
of .alpha.-(RS)-propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylami 
ne trifluoroacetate as a brown oil which was used in the next step without 
further purification. 
iii) 0.2 g (0.218 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine was dissolved in 2 ml of dimethylformamide and 6 ml of 
dichloromethane. 0.12 ml (1.1 mmol) of N-methylmorpholine was added and 
the solution was cooled to -15.degree. C. under a nitrogen atmosphere. 40 
mg (0.31 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 10 minutes at -15.degree. C. 0.14 g (0.44 mmol) of 
.alpha.-(RS)-propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate was added and the mixture was stirred at room temperature 
for 66 hours. After evaporation the residue was partitioned between ethyl 
acetate and 2M hydrochloric acid. The organic layer was washed with 2M 
hydrochloric acid, water and saturated sodium chloride solution and then 
dried over anhydrous sodium sulphate. After evaporation there was obtained 
0.17 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-N1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-l 
eucinamide in the form of a solid; NMR (DMSO, 400 MHz) .delta.: 0.75-0.9 
(m,17H), 1.01-1.08 (m,6H), 1.15-1.25 (m,1H), 1.35 9s,36H), 1.4-1.7 (m,4H), 
1.75-1.8 (m,1H), 2.05-2.15 (m,2H), 2.23 (s,3H), 2.29-2.41 (m,6H), 2.55-2.6 
(m,1H), 2.7-2.74 (m,1H), 2.95-3.05 (m,1H), 4.15-4.25 (m,3H), 4.48-4.55 
(m,1H), 4.6-4.7 (m,1H), 7.05-7.11 (m,4H), 7.7-7.81 (m,2H), 8.05-8.12 
(m,2H), 8.15-8.25 (m,2H). 
EXAMPLE 8 
0.126 g (0.116 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1[3,3-difluoro-[1(S)-(dimethoxymethyl)-butyl]-L-leucinamide was 
dissolved in 5 ml of trifluoroacetic acid and 5 ml of dichloromethane. A 
few drops of water were added and the solution was stirred at room 
temperature for 1 hour. The residue was evaporated, the residue was 
triturated with diethyl ether and the resulting solid was filtered off. 
The solid was purified by chromatography on silica gel using 
dichloromethane/methanol/acetic acid/water (75:15:3:2) for the elution. 
There were obtained 67 mg of 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4-difl 
uorovaleraldehyde as a cream coloured solid of melting point 
128-130.degree. C. 
The starting material was prepared as follows: 
i) 1.5 g (4.62 mmol) of 4,4-difluoro-L-norvaline p-toluenesulphonate were 
dissolved in dimethylformamide. 1.71 g (7.85 mmol) of di-tert-butyl 
dicarbonate and 3.23 ml (23.25 mmol) of triethylamine were added and the 
solution was stirred at 60.degree. C. for 3 hours. The solution was 
evaporated and the residue was partitioned between ethyl acetate and 2M 
hydrochloric acid. The organic layer was dried over anhydrous sodium 
sulphate and evaporated. The resulting oil was purified by chromatography 
on silica gel using ethyl acetate for the elution. There were obtained 
1.16 g of N-(tert-butoxycarbonyl)-4,4-difluoro-L-norvaline as an orange 
oil which was used directly in the next step. 
ii) 1.16 g (4.62 mmol) of N-(tert-butoxycarbonyl)-4,4-difluoro-L-norvaline 
were dissolved in 30 ml of dichloromethane. 6.4 ml (46.2 mmol) of 
triethylamine, 564 mg (4.62 mmol) of N,N-dimethylaminopyridine, 1.77 g 
(9.24 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
and 1.8 g (18.5 mmol) of N,O-dimethylhydroxylamine hydrochloride were 
added and the solution was stirred at room temperature for 18 hours. The 
mixture was diluted with ethyl acetate, washed with 2M hydrochloric acid 
and aqueous sodium hydrogen carbonate solution, dried over anhydrous 
sodium sulphate and evaporated to give an oil which was purified by 
chromatography on silica gel using ethyl acetate for the elution. There 
were obtained 547 mg of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4,4-difluorovalerohydroxamate as a colourless 
oil; MS: m/e 297 [M+H]. 
iii) 547 mg (1.85 mmol) of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4,4-difluorovalerohydroxamate were dissolved 
in 12 ml of tetrahydrofuran and the solution was stirred at 0.degree. C. 
1.76 ml (1.76 mmol) of 1M lithium aluminium hydride in tetrahydrofuran 
were added and the solution was stirred for 15 minutes. The mixture was 
partitioned between ethyl acetate and saturated aqueous potassium hydrogen 
sulphate solution. The organic layer was evaporated and the residue was 
dissolved in freshly prepared methanolic hydrogen chloride solution. After 
1 hour the solution was evaporated to give 372 mg of 
3,3-difluoro-1(S)-(dimethoxymethyl)butylamine hydrochloride as a white 
solid; MS: m/e 184 [M+H]. 
iv) 0.3 g (0.33 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine was dissolved in 15 ml of dichloromethane. 0.22 ml (1.98 
mmol) of N-methylmorpholine, 96 mg (0.5 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 45 mg (0.33 
mmol) of hydroxybenzotriazole and 217 mg (0.99 mmol) of 
3,3-difluoro-1(S)-(dimethoxymethyl)butylamine hydrochloride were added and 
the solution was stirred at room temperature for 18 hours. The mixture was 
washed with 2M hydrochloric acid and aqueous sodium hydrogen carbonate 
solution, dried over anhydrous sodium sulphate and evaporated. The residue 
was triturated with diethyl ether and the resulting solid was filtered off 
and dried. There were obtained 143 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[3,3-difluoro-1(S)-dimethoxymethyl)butyl]-L-leucinamide; MS: 
m/e 1106 [M+Na]+. 
EXAMPLE 9 
80 mg (0.075 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N 1-[1(R)-dimethoxymethyl)-2-(methylthio)ethyl]-L-leucinamide 
were dissolved in 10 ml of trifluoroacetic acid/dichloromethane (1:1) 
containing 3 drops of water and the solution was stirred for 90 minutes 
under a nitrogen atmosphere. The solution was evaporated to dryness under 
a vacuum and the residue was re-evaporated twice with toluene. The solid 
was triturated with 10 ml of diethyl ether to give 60 mg of 
2(R)-[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(methyl 
thio)propionaldehyde as a white solid; MS: m/e 851.5 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 2 g (8.51 mmol) of N-(tert-butoxycarbonyl)-S-methyl-L-cysteine were 
dissolved in 60 ml of anhydrous tetrahydrofuran and then 1.81 g (11.9 
mmol) of 1-hydroxybenzotriazole hydrate, 2.28 g (11.88 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.16 g (11.90 
mmol) of N,O-dimethylhydroxylamine hydrochloride and 5.9 ml (33.87 mmol) 
of N,N-diisopropylethylamine were added. The mixture was stirred overnight 
at room temperature. The solvent was removed by evaporation and the 
residue was partitioned between ethyl acetate and 5% (w/v) aqueous citric 
acid. The organic phase was washed with saturated aqueous sodium 
bicarbonate solution and then with saturated sodium chloride solution, 
dried over magnesium sulphate and evaporated under a vacuum to give 2.27 g 
of N,O-dimethyl 
2(R)-(tert-butoxyformamido)-3-(methylthio)propionohydroxamate as a 
colourless oil; MS: m/e 279 [M+H].sup.+. 
ii) 2.22 g (7.90 mmol) of N,O-dimethyl 
2(R)-(tert-butoxyformamido)-3-(methylthio)propionohydroxamate were 
dissolved in 25 ml of anhydrous tetrahydrofuran and the solution was 
cooled to 0.degree. C. 4.69 ml (4.69 mmol) of a 1M solution of lithium 
aluminium hydride in tetrahydrofuran were added dropwise and the mixture 
was stirred for 15 minutes. The reaction was quenched by the dropwise 
addition of saturated aqueous potassium hydrogen sulphate solution and 
then 50 ml of diethyl ether were added. The mixture was stirred vigorously 
for 20 minutes. The organic phase was separated, washed with saturated 
aqueous sodium bicarbonate solution, dried over magnesium sulphate and 
evaporated to give 1.75 g of aldehyde which, without further purification, 
was dissolved in 20 ml of saturated methanolic hydrogen chloride solution 
and stirred for 2 hours under a nitrogen atmosphere at room temperature. 
The solvent was removed by evaporation and the residue was re-evaporated 
twice with toluene to give 1.3 g of dimethyl acetal as a colourless oil. 
90 mg (0.45 mmol) of the dimethyl acetal were dissolved in 40 ml 
dichloromethane and then 200 mg (0.22 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 100 mg (0.87 mmol) of N-ethylmorpholine, 40 mg (0.26 
mmol) of 1-hydroxybenzotriazole hydrate and 50 mg (0.26 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. 
The solution was stirred overnight at room temperature. The organic phase 
was washed with 5% (w/v) aqueous citric acid and then with saturated 
aqueous sodium bicarbonate solution, dried over magnesium sulphate and 
evaporated under a vacuum. The resulting oil was triturated with 10 ml of 
diethyl ether to give 165 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(R)-(dimethoxymethyl)-2-(methylthio)ethyl]-L-leucinamide as 
a white solid; MS: m/e 1065.7 [M+H].sup.+. 
EXAMPLE 10 
50 mg (0.048 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-butenyl]-L-leucinamide were 
dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing 
3 drops of water and the solution was stirred for 1 hour under nitrogen. 
The solution was evaporated to dryness under a vacuum and the residue was 
re-evaporated twice with toluene. The solid was triturated with 10 ml of 
diethyl ether to give 30 mg of 
2(RS)-[[N[[N-(N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pente 
naldehyde; MS: m/e 831.5 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 1.13 g (7.46 mmol) of L-allylglycine hydrochloride were dissolved in 20 
ml of saturated aqueous sodium bicarbonate solution and 20 ml of dioxan. 
1.95 g (8.93 mmol) of di-tert-butyl dicarbonate were added and the 
solution was stirred overnight and then evaporated to dryness under a 
vacuum. The residue was partitioned between diethyl ether and water. The 
aqueous phase was acidified with 2M hydrochloric acid and extracted with 
ethyl acetate. The organic phase was dried over magnesium sulphate and 
evaporated under a vacuum to give 1.6 g of 
N-(tert-butoxycarbonyl)-L-allylglycine as a colourless oil. .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 2.4-2.7 (m,2H), 4.3-4.5 (m,1H), 
5.0 (br.d,1H), 5.1-5.2 (m,2H), 5.6-5.8 (m, 1H) 
ii) N,O-Dimethyl 2(S)-(tert-butoxyformamido)-4-pentenohydroxamate was 
obtained in a manner analogous to that described in Example 10 i) from 1.6 
g (7.44 mmol) of N-(tert-butoxycarbonyl)-L-allylglycine, 1.4 g (10.4 mmol) 
of 1-hydroxybenzotriazole, 1.99 g (10.4 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.02 g (10.46 
mmol) of N,O-dimethylhydroxylamine hydrochloride and 2.6 ml (14.93 mmol) 
of ethyl diisopropylamine. This gave 1.9 g of product as a colourless oil. 
.sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 2.3-2.6 (m,2H), 
3.2 (s,3H), 3.8 (s,3H), 4.6-4.7 (m,1H), 5.0-5.4 (m,3H), 5.6-5.8 (m,1H). 
iii) 1.9 g (7.36 mmol) of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4-pentenohydroxamate were dissolved in 20 ml 
of anhydrous tetrahydrofuran and the solution was cooled to 0.degree. C. 
5.40 ml (5.4 mmol) of a 1M solution of lithium aluminium hydride in 
tetrahydrofuran were added dropwise and the mixture was stirred for 25 
minutes. The reaction was quenched by the dropwise addition of saturated 
aqueous potassium hydrogen sulphate and then 50 ml of diethyl ether were 
added. The mixture was stirred vigourously for 20 minutes. The organic 
phase was separated, washed with saturated aqueous sodium bicarbonate 
solution, dried over magnesium sulphate and evaporated to give the 
aldehyde which, without further purification, was dissolved in 25 ml of 
saturated methanolic hydrogen chloride solution and stirred for 2 hours at 
room temperature. The solvent was removed by evaporation and the residue 
was re-evaporated twice with toluene to give the amino acid acetal as a 
brown oil. 
iv) 40 mg (0.22 mmol) of the amino acid acetal were dissolved in 4 ml of 
dichloromethane and then 200 mg (0.22 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 0.1 ml (0.78 mmol) of N-ethylmorpholine, 35 mg (0.22 
mmol) of 1-hydroxybenzotriazole monohydrate and 50 mg (0.26 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. 
The solution was stirred overnight at room temperature. The organic phase 
was washed with 5% (w/v) aqueous citric acid solution and then with 
saturated aqueous sodium bicarbonate solution, dried over magnesium 
sulphate and evaporated under a vacuum. The resulting oil was triturated 
with 10 ml of diethyl ether to give 148 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-butenyl]-L-leucinamide as a white 
solid; MS: m/e 1013.6 [M+H-MeOH].sup.+. 
EXAMPLE 11 
90 mg (0.081 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[2-(butylthio)-1(R)-(dimethoxymethyl)ethyl]-L-leucinamide were 
dissolved in 10 ml of trifluoroacetic acid/dichloromethane (1:1) 
containing 3 drops of water and the solution was stirred for 90 minutes 
under nitrogen. The solution was evaporated to dryness under a vacuum and 
the residue was re-evaporated twice with toluene. The solid was triturated 
with 10 ml of diethyl ether to give 80 mg of 
2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(butylt 
hio)propionaldehyde as a white solid. MS: m/e 893.4 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 2 g (16.53 mmol) of L-cysteine were dissolved in 40 ml of water/ethanol 
(1:1) together with 1.33 g (33.25 mmol) of sodium hydroxide pellets. 3.04 
g (16.53 mmol) of butyl iodide were added and the mixture was stirred for 
2 hours. The resulting S-alkylated product was treated with 3.96 g (18.14 
mmol) of di-tert-butyl dicarbonate and the mixture was stirred for 1 hour. 
A further 3.61 g (16.53 mmol) of di-tert-butyl dicarbonate were added and 
the mixture was stirred overnight. The solution was evaporated to dryness 
under a vacuum and the residue was partitioned between diethyl ether and 
saturated aqueous sodium hydrogen carbonate solution. The aqueous phase 
was acidified by partitioning in 2M hydrochloric acid and ethyl acetate, 
the separated organic phase was dried over magnesium sulphate and the 
solvent was removed by evaporation to give 4.3 g of 
N-(tert-butoxycarbonyl)-S-butyl-L-cysteine as a brown oil; .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 0.9 (t,3H), 1.3-1.6 (m,4H), 1.4 (s,9H), 
2.55 (t,2H), 3.0 (br.d,2H), 4.5 (m,1H), 5.3 (br.d,1H). 
ii) N,O-Dimethyl 
2(R)-(tert-butoxyformamido)-3-(butylthio)-propionohydroxamate was obtained 
in a manner analogous to that described in Example 10 i) from 2.15 g (7.76 
mmol) of N-(tert-butoxycarbonyl)-S-butyl-L-cysteine, 1.19 g (7.77 mmol) of 
1-hydroxybenzotriazole monohydrate, 2.24 g (11.68 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.14 g (11.68 
mmol) of N,O-dimethylhydroxylamine hydrochloride and 1.34 g (11.64 mmol) 
of N-ethylmorpholine in 30 ml of dichloromethane. This gave 2.0 g of 
product as a colourless oil after column chromatography using ethyl 
acetate/petrol (1:2) as the eluent. .sup.1 H NMR (250 MHz, CDCl.sub.3) 
.delta.: 0.9 (t,3H), 1.3-1.6 (m,4H), 1.4 (s,9H), 2.55 (t,2H), 2.6 -2.7 
(dd,1H), 2.8-2.9 (dd,1H), 3.2 (s,3H), 3.75 (s,3H), 4.8-4.9 (m,1H), 5.3 
(br.d,1H). 
iii) 0.3 g (0.94 mmol) of N,O-dimethyl 
2(R)-(tert-butoxyformamido)-3-(butylthio)propionohydroxamate was dissolved 
in 10 ml of anhydrous tetrahydrofuran and the solution was cooled to 
0.degree. C. 0.55 ml (0.55 mmol) of a 1M solution of lithium aluminium 
hydride in tetrahydrofuran was added dropwise and the mixture was stirred 
for 15 minutes. The reaction was quenched by the dropwise addition of 
saturated aqueous potassium hydrogen sulphate and then 20 ml of diethyl 
ether were added. The mixture was stirred vigorously for 20 minutes. The 
organic phase was separated, washed with saturated aqueous sodium 
bicarbonate solution, dried over magnesium sulphate and evaporated to give 
the aldehyde which, without further purification, was dissolved in 20 ml 
of saturated methanolic hydrogen chloride solution and stirred for 2 hours 
under a nitrogen atmosphere at room temperature. The solvent was removed 
by evaporation and the residue was re-evaporated twice with toluene to 
give the amino acid acetal as a brown oil. 
200 mg (0.82 mmol) of the amino acid acetal were dissolved in 40 ml of 
dichloromethane and then 200 mg (0.22 mmol) of 
[N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl) 
propionyl]-O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.alpha.-glutamy 
l]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine, 100 mg (0.87 mmol) 
of N-ethylmorpholine, 40 mg (0.26 mmol) of 1-hydroxybenzotriazole and 50 
mg (0.26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride were added. The solution was stirred for 2 hours at room 
temperature. The organic phase was washed with 5% (w/v) aqueous citric 
acid solution and then with saturated aqueous sodium bicarbonate solution, 
dried over magnesium sulphate and evaporated under a vacuum. The resulting 
oil was triturated with 10 ml of diethyl ether to give 160 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[2-(butylthio)-[1(R)-(dimethoxymethyl)ethyl]-L-leucinamide as 
a white solid; MS: m/e 1075.6 [M+H-MeOH].sup.+. 
EXAMPLE 12 
56 mg (0.049 mmol) of 
N1-[2-(benzylthio)-1(R)-(dimethoxymethyl)ethyl]-N2-[N-[N-[N-[N-[3-(tert-bu 
toxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.al 
pha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucinamide 
were dissolved in 10 ml of trifluoroacetic acid/dichloromethane (1:1) 
containing 3 drops of water and the solution was stirred for 90 minutes. 
The solution was evaporated to dryness under a vacuum and the residue was 
re-evaporated twice with toluene. The solid was triturated with 10 ml of 
diethyl ether to give 40 mg of 
3-(benzylthio)-2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-asparty 
l]-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl] 
amino]propionaldehyde as a white solid. MS: m/e 927.6 (M+H].sup.+. 
