Matrix metalloprotease inhibitors

Compounds of formula (I): ##STR1## as single stereoisomers or mixtures thereof and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as interstitial collagenases, and are useful in the treatment of mammals having disease states alleviated by the inhibition of such matrix metalloproteases, for example arthritic diseases or bone resorption diseases, such as osteoporosis.

FIELD OF THE INVENTION 
The present invention is directed to compounds and their pharmaceutically 
acceptable salts, which inhibit matrix metalloproteases, particularly 
interstitial collagenases, and are therefore useful in the treatment of 
mammals having disease states alleviated by the inhibition of such matrix 
metalloproteases. 
BACKGROUND OF THE INVENTION 
Matrix metalloproteases are a family of proteases responsible for 
degradation and remodeling of connective tissues. Members of this family 
of enzymes share a number of properties, including zinc and calcium 
dependence, secretion as zymogens, and 40-50% amino acid sequence 
homology. 
The matrix metalloprotease family includes interstitial collagenases, 
derived from fibroblasts/macrophages and neutrophils, which catalyze the 
initial and rate-limiting cleavage of native collagen types I, II, III and