The starting material was prepared as follows: 
i) S-Benzyl-N-(tert-butoxycarbonyl)-L-cysteine was obtained in a manner 
analogous to that described in Example 10 i) from 1 g (4.74 mmol) of 
S-benzyl-L-cysteine, 0.8 g (9.5 mmol) of sodium bicarbonate and 1.4 g (6.4 
mmol) of di-tert-butyl dicarbonate. There were obtained 1.4 g of a 
colourless oil; .sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 
2.8-2.9 (m,2H), 3.7 (s,2H), 4.4-4.5 (m,1H), 5.3 (d,1H), 7.2-7.4 (m,5H) 
ii) N,O-Dimethyl 3-(benzyl)-2(R)-(tert-butoxyformamido)propionohydroxamate 
was obtained in a manner analogous to that described in Example 9 i) from 
1.4 g (4.52 mmol) of S-benzyl-N-(tert-butoxycarbonyl)-L-cysteine, 0.70 g 
(4.6 mmol) of 1-hydroxybenzotriazole monohydrate, 1.30 g (6.77 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 0.66 g (6.77 
mmol) of N,O-dimethylhydroxylamine hydrochloride and 0.78 g (6.77 mmol) of 
N-ethylmorpholine in 40 ml of dichloromethane. There were obtained 0.60 g 
of a colourless oil; .sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 
(s,9H), 2.55-2.65 (dd,1H), 2.75-2.85, (dd,1H), 3.2 (s,3H), 3.7 (s,3H), 
3.72 (s,2H), 4.9 (m,1H), 5.3 (d,1H), 7.2-7.35 (m,5H). 
iii) 0.48 g (1.36 mmol) of N,O-dimethyl 
3-(benzyl)-2(R)-(tert-butoxyformamido)propionohydroxamate was dissolved in 
10 ml of anhydrous tetrahydrofuran and the solution was cooled to 
0.degree. C. 0.95 ml (0.95 mmol) of a 1 M solution of lithium aluminium 
hydride in tetrahydrofuran was added dropwise and the mixture was stirred 
for 15 minutes. The reaction was quenched by the dropwise addition of 
saturated aqueous potassium hydrogen sulphate and then 20 ml of diethyl 
ether were added. The mixture was stirred vigorously for 20 minutes. The 
organic phase was separated, washed with saturated aqueous sodium 
bicarbonate solution, dried magnesium sulphate and evaporated to give the 
aldehyde which, without further purification, was dissolved in 10 ml of 
saturated methanolic hydrogen chloride solution and stirred for 2 hours at 
room temperature. The solvent was removed by evaporation and the residue 
was re-evaporated twice with toluene to give the amino acid acetal as a 
brown oil. 
100 mg (0.36 mmol) of the amino acid acetal were dissolved in 40 ml of 
dichloromethane and then 200 mg (0.22 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 100 mg (0.87 mmol) of N-ethylmorpholine, 40 mg (0.30 
mmol) of 1-hydroxybenzotriazole and 50 mg (0.26 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. 
The solution was stirred overnight at room temperature. The organic phase 
was washed with 5% (w/v) aqueous citric acid solution and then with 
saturated aqueous sodium bicarbonate solution, dried over magnesium 
sulphate and evaporated under a vacuum. The resulting oil was triturated 
with 10 ml of diethyl ether to give 160 mg of 
N1-[2-(benzylthio)-1(R)-(dimethoxymethyl)ethyl]-N2-[N-[N-[N-[N-[3-(tert-bu 
toxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-aspartyl]-O-tert-butyl-L-.al 
pha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucinamide as 
a white solid; MS: m/e 1109.8 [M+H-MeOH].sup.+. 
EXAMPLE 13 
49 mg (0.046 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentynyl]-L-leucinamide were 
dissolved in 4 ml of trifluoroacetic acid/dichloromethane (1:1) containing 
3 drops of water and the solution was stirred for 1 hour under a nitrogen 
atmosphere. The solution was evaporated to dryness under a vacuum and the 
residue was re-evaporated twice with toluene. The solid was triturated 
with 10 ml of diethyl ether to give 30 mg of 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexyna 
l as a white solid; MS: m/e 843.6 [M+H].sup.+. 
The starting material was prepared as follows: 
i) N-(tert-Butoxycarbonyl)-L-(2-butynyl)glycine was obtained in a manner 
analogous to that described in Example 10 i) from 1.0 g (7.80 mmol) of 
L-(2-butynyl)glycine (prepared according to Sasaki et al. Int. J. Peptide 
Protein Res 1986, 27, 360-365), 2.66 g 1 5 (31.7 mmol) of sodium 
bicarbonate and 1.89 g (8.66 mmol) of di-tert-butyl dicarbonate. There was 
obtained 1.94 g of a colourless oil; .sup.1 H NMR (250 MHz, CDCl.sub.3) 
.delta.: 1.45 (s,9H), 1.75 (t,3H), 2.6-2.9 (m,2H), 4.4-4.5 (m,1H), 5.3 
(br.d,1H). 
ii) N,O-Dimethyl 2(S)-(tert-butoxyformamido)-4-hexynohydroxamate was 
obtained in a manner analogous to that described in Example 9 i) from 1.74 
g (7.67 mmol) of N-(tert-butoxycarbonyl)-L-(2-butynyl)glycine, 1.45 g (9.5 
mmol) of 1-hydroxybenzotriazole, 2.06 g (10.73 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.05 g (10.77 
mmol) of N,O-dimethylhydroxylamine hydrochloride and 5.3 ml (30.43 mmol) 
of ethyldiisopropylamine in 80 ml of tetrahydrofuran. There were obtained 
2.0 g of a colourless oil; 1H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 
(s,9H), 1.75 (t,3H), 2.55 (m,2H), 3.2 (s,3H), 3.5 (s,3H), 4.7-4.8 (m,1H), 
5.35 (br.d,1H). 
iii) 1.0 g (3.70 mmol) of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-4-hexynohydroxamate was dissolved in 10 ml of 
anhydrous tetrahydrofuran and the solution was cooled to 0.degree. C. 2.59 
ml (2.59 mmol) of a 1M solution of lithium aluminium hydride in 
tetrahydrofuran were added dropwise and the mixture was stirred for 30 
minutes. The reaction was quenched by the dropwise addition of 20 ml of 
saturated aqueous potassium hydrogen sulphate and then 50 ml of diethyl 
ether were added. The mixture was stirred vigorously for 30 minutes. The 
organic phase was separated, washed with saturated aqueous sodium 
bicarbonate solution, dried over magnesium sulphate and evaporated to give 
the aldehyde which, without further purification, was dissolved in 10 ml 
of saturated methanolic hydrogen chloride solution and stirred for 2 hours 
under a nitrogen atmosphere at room temperature. The solvent was removed 
by evaporation and the residue was re-evaporated twice with toluene to 
give the amino acid acetal as a brown oil. 
47 mg (0.24 mmol) of the amino acid acetal were dissolved in 20 ml of 
dichloromethane and then 200 mg (0.22 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 0.1 ml (0.78 mmol) of N-ethylmorpholine, 42 mg (0.27 
mmol) of 1-hydroxybenzotriazole and 59 mg (0.31 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. 
The solution was stirred overnight at room temperature. The organic phase 
was washed with 5% (w/v) aqueous citric acid solution and then with 
saturated aqueous sodium bicarbonate solution, dried over magnesium 
sulphate and evaporated under a vacuum. The resulting oil was triturated 
with 10 ml of diethyl ether to give 110 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentynyl]-L-leucinamide as a white 
solid. MS: m/e 1025.8 [M+H-MeOH].sup.+. 
EXAMPLE 14 
0.065 g (0.06 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(dimethoxymethyl)-2-(3-thienyl)ethyl]-L-leucinamide was 
dissolved in 10 ml of dichloromethane/trifluoroacetic acid (1:1) 
containing 3 drops of water. The solution was stirred for 3 hours at room 
temperature. After removal of the solvent by evaporation the crude product 
was chromatographed on silica gel using dichloromethane:methanol:acetic 
acid:water (120:15:3:2) as the eluent to give 0.035 g of 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3(3-thie 
nyl)propionaldehyde as a white solid; MS: m/e 887.7 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 0.5 g (2.92 mmol) of 3-(3-thienyl)-DL-alanine was dissolved in 15 ml of 
water and 15 ml of dioxan. 2.5 g (29.76 mmol) of sodium hydrogen carbonate 
and 3.53 g (16.19 mmol) of di-tert-butyl dicarbonate were added and the 
solution was stirred for 2 hours and then evaporated to dryness under a 
vacuum. The residue was partitioned between diethyl ether and saturated 
aqueous sodium hydrogen carbonate solution. The aqueous phase was 
acidified with 2M hydrochloric acid and extracted with ethyl acetate. The 
organic phase was dried over magnesium sulphate and the solvent was 
evaporated under a vacuum to give 0.685 g of 
N-(tert-butoxycarbonyl)-3-(3-thienyl)-DL-alanine as a colourless oil; 
.sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 2.9 (dd,1H), 3.15 
(dd,1H), 4.3 (m,1H), 7.0 (d,1H), 7.1 (br s,H), 7.3 (m,1H). 
ii) 0.69 g (2.55 mmol) of N-(tert-butoxycarbonyl)-3-(3-thienyl)-DL-alanine 
was dissolved in 40 ml of dichloromethane. 0.34 g (3.56 mmol) of 
N,O-dimethylhydroxylamine hydrochloride, 0.54 g (3.53 mmol) of 
1-hydroxybenzotriazole monohydrate, 0.68 g (3.55 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.0 g 
(8.70 mmol) of 4-ethylmorpholine were added and the resulting solution was 
stirred at room temperature overnight. The solution was then washed with 
5% citric acid solution, saturated sodium hydrogen carbonate solution and 
saturated sodium chloride solution and dried over anhydrous magnesium 
sulphate. After evaporation of the solvent the crude product was 
chromatographed on silica gel using 30% ethyl acetate in petroleum ether 
as the eluent to give 0.75 g of N,O-dimethyl 
2(RS)-(tert-butoxyformamido)-3-(3-thienyl)propionohydroxamate as a white 
solid; .sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 2.95 
(dd,1H), 3.05 (dd,1H), 3.15 (s,3H), 3.65 (s,3H), 4.9 (m,1H), 5.15 (br 
d,1H), 6.9 (d,1H), 7.0 (d,1H), 7.2 (m,1H). 
iii) 0.2 g (0.64 mmol) of N,O-dimethyl 
2(RS)-(tert-butoxyformamido)-3-(3-thienyl)propionohydroxamate was 
dissolved in 10 ml of anhydrous tetrahydrofuran and the solution was 
cooled to 0.degree. C. 0.5 ml (0.5 mmol) of a 1M solution of lithium 
aluminium hydride in tetrahydrofuran was added dropwise and the solution 
was stirred for 15 minutes. The reaction was quenched by the dropwise 
addition of saturated potassium hydrogen sulphate solution and then 30 ml 
of diethyl ether were added. The resulting two phase system was stirred 
vigorously for 1 hour. The organic phase was separated, washed with 
saturated sodium hydrogen carbonate solution and saturated sodium chloride 
solution, dried over magnesium sulphate and evaporated to give the 
aldehyde which, without purification, was dissolved in 10 ml of a 
saturated methanolic hydrogen chloride solution and stirred at room 
temperature for 2 hours. After removal of the solvent by evaporation the 
dimethyl acetal was used in the next step without purification. 
The dimethyl acetal was dissolved in 40 ml of dichloromethane and then 0.15 
g (0.16 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 0.03 g (0.2 mmol) of 1-hydroxybenzotriazole, 0.038 g 
(0.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
and 0.08 g (0.65 mmol) of N-ethylmorpholine were added and the resulting 
solution was stirred at room temperature for 2 hours. The solution was 
washed with 5% citric acid solution, saturated sodium hydrogen carbonate 
solution and saturated sodium chloride solution and dried over anhydrous 
magnesium sulphate. After removal of the solvent by evaporation the crude 
product was chromatographed on silica gel using 5% methanol in 
dichloromethane as the eluent to give 0.07 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(dimethoxymethyl)-2-(3-thienyl)ethyl-L-leucinamide as a 
white solid; MS: m/e 1069 [M+H-MeOH].sup.+. 
EXAMPLE 15 
0.08 g (0.07 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-2-(2-thienyl)ethyl]-L-leucinamide was 
dissolved in 10 ml of dichloromethane/trifluoroacetic acid (1:1) 
containing 3 drops of water and the solution was stirred for 2 hours at 
room temperature. After removal of the solvent by evaporation the crude 
product was chromatographed on silica gel using 
dichloromethane:methanol:acetic acid:water (120:15:3:2) as the eluent to 
give 0.021 g of 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3(2-thien 
yl)propionaldehyde as a white solid; MS: m/e 887.4 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 0.63 g (2.33 mmol) of N-(tert-butoxycarbonyl)-3-(2-thienyl)-L-alanine 
was dissolved in 50 ml of dichloromethane and then 0.34 g (3.48 mmol) of 
N,O-dimethylhydroxylamine hydrochloride, 0.36 g (2.35 mmol) of 
1-hydroxybenzotriazole monohydrate, 0.67 g (3.49 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.40 g 
(3.47 mmol) of N-ethylmorpholine were added. The resulting solution was 
stirred at room temperature overnight. The solution was washed with 5% 
citric acid, then with saturated sodium hydrogen carbonate solution and 
saturated sodium chloride solution, dried over anhydrous magnesium 
sulphate and evaporated to give 0.70 g of N,O-dimethyl 
2(S)-(tert-butoxyformamido)-3-(2-thienyl)propionohydroxamate as a white 
solid; .sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s,9H), 3.1 
(dd,1H), 3.15 (s,3H), 3.2 (dd,1H), 3.7 (s,3H), 4.9 (br d,1H), 5.8 (m,1H), 
6.8 (d,1H), 6.9 (dd,1H), 7.15 (d,1H). 
ii) 0.4 g (1.27 mmol) of N,O-dimethyl 
2(S)-(tert-butoxy-formamido)-3-(2-thienyl)propionohydroxamate was 
dissolved in 10 ml of anhydrous tetrahydrofuran and the solution was 
cooled to 0.degree. C. 0.9 ml (0.9 mmol) of a 1M solution of lithium 
aluminium hydride in tetrahydrofuran was added and the resulting solution 
stirred for 15 minutes. The reaction was quenched by the dropwise addition 
of 15 ml of saturated potassium hydrogen sulphate solution and then 30 ml 
of diethyl ether were added. The resulting two phase system was stirred 
vigorously for 40 minutes. The organic phase was separated, washed with 
saturated sodium hydrogen carbonate solution and saturated sodium chloride 
solution and dried over anhydrous magnesium sulphate. After removal of the 
solvent by evaporation the aldehyde, without further purification, was 
dissolved in 10 ml of a saturated methanolic hydrogen chloride solution 
and stirred at room temperature for 2 hours. After removal of the solvent 
by evaporation the dimethyl acetal was used in the next step without 
purification. 
The dimethyl acetal was dissolved in 40 ml of dichloromethane and then 0.20 
g (0.22 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 0.04 mg (0.26 mmol) of 1-hydroxybenzotriazole, 0.05 g 
(0.26 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 
and 0.10 g (0.87 mmol) of N-ethylmorpholine were added. The resulting 
solution was stirred at room temperature for 2 hours, then washed in 
sequence with 5% citric acid solution, saturated sodium hydrogen carbonate 
solution and saturated sodium chloride solution and dried over anhydrous 
magnesium sulphate. After removal of the solvent by evaporation the crude 
product was triturated with diethyl ether to give 0.16 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-2-(2-thienyl)ethyl-L-leucinamide as a 
white solid. MS: m/e 1069.6 [M+H-MeOH]+.sup.+. 
EXAMPLE 16 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-L-cyclohexyl-glycine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-2-cyclohe 
xylglycyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4 
-trifluorobutyraldehyde as a white solid; MS: m/e 883.5 [M+H]. 
EXAMPLE 17 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-L-valine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-valyl]-2- 
methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobut 
yraldehyde as a white solid; MS: m/e 843.5 [M+H]. 
EXAMPLE 18 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-D-alanine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-alanyl]-2 
-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobu 
tyraldehyde as a white solid; MS: m/e 815.4 [M+H]. 
EXAMPLE 19 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-D-valine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-valyl]-2- 
methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobut 
yraldehyde as a white solid; MS: m/e 843.4 [M+H]. 
EXAMPLE 20 
0.2 g (0.2 mmol) of 
N2-[N-[N-[N-[N-(carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl]- 
2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(R)-(3a(S),4(S),5,6(S),7,7a 
(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl)penty 
l]-L-leucinamide was dissolved in 12 ml of acetone and 12 ml of 0.1M 
ammonium acetate in water were added. 0.21 g (1 mmol) of sodium periodate 
was added and the resulting mixture was stirred at room temperature for 22 
hours. 7 ml of water were then added together with a small amount of 
sodium periodate. The resulting solution was stirred for a further 5 
hours. The acetone was removed under a vacuum and the aqueous residue was 
acidified with 2N hydrochloric acid and then extracted with ethyl acetate. 
Saturated aqueous sodium chloride was added to the aqueous layer which was 
then extracted with ethyl acetate. The organic extracts were combined, 
dried over sodium sulphate and evaporated. The residue was trituated with 
diethyl ether, filtered off and dried to give 167 mg of 1 
(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]pentylboro 
nic acid as a white solid; MS: m/e 845.4 [M+H-H.sub.2 O].sup.+. 
The starting material was prepared as follows: 
i) In an analogous manner to that described in Example 21 i) and ii), by 
replacing 3-butenylmagnesium bromide with butylmagnesium bromide there was 
obtained .alpha.-(R)-butyl-3a(S),4(S), 
5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaboro 
le-2-methylamine trifluoroacetate (1:1) which was used in the next step 
without further purification. 
ii) 0.25 g (0.27 mmol) of 
N-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-ter 
t-butyl-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine 
was dissolved in 2 ml of dimethylformamide and 4 ml of dichloromethane. 
0.15 ml (1.4 mmol) of N-methylmorpholine was added and the solution was 
cooled to -10.degree. C. under a nitrogen atmosphere. 45 mg (0.32 mmol) of 
isobutyl chloroformate were added and the solution was stirred for 10 
minutes at -10.degree. C. 0.2 g (0.54 mmol) of 
.alpha.-(R)-butyl-3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6 
-methano-1,3,2-benzodioxaborole-2-methylamine trifluoroacetate (1.1) was 
added and the mixture was stirred at room temperature for 16 hours. The 
solution was diluted with dichloromethane, washed with 2M hydrochloric 
acid and water and dried over anhydrous sodium sulphate. After evaporation 
the residue was triturated with diethyl ether and dried. There was 
obtained 0.227 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-a-asparty 
l]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-val 
yl]-N1-[1(R)-(3a(S), 4(S),5,6(S), 
7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl) 
pentyl]-L-leucinamide as a white solid; MS: m/e 1165.9 [M+H].sup.+. 
iii) 300 mg (0.26 mmol) of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1- 
[1(R)-(3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3 
,2-benzodioxaborol-2-yl)-4-pentenyl]-L-leucinamide were dissolved in 3.5 ml 
of trifluoroacetic acid and 3.5 ml of dichloromethane. The solution was 
stirred at room temperature for 45 minutes, then diluted with toluene and 
evaporated. The residue was triturated with diethyl ether and the 
resulting solid was filtered off and dried and then purified by 
chromatography on silica gel using dichlomethane/methanol/acetic 
acid/water (170:15:3:2) for the elution. There were obtained 135 mg of 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-a-glutamyl]-2-me 
thyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(R)-(3a(S), 
4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1 
,3,2-benzodioxaborol-2-yl)-4-pentenyl]-L-leucinamide as a white solid: MS: 
m/e 995.3 [M+H].sup.+. 
EXAMPLE 21 
N2-[N-[N-[N-[N-(3-Carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1 
(R)-(3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3, 
2-benzodioxaborol-2-yl)-4-pentenyl]-L-leucinamide can be converted into 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-pentenylboro 
nic acid in an analogous manner to that described in the first paragraph of 
Example 20. 
The starting material was prepared as follows: 
i) 0.5 g (1.9 mmol) of 2-(dichloromethyl)-3a(S),4(S),5,6(S), 
7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1 ,3,2-benzodioxaborole was 
dissolved in 5 ml of tetrahydrofuran and the solution was cooled to 
-78.degree. C. under a nitrogen atmosphere. 4.5 ml (2.3 mmol) of 0.5M 
3-butenylmagnesium bromide in tetrahydrofuran were added dropwise and the 
resulting solution was stirred for 2 minutes. 3 ml (1.52 mmol) of 0.5M 
zinc (II) chloride solution were then added and the mixture was stirred 
for 16 hours while slowly warming to room temperature. The mixture was 
diluted with ethyl acetate and then washed with 2M hydrochloric acid and 
brine. The organic phase was dried over sodium sulphate and then 
evaporated under a vacuum. The residue was purified by chromatography on 
silica gel using diethyl ether/hexane (1:9) for the elution to give 177 mg 
of 
2-[1(S)-chloro-4-pentenyl]-3a(S)-4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trim 
ethyl-4,6-methano-1,3,2-benzodioxaborole. NMR: (CDCl.sub.3) 0.83 (s, 3H), 
1.15 (d, 1H, 1.30 (s, 3H), 1.42 (s, 3H), 1.42 (s, 3H), 1.85-1.95 (m, 4H), 
2.08 (t, 1H), 2.15-2.35 (m, 4H), 3.49 (dd, 1H), 4.35 (dd, 1H), 5.0 (dd, 
1H), 5.07 (dd, 1H), 5.78 (m, 1 H). 
ii) 0.158 g (0.56 mmol) of 
2-[1(S)-chloro-4-pentenyl]-(3a(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethy 
l-4,6-methano-1,3,2-benzodioxaborole was dissolved in 2 ml of 
tetrahydrofuran and then cooled to -78.degree. C. under a nitrogen 
atmosphere. 0.56 ml (0.56 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran was added dropwise. The solution was then stirred 
overnight while slowly warming to room temperature. The solvent was 
removed by evaporation and the residue was taken up in diethyl ether. 
Insoluble material was removed by filtration. The solvent was removed by 
evaporation, the residue was dissolved in 2 ml of diethyl ether and the 
solution was cooled to 0.degree. C. 0.12 ml (1.7 mmol) of trifluoroacetic 
acid was added and the solution was stirred at 0.degree. C. for 30 
minutes. The solution was evaporated and the residue was co-evaporated 
with toluene to give 0.0226 g of a-(R)-(3-butenyl)-3a(S),4(S),5,6(S),7, 
7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole-2-meth 
ylamine trifluoroacetate (1:1) as an oil which was used in the next step 
without further purification. 
iii) 0.35 g (0.38 mmol) of 
N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-tert-b 
utyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leuci 
ne was dissolved in 2 ml of dimethylformamide and 6 ml of dichloromethane. 
0.21 ml (1.9 mmol) of N-methylmorpholine was added and the solution was 
cooled to -15.degree. C. under a nitrogen atmosphere. 66 mg (0.46 mmol) of 
isobutyl chloroformate were added and the solution was stirred for 10 
minutes at -15.degree. C. 0.2 g (0.53 mmol) of 
.alpha.-(R)-(3-butenyl)-3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimeth 
yl-4,6-methano-1,3,2-benzoxaborole-2-methylamine trifluoroacetate (1.1) was 
added and the mixture was stirred at room temperature for 5 hours. The 
solution was diluted with dichloromethane, washed with 2M hydrochloric 
acid and water and dried over anhydrous sodium sulphate. After evaporation 
the residue was triturated with diethyl ether and dried. There was 
obtained 0.309 g of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1- 
[1(R)-(3a(S),4(S),5,6(S),7,7a(S)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3 
,2-benzodioxaborol-2-yl)-4-pentenyl-L-leucinamide as as solid which was 
used without further purification. 
iv) 300 mg (0.26 mmol) of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl-3-methyl-L-valyl]-N1-[ 
1(R)-(3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3, 
2-benzodioxaborol-2-yl)-4-pentenyl]-L-leucinamide were dissolved in 3.5 ml 
of trifluoroacetic acid and 3.5 ml of dichloromethane. The solution was 
stirred at room temperature for 45 minutes, then diluted with toluene and 
evaporated. The residue was triturated with diethyl ether and the 
resulting solid was filtered off and dried and then purified by 
chromatography on silica gel using dichlomethane/methanol/acetic 
acid/water (170:15:3:2) for the elution. There were obtained 135 mg of 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(R)-(3a(S), 
4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1 
,3,2-benzodioxaborol-2-yl)-4-pentenyl]-L-leucinamide as a white solid: MS: 
m/e 995.3 [M+H].sup.+. 
EXAMPLE 22 
N2-[N-[N-[N-[N-(3-Carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gluatamyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(R)-(3a(S),4(S),5,6(S),7, 
7a(R)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl)pro 
pyl]-L-leucinamide can be converted into 1 
(R)-[[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutam 
yl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic 
acid in a manner analogous to that described in the first paragraph of 
Example 20. 
The starting material was prepared as follows: 
i) In an analogous manner to that described in Example 21 i) and ii), by 
replacing 3-butenylmagnesium bromide with ethylmagnesium bromide there was 
obtained 
.alpha.(R)-ethyl-3a(R)-ethyl-3a(S),4,(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-t 
rimethyl-4,6-methano-1,3,2-benzodioxaborole-2-methylamine trifluoroacetate 
(1:1) which was used in the next step without further purification. 
ii) 0.35 g (0.38 mmol) of 
N-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-ter 
t-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl-3-methyl-L-valyl]-L-val 
yl]-L-leucine was dissolved in 3 ml of dimethylformamide and 7 ml of 
dichloromethane. 0.2 ml (1.9 mmol) of N-methylmorpholine was added and the 
solution was cooled to -10.degree. C. under a nitrogen atmosphere. 68 mg 
(0.53 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 10 minutes at -10.degree. C. 0.18 g (0.53 mmol) of 
.alpha.(R)-ethyl-3a(S)4(S),5,6,(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4,6- 
methano-1,3,2-benzodioxaborole-2-methylamine trifluoroacetate (1:1) was 
added and the mixture was stirred at room temperature for 16 hours. After 
evaporation the residue was partitioned between ethyl acetate and 2M 
hydrochloric acid. The organic layer was washed with water and saturated 
sodium chloride solution and then dried over anhydrous sodium sulphate. 
The solution was evaporated and the residue was trituated with diethyl 
ether, filtered off and dried to give 0.22 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)-propionyl]-O-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-N1-[1(R)-(3a(S),4(S),5,6(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4 
,6-methano-1,3,2-benzodioxaborol-2-yl)propyl]-L-leucinamide as a solid 
which was used without further purification. 
iii) 0.22 g (0.19 mmol) of 
N2-[N-[N-[N-[N-[3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methy 
l-L-valyl]-N1-[1(R)-3a(S),4(S),5,6,(S),7,7a(R)-hexahydro-3a,5,5-trimethyl-4 
,6-methano-1,3,2-benzodioxaborol-2-yl)propyl]-L-leucinamide was dissolved 
in 5 ml of trifluoroacetic acid and 5 ml of dichloromethane, the solution 
was stirred at room temperature for 1 hour and then diluted with toluene 
and evaporated. The residue was triturated with diethyl ether and the 
resulting solid was filtered off and dried to give 170 mg of 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gluatamy 
l]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(R)-(3a(S),4(S),5,6(S),7 
,7a(R)-hexahydro-3a, 
5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl)propyl]-L-leucinamide 
as a white solid; MS: m/e 969.4 [M+H].sup.+. 
EXAMPLE 23 
4 g of 0.25 mmol/g 5-[2-[1 
(RS)-[[N-[(9-fluorenyl)methoxy-carbonyl]-L-leucyl]amino]propyl]-4(RS),5,5- 
trimethyl-1,3,2-dioxoborolan-4-yl]-3(RS)-methyl-N-[a(RS)-(4-methylphenyl)be 
nzyl]valeramide-polystyrene conjugate were swollen in dimethylformamide for 
20 minutes and then suspended and agitated in dimethylformamide/piperidine 
(4.1). After 5 minutes the resin was drained and then suspended in and 
agitated with dimethylformamide/piperidine (4.1) for a further 5 minutes. 
The resin was then drained and washed five times with dimethylformamide. 
The resin was then suspended in a solution of 2.1 g (6 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valine in dimethylformamide 
and then a mixture of 1.9 g of 2-(1H-benzotriazol-1 
-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 1.3 ml of 
N-methylmorpholine dissolved in dimethylformamide was added. After 
agitating for 40 minutes the resin was drained and washed five times with 
dimethylformamide. 
The resin was resuspended in and agitated with dimethylformamide/piperidine 
(4:1). After 5 minutes the resin was drained and resuspended in and 
agitated with dimethylformamide/piperidine (4:1) for a further 5 minutes. 
Then, the residue was drained and washed five times with dimethyl 
formamide. 
The resin was then suspended in a solution of 2.4 g (6 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine in 
dimethylformamide and a mixture of 1.9 g of 
2(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 
1.3 ml of N-methylmorpholine dissolved in dimethylformamide was added. 
After agitating for 40 minutes the resin was drained and washed five times 
with dimethyl formamide. 
40 mg of this resin were resuspended in and agitated with 0.7 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and resuspended in and agitated with dimethylformamide/piperidine (4:1) 
for a further 5 minutes. Then, the resin was drained and washed five times 
with dimethylformamide. 
The resin was then suspended in 0.5 ml of a 0.2M solution of 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid in 
dimethyl sulphoxide and then 0.5 ml of a mixture of 0.2M 
2-(1H-benzotriazol-1 -yl)-1 ,1,3,3-tetramethyluronium tetrafluoroborate 
and 0.4M N-methylmorpholine in dimethylformamide was added. After 
agitating for 1 hour the resin was drained and washed five times with 1 ml 
of dimethylformamide 
The resin was resuspended in and agitated with 0.7 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and resuspended in and agitated with dimethylformamide/piperidine (4:1) 
for a further 5 minutes. Then, the resin was drained and washed five times 
with 1 ml of dimethylformamide. 
The resin was suspended in 0.5 ml of a solution of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-tyrosine in dimethyl 
sulphoxide and 0.5 ml of a mixture of 0.2M 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 
0.4M N-methylmorpholine in dimethylformamide was added. After agitating 
for 1 hour the resin was drained and washed five times with 1 ml of 
dimethylformamide. 
The resin was resuspended in and agitated with 0.7 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and resuspended in and agitated with dimethylformamide/piperidine (4:1) 
for a further 5 minutes. Then, the resin was drained and washed five times 
with 1 ml of dimethylformamide. 
The residue was suspended in 0.5 ml of a 0.2M solution of tert-butyl 
hydrogen succinate in dimethylformamide and then 0.5 ml of 0.2M 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 
0.4M N-methylmorpholine dissolved in dimethylformamide was added. After 
agitating for 1 hour the resin was drained and washed five times with 1 ml 
of dimethylformamide and then twice with 1 ml of dichloromethane. 
0.2 ml of dichloromethane was added to the resin which was then treated 
with 0.7 ml of trifluoroacetic acid/water (19:1) and agitated for 90 
minutes. The resin was then filtered off and washed with 0.7 ml of 
trifluoroacetic acid/water (19:1). The combined trifluoroacetic acid and 
water solutions were then evaporated in a vacuum centrifuge and the 
residue was suspended in acetonitrile/water (1:1) and freeze dried. There 
were obtained 16.8 mg of 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-tyrosyl]-L-.alpha.-glutamyl]- 
2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic 
acid as a white solid; MS m/e 807.4 [M+H-H.sub.2 O].sup.+. 
The starting material was prepared as follows: 
i) 25 ml of isobutylene were condensed at -78.degree. C. and added to a 
mixture of 19.4 g (114 mmol) of 3(RS),7-dimethyl-6-octenoic acid and 1 ml 
of concentrated sulphuric acid in 25 ml of dichloromethane. The mixture 
was stirred for 24 hours under a dry ice condenser. A further 20 ml of 
isobutylene were added and the mixture was stirred for 24 hours under a 
dry ice condenser. The mixture was diluted with dichloromethane, washed 
with saturated sodium bicarbonate solution, dried over anhydrous magnesium 
sulphate and evaporated under a vacuum. The resulting oil was purified by 
chromatography on silica gel using ethyl acetate/hexane (1:9) for the 
elution. There were obtained 20.8 g of tert-butyl 
3(RS),7-dimethyl-6-octenoate as a colourless oil. .sup.1 H NMR (250 MHz, 
CDCl.sub.3) d: 0.9 (d, 3H), 1.1-1.3 (m, 3H), 1.4 (s, 9H), 1.6 (s, 3H), 
1.65, (s, 3H), 1.8-2.2 (br m, 4H), 5.05, (m, 1H). 
ii) 1.5 g (6.64 mmol) of tert-butyl 3(RS),7-dimethyl-6-octenoate were 
dissolved in a mixture of 10 ml of acetone, 2 ml of water and 2 ml of 
glacial acetic acid. 2 g (12.6 mmol) of potassium permanganate were added 
and the resulting mixture was stirred at 30.degree. C. for 2 hours. 22 ml 
of 2M sulphuric acid and 0.8 g (11.3 mmol) of sodium nitrite were added 
and the organic phase was separated. The aqueous phase was extracted with 
dichloromethane and the combined organic phases were washed with water, 
dried over magnesium sulphate and evaporated under a vacuum to give 1.55 g 
of tert-butyl 7-hydroxy-3(RS),7-dimethyl6-oxo-octenoate as a clear oil; 
MS: m/e 259 [M+H].sup.+. 
iii) 0.25 g (0.97 mmol) of tert-butyl 
7-hydroxy-3(RS),7-dimethyl-6-oxo-octenoate was dissolved in 3 ml of 
diethyl ether at 0.degree. C. under a nitrogen atmosphere. 0.36 ml (1.1 
mmol) of 3M methylmagnesium bromide in diethyl ether was added dropwise 
and the resulting solution was stirred at 0.degree. C. for 2 hours, 
refluxed for 6 hours and then stirred at room temperature for 16 hours. 
The solution was diluted with ethyl acetate and then extracted with 2M 
hydrochloric acid and saturated sodium chloride solution. The organic 
phase was dried over anhydrous sodium sulphate and evaporated under a 
vacuum. The resulting oil was purified by chromatography on silica gel 
using ethyl acetate/ hexane (1:2) for the elution. There were obtained 118 
mg of tert-butyl 6(RS),7-dihydroxy-3(RS),6,7-trimethyl-6-octenoate as a 
clear oil; MS: m/e 275 [M+H].sup.+. 
iv) 0.64 g (2.3 mmol) of tert-butyl 6(RS),7-dihydroxy-3-(RS), 
6,7-trimethyl-6-octenoate was stirred in 3 ml of tetrahydrofuran with 0.5 
g (2.5 mmol) of dichloromethyl diisopropoxyborane at room temperature for 
16 hours. The resulting mixture was evaporated and the residue was 
co-evaporated with toluene to give 0.86 g of tert-butyl 
5-[2-(dichloromethyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-m 
ethylvalerate as an oil which was used in the next step without further 
purification. 
v) 0.86 g (2.3 mmol) of tert-butyl 5-[2-(dichloromethyl)-4(RS), 
5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved 
in 5 ml of tetrahydrofuran and the solution was cooled to -78.degree. C. 
under a nitrogen atmosphere. 2.6 ml (2.6 mmol) of 1M ethylmagnesium 
bromide in tetrahydrofuran were added dropwise, the resulting solution was 
stirred for 16 hours while slowly warming to room temperature and then 
diluted with ethyl acetate and extracted with 2M hydrochloric acid and 
brine. The organic phase was dried over sodium sulphate and then evporated 
under a vacuum to give 0.83 g of tert-butyl 
5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1 
,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in 
the next step without purification. 
vi) 0.82 g (2.27 mmol) of tert-butyl 
5-[2-(1(RS)-chloropropyl)-4(RS),5,5-trimethyl-1 
,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate was dissolved in 10 ml of 
tetrahydrofuran and then cooled to -78.degree. C. under a nitrogen 
atmosphere. 2.3 ml (2.3 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise. The solution was then stirred 
overnight while slowly warming to room temperature. The solvent was 
removed by evaporation and the residue was taken up in diethyl ether. 
Insoluble material was removed by filtration and the filtrate was cooled 
to 0.degree. C. 0.52 ml (6.8 mmol) of trifluoroacetic acid was added and 
the solution was stirred at 0.degree. C. for 30 minutes. The solution was 
evaporated and the residue was co-evaporated with toluene to give 1 g of 
tert-butyl 5-[2-(1(RS)-aminopropyl)-4(RS), 5,5-trimethyl-1 
,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil which was used in 
the next step without purification. 
vii) 0.5 g (1.42 mmol) of N-[(9-fluorenyl)methoxycarbonyl]-L-leucine was 
dissolved in 7 ml of dichloromethane. 0.6 ml (5.7 mmol) of 
N-methylmorpholine was added and the solution was cooled to -10.degree. C. 
under a nitrogen atmosphere. 0.22 ml (1.7 mmol) of isobutyl chloroformate 
was added and the solution was stirred for 7 minutes at -10.degree. C. 1 g 
(2.13 mmol) of tert-butyl 
5-[2-(1(RS)-aminopropyl)-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS 
)-methylvalerate was added and the mixture was stirred at room temperature 
for 16 hours, then diluted with dichloromethane and extracted with 2M 
hydrochloric acid. The organic phase was extracted with 2M hydrochloric 
acid and saturated sodium hydrogen carbonate solution and then dried over 
anhydrous magnesium sulphate. After evaporation the residue was purified 
by chromatography on silica gel using ethyl acetate/hexane (1:2) for the 
elution. There was obtained 0.56 g of tert-butyl 
5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS 
) ,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate as an oil; 
MS: m/e 677 [M+H].sup.+. 
viii) 50 mg (0.074 mmol) of tert-butyl 
5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS 
) ,5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate were 
dissolved in 1 ml of trifluoroacetic acid and 1 ml of dichloromethane. The 
solution was stirred at room temperature for 15 minutes and then 
evaporated under a vacuum. The residue was co-evaporated with toluene to 
give 46 mg of 5-[2-[1 
(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-t 
rimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvaleric acid as an oil; MS: 
m/e 621 [M+H].sup.+. 
ix) 5 g (5.25 mmol) of 4-methylbenzhydrylamine resin were swollen in 
dimethylformamide and excess solvent was drained from the resin. The resin 
was then resuspended in dimethylformamide containing 3.4 g (5.48 mmol) of 
5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS 
),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvaleric acid and 3 g 
(8.2 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium 
hexafluorophosphate. Thereto there were added 3.0 ml (16.5 mmol) of 
diisopropylamine. The resulting mixture was agitated for 100 minutes and 
the resin was then drained and washed three times with dimethylformamide. 
The resin was then resuspended in dimethylformamide containing 5 ml (54.8 
mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. 
The mixture was agitated for 30 minutes and the resin was then drained. 
The resin was then resuspended in dimethylformamide containing 5 ml (54.8 
mmol) of acetic anhydride and 11.5 ml (110 mmol) of N-methylmorpholine. 
The mixture was agitated for 30 minutes and the resin was then drained and 
washed three times with dimethylformamide, twice with ethyl acetate, twice 
with dichloromethane and twice with diethyl ether and then dried under a 
vacuum. After drying there was obtained 6 g of 
5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4-(R 
S),5,5-trimethyl-1,3,2-dioxoborolan-4-yl]-3(RS)-methyl-N-[a(RS)-(4-methylph 
enyl)benzyl]valeramide-polystyrene conjugate as a pale brown solid (0.25 
mmol/g loading estimated by quantitation of dibenzofulvene at 301 nM). 
EXAMPLE 24 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-3-cyclopentyl-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 
-yl)-3-butenyl]-L-alaninamide there was obtained 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanyl] 
amino]-3-butenylboronic acid as a white solid; MS: m/e 855 [M+H-H.sub.2 O]. 
The starting material was prepared as follows: 
i) A mixture of 1.2 g (4.67 mmol) of 
N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine, 540 mg (5 mmol) of benzyl 
alcohol, 675 mg (5 mmol) of 1-hydroxybenzotriazole, 1.152 g (6 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.031 g 
(0.25 mmol) of 4-dimethylaminopyridine was stirred in 20 ml of 
dichloromethane for 1 hour and then a further 610 mg (5 mmol) of 
4-dimethylaminopyridine were added. After 4 hours the solution was 
extracted with 2M hydrochloric acid and saturated sodium bicarbonate 
solution, dried over anhydrous magnesium sulphate and evaporated. The oil 
obtained was chromatographed on silica gel using ethyl acetate/ petrol 
(1:6) for the elution to give 1.55 g of 
N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine benzyl ester as a 
colourless oil; MS: m/e 348 [M+H]. 
ii) 1.54 g (4.44 mmol) of N-(tert-butoxycarbonyl)-3-cyclopentyl-L-alanine 
benzyl ester and 2.53 g (13.32 mmol) of 4-toluenesulphonic acid hydrate 
were dissolved in 20 ml of acetonitrile and the solution was left to stand 
at room temperature for 18 hours. The white precipitate formed was 
filtered off and added to a mixture of 867 mg (3.75 mmol) of 
N-(tert-butoxycarbonyl)-3-methyl-L-valine, 557 mg (3.64 mmol) of 
1-hydroxybenzotriazole, 793 mg (4.14 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 475 mg 
(4.13 mmol) of N-ethylmorpholine in 25 ml of dichloromethane and stirred 
at room temperature for 18 hours. The solution was extracted with 2M 
hydrochloric acid and saturated sodium bicarbonate solution and then dried 
over anhydrous magnesium sulphate. Evaporation and chromatography on 
silica gel using ethyl acetate/petrol (1:3) for the elution gave 1.06 g of 
N-[N-(tert-butoxycarbonyl)-3-methyl-L-valyl]-3-cyclopentyl-L-alanine 
benzyl ester as an off-white foam; MS: m/e 461 [M+H]. 
iii) 993 mg (2.16 mmol) of 
N-[N-(tert-butoxycarbonyl)-3-methyl-L-valyl]-3-cyclopentyl-L-alanine 
benzyl ester and 1.23 g (6.47 mmol) of 4-toluenesulphonic acid hydrate 
were dissolved in 20 ml of acetonitrile and the solution was stirred at 
room temperature for 2 hours. The solvent was removed by evaporation and 
the residue was triturated with diethyl ether and filtered off. The solid 
obtained was added to a mixture of 602 mg (2.16 mmol) of 
N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanine, 338 mg (2.21 mmol) of 
1-hydroxybenzotriazole, 576 mg (3 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 345 mg (3 
mmol) of N-ethylmorpholine in 20 ml of dichloromethane and stirred at room 
temperature for 18 hours. The solution was extracted with 2M hydrochloric 
acid and saturated sodium bicarbonate solution, then dried over anhydrous 
magnesium sulphate and evaporated. Chromatography of the residue on silica 
gel using ethyl acetate/ petrol (3:7) for the elution gave 990 mg of 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3 
-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 622 [M+H]. 
iv) 980 mg (1.578 mmol) of 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3 
-cyclopentyl-L-alanine benzyl ester and 900 mg (4.73 mmol) of 
4-toluenesulphonic acid hydrate were dissolved in 16 ml of acetonitrile 
and the solution was stirred at room temperature for 2 hours. The solvent 
was removed by evaporation and the residue was triturated with diethyl 
ether and filtered off. The solid obtained was added to a mixture of 671 
mg (1.578 mmol) of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-glutamic acid, 247 
mg (1.614 mmol) of 1-hydroxybenzotriazole, 419 mg (2.19 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 252 mg 
(2.19 mmol) of N-ethylmorpholine in 16 ml of dichloromethane and stirred 
at room temperature for 18 hours. The solution was extracted with 2M 
hydrochloric acid and saturated sodium bicarbonate solution and then dried 
over anhydrous magnesium sulphate. Evaporation and chromatography on 
silica gel using methanol/dichloromethane (1:49) for the elution gave 530 
mg of 
N-[N-[N-[O-tert-butyl-N-(9-fluorenylmethoxycarbonyl)-L-.alpha.-glutamyl]-2 
-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl 
ester as a white solid; MS: m/e 929 [M+H]. 
v) A solution of 520 mg (0.56 mmol) of 
N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-glutamyl]-2-met 
hyl-L-phenylalanyl]-3-methyl-L-valyl]-3-cyclopentyl-L-alanine benzyl ester 
in 3 ml of piperidine and 12 ml of dichloromethane was stirred at room 
temperature for 30 minutes. The solvent was removed by evaporation and the 
residue was chromatographed on silica gel using firstly ethyl 
acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the 
elution. The resulting amine was added to a solution of 207 mg (0.504 
mmol) of N-(9-fluorenyl-methoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartic 
acid, 78 mg (0.51 mmol) of 1-hydroxybenzotriazole and 134 mg (0.7 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 10 ml of 
dichloromethane and stirred at room temperature for 18 hours. The solution 
was then extracted with 2M hydrochloric acid and saturated sodium 
bicarbonate solution and dried over anhydrous magnesium sulphate. 
Evaporation, trituration with diethyl ether and filtration gave 440 mg of 
N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-a-aspartyl]-O-t 
ert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-3- 
cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1101 [M+H]. 
vi) A solution of 430 mg (0.39 mmol) of 
N-[N-[N-[N-O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-asparty 
l]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-val 
yl]-3-cyclopentyl-L-alanine benzyl ester in 4 ml of piperidine and 16 ml of 
dichloromethane was stirred at room temperature for 30 minutes and then 
evaporated. The residue was chromatographed on silica gel using firstly 
ethyl acetate/petrol (1:1) and then methanol/dichloromethane (1:9) for the 
elution. The amine obtained was added to a solution of 174 mg (1 mmol) of 
tert-butyl hydrogen succinate, 135 mg (1 mmol) of 1-hydroxybenzotriazole 
and 192 mg (1 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride in 15 ml of dichloromethane and the mixture was stirred at 
room temperature for 18 hours, extracted with 2M hydrochloric acid and 
saturated sodium bicarbonate solution and then dried over anhydrous 
magnesium sulphate. Evaporation and chromatography on silica gel using 
methanol/dichloromethane (1:24) for the elution followed by trituration 
with diethyl ether gave 240 mg of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-a-aspartyl 
]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valy 
l]-3-cyclopentyl-L-alanine benzyl ester as a white solid; MS: m/e 1035 
[M+H]. 
vii) A solution of 230 mg (0.223 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-3-cyclopentyl-L-alanine benzyl ester in 10 ml of dimethylformamide 
was hydrogenated over 25 mg of 10% palladium/carbon for 3 hours. The 
catalyst was removed by filtration, the filtrate was evaporated and the 
residue was triturated with diethyl ether to give 206 mg of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyll-3-methyl- 
L-valyl]-3-cyclopentyl-L-alanine as a white solid; MS: m/e 944 [M+H]. 
viii) 163 mg (0.173 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-3-cyclopentyl-L-alanine were dissolved in 2 ml of 
dimethylformamide and 4 ml of dichloromethane. 80 mg (0.69 mmol) of 
N-ethylmorpholine were added and the solution was cooled to -10.degree. C. 
26 mg (0.19 mmol) of isobutyl chloroformate were added and the solution 
was stirred for 30 minutes at -10.degree. C. 107 mg (0.345 mmol) of 
.alpha.-(RS)-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate in 1 ml of dichloromethane were added and the mixture was 
stirred at -10.degree. C. for 30 minutes and at room temperature for 3 
hours. The solution was extracted with 2M hydrochloric acid and saturated 
sodium bicarbonate solution and then dried over anhydrous magnesium 
sulphate. Evaporation and chromatography on silica gel using 
methanol/dichloromethane (1:24) for the elution gave 54 mg of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyll-3-methyl 
-L-valyl]-3-cyclopentyl-N1 -[1 
(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-butenyl]-L-alaninamid 
e as a white solid; MS: m/e 1024 [M+H-C.sub.6 H.sub.12 O]. 
EXAMPLE 25 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-0-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-cycloh 
exyl-L-alanyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-bu 
tenyl-L-leucinamide, MS: m/e 1037 [M+H-C.sub.6 H.sub.1 O], there was 
obtained 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-cyclohexyl-L-alanyl]-L-leucyl]amino]-3 
-butenylboronic acid; MS: m/e 869 [M+H-H.sub.2 O]. 
The starting material was prepared in an analogous manner to that described 
in Example 5 via the following intermediates: 
i) N-[N-(tert-Butoxycarbonyl)-3-cyclohexyl-L-alanyl]-L-leucine benzyl 
ester; MS: mie 475 [M+H]; 
ii) 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-3-cyclohexyl-L-alan 
yl]-L-leucine benzyl ester; MS: m/e 636 [M+H]; 
iii) 
N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-3-cyclohexyl-L-alanyl]-L-leucine benzyl ester; 
MS: m/e 944 [M+H]; 
iv) 
N-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-cyclohexyl- 
L-alanyl]-L-leucine benzyl ester; MS: m/e 1114 [M+H]; 
v) 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-cyclohe 
xyl-L-alanyl]-L-leucine benzyl ester; MS: m/e 1049 [M+H]; and 
vi) 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-cyclohe 
xyl-L-alanyl]-L-leucine; MS: m/e 958 [M+H]. 
EXAMPLE 26 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-phen 
ylglycyl]-N1-[1 (RS)-(4,4,5,5-tetramethyl-1 
,3,2-dioxaborolan-2-yl)-3-butenyl-L-leucinamide, MS: m/e 1017 [M+H-C.sub.6 
H.sub.12 O], there was obtained 1 
(RS)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-L-2-phenylglycyl]-L-leucyl]amino]-3-buten 
ylboronic acid; MS: m/e 849 [M+H-H.sub.2 O]. 
The starting material was prepared in an analogous manner to that described 
in Example 5 via the following intermediates: 
i) N-[N-(tert-Butoxycarbonyl)-L-2-phenylglycyl]-L-leucine benzyl ester; MS: 
m/e 455 [M+H]; 
ii) 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-L-2-phenylglycyl]-L 
-leucine benzyl ester; MS: m/e 616 [M+H]; 
iii) 
N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-L-2-phenylglycyl]-L-leucine benzyl ester; MS: m/e 
923 [M+H]; 
iv) 
N-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-phenylgly 
cyl]-L-leucine benzyl ester; MS: m/e 1094 [M+H]; 
v) 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-pheny 
lglycyl]-L-leucine benzyl ester; MS: m/e 1028 [M+H]; and 
vi) N- N- 
N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-aspartyl 
]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-phenylglycy 
l]-L-leucine; MS: m/e 938 [M+H]. 
EXAMPLE 27 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-cycl 
ohexylglycyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-but 
enyl-L-leucinamide, MS: m/e 1023 [M+H-C.sub.6 H.sub.12 O], there was 
obtained 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-L-2-cyclohexylglycyl]-L-leucyl]amino]-3-b 
utenylboronic acid; MS: m/e 855 [M+H-H.sub.2 O]. 
The starting material was prepared in an analogous manner to that described 
in Example 5 via the following intermediates: 
i) N-[N-(tert-Butoxycarbonyl)-L-2-cyclohexylglycyl]-L-leucine benzyl ester; 
MS: m/e 461 [M+H]; 
ii) 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-L-2-cyclohexylglycy 
l]-L-leucine benzyl ester; MS: m/e 622 [M+H]; 
iii) 
N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-L-2-cyclohexylglycyl]-L-leucine benzyl ester; MS: 
m/e 929 [M+H]; 
iv) 
N-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-cyclohexy 
lglycyl]-L-leucine benzyl ester; MS: m/e 1100 [M+H]; 
v) 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-cyclo 
hexylglycyl]-L-leucine benzyl ester; MS: m/e 1034 [M+H]; and 
vi) 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-2-cyclo 
hexylglycyl]-L-leucine; MS: m/e 944 [M+H]. 
EXAMPLE 28 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-butenyl 
-L-prolinamide, MS: m/e 981 [M+H-C.sub.6 H.sub.12 O], there was obtained 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-prolyl]amino]-3-bute 
nylboronic acid as a white solid; MS: m/e 813 [M+H-H.sub.2 O]. 
The starting material was prepared in an analogous manner to that described 
in Example 5 via the following intermediates: 
i) N-[N-(tert-Butoxycarbonyl)-3-methyl-L-valyl]-L-proline benzyl ester; 
ii) 
N-[N-[N-(tert-butoxycarbonyl)-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L 
-proline benzyl ester; 
iii) 
N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-proline benzyl ester; 
iv) 
N-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-va 
lyl]-L-proline benzyl ester; 
v) 
N-[N-[N-[N-[O-tert-butyl-N-[3-(tert-butoxycarbonyl)-propionyl]-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl-L-proline benzyl ester; MS: m/e 992 [M+H]; and 
vi) 
N-[N-[N-[N-[O-tert-butyl-N-[3-(tert-butoxycarbonyl)-propionyl]-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl-L-proline. 
EXAMPLE 29 
In an analogous manner to that described in Example 5, from 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-phenyl 
alanyl]-N1-[1 
(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-butenyl-L-leucinamide 
, MS: m/e 1031 [M+H-C.sub.6 H.sub.2 O], there was obtained 
1(RS)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-L-phenylalanyl]-L-leucyl]amino]-3-buteny 
lboronic acid as a white solid; MS: m/e 863 [M+H-H.sub.2 O]. 
The starting material was prepared in an analogous manner to that described 
in Example 5 via the following intermediates: 
i) 
N-[N-[N-[O-tert-Butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-glutamyl] 
-2-methyl-L-phenylalanyl]-L-phenylalanyl]-L-leucine benzyl ester; 
ii) 
N-[N-[N-[N-[O-tert-butyl-N-[(9-fluorenyl)methoxycarbonyl]-L-.alpha.-aspart 
yl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-phenylalany 
l]-L-leucine benzyl ester; 
iii) 
N-[N-[N-[N-N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-asp 
artyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-phenylal 
anyl]-L-leucine benzyl ester; MS m/e 1042 [M+H]; and 
iv) 
N-[N-[N-[N-N-[3-(tert-butoxycarbonyl)propionyl]-3-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-L-phenyl 
alanyl]-L-leucine. 
EXAMPLE 30 
0.04 g (0.03 mmol) of 
(E)-N2-[N-[N-[N-[N-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha. 
-aspartyl]-O-tert-butyl-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentyl]-L-leucinamide was dissolved 
in 4 ml of a 1:1 solution of dichloromethane and trifluoroacetic acid 
containing 3 drops of water. The resulting solution was stirred at room 
temperature for 1 hour. After removal of the solvent by evaporation and 
trituration of the residue with diethyl ether there was obtained 0.014 g 
of (E)-2(S)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.a 
lpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]- 
4-hexenal; MS: m/e 845.7 [M+H]+. 
The starting material was prepared as follows: 
i) 25 g (347 mmol) of trans-2-buten-1-ol were dissolved in 750 ml of 
anhydrous diethyl ether. 7.25 ml (89.63 mmol) of anhydrous pyridine were 
added and the resulting solution was cooled to 0.degree. C. 88.25 ml of 
phosphorus tribromide were added dropwise and the mixture was stirred for 
2 hours at 0.degree. C. The reaction was quenched by pouring the solution 
on to ice. The organic phase was washed with saturated sodium chloride 
solution and dried over anhydrous magnesium sulphate. After removal of the 
solvent by evaporation there was obtained (E)-1-bromo-2-butane which was 
used in the next step without purification. 
ii) 3.86 g (168 mmol) of sodium metal were dissolved in 106 ml of anhydrous 
ethanol. 36.35 g (168 mmol) of diethyl acetamidomalonate dissolved in 225 
ml of anhydrous ethanol were added and the mixture was heated under reflux 
for 10 minutes. 22.66 g (168 mmol) of (E)-1-bromo-2-butene were added 
dropwise at room temperature and the mixture was stirred overnight and 
then evaporated to dryness under a vacuum. The residue was partitioned 
between ethyl acetate and 0.1M hydrochloric acid. The organic phase was 
washed with saturated sodium hydrogen carbonate solution and then with 
saturated sodium chloride solution and dried over anhydrous magnesium 
sulphate. The solvent was evaporated to give 40 g of diethyl 
(E)-2-acetamido-2-(2-butenyl)malonate as a colourless oil; .sup.1 H NMR 
(250 MHz, CDCl.sub.3) d: 1.25 (t, 6H), 1.6 (d, 3H), 2.0 (s, 3H), 2.9 (d, 
2H), 4.2 (q, 4H), 5.15 (m, 1H) 5.5 (m, 1H), 6.7 s, 1H). 
iii) 39.63g (146 mmol) of diethyl (E)-2-acetamido-2-(2-butenyl)malonate 
were dissolved in 200 ml of ethanol and a solution of 19.24 g (481 mmol) 
of sodium hydroxide in 100 ml of water was added. The mixture was stirred 
for 2 hours at 60.degree. C., evaporated to dryness under a vacuum and the 
residue was partitioned between diethyl ether and water. The aqueous phase 
was acidified with 2M hydrochloric acid and extracted with ethyl acetate. 
The organic phase was dried over magnesium sulphate and the solvent was 
removed by evaporation under a vacuum to give 26.1 g of 
(E)-2-acetamido-2-(2-butenyl)malonic acid as a white solid which was used 
in the next step without further purification. .sup.1 H NMR (250 MHz, 
MeOD) .delta.: 1.65 (d, 3H), 2.0 (s, 3H), 2.9 (d, 2H), 5.25 (m, 1H), 5.5 
(m, 1H). 
iv) 26.1 g (121 mmol) of (E)-2-acetamido-2-(butenyl)malonic acid were 
dissolved in 200 ml of toluene. 34 ml (242 mmol) of triethylamine were 
added and the mixture was heated under reflux for 1 hour. The solution was 
extracted with 1M hydrochloric acid and the aqueous layer was extracted 
with ethyl acetate. The combined organic phases were dried over magnesium 
sulphate and the solvent was removed under a vacuum to give 18.73 g of 
(E)-N-acetyl-DL-2-(2-butenyl)glycine as a white solid which was used in 
the next step without purification. .sup.1 H NMR (250 Hz, MeOD) .delta.: 
1.65 (d, 3H), 2.0 (s, 3H), 2.4 (m, 2H), 4.3 (m, 1H), 5.4 (m, 1H), 5.5 (m, 
1H). 
v) 9 g (52.63 mmol) of (E)-N-acetyl-DL-2-(2-butenyl)glycine were dissolved 
in 100 ml of water and the pH adjusted to 7.5 using ammonia solution. 0.09 
g of acylase I extracted from porcine kidney, and 0.042 g (0.3 mmol) of 
cobalt (II) chloride were added and the mixture was stirred at 37.degree. 
C. overnight. A further 0.09 g of acylase l extracted from porcine kidney 
was added and the pH adjusted to 7.5 using ammonia solution. The mixture 
was stirred at 37.degree. C. overnight and the solution was then heated at 
80.degree. C. for 30 minutes and was then acidified to pH 1 using 2 M 
hydrochloric acid. The solvent was removed by evaporation under vacuum and 
the crude product purified by trituration using ethyl acetate to yield 4.2 
g of (E)-L-2-(2-butenyl)glycine hydrochloride. .sup.1 H NMR (250 MHz, 
D.sub.2 O) .delta.: 1.7 (d, 3H), 2.6 (m, 2H), 4.0 (m, 1H), 5.35 (m, 1H), 
5.7 (m, 1H). 
vi) 2.1 g (12.69 mmol) of (E)-L-(2-butenyl)glycine hydrochloride were 
suspended in 20 ml of water and 20 ml of dioxan. 8.26 g (98.32 mmol) of 
sodium hydrogen carbonate and 8.15 g (37.33 mmol) of di-tert-butyl 
dicarbonate were added and the resulting solution was stirred for 
overnight. The solution was evaporated to dryness under a vacuum and the 
residue was partitioned between diethyl ether and saturated aqueous sodium 
hydrogen carbonate solution. The aqueous phase was acidified with 2M 
hydrochloric acid while partitioning in ethyl acetate. The organic phase 
was dried over magnesium sulphate and the solvent was removed by 
evaporation to give 1.34 g of 
(E)-N-(tert-butoxycarbonyl)-L-2-(2-butenyl)glycine; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) d: 1.4 (s, 9H), 1.65 (d, 3H), 2.5 (m, 2H), 4.3 (m, 1H), 5.0 
(m, 1H), 5.35 (m, 1H), 5.6 (m, 1H). 
vii) 1.34 g (5.85 mmol) of 
(E)-N-(tert-butoxycarbonyl)-L-2-(2-butenyl)glycine were dissolved in 50 ml 
of anhydrous tetrahydrofuran and the solution was treated in sequence with 
0.80 g (8.20 mmol) of N,O-dimethylhydroxylamine hydrochloride, 1.10 g 
(7.19 mmol) of 1-hydroxybenzotriazole monohydrate, 1.57 g (8.22 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4 ml 
(22.96 mmol) of ethyldiisopropylamine. The solution obtained was stirred 
at room temperature overnight, then washed with saturated sodium hydrogen 
carbonate solution and with saturated sodium chloride solution and dried 
over magnesium sulphate. Removal of the solvent by evaporation yielded 
1.56 g of N,O-dimethyl (E)-2(S)-(tert-butoxyformamido)-4-hexenohydroxamate 
as a colourless oil which was used in the next step without purification. 
.sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.65 (d, 3H), 2.3 
(m, 2H), 3.15 (s, 3H), 3.75 (s, 3H), 4.7 (m, 1H), 5.1 (d, 1H), 5.35 (m, 
1H), 5.5 (m, 1H). 
viiii) 1.56 g (5.74 mmol) of N,O-dimethyl 
(E)-2(S)-(tert-butoxy-formamido)-4-hexenohydroxamate were dissolved in 10 
ml of anhydrous tetrahydrofuran and cooled to 0.degree. C. 4.0 ml of a 1M 
solution of lithium aluminium hydride in tetrahydrofuran were added and 
the resulting solution was stirred for 30 minutes. The reaction was 
quenched by the dropwise addition of saturated potassium hydrogen sulphate 
solution followed by diethyl ether. The resulting two-phase system was 
stirred vigorously for 3 minutes. The organic phase was washed with 
saturated sodium hydrogen carbonate solution followed by saturated sodium 
chloride solution and dried over anhydrous magnesium sulphate. After 
removal of the solvent by evaporation the resulting aldehyde was used 
without purification. 
1 g (4.69 mmol) of the aldehyde was dissolved in a saturated solution of 
hydrogen chloride in methanol and stirred at room temperature for 2 hours. 
After removal of the solvent by evaporation the dimethyl acetal obtained 
was used without purification. 
0.15 mg (0.16 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-L-leucine, 0.033 g (0.22 mmol) of 1-hydroxybenzotriazole 
monohydrate, 0.047 g (0.25 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.77 g 
(6.69 mmol) of 4-ethylmorpholine were dissolved in 15 ml of 
dichloromethane. 0.05 g (0.22 mmol) of the dimethyl acetal dissolved in 5 
ml of dichloromethane was added and the resulting solution was stirred at 
room temperature for 3 days. The mixture was washed with 5% citric acid 
solution followed by saturated sodium hydrogen carbonate solution and 
saturated sodium chloride solution and then dried over anhydrous magnesium 
sulphate. After evaporation of the solvent the crude product was 
chromatographed on silica gel using 2% methanol in dichloromethane for the 
elution to give 0.079 g of 
(E)-N2-[N-[N-[N-[N-(3-tert-butoxycarbonyl)propionyl]-tert-butyl-L-.alpha.- 
aspartyl]-O-tert-butyl-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-N1-[1(S)-(dimethoxymethyl)-3-pentyl]-L-leucinamide as a white 
solid foam; m/e 1027.9 [M+H-MeOH]+. 
EXAMPLE 31 
0.05 g (0.04 mmol) of 
(Z)-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alph 
a.-aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-me 
thyl-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-3-pentenyl]-L-leucinamide was 
dissolved in 4 ml of a 1:1 solution of dichloromethane and trifluoroacetic 
acid and containing 3 drops of water. The solution was stirred at room 
temperature for 1 hour. After removal of the solvent by evaporation the 
crude product was triturated using diethyl ether to afford 0.03 g of 
(Z)-2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-alpha-aspartyl]-L-alpha-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4-hexena 
l as a white solid; MS: m/e 845.7 [M+H].sup.+. 
The starting material was prepared as follows: 
i) 25 g (347 mmol) of cis-2-buten-1-ol were dissolved in 750 ml of 
anhydrous diethyl ether. 7.25 ml of anhydrous pyridine were added and the 
resulting solution cooled to OOC. 88.25 ml of phosphorus tribromide was 
added dropwise and the mixture was stirred for 2 hours at 0.degree. C. The 
reaction was quenched by pouring the solution onto ice. The organic phase 
was washed with saturated sodium chloride solution and dried over 
anhydrous magnesium sulphate. After removal of the solvent by evaporation 
there was obtained 25.65 g of (Z)-1-bromo-2-butene; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.: 1.65 (d, 3H), 3.9 (d, 2H), 5.6 (m, 2H). 
ii) 4.37 g (190 mmol) of sodium metal were dissolved in 110 ml of anhydrous 
ethanol. 41.14 g (189.6 mmol) of diethyl acetamidomalonate dissolved in 
270 ml of anhydrous ethanol were added and the mixture was heated under 
reflux for 10 minutes. 25.65 g (168 mmol) of (Z)-1-bromo-2-butene were 
added dropwise at room temperature and the mixture was stirred overnight, 
then evaporated to dryness under vacuum and the residue was partitioned 
between ethyl acetate and 0.1 M hydrochloric acid. The organic phase was 
washed with saturated sodium hydrogen carbonate solution followed by 
saturated sodium chloride solution and dried over anhydrous magnesium 
sulphate. After removal of the solvent by evaporation the crude product 
was chromatographed on silica gel using 66% ethyl acetate in petroleum 
ether as eluent to obtain 44.69 g of diethyl 
(Z)-2-acetamido-2-(2-butenyl)malonate as a colourless oil;.sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 1.2 (t, 6H), 1.6 (d, 3H), 2.0 (s, 3H), 3.1 
(d, 2H), 4.2 (q, 4H), 5.1(m, 1H), 5.6 (m, 1H), 6.7 (s, 1H). 
iii) 44.69 g (165 mmol) of diethyl (Z)-2-acetamido-2-(2-butenyl)malonate 
were dissolved in 230 ml of ethanol and a solution of 21.69 g (542 mmol) 
of sodium hydroxide in water was added. The mixture was stirred for 2 
hours at 60.degree. C., evaporated to dryness under a vacuum and the 
residue was partitioned between diethyl ether and water. The aqueous phase 
was acidified using 2M hydrochloric acid and extracted with ethyl acetate. 
The organic phase was dried over magnesium sulphate and the solvent 
removed by evaporation in a vacuum to give 33.5 g of 
(Z)-2-acetamido-2-(2-butenyl)malononic acid as a white solid; 1 H NMR (250 
MHz, MeOD) .delta.: 1.6 (d, 3H), 2.0 (s, 3H), 2.85 (d, 2H), 5.25 (m, 1H), 
5.6 (m, 1H). 
iv) 16.82 g (78.23 mmol) of (Z)-2-acetamido-2-(2-butenyl)-malononic acid 
were dissolved in 100 ml of toluene. 34 ml (242 mmol) of triethylamine 
were added and the mixture was heated under reflux for 1 h, then washed 
with 1M hydrochloric acid and the aqueous phase was extracted with ethyl 
acetate. The combined organic phases were dried over magnesium sulphate 
and the solvent was removed under a vacuum to give 9.4 g of 
(Z)-N-acetyl-DL-2-(2-butenyl)glycine as a white solid; 1 H NMR (250 MHz, 
MeOD) .delta.: 1.6 (d, 3H), 2.0 (s, 3H), 2.5 (m, 2H), 4.4 (m, 1H), 5.4 (m, 
1H), 5.6 (m, 1H). 
v) 9.4 g (54.97 mmol) of (Z)-N-acetyl-DL-2-(2-butenyl)glycine were 
dissolved in 100 ml of water and the pH was adjusted to 7.8 with ammonia 
solution. 0.09 g of acylase I extracted from porcine kidney, and 0.042 g 
(0.3 mmol) of cobalt (II) chloride were added and the resulting reaction 
mixture was stirred at 37.degree. C. overnight. The pH was adjusted to 7.8 
using ammonia solution. The mixture was stirred at 370C overnight and was 
then heated at 80.degree. C. for 30 minutes and was then acidified to pH 1 
using 2M hydrochloric acid. The solution was acidified to pH 1 using 2M 
hydrochloric acid and then heated at 80.degree. C. for 30 minutes. The 
solvent was removed by evaporation under a vacuum and the crude product 
obtained purified by trituration using ethyl acetate to yield 5.86 g of 
(Z)-L-2-(2-butenyl)glycine hydrochloride; .sup.1 H NMR (250 MHz, D.sub.2 
O) .delta.: 1.6 (d, 3H), 2.7 (t, 2H), 4.1 (t, 1H), 5.3 (m, 1H), 5.8 (m, 
1H). 
vi) 2.9 g (17.52 mmol) of (Z)-L-2-(2-butenyl)glycine hydrochloride were 
suspended in 25 ml of water and 25 ml of dioxan. 11.4 g (136 mmol) of 
sodium hydrogencarbonate and 8.49 g (38.94 mmol) of di-tert-butyl 
dicarbonate were added and the resulting solution was stirred for 48 
hours. The solution was evaporated to dryness under a vacuum and the 
residue was partitioned between diethyl ether and saturated aqueous sodium 
hydrogen carbonate solution. The aqueous phase was acidified using 2M 
hydrochloric acid whilst being partitioned with ethyl acetate. The organic 
phase was dried over magnesium sulphate and the solvent removed by 
evaporation to give 2.26 g of 
(Z)-N-(tert-butoxycarbonyl)-L-2-(2-butenyl)glycine; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.6 (d, 3H), 2.6 (m, 2H), 4.4 (m, 1H), 
5.05 (m, 1H), 5.3 (m, 1H), 5.6 (m, 1H). 
vii) 2.26 g (9.87 mmol) of 
(Z)-N-(tert-butoxycarbonyl)-L-2-(2-butenyl)glycine were dissolved in 50 ml 
of anhydrous tetrahydrofuran. 1.15 g (11.79 mmol) of 
N,O-dimethylhydroxylamine hydrochloride, 1.6 g (10.46 mmol) of 1- 
hydroxybenzotriazole monohydrate, 2.27 g (11.88 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 5.8 ml of 
ethyldiisopropylamine were added and the resulting solution was stirred at 
room temperature overnight. The solution was washed with saturated sodium 
hydrogen carbonate solution followed by saturated sodium chloride solution 
and then dried over anhydrous magnesium sulphate. Removal of the solvent 
by evaporation yielded 2.46 g of N,O-dimethyl 
(Z)-2(S)-(tert-butoxyformamido)-4-hexenohydroxamate as a colourless oil; 
.sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.6 (d, 3H), 2.35 
(m, 1H), 2.5 (m, 1H), 3.2 (s, 3H), 3.75 (s, 3H), 4.7 (m, 1H), 5.2 (d, 1H), 
5.35 (m, 1H), 5.6 (m, 1H). 
viii) 1.01 g (3.71 mmol) of N,O-dimethyl 
(Z)-2(S)-(tert-butoxyformamido)-4-hexenohydroxamate were dissolved in 10 
ml of anhydrous tetrahydrofuran and cooled to 0.degree. C. 2.6 ml of a 1M 
solution of lithium aluminium hydride in tetrahydrofuran were added and 
the resulting solution was stirred for 30 minutes. The reaction was 
quenched by the dropwise addition 15 ml of saturated potassium hydrogen 
sulphate solution followed by 30 ml of diethyl ether. The resulting 
two-phase system was stirred vigorously for one hour. The organic phase 
was washed with saturated sodium hydrogen carbonate solution followed by 
saturated sodium chloride solution and dried over magnesium sulphate. 
After removal of the solvent by evaporation the aldehyde was used without 
further purification. 0.79 g (3.71 mmol) of the aldehyde was dissolved in 
a saturated solution of hydrogen chloride in 10 ml of methanol and stirred 
at room temperature for 2 hours. After removal of the solvent by 
evaporation the dimethylacetal obtained was used without purification 
0.15 g (0.16 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-L-leucine, 0.033 g (0.22 mmol) of 1-hydroxybenzotriazole mono 
hydrate, 0.047 g (0.25 mmol) of 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 0.77 g 
(6.69 mmol) of 4-ethylmorpholine were dissolved in 15 ml of 
dichloromethane. 0.05 g (0.22 mmol) of the foregoing dimethyl acetal 
dissolved in 5 ml of dichloromethane was added and the resulting solution 
was stirred at room temperature for 3 days. The solution was washed with 
5% citric acid solution followed by saturated sodium hydrogen carbonate 
solution and saturated sodium chloride solution and then dried over 
magnesium sulphate. After removal of the solvent by evaporation the crude 
product was chromatographed on silica gel using 2% methanol in 
dichloromethane for the elution to give 0.092 g of 
(Z)-N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alph 
a.-aspartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-me 
thyl-L-valyl]-N1-[1 (S)-(dimethoxymethyl)-3-pentenyl]-L-leucinamide, as a 
white solid foam; MS: m/e 1027.9 [M+H-MeOH].sup.+. 
EXAMPLE 32 
In an analogous manner to that described in Example 10, but using 
N-(tert-butoxycarbonyl)-3-(2-furyl)-L-alanine in place of 
N-(tert-butoxycarbonyl)-L-allylglycine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-a-aspartyl]-L-a-glutamyl]-2-m 
ethyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3-(2-furyl)propiona 
ldehyde; MS: m/e 871.4 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) N,O-Dimethyl 
2(S)-(tert-butoxyformamido)-2-(2-furyl)-propionohydroxamate; .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 1.4 (s, 9H), 3.0 (m, 2H), 3.2 (s, 3H), 3.7 
(s, 3H), 4.9 (m, 1H), 5.3 (br. d, 1H), 6.1 (br. s, 1H), 6.3 (br. s, 1H), 
7.3 (br. s, 1H). 
ii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[2-(2-furyl)-1(S)-(dimethoxymethyl)ethyl]-L-leucinamide; used 
directly in the next step. 
EXAMPLE 33 
In an analogous manner to that described in Example 10, but using 
N-(tert-butoxycarbonyl)-L-norvaline in place of 
N-(tert-butoxycarbonyl)-L-allylglycine there was obtained 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-a-aspartyl]-L-a-glutamyl1-2-me 
thyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]valeraldehyde; MS: 
m/e 833.4 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
N,O-Dimethyl 2(S)-(tert-butoxyformamido)valerohydroxamate; .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 0.8 (m, 3H), 1.2-1.7 (m, 4H), 1.4 (s, 9H), 
3.1 (s, 3H), 3.7 (s, 3H), 4.6 (m, 1H), 5.1 (br. d, 1H). 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl- 
L-valyl]-N1-[1(S)-(dimethoxymethyl)butyl]-L-leucinamide; MS: m/e 1069.6 
[M+Na].sup.+. 
EXAMPLE 34 
In an analogous manner to that described in Example 10, but using 
N-(tert-butoxycarbonyl)-L-butylglycine in place of 
N-(tert-butoxycarbonyl)-L-allylglycine there was obtained 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L- 
a-aspartyl]-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leu 
cyl]amino]hexanal; MS: m/e 847.4 [M+H]+. 
The starting material was prepared in an analogous manner to that described 
in example 10 via the following intermediates: 
i) N,O-Dimethyl 2(S)-(tert-butoxyformamido)hexanohydroxamate; .sup.1 H NMR 
(250 MHz, CDCl.sub.3) .delta.: 0.9 (m, 3H), 1.2-1.8 (m, 6H), 1.4 (s, 9H), 
3.2 (s, 3H), 3.7 (s, 3H), 4.6 (m, 1H), 5.1 (br. d, 1H). 
ii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-pentyl]-L-leucinamide; MS: m/e 1083 
[M+Na].sup.+. 
EXAMPLE 35 
In an analogous manner to that described in Example 10, but using 
DL-hexylglycine in place of L-allylglycine hydrochloride there was 
obtained 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L- 
.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino 
]octanal; MS: m/e 875.5 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) 2(RS)-(tert-Butoxyformamido)octanoic acid; .sup.1 H NMR (250 MHz, 
CDCl.sub.3) .delta.: 0.9 (m, 3H), 1.2-1.9 (m, 10H), 1.4 (s, 9H), 4.3 (m, 
1H), 5.0 (br. d, 1H) 
ii) N,O-Dimethyl 2(RS)-(tert-butoxyformamido)octanohydroxamate; .sup.1 H 
NMR (250 MHz, CDCl.sub.3) .delta.: 0.9 (m, 3H), 1.2-1.8 (m, 1OH), 1.4 (s, 
9H), 3.2 (s, 3H), 3.7 (s, 3H) 4.6 (m, 1H), 5.1 (br. d, 1H) 
iii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(RS)-(dimethoxymethyl)heptyl]-L-leucinamide; MS: m/e 1111.6 
[M +Na].sup.+. 
EXAMPLE 36 
In an analogous manner to that described in Example 10, but using 
2(S)-amino-5-methylhexanoic acid in place of L-allylglycine hydrochloride 
there was obtained 
2(S)-[[N-[N-[N-[N-N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glu 
tamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5-methylh 
exanal; MS: m/e 861.3 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) 2(S)-(tert-Butoxyformamido)-5-methylhexanoic acid; 1H NMR (250 MHz, 
CDCl.sub.3) .delta.: 0.9 (d, 6H), 1.2 (m, 2H), 1.4 (s, 9H), 1.5 (m, 1H), 
1.7 (m, 1H), 1.9 (m, 1H), 4.3 (m, 1H), 4.9 (br. d, 1H). 
ii) N,O-Dimethyl 2(S)-(tert-butoxyformamido)-5-methyl-hexanohydroxamate; 1H 
NMR (250 MHz, CDCl.sub.3) .delta.: 0.85 (d, 3H), 0.9 (d, 3H), 1.2 (m, 2H), 
1.4 (s, 9H), 1.4-1.8 (m, 3H), 3.2 (s, 3H), 3.8 (s, 3H), 4.6 (m, 1H), 5.1 
(br. d, 1H). 
iii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1 (S)-(dimethoxymethyl)-4-methylpentyl]-L-leucinamide; MS: 
m/e 1043.8 [M+H-MeOH].sup.+. 
EXAMPLE 37 
In an analogous manner to that described in Example 10, but using 
2(S)-amino-5-hexenoic acid in place of L-allylglycine hydrochloride there 
was obtained 
2(S)-[[N-[N-[N-[N-[N-(3-carboxy-propionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5-hexen 
al; MS: m/e 845.3 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) 2(S)-tert-Butoxyformamido)-5-hexenoic acid; 1 H NMR (250 MHz, 
CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.8 (m, 1H), 1.95 (m, 1H), 2.2 (m, 2H), 
4.3 (m, 1H), 5.0 (m, 3H), 5.8 (m, 1H). 
ii) N,O-Dimethyl 2(S)-(tert-butoxyformamido)-5-hexenohydroxamate; 1H NMR 
(250 MHz, CDCl.sub.3) .delta.: 1.4(s, 9H), 1.6-1.8 (m, 2H), 2.1 (m, 2H), 
3.2 (s, 3H), 3.7 (s, 3H) 4.7 (m, 1H), 5.0 (m, 3H), 5.8 (m, 1H). 
iii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-4-pentenyl]-L-leucinamide; MS: m/e 
1081.6 [M+Na]+. 
EXAMPLE 38 
In an analogous manner to that described in Example 10, but using 
2(S)-amino-5-hexynoic acid in place of L-allylglycine hydrochloride there 
was obtained 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-5-hexyna 
l; MS: m/e 843.3 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) 2(S)-(tert-Butoxyformamido)-5-hexynoic acid; 1H NMR (250 MHz, MeOD) 
.delta.: 1.4 (s, 9H), 1.8 (m, 1H), 2.0 (m, 1H), 2.3 (m, 3H), 4.2 (m, 1H). 
ii) N,O-Dimethyl 2(S)-(tert-butoxyformamido)-5-hexynohydroxamate; 1H NMR 
(250 MHz, MeOD) .delta.: 1.4 (s, 9H), 1.7 (m, 1H), 1.9 (m, 1H), 2.3 (m, 
3H), 3.2 (s, 3H), 3.8 (s, 3H), 4.7 (m, 1H) 
iii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N 1-[1(S)-(dimethoxymethyl)-4-pentynyl]-L-leucinamide; MS: m/e 
1079.5 [M+Na].sup.+ 
EXAMPLE 39 
In an analogous manner to that described in Example 10, but using 
N-(tert-butoxycarbonyl)-L-methionine in place of 
N-(tert-butoxycarbonyl)-L-allylglycine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyll-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]aminol-4-(meth 
ylthio)butyraldehyde; MS: m/e 865.3 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) N,O-Dimethyl 
2(S)-(tert-butoxyformamido)-4-(methylthio)butyrohydroxamate; 1H NMR (250 
MHz, CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.75 (m, 1H), 2.0 (m, 1H), 2.05 (s, 
3H), 2.5 (m, 2H), 3.2 (s, 3H), 3.75 (s, 3H), 4.7 (m, 1H), 5.2 (m, 1H). 
ii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1(S)-(dimethoxymethyl)-2-(methylthio)propyl]-L-leucinamide; 
MS: m/e 1047.5 [M+H-MeOH].sup.+. 
EXAMPLE 40 
In an analogous manner to that described in Example 10, but using 
S-(3-phenylpropyl)-L-cysteine in place of L-allylglycine hydrochloride 
there was obtained 
2(R)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-2-[3-(ph 
enyl)propylthio]propionaldehyde; MS: m/e 955.4 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 10 via the following intermediates: 
i) N-(tert-Butoxycarbonyl)-S-(3-phenylpropyl)-L-cysteine; 1H NMR (250 MHz, 
CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.9 (m, 2H), 2.55 (t, 2H), 2.7 (t, 2H), 
3.0 (m, 2H), 4.5 (m, 1H), 5.4 (m, 1H), 7.2 (m, 5H). 
ii) N,O-Dimethyl 
2(S)-(tert-butoxyformamido)-3-(3-phenyl-propylthio)propionohydroxamate; 1H 
NMR (250 MHz, CDCl.sub.3) .delta.: 1.4 (s, 9H), 1.9 (m, 2H), 2.5 (t, 2H), 
2.7 (t, 2H), 2.8 (m, 2H), 3.2 (s, 3H), 3.7 (s, 3H), 4.8 (m, 1H), 5.3 (m, 
1H), 7.2 (m, 5H). 
iii) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl 
-L-valyl]-N1-[1 
(R)-(dimethoxymethyl)-2-(3-phenylpropylthio)ethyl]-L-leucinamide; MS: m/e 
1191.8 [M+Na].sup.+. 
EXAMPLE 41 
In an analogous manner to that described in Example 1, but sing 
N,O-Dimethyl 2(S)-(tert-butoxyformamido)hexanohydroxamate in place of 
N,O-Dimethyl 2(S)-(tert-butoxyformamido)butyrohydroxamate and 
N-(9-fluorenylmethoxycarbonyl)-D-valine in place of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-glutamic acid there 
was obtained 
2(S)-[[N-[N-[N-[N-N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-valyl]-2-me 
thyl-L-phenyl-alanyl]-3-methyl-L-valyl]-L-leucyl]amino]hexanal; MS: m/e 
817.4 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 1 via the following intermediates: 
i) 
N-[N-[N-[N-[(9-Fluorenyl)methoxycarbonyl]-D-valyl]-2-methyl-L-phenylalanyl 
]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 817.4 [M+H].sup.+. 
ii) N 
N-[N-[N-[N-[(9-Fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspartyl] 
-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl] L-leucine benzyl 
ester; MS: m/e 988.4 [M+H].sup.+. 
iii) 
N-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine 
benzyl ester; MS: m/e 922.5 [M+H].sup.+. 
iv) 
N-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-as 
partyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine; MS: 
m/e 832.5 [M+H].sup.+. 
v) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-D-valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dime 
thoxymethyl)pentyl]-L-leucinamide; MS: m/e 997.5 [M+Na].sup.+. 
EXAMPLE 42 
In an analogous manner to that described in Example 1, but using 
N,O-dimethyl 2(S)-(tert-butoxyformamido)hexanohydroxamate in place of 
N,O-dimethyl 2(S)-(tert-butoxyformamido)butyrohydroxamate, using 
N-(9-fluorenylmethoxycarbonyl)-D-valine in place of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-glutamic acid and 
using O-tert-butyl-N-[(9-florenyl)methoxycarbonyl]-L-serine in place of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartic acid there 
was obtained 
2(S)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-seryl]-D-valyl]-2-methyl-L-phe 
nyl-alanyl]-3-methyl-L-valyl]-L-leucyl]amino]hexanal; MS: m/e 789.3 
[M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 1 via the following intermediates: 
i) 
N-[N-[N-[N-[N-[(9-Fluorenyl)methoxycarbonyl]-O-tert-butyl-L-seryl]-D-valyl 
]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: 
m/e 960.4 [M+H].sup.+. 
ii) 
N-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-seryl]-D-v 
alyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester; 
MS: m/e 894.5 [M+H].sup.+. 
iii) 
N-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-seryl]-D-v 
alyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine; MS: m/e 804.4 
[M+H].sup.+. 
iv) 
N2-[N-[N-[N-[N-[3-(tert-Butoxycarbonyl)propionyl]-O-tert-butyl-L-seryl]-D- 
valyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxymethyl 
)pentyl]-L-leucinamide; MS: m/e 969.7 [M+Na].sup.+. 
EXAMPLE 43 
In an analogous manner to that described in Example 1, but using 
N,O-dimethyl 2(S)-(tert-butoxyformamido)hexanohydroxamate in place of 
N,O-dimethyl 2(S)-(tert-butoxyformamido)butyrohydroxamate using 
N-(9-fluorenylmethoxycarbonyl)-D-valine in place of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-glutamic acid, using 
O-tert-butyl-N-[(9-florenyl)methoxycarbonyl]-L-serine in place of 
N-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartic acid and 
using acetic anhydride in place of tert-butyl hydrogen succinate there was 
obtained 
2(S)-[[N-[N-[N-[N-(N-acetyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-m 
ethyl-L-valyl]-L-leucyl]amino]hexanal; MS: m/e 731.3 [M+H].sup.+. 
The starting material was prepared in an analogous manner to that described 
in Example 1 via the following intermediates: 
i) 
N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalany 
l]-3-methyl-L-valyl]-L-leucine; MS: m/e 690.4 [M+H].sup.+. 
ii) 
N2-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalan 
yl]-3-methyl-L-valyl]-N1-[1(S)-(dimethoxy-methyl)pentyl]-L-leucinamide; MS: 
mle 833.5 [M+H]+. 
The reaction with acetic anhydride was carried out as follows: 
0.5 ml of N-ethylmorpholine and 0.37 ml of acetic anhydride were added in 
sequence to a solution of 1.95 g of 
N-[N-[N-[N-(O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalanyl]-3-meth 
yl-L-valyl]-L-leucine benzyl ester in 70 ml of anhydrous dichloromethane. 
The mixture was stirred at room temperature for 1 hour and was then washed 
in sequence with 5% aqueous citric acid solution, saturated aqueous sodium 
bicarbonate solution and saturated brine. The organic phase was dried over 
anhydrous magnesium sulphate and evaporated. Chromatography of the residue 
on silica using 5% methanol in dichloromethane for the elution gave 
afforded 1.45 g of 
N-[N-[N-[N-(N-acetyl-O-tert-butyl-L-seryl)-D-valyl]-2-methyl-L-phenylalany 
l]-3-methyl-L-valyl]-L-leucine benzyl ester; MS: m/e 780.6 [M+H]+. 
EXAMPLE 44 
59 mg (0.058 mmol) of 
N1-[4-bromo-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)butyl]-N2-[ 
N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl]-2-m 
ethylL-phenylalanyl]-3-methyl-L-valyl]-L-leucinamide were dissolved in 3 ml 
of trifluoroacetic acid and 3 ml of dichloromethane. 5 drops of water were 
added and the solution was stirred at room temperature for 3 hours. The 
solution was diluted with toluene and evaporated. The residue was 
triturated with diethyl ether and the resulting solid was filtered off and 
dried and then redissolved in 5 ml of trifluoroacetic acid and 5 ml of 
dichloromethane. The solution was stirred at room temperature for 3 hours 
and then diluted with toluene and evaporated. The residue was triturated 
with diethyl ether and the solid obtained was filtered off and dried to 
give 30 mg of 
4-bromo-1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-. 
alpha.-glutamyl]-2-methylL-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]b 
utylboronic acid in the form of a solid; MS: m/e 911.3 [M+H-H.sub.2 
O].sup.+. 
The starting material was prepared as follows: 
i) 1.7 ml (1.7 mmol) of 1 M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise to a solution of 0.5 g (1.7 mmol) of 
2-(4-bromo-1(RS)-chlorobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 
(prepared according to EP-A-0 293 881) in 5 ml of tetrahydrofuran under 
nitrogen at -78.degree. C. The solution was then stirred overnight at room 
temperature. The solvent was removed by evaporation and the residue was 
taken up in diethyl ether. Insoluble material was removed by filtration 
and the solvent was removed by evaporation to give 0.63 g of product which 
was immediately redissolved in diethyl ether and cooled to 0.degree. C. 
0.34 ml 0.34 ml (5.0 mmol) of trifluoroacetic acid was added and the 
solution was stirred at 0.degree. C. for 30 minutes. The solution was 
evaporated and the residue was evaporated with toluene to give 0.58 g of 
.alpha.-(RS)-3-bromopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methy 
lamine trifluoroacetate (1:1) as a brown oil which was used in the next 
step without purification. 
ii) 0.20 g (0.22 mmol) of 
N-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-ter 
t-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-le 
ucine was dissolved in 2 ml of dimethylformamide and 6 ml of 
dichloromethane. 0.2 ml (1.52 mmol) of N-methylmorpholine was added and 
the solution was cooled to -10.degree. C. under a nitrogen atmosphere. 44 
mg (0.3 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 15 minutes at -10.degree. C. 0.3 g (0.66 mmol) of 
a(RS)-3-bromopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate (1:1) was added and the mixture was stirred at room 
temperature for 5 hours. Dichloromethane was added and the solution was 
extracted with 2M hyrochloric acid and water and then dried over anhydrous 
sodium sulphate. After evaporation there was obtained 0.122 g of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-methyl-L-v 
alyl]-N1-[4-bromo-1 
(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leucinamide in 
the form of a solid; MS: m/e 1079.5 [M+H-100].sup.+. 
iii) 115 mg (0.098 mmol) of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1- 
[4-bromo-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leucin 
amide were dissolved in 3 ml of trifluoroacetic acid and 3 ml of 
dichloromethane. 5 drops of water were added and the solution was stirred 
at room temperature for 3 hours. The solution was diluted with toluene and 
evaporated. The residue was triturated with ether and the resulting solid 
was filtered off and dried to give 72 mg of 
N1-[4-bromo-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)butyl]-N2-[ 
N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl-L-.alpha.-glutamyl]-2-me 
thyl-L-phenylalanyl]-3-methyl-L-methyl-valyl]-L-leucinamide as a white 
solid; MS: m/e 911.3 [M+H-100].sup.+ 
EXAMPLE 45 
In an analogous manner to that described in Example 23, but replacing 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-tyrosine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-aspartic acid and 
replacing N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valine with 
N-[(9-fluorenyl)methoxycarbonyl]-L-2-cyclohexylglycine there was obtained 
1 (RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methylL-phenylalanyl]-L-2-cyclohexylglycyl]-L-leucyl]amino]prop 
ylboronic acid as a white solid; MS: m/e 843.4 [M+H-H.sub.2 O].sup.+. 
EXAMPLE 46 
In an analogous manner to that described in Example 23, but replacing 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-tyrosine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-aspartic acid and 
replacing N-[(9-fluorenyl)methoxycarbonyl-2-methyl-L-phenylalanine with 
N-[(9-fluorenyl)methoxycarbonyl]-L-2-cyclohexylglycine there was obtained 
1 (RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-L-2-cyclohexyl-glycyl]-3-methyl-L-valyl]-L-leucyl]amino]propylbor 
onic acid as a white solid; MS: m/e 795.5 [M+H-H.sub.2 O].sup.+. 
EXAMPLE 47 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-3-cyclohexyl-L-alanine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-3-cyclohexy 
l-L-alanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4, 
4-trifluorobutyraldehyde as a white solid; MS m/e 897.6 [M+H]. 
EXAMPLE 48 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-D-valine and replacing 
N-[(9-fluorenyl)methoxycarbonyl]-O-t-butyl-L-.alpha.-aspartic acid with 
N-[(9-fluorenyl)methoxycarbonyl]-O-t-butyl-L-serine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-seryl]-D-valyl]-2-methyl-L-ph 
enylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobutyraldehyde 
as a white solid; MS: m/e 815.5 [M+H]. 
EXAMPLE 49 
In an analogous manner to Example 4, by replacing 
N-[(9-flurenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
[(9-fluorenyl)methoxycarbonyll-D-norleucine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carbonylpropionyl)-L-a-aspartyl]-D-norleucyl]-2-m 
ethyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-trifluorobuty 
raldehyde as a white solid;MS: m/e 857.4 [M+H]. 
EXAMPLE 50 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-D-norvaline there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-norvalyl] 
-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]-amino]-4,4,4-trifluor 
obutyraldehyde as a white solid; MS: m/e 843.4 [M+H]. 
EXAMPLE 51 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-D-2-cyclohexylglycine there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-D-2-cyclohe 
xylglycyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4 
-trifluorobutyraldehyde as a white solid, MS: m/e 897.4 [M+H]. 
EXAMPLE 52 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-4-nitro-D-phenylalanine there was 
obtained 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-4- 
nitro-D-phenylalanyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]a 
mino]-4,4,4-trifluorobutyraldehyde as a white solid; MS: m/e 936.3 [M+H]. 
EXAMPLE 53 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valine with 
N-[(9-fluorenyl)methoxycarbonyl]-L-2-cyclohexylglycine and by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid 
there was obtained 
2(RS)-[[N-[N-[N-(N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-L-2-cyclohexylglycyl]-L-leucyl]amino]-4,4 
,4-trifluorobutyraldehyde as a white solid; MS: m/e 899.5 [M+H]. 
EXAMPLE 54 
In an analogous manner to Example 4, by replacing 
N-[(9-methoxycarbonyl]-3-(2-methylphenyl)-L-alanine with 
N-[(9-methoxycarbonyl]-L-2-cyclohexylglycine and by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-t-butyl-L-.alpha.-glutamic acid there 
was obtained 
2(RS)-[[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glut 
amyl]-L-2-cyclohexylglycyl]-3-methyl-L-valyl]-L-leucyl]-amino]-4,4,4-triflu 
orobutyraldehyde as a white solid; MS: m/e 851.4 [M+H]. 
EXAMPLE 55 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-t-butyl-L-.alpha.-glutamic acid and by 
replacing tert-butyl hydrogen succinate with 3-acetamidobenzoic acid there 
was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-acetamido-benzoyl)-L-.alpha.-aspartyl]-L-.alpha.- 
glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino-4,4,4-t 
rifluororbutyraldehyde as a white solid; MS: m/e 934.4 [M+H]. 
EXAMPLE 56 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-t-butyl-L-.alpha.-glutamic acid and by 
rep[lacing tert-butyl hydrogen succinate with 4-acetamido-3-nitrobenzoic 
acid there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(4-acetamido-3-nitrobenzoyl)-L-.alpha.-aspartyl]-L-. 
alpha.-glutamyl]-2-methyl-L-phenylalanyl-3-methyl-L-valyl]-L-leucyl]amino]- 
4,4,4-trifluoro-butyraldehyde as a white solid; MS: m/e 979.4 [M+H]. 
EXAMPLE 57 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid and 
by replacing tert-butyl hydrogen succinate with 4-acetamidobenzoic acid 
there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(4-acetamidobenzoyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-t 
rifluorobutyraldehyde as a white solid; MS: m/e 934.4 [M+H]. 
EXAMPLE 58 
In an analogous manner to Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-L-.alpha.-glutamic acid and by 
replacing tert-butyl hydrogen succinate with 3,5-dichlorobenzoic acid 
there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(3,5-dichloro-benzoyl)-L-.alpha.-aspartyl]-L-.alpha. 
-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4 
-trifluorobutyraldehyde as a white solid; MS: m/e 945.3 [M+H]. 
EXAMPLE 59 
0.78 g of 0.235 mmol/g 5-[2-[1 
(RS)-[[N-[(9-fluorenyl)-methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5- 
trimethyl-1,3,2-dioxoborolan-4-yl]-3(RS)-methyl-N-[.alpha.(RS)-(4-methyl-ph 
enyl)benzyl]valeramide-polystyrene conjugate was swollen in 
dimethylformamide for 20 minutes and then suspended and agitated in 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained 
and then resuspended in and agitated with dimethylformamide/ piperidine 
(4:1) for a further five minutes. The resin was then drained and washed 
five times with dimethylformamide. 
The resin was then suspended in a solution of 0.4 g, 1.08 mmol of 
N-[(9-fluorenyl)methoxycarbonyl]-3-methyl-L-valine in dimethylformamide 
and then a mixture of 0.42 g (1.08 mmol) 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 
0.25 ml (2.2 mmol) of N-methylmorpholine dissolved in dimethylformamide 
was added. After agitating for 40 minutes the resin was drained and washed 
five times with dimethylformamide. 
The resin was resuspended in and agitated with dimethylformamide/piperidine 
(4:1). After 5 minutes the resin was drained, resuspended in and agitated 
with dimethylformamide/piperidine (4:1) for a further 5 minutes. Then the 
resin was drained and washed five times with dimethyl formamide. 
The resin was then suspended in a solution of 0.44 g (1.08 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-methylphenyl)-L-alanine in 
dimethylformamide and then a mixture of 0.42 g 
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 
0.25 ml (2.2 mmol) of N-methylmorpholine dissolved in dimethylformamide 
was added. After agitating for 40 minutes the resin was drained and washed 
five times with dimethylformamide. 
The resin was resuspended in and agitated with dimethylformamide/piperidine 
(4:1). After 5 minutes the resin was drained, resuspended in and agitated 
with dimethylformamide/piperidine (4:1) for a further 5 minutes. Then the 
resin was drained and washed five times with dimethyl formamide. 
The resin was then suspended in a solution of 0.37 g (1.08 mmol) of 
N-[(9-fluorenyl)methoxycarbonyl]-D-valine in dimethylformamide and then a 
mixture of 0.42 g of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium 
tetrafluoroborate and 0.25 ml (2.2 mmol) of N-methylmorpholine dissolved 
in dimethylformamide was added. After agitating for 40 minutes the resin 
was drained and washed five times with dimethylformamide. 
The resin was resuspended in and agitated with 0.7 ml of 
dimethylformamide/piperidine (4:1). After 5 minutes the resin was drained, 
resuspended in and agitated with dimethylformamide/piperidine (4:1) for a 
further 5 minutes. Then, the resin was drained and washed five times with 
1 ml of dimethylformamide. 
98 mg of this resin were then suspended in a solution of 0.06 g (0.19 mmol) 
of N-(benzyloxycarbonyl)-O-tert-butyl-L-.alpha.-aspartic acid in 
dimethylformamide and then a mixture of 0.06 g (0.19 mmol) of 2-(1 
H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate and 0.1 
ml (0.88 mmol) of N-methylmorpholine dissolved in dimethylformamide was 
added. After agitating for 40 minutes the resin was drained and washed 
three times with dimethylformamide, three times with ethyl acetate and 
three times with dichloromethane. 
1 ml of dichloromethane was added to the resin which was then treated with 
3 ml of a 9:1 mixture of trifluoroacetic acid and water and then agitated 
for 30 minutes. The resin was then filtered off and washed with 
dichloromethane. The filtrate and washings were combined and evaporated 
and then co-evaporated with toluene. The residue was triturated with 
diethyl ether and dried. There were obtained 12 mg of 1 
(RS)-[[N-[N-[N-[N-[N-(benzyloxycarbonyl)-L-.alpha.-aspartyl]-D-valyl]-2-me 
thyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]propylboronic acid; 
MS: m/e 821.4 [M+H-H.sub.2 O].sup.+. 
EXAMPLE 60 
200 mg (0.18 mmol) of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1- 
[4-fluoro-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leuci 
namide were dissolved in 4.75 ml of trifluoroacetic acid and 0.25 ml of 
water. 2 ml of dichloromethane were added and the solution was stirred at 
room temperature for 3 hours. The solution was diluted with toluene and 
evaporated. The residue was triturated with diethyl ether and the 
resulting solid was filtered off and dried to give 95 mg of 
4-fluoro-1(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L- 
.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino 
]butylboronic acid; MS: m/e 849.4 [M+H-H.sub.2 O].sup.+ 
The starting material was prepared as follows: 
i) 2.5 ml (25 mmol) of borane-dimethyl sulphide (1:1) complex were 
dissolved in 50 ml of dimethoxyethane and the solution was cooled to 
0.degree. C. under nitrogen. 5.3 ml (52.5 mmol) of cyclohexene were then 
added. The solution was stirred at 0.degree. C. for 15 minutes, then at 
room temperature for 1 hour and then cooled to -10.degree. C. 1.6 g (27 
mmol) of 3-fluoropropene were condensed and then added to the foregoing 
solution which was then stirred at room temperature under a dry ice 
condenser. After 1 hour the condenser was removed and stirring was 
continued for a further 1 hour. 3.9 g (52 mmol) of trimethylamine N-oxide 
were added and the solution was stirred for 1 hour. 3.1 g (26.3 mmol) of 
2,3-dimethyl-2,3-butanediol were added and the solution was stirred for 16 
hours. The solution was evaporated and the residue was distilled. The 
distillate boiling at 35-65.degree. C./1mm Hg was collected and purified 
by chromatography on silica gel using diethyl ether/ hexane (1:9) for the 
elution to give 1.67 g of 
4,4,5,5-tetramethyl-2-(3-fluoropropyl)-1,3,2-dioxaborolane as a colourless 
oil; .sup.1 H NMR (250 MHz, CDCl.sub.3) .delta.: 0.75-0.85 (m, 2H), 1.25 
(s, 12H), 1.7-1.9 (m, 2H), 4.28 (t, 1H), 4.48 (t, 1H). 
ii) 1.3 ml (8.8 mmol) of diisopropylamine and 5.5 ml (8.8 mmol) of 
butyllithium in hexane were added to 7 ml of tetrahydrofuran at 
-78.degree. C. The cooled solution was added to a solution of 1.65 g (8.8 
mmol) of 4,4,5,5-tetramethyl-2-(3-fluoropropyl)-1,3,2-dioxaborolane in 0.7 
ml of dichloromethane, 15 ml of cyclohexane and 8 ml of tetrahydrofuran at 
-20.degree. C. under nitrogen. The solution was then stirred for 16 hours 
while slowly warming to room temperature. The solution was partitioned 
between 2M hydrochloric acid, brine and ethyl acetate, and the aqueous 
layer was extracted with ethyl acetate. The organic extracts were 
combined, washed with brine and dried over sodium sulphate. After 
evaporation the residue was purified by chromatography on silica gel using 
diethyl ether/hexane (1:9) for the elution to give 1.0 g of 
2-(4-fluoro-1(RS)-chlorobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as 
a colourless oil; .sup.1 H NMR (250 MHz, CDCI.sub.3) .delta.: 0.75-0.85 
(m, 2H), 1.3 (s, 12H), 1.9-2.1 (m, 2H), 3.45 (m, 1H) 4.35 (m, 1H), 4.55 
(m, 1H). 
iii) 4.2 ml (4.2 mmol) of 1M lithium bis(trimethylsilyl)amide in 
tetrahydrofuran were added dropwise to a solution of 1.0 g (4.2 mmol) of 
2-(4-fluoro-1(RS)-chlorobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 
7 ml of tetrahydrofuran under nitrogen at -78.degree. C. The solution was 
then stirred overnight at room temperature. The solvent was removed by 
evaporation and the residue was taken up in diethyl ether. Insoluble 
material was removed by filtration and the solvent was removed by 
evaporation to give 1.53 g of material which was immediately redissolved 
in 7 ml of diethyl ether and cooled to 0.degree. C. 0.95 ml (12.6 mmol) of 
trifluoroacetic acid was added and the solution was stirred at 0.degree. 
C. for 30 minutes. The solution was evaporated and the residue was 
evaporated with toluene to give 1.36 g of 
.alpha.(RS)-3-fluoropropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methy 
lamine trifluoroacetate (1:1) as a brown oil which was used in the next 
step without further purification. 
iv) 0.20 g (0.22 mmol) 
N-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-ter 
t-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-le 
ucine was dissolved in 2 ml of dimethylformamide and 4 ml of 
dichloromethane. 0.2 ml (1.52 mmol) of N-methylmorpholine was added and 
the solution was cooled to -10.degree. C. under a nitrogen atmosphere. 40 
mg (0.27 mmol) of isobutyl chloroformate were added and the solution was 
stirred for 10 minutes at -100.degree. C. 0.2 g (0.44 mmol) of 
.alpha.(RS)-3-fluoropropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methy 
lamine trifluoroacetate (1:1) was added and the mixture was stirred at room 
temperature for 16 hours. Dichloromethane was added and the solution was 
washed with 2M hydrochloric acid and water and then dried over anhydrous 
sodium sulphate. After evaporation there was obtained 0.21 g of 
N2-[N-[N-[N-[N-(tert-butoxycarbonyl)-O-tert-butyl-L-.alpha.-aspartyl]-O-te 
rt-butyl-L-.alpha.-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1- 
[4-fluoro-1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leuci 
namide in the form of a solid; MS: m/e 1017.3 [M+H-100].sup.+. 
EXAMPLE 61 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid and 
by replacing N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanine 
with N-[(9-fluorenyl)methoxycarbonyl]-4-chloro-L-phenylalanine there was 
obtained 
2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl-L-.alpha.-gl 
utamyl]-4-chloro-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4-tr 
ifluorobutyraldehyde as a white solid; MS: m/e 893.3 [M+H]. 
EXAMPLE 62 
In an analogous manner to that described in Example 4, by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine with 
N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-glutamic acid, by 
replacing N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-.alpha.-aspartic 
acid with N-(benzyloxycarbonyl)-O-tert-butyl-L-.alpha.-aspartic acid and 
by omitting the reaction with tert-butyl succinate there was obtained 
2(RS)-[[N-[N-[N-[N-[N-(benzyl-oxycarbonyl)-L-.alpha.-aspartyl]-L-.alpha.-g 
lutamyl]-2-methyl-L-phenyl-alanyl]-3-methyl-L-valyl]-L-leucyl]amino]-4,4,4- 
trifluoro-butyraldehyde as a white solid; MS: m/e 907.4 [M+H]. 
EXAMPLE 63 
88 mg (0.09 mmol) of 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl 
]-4-chloro-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(RS)-(4,4,5,5-te 
tramethyl-1,3,2-dioxoborolan-2-y;)-3-butenyl]-L-leucinamide were dissolved 
in 5 ml of trifluoroacetic acid and 5 ml of dichloromethane. 5 drops of 
water were added and the solution was stirred at room temperature for 4 
hours. The solution was diluted with toluene and evaporated. The residue 
was triturated with diethyl ether and the resulting solid was filtered off 
and dried to give 72 mg of 1 
(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-gl 
utamyl]-4-chloro-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino] 
-3-butenylboronic acid; MS: m/e 863 [M+H-H.sub.2 O].sup.+. 
The starting material was prepared as follows: 
i) In an analogous manner to Example 1 iii)-x), by replacing 
N-[(9-fluorenyl)methoxycarbonyl]-2-methyl-L-phenylalanine with 
N-[(9-fluorenyl)methoxycarbonyl]-4-chloro-2-methyl-L-phenylalanine there 
was obtained 
N-[N-[N-[N-[N-[3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-4-chloro-2-methyl-L-phenylalanyl] 
-3-methyl-L-valyl]-L-leucine as a white solid; MS: m/e 952 [M+H].sup.+. 
ii) 0.18 g (0.19 mmol) of 
N-[N-[N-[N-[N-[3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-4-chloro-2-methyl-L-phenylalanyl] 
-3-methyl-L-valyl]-L-leucine was dissolved in 2 ml of dimethylformamide and 
5 ml of dichloromethane. 0.1 ml (0.94 mmol) of N-methylmorpholine was 
added and the solution was cooled to -15.degree. C. under a nitrogen 
atmosphere. 35 mg (0.25 mmol) of isobutylchloroformate were added and the 
solution was stirred for 10 minutes at -10.degree. C. 0.12g (0.38 mmol) 
.alpha.(RS)-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine 
trifluoroacetate (1:1) was added and the mixture was stirred at room 
temperature for 2 hours. The solution was diluted with dichloromethane, 
washed with 2M hydrochloric acid and water and dried over anhydrous sodium 
sulphate. After evaporation there was obtained 0.18 g of 
N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-.alpha.-a 
spartyl]-O-tert-butyl-L-.alpha.-glutamyl]-4-chloro-2-methyl-L-phenylalanyl] 
-3-methyl-L-valyl]-N1-[1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 
3-butenyl]-L-leucinamide in the form of a white solid; MS: m/e 1131.6 
[M+H].sup.+. 
iii) 166 mg (0.147 mmol) of 
N2-[N-[N-[N-[N-(3-(tert-butoxy-carbonyl)propionyl]-O-tert-butyl-L-.alpha.- 
aspartyl-O-tert-butyl-L-.alpha.-glutamyl]-4-chloro-2-methyl-L-phenylalanyl] 
-3-methyl-L-valyl]-N1-[1 
(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-3-butenyl]-L-leucinamid 
e were dissolved in 5 ml of trifluoroacetic acid and 5 ml of 
dichloromethane. The solution was stirred at room temperature for 30 
minutes, then diluted with toluene and evaporated. The residue was 
triturated with ether and the resulting solid was filtered off, dried and 
then redissolved in 5 ml of trifluoroacetic acid and 5 ml of 
dichloromethane. The solution was stirred at room temperature for 30 
minutes, diluted with toluene and evaporated. The residue was triturated 
with diethyl ether and the resulting solid was filtered off and dried to 
give 100 mg of 
N2-[N-[N-[N-[N-(3-carboxypropionyl)-L-.alpha.-aspartyl]-L-.alpha.-glutamyl 
]-4-chloro-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(RS)-(4,4,5,5-te 
tramethyl-1,3,2-dioxoborolan-2-yl)-3-butenyl]-L-leucinamide as a white 
solid; MS: m/e 863 [M+H-100].sup.+. 
The following Examples illustrate pharmaceutical preparations containing 
compounds of formula I: 
EXAMPLE A 
Tablets containing the following ingredients may be produced in a 
conventional manner: 
______________________________________ 
Ingredient Per tablet 
______________________________________ 
Compound of formula I 10.0 mg 
Lactose 125.0 mg 
Corn starch 75.0 mg 
Talc 4.0 mg 
Magnesium stearate 1.0 mg 
Total weight 215.0 mg 
______________________________________ 
EXAMPLE B 
Capsules containing the following ingredients may be produced in a 
conventional manner: 
______________________________________ 
Ingredient Per capsule 
______________________________________ 
Compound of formula I 10.0 mg 
Lactose 165.0 mg 
Corn starch 20.0 mg 
Talc 5.0 mg 
Capsule fill weight 200.0 mg 
______________________________________ 
__________________________________________________________________________ 
# SEQUENCE LISTING 
- - - - (1) GENERAL INFORMATION: 
- - (iii) NUMBER OF SEQUENCES: 2 
- - - - (2) INFORMATION FOR SEQ ID NO:1: 
- - (i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 7475 base - #pairs 
(B) TYPE: nucleic acid 
(C) STRANDEDNESS: double 
(D) TOPOLOGY: circular 
- - (ii) MOLECULE TYPE: DNA (genomic) 
- - (iii) HYPOTHETICAL: NO 
- - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: 
- - CCGACACCAT CGAATGGTGC AAAACCTTTC GCGGTATGGC ATGATAGCGC CC - 
#GGAAGAGA 60 
- - GTCAATTCAG GGTGGTGAAT GTGAAACCAG TAACGTTATA CGATGTCGCA GA - 
#GTATGCCG 120 
- - GTGTCTCTTA TCAGACCGTT TCCCGCGTGG TGAACCAGGC CAGCCACGTT TC - 
#TGCGAAAA 180 
- - CGCGGGAAAA AGTGGAAGCG GCGATGGCGG AGCTGAATTA CATTCCCAAC CG - 
#CGTGGCAC 240 
- - AACAACTGGC GGGCAAACAG TCGTTGCTGA TTGGCGTTGC CACCTCCAGT CT - 
#GGCCCTGC 300 
- - ACGCGCCGTC GCAAATTGTC GCGGCGATTA AATCTCGCGC CGATCAACTG GG - 
#TGCCAGCG 360 
- - TGGTGGTGTC GATGGTAGAA CGAAGCGGCG TCGAAGCCTG TAAAGCGGCG GT - 
#GCACAATC 420 
- - TTCTCGCGCA ACGCGTCAGT GGGCTGATCA TTAACTATCC GCTGGATGAC CA - 
#GGATGCCA 480 
- - TTGCTGTGGA AGCTGCCTGC ACTAATGTTC CGGCGTTATT TCTTGATGTC TC - 
#TGACCAGA 540 
- - CACCCATCAA CAGTATTATT TTCTCCCATG AAGACGGTAC GCGACTGGGC GT - 
#GGAGCATC 600 
- - TGGTCGCATT GGGTCACCAG CAAATCGCGC TGTTAGCGGG CCCATTAAGT TC - 
#TGTCTCGG 660 
- - CGCGTCTGCG TCTGGCTGGC TGGCATAAAT ATCTCACTCG CAATCAAATT CA - 
#GCCGATAG 720 
- - CGGAACGGGA AGGCGACTGG AGTGCCATGT CCGGTTTTCA ACAAACCATG CA - 
#AATGCTGA 780 
- - ATGAGGGCAT CGTTCCCACT GCGATGCTGG TTGCCAACGA TCAGATGGCG CT - 
#GGGCGCAA 840 
- - TGCGCGCCAT TACCGAGTCC GGGCTGCGCG TTGGTGCGGA TATCTCGGTA GT - 
#GGGATACG 900 
- - ACGATACCGA AGACAGCTCA TGTTATATCC CGCCGTTAAC CACCATCAAA CA - 
#GGATTTTC 960 
- - GCCTGCTGGG GCAAACCAGC GTGGACCGCT TGCTGCAACT CTCTCAGGGC CA - 
#GGCGGTGA 1020 
- - AGGGCAATCA GCTGTTGCCC GTCTCACTGG TGAAAAGAAA AACCACCCTG GC - 
#GCCCAATA 1080 
- - CGCAAACCGC CTCTCCCCGC GCGTTGGCCG ATTCATTAAT GCAGCTGGCA CG - 
#ACAGGTTT 1140 
- - CCCGACTGGA AAGCGGGCAG TGAGCGCAAC GCAATTAATG TGAGTTAGCT CA - 
#CTCATTAG 1200 
- - GCACAATTCT CATGTTTGAC AGCTTATCAT CGACTGCACG GTGCACCAAT GC - 
#TTCTGGCG 1260 
- - TCAGGCAGCC ATCGGAAGCT GTGGTATGGC TGTGCAGGTC GTAAATCACT GC - 
#ATAATTCG 1320 
- - TGTCGCTCAA GGCGCACTCC CGTTCTGGAT AATGTTTTTT GCGCCGACAT CA - 
#TAACGGTT 1380 
- - CTGGCAAATA TTCTGAAATG AGCTGTTGAC AATTAATCAT CGGCTCGTAT AA - 
#TGTGTGGA 1440 
- - ATTGTGAGCG GATAACAATT TCACACAGGA AACAGCCAGT CCGTTTAGGT GT - 
#TTTCACGA 1500 
- - GCACTTCACC AACAAGGACC ATAGATTATG AAAACTGAAG AAGGTAAACT GG - 
#TAATCTGG 1560 
- - ATTAACGGCG ATAAAGGCTA TAACGGTCTC GCTGAAGTCG GTAAGAAATT CG - 
#AGAAAGAT 1620 
- - ACCGGAATTA AAGTCACCGT TGAGCATCCG GATAAACTGG AAGAGAAATT CC - 
#CACAGGTT 1680 
- - GCGGCAACTG GCGATGGCCC TGACATTATC TTCTGGGCAC ACGACCGCTT TG - 
#GTGGCTAC 1740 
- - GCTCAATCTG GCCTGTTGGC TGAAATCACC CCGGACAAAG CGTTCCAGGA CA - 
#AGCTGTAT 1800 
- - CCGTTTACCT GGGATGCCGT ACGTTACAAC GGCAAGCTGA TTGCTTACCC GA - 
#TCGCTGTT 1860 
- - GAAGCGTTAT CGCTGATTTA TAACAAAGAT CTGCTGCCGA ACCCGCCAAA AA - 
#CCTGGGAA 1920 
- - GAGATCCCGG CGCTGGATAA AGAACTGAAA GCGAAAGGTA AGAGCGCGCT GA - 
#TGTTCAAC 1980 
- - CTGCAAGAAC CGTACTTCAC CTGGCCGCTG ATTGCTGCTG ACGGGGGTTA TG - 
#CGTTCAAG 2040 
- - TATGAAAACG GCAAGTACGA CATTAAAGAC GTGGGCGTGG ATAACGCTGG CG - 
#CGAAAGCG 2100 
- - GGTCTGACCT TCCTGGTTGA CCTGATTAAA AACAAACACA TGAATGCAGA CA - 
#CCGATTAC 2160 
- - TCCATCGCAG AAGCTGCCTT TAATAAAGGC GAAACAGCGA TGACCATCAA CG - 
#GCCCGTGG 2220 
- - GCATGGTCCA ACATCGACAC CAGCAAAGTG AATTATGGTG TAACGGTACT GC - 
#CGACCTTC 2280 
- - AAGGGTCAAC CATCCAAACC GTTCGTTGGC GTGCTGAGCG CAGGTATTAA CG - 
#CCGCCAGT 2340 
- - CCGAACAAAG AGCTGGCAAA AGAGTTCCTC GAAAACTATC TGCTGACTGA TG - 
#AAGGTCTG 2400 
- - GAAGCGGTTA ATAAAGACAA ACCGCTGGGT GCCGTAGCGC TGAAGTCTTA CG - 
#AGGAAGAG 2460 
- - TTGGCGAAAG ATCCACGTAT TGCCGCCACC ATGGAAAACG CCCAGAAAGG TG - 
#AAATCATG 2520 
- - CCGAACATCC CGCAGATGTC CGCTTTCTGG TATGCCGTGC GTACTGCGGT GA - 
#TCAACGCC 2580 
- - GCCAGCGGTC GTCAGACTGT CGATGAAGCC CTGAAAGACG CGCAGACTAA TT - 
#CGAGCTCG 2640 
- - AACAACAACA ACAATAACAA TAACAACAAC CTCGGGATCG AGGGAAGGAT TT - 
#CAGAATTC 2700 
- - ATGGGGAGGG AGATACATCT GGGACCGGCA GACAGCCTTG AAGGGCAGGG GT - 
#GGCGACTC 2760 
- - CTCGCGCATA TTACGGCCTA CTCTCAACAG ACGCGGGGCC TACTTGGCTG CA - 
#TCATCACT 2820 
- - AGCCTCACAG GCCGGGACAG GAACCAGGTC GAGGGGGAGG TCCAAATGGT CT - 
#CCACCGCA 2880 
- - ACACAATCTT TCCTGGCGAC CTGCGTCAAT GGCGTGTGTT GGACTGTCTA TC - 
#ATGGTGCC 2940 
- - GGCTCAAAGA CCCTTGCCGG CCCAAAGGGC CCAATCACCC AAATGTACAC CA - 
#ATGTGGAC 3000 
- - CAGGACCTCG TCGGCTGGCA AGCGCCCCCC GGGGCGCGCT CCTTGACACC AT - 
#GCACCTGC 3060 
- - GGCAGCTCAG ACCTTTACTT GGTCACGAGG CATGCCGATG TCATTCCGGT GC - 
#GCCGGCGG 3120 
- - GGCGACAGCA GGGGAAGCCT ACTCTCCCCC AGGCCCGTCT CCTACTTGAA GG - 
#GCTCTTCG 3180 
- - GGCGGTCCAC TGCTCTGCCC CTCGGGGCAC GCTGTGGGCA TCTTCCGGGC TG - 
#CCGTGTGC 3240 
- - ACCCGAGGGG TTGCGAAGGC GGTGGACTTT GTACCCGTCG AGTCTATGGA AA - 
#CCACTATG 3300 
- - CGGTCCCCGG TCTTCACGGA CAACTCGTCC CCTCCGGCCG TATGCATGGG AG - 
#GAGGAGGA 3360 
- - GGAGGAGGAG GAGGAGGAGG AGGATCCATG AGCACCTGGG TGCTAGTAGG CG - 
#GAGTCCTA 3420 
- - GCAGCTCTGG CCGCGTATTG CCTGACAACA GGCAGCGTGG TCATTGTGGG CA - 
#GGATCGTC 3480 
- - TTGTCCGGAA AGCCGGCCAT CATTCCCGAC AGGGAAGTCC TCTACCGGGA GT - 
#TCGATGAG 3540 
- - ATGGAAGAGT GCTAGAAGCT TGGCACTGGC CGTCGTTTTA CAACGTCGTG AC - 
#TGGGAAAA 3600 
- - CCCTGGCGTT ACCCAACTTA ATCGCCTTGC AGCACATCCC CCTTTCGCCA GC - 
#TGGCGTAA 3660 
- - TAGCGAAGAG GCCCGCACCG ATCGCCCTTC CCAACAGTTG CGCAGCCTGA AT - 
#GGCGAATG 3720 
- - GCAGCTTGGC TGTTTTGGCG GATGAGATAA GATTTTCAGC CTGATACAGA TT - 
#AAATCAGA 3780 
- - ACGCAGAAGC GGTCTGATAA AACAGAATTT GCCTGGCGGC AGTAGCGCGG TG - 
#GTCCCACC 3840 
- - TGACCCCATG CCGAACTCAG AAGTGAAACG CCGTAGCGCC GATGGTAGTG TG - 
#GGGTCTCC 3900 
- - CCATGCGAGA GTAGGGAACT GCCAGGCATC AAATAAAACG AAAGGCTCAG TC - 
#GAAAGACT 3960 
- - GGGCCTTTCG TTTTATCTGT TGTTTGTCGG TGAACGCTCT CCTGAGTAGG AC - 
#AAATCCGC 4020 
- - CGGGAGCGGA TTTGAACGTT GCGAAGCAAC GGCCCGGAGG GTGGCGGGCA GG - 
#ACGCCCGC 4080 
- - CATAAACTGC CAGGCATCAA ATTAAGCAGA AGGCCATCCT GACGGATGGC CT - 
#TTTTGCGT 4140 
- - TTCTACAAAC TCTTTTTGTT TATTTTTCTA AATACATTCA AATATGTATC CG - 
#CTCATGAG 4200 
- - ACAATAACCC TGATAAATGC TTCAATAATA TTGAAAAAGG AAGAGTATGA GT - 
#ATTCAACA 4260 
- - TTTCCGTGTC GCCCTTATTC CCTTTTTTGC GGCATTTTGC CTTCCTGTTT TT - 
#GCTCACCC 4320 
- - AGAAACGCTG GTGAAAGTAA AAGATGCTGA AGATCAGTTG GGTGCACGAG TG - 
#GGTTACAT 4380 
- - CGAACTGGAT CTCAACAGCG GTAAGATCCT TGAGAGTTTT CGCCCCGAAG AA - 
#CGTTCTCC 4440 
- - AATGATGAGC ACTTTTAAAG TTCTGCTATG TGGCGCGGTA TTATCCCGTG TT - 
#GACGCCGG 4500 
- - GCAAGAGCAA CTCGGTCGCC GCATACACTA TTCTCAGAAT GACTTGGTTG AG - 
#TACTCACC 4560 
- - AGTCACAGAA AAGCATCTTA CGGATGGCAT GACAGTAAGA GAATTATGCA GT - 
#GCTGCCAT 4620 
- - AACCATGAGT GATAACACTG CGGCCAACTT ACTTCTGACA ACGATCGGAG GA - 
#CCGAAGGA 4680 
- - GCTAACCGCT TTTTTGCACA ACATGGGGGA TCATGTAACT CGCCTTGATC GT - 
#TGGGAACC 4740 
- - GGAGCTGAAT GAAGCCATAC CAAACGACGA GCGTGACACC ACGATGCCTG TA - 
#GCAATGGC 4800 
- - AACAACGTTG CGCAAACTAT TAACTGGCGA ACTACTTACT CTAGCTTCCC GG - 
#CAACAATT 4860 
- - AATAGACTGG ATGGAGGCGG ATAAAGTTGC AGGACCACTT CTGCGCTCGG CC - 
#CTTCCGGC 4920 
- - TGGCTGGTTT ATTGCTGATA AATCTGGAGC CGGTGAGCGT GGGTCTCGCG GT - 
#ATCATTGC 4980 
- - AGCACTGGGG CCAGATGGTA AGCCCTCCCG TATCGTAGTT ATCTACACGA CG - 
#GGGAGTCA 5040 
- - GGCAACTATG GATGAACGAA ATAGACAGAT CGCTGAGATA GGTGCCTCAC TG - 
#ATTAAGCA 5100 
- - TTGGTAACTG TCAGACCAAG TTTACTCATA TATACTTTAG ATTGATTTAC CC - 
#CGGTTGAT 5160 
- - AATCAGAAAA GCCCCAAAAA CAGGAAGATT GTATAAGCAA ATATTTAAAT TG - 
#TAAACGTT 5220 
- - AATATTTTGT TAAAATTCGC GTTAAATTTT TGTTAAATCA GCTCATTTTT TA - 
#ACCAATAG 5280 
- - GCCGAAATCG GCAAAATCCC TTATAAATCA AAAGAATAGC CCGAGATAGG GT - 
#TGAGTGTT 5340 
- - GTTCCAGTTT GGAACAAGAG TCCACTATTA AAGAACGTGG ACTCCAACGT CA - 
#AAGGGCGA 5400 
- - AAAACCGTCT ATCAGGGCGA TGGCCCACTA CGTGAACCAT CACCCAAATC AA - 
#GTTTTTTG 5460 
- - GGGTCGAGGT GCCGTAAAGC ACTAAATCGG AACCCTAAAG GGAGCCCCCG AT - 
#TTAGAGCT 5520 
- - TGACGGGGAA AGCCGGCGAA CGTGGCGAGA AAGGAAGGGA AGAAAGCGAA AG - 
#GAGCGGGC 5580 
- - GCTAGGGCGC TGGCAAGTGT AGCGGTCACG CTGCGCGTAA CCACCACACC CG - 
#CCGCGCTT 5640 
- - AATGCGCCGC TACAGGGCGC GTAAAAGGAT CTAGGTGAAG ATCCTTTTTG AT - 
#AATCTCAT 5700 
- - GACCAAAATC CCTTAACGTG AGTTTTCGTT CCACTGAGCG TCAGACCCCG TA - 
#GAAAAGAT 5760 
- - CAAAGGATCT TCTTGAGATC CTTTTTTTCT GCGCGTAATC TGCTGCTTGC AA - 
#ACAAAAAA 5820 
- - ACCACCGCTA CCAGCGGTGG TTTGTTTGCC GGATCAAGAG CTACCAACTC TT - 
#TTTCCGAA 5880 
- - GGTAACTGGC TTCAGCAGAG CGCAGATACC AAATACTGTC CTTCTAGTGT AG - 
#CCGTAGTT 5940 
- - AGGCCACCAC TTCAAGAACT CTGTAGCACC GCCTACATAC CTCGCTCTGC TA - 
#ATCCTGTT 6000 
- - ACCAGTGGCT GCTGCCAGTG GCGATAAGTC GTGTCTTACC GGGTTGGACT CA - 
#AGACGATA 6060 
- - GTTACCGGAT AAGGCGCAGC GGTCGGGCTG AACGGGGGGT TCGTGCACAC AG - 
#CCCAGCTT 6120 
- - GGAGCGAACG ACCTACACCG AACTGAGATA CCTACAGCGT GAGCTATGAG AA - 
#AGCGCCAC 6180 
- - GCTTCCCGAA GGGAGAAAGG CGGACAGGTA TCCGGTAAGC GGCAGGGTCG GA - 
#ACAGGAGA 6240 
- - GCGCACGAGG GAGCTTCCAG GGGGAAACGC CTGGTATCTT TATAGTCCTG TC - 
#GGGTTTCG 6300 
- - CCACCTCTGA CTTGAGCGTC GATTTTTGTG ATGCTCGTCA GGGGGGCGGA GC - 
#CTATGGAA 6360 
- - AAACGCCAGC AACGCGGCCT TTTTACGGTT CCTGGCCTTT TGCTGGCCTT TT - 
#GCTCACAT 6420 
- - GTTCTTTCCT GCGTTATCCC CTGATTCTGT GGATAACCGT ATTACCGCCT TT - 
#GAGTGAGC 6480 
- - TGATACCGCT CGCCGCAGCC GAACGACCGA GCGCAGCGAG TCAGTGAGCG AG - 
#GAAGCGGA 6540 
- - AGAGCGCCTG ATGCGGTATT TTCTCCTTAC GCATCTGTGC GGTATTTCAC AC - 
#CGCATATG 6600 
- - GTGCACTCTC AGTACAATCT GCTCTGATGC CGCATAGTTA AGCCAGTATA CA - 
#CTCCGCTA 6660 
- - TCGCTACGTG ACTGGGTCAT GGCTGCGCCC CGACACCCGC CAACACCCGC TG - 
#ACGCGCCC 6720 
- - TGACGGGCTT GTCTGCTCCC GGCATCCGCT TACAGACAAG CTGTGACCGT CT - 
#CCGGGAGC 6780 
- - TGCATGTGTC AGAGGTTTTC ACCGTCATCA CCGAAACGCG CGAGGCAGCT GC - 
#GGTAAAGC 6840 
- - TCATCAGCGT GGTCGTGCAG CGATTCACAG ATGTCTGCCT GTTCATCCGC GT - 
#CCAGCTCG 6900 
- - TTGAGTTTCT CCAGAAGCGT TAATGTCTGG CTTCTGATAA AGCGGGCCAT GT - 
#TAAGGGCG 6960 
- - GTTTTTTCCT GTTTGGTCAC TTGATGCCTC CGTGTAAGGG GGAATTTCTG TT - 
#CATGGGGG 7020 
- - TAATGATACC GATGAAACGA GAGAGGATGC TCACGATACG GGTTACTGAT GA - 
#TGAACATG 7080 
- - CCCGGTTACT GGAACGTTGT GAGGGTAAAC AACTGGCGGT ATGGATGCGG CG - 
#GGACCAGA 7140 
- - GAAAAATCAC TCAGGGTCAA TGCCAGCGCT TCGTTAATAC AGATGTAGGT GT - 
#TCCACAGG 7200 
- - GTAGCCAGCA GCATCCTGCG ATGCAGATCC GGAACATAAT GGTGCAGGGC GC - 
#TGACTTCC 7260 
- - GCGTTTCCAG ACTTTACGAA ACACGGAAAC CGAAGACCAT TCATGTTGTT GC - 
#TCAGGTCG 7320 
- - CAGACGTTTT GCAGCAGCAG TCGCTTCACG TTCGCTCGCG TATCGGTGAT TC - 
#ATTCTGCT 7380 
- - AACCAGTAAG GCAACCCCGC CAGCCTAGCC GGGTCCTCAA CGACAGGAGC AC - 
#GATCATGC 7440 
- - GCACCCGTGG CCAGGACCCA ACGCTGCCCG AAATT - # 
- # 7475 
- - - - (2) INFORMATION FOR SEQ ID NO:2: 
- - (i) SEQUENCE CHARACTERISTICS: 
(A) LENGTH: 675 amino - #acids 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- - (ii) MOLECULE TYPE: protein 
- - (iii) HYPOTHETICAL: NO 
- - (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: 
- - Met Lys Thr Glu Glu Gly Lys Leu Val Ile Tr - #p Ile Asn Gly Asp 
Lys 
1 5 - # 10 - # 15 
- - Gly Tyr Asn Gly Leu Ala Glu Val Gly Lys Ly - #s Phe Glu Lys Asp Thr 
20 - # 25 - # 30 
- - Gly Ile Lys Val Thr Val Glu His Pro Asp Ly - #s Leu Glu Glu Lys Phe 
35 - # 40 - # 45 
- - Pro Gln Val Ala Ala Thr Gly Asp Gly Pro As - #p Ile Ile Phe Trp Ala 
50 - # 55 - # 60 
- - His Asp Arg Phe Gly Gly Tyr Ala Gln Ser Gl - #y Leu Leu Ala Glu Ile 
65 - #70 - #75 - #80 
- - Thr Pro Asp Lys Ala Phe Gln Asp Lys Leu Ty - #r Pro Phe Thr Trp Asp 
85 - # 90 - # 95 
- - Ala Val Arg Tyr Asn Gly Lys Leu Ile Ala Ty - #r Pro Ile Ala Val Glu 
100 - # 105 - # 110 
- - Ala Leu Ser Leu Ile Tyr Asn Lys Asp Leu Le - #u Pro Asn Pro Pro Lys 
115 - # 120 - # 125 
- - Thr Trp Glu Glu Ile Pro Ala Leu Asp Lys Gl - #u Leu Lys Ala Lys Gly 
130 - # 135 - # 140 
- - Lys Ser Ala Leu Met Phe Asn Leu Gln Glu Pr - #o Tyr Phe Thr Trp Pro 
145 1 - #50 1 - #55 1 - 
#60 
- - Leu Ile Ala Ala Asp Gly Gly Tyr Ala Phe Ly - #s Tyr Glu Asn Gly 
Lys 
165 - # 170 - # 175 
- - Tyr Asp Ile Lys Asp Val Gly Val Asp Asn Al - #a Gly Ala Lys Ala Gly 
180 - # 185 - # 190 
- - Leu Thr Phe Leu Val Asp Leu Ile Lys Asn Ly - #s His Met Asn Ala Asp 
195 - # 200 - # 205 
- - Thr Asp Tyr Ser Ile Ala Glu Ala Ala Phe As - #n Lys Gly Glu Thr Ala 
210 - # 215 - # 220 
- - Met Thr Ile Asn Gly Pro Trp Ala Trp Ser As - #n Ile Asp Thr Ser Lys 
225 2 - #30 2 - #35 2 - 
#40 
- - Val Asn Tyr Gly Val Thr Val Leu Pro Thr Ph - #e Lys Gly Gln Pro 
Ser 
245 - # 250 - # 255 
- - Lys Pro Phe Val Gly Val Leu Ser Ala Gly Il - #e Asn Ala Ala Ser Pro 
260 - # 265 - # 270 
- - Asn Lys Glu Leu Ala Lys Glu Phe Leu Glu As - #n Tyr Leu Leu Thr Asp 
275 - # 280 - # 285 
- - Glu Gly Leu Glu Ala Val Asn Lys Asp Lys Pr - #o Leu Gly Ala Val Ala 
290 - # 295 - # 300 
- - Leu Lys Ser Tyr Glu Glu Glu Leu Ala Lys As - #p Pro Arg Ile Ala Ala 
305 3 - #10 3 - #15 3 - 
#20 
- - Thr Met Glu Asn Ala Gln Lys Gly Glu Ile Me - #t Pro Asn Ile Pro 
Gln 
325 - # 330 - # 335 
- - Met Ser Ala Phe Trp Tyr Ala Val Arg Thr Al - #a Val Ile Asn Ala Ala 
340 - # 345 - # 350 
- - Ser Gly Arg Gln Thr Val Asp Glu Ala Leu Ly - #s Asp Ala Gln Thr Asn 
355 - # 360 - # 365 
- - Ser Ser Ser Asn Asn Asn Asn Asn Asn Asn As - #n Asn Asn Leu Gly Ile 
370 - # 375 - # 380 
- - Glu Gly Arg Ile Ser Glu Phe Met Gly Arg Gl - #u Ile His Leu Gly Pro 
385 3 - #90 3 - #95 4 - 
#00 
- - Ala Asp Ser Leu Glu Gly Gln Gly Trp Arg Le - #u Leu Ala His Ile 
Thr 
405 - # 410 - # 415 
- - Ala Tyr Ser Gln Gln Thr Arg Gly Leu Leu Gl - #y Cys Ile Ile Thr Ser 
420 - # 425 - # 430 
- - Leu Thr Gly Arg Asp Arg Asn Gln Val Glu Gl - #y Glu Val Gln Met Val 
435 - # 440 - # 445 
- - Ser Thr Ala Thr Gln Ser Phe Leu Ala Thr Cy - #s Val Asn Gly Val Cys 
450 - # 455 - # 460 
- - Trp Thr Val Tyr His Gly Ala Gly Ser Lys Th - #r Leu Ala Gly Pro Lys 
465 4 - #70 4 - #75 4 - 
#80 
- - Gly Pro Ile Thr Gln Met Tyr Thr Asn Val As - #p Gln Asp Leu Val 
Gly 
485 - # 490 - # 495 
- - Trp Gln Ala Pro Pro Gly Ala Arg Ser Leu Th - #r Pro Cys Thr Cys Gly 
500 - # 505 - # 510 
- - Ser Ser Asp Leu Tyr Leu Val Thr Arg His Al - #a Asp Val Ile Pro Val 
515 - # 520 - # 525 
- - Arg Arg Arg Gly Asp Ser Arg Gly Ser Leu Le - #u Ser Pro Arg Pro Val 
530 - # 535 - # 540 
- - Ser Tyr Leu Lys Gly Ser Ser Gly Gly Pro Le - #u Leu Cys Pro Ser Gly 
545 5 - #50 5 - #55 5 - 
#60 
- - His Ala Val Gly Ile Phe Arg Ala Ala Val Cy - #s Thr Arg Gly Val 
Ala 
565 - # 570 - # 575 
- - Lys Ala Val Asp Phe Val Pro Val Glu Ser Me - #t Glu Thr Thr Met Arg 
580 - # 585 - # 590 
- - Ser Pro Val Phe Thr Asp Asn Ser Ser Pro Pr - #o Ala Val Cys Met Gly 
595 - # 600 - # 605 
- - Gly Gly Gly Gly Gly Gly Gly Gly Gly Gly Gl - #y Ser Met Ser Thr Trp 
610 - # 615 - # 620 
- - Val Leu Val Gly Gly Val Leu Ala Ala Leu Al - #a Ala Tyr Cys Leu Thr 
625 6 - #30 6 - #35 6 - 
#40 
- - Thr Gly Ser Val Val Ile Val Gly Arg Ile Va - #l Leu Ser Gly Lys 
Pro 
645 - # 650 - # 655 
- - Ala Ile Ile Pro Asp Arg Glu Val Leu Tyr Ar - #g Glu Phe Asp Glu Met 
660 - # 665 - # 670 
- - Glu Glu Cys 
675 
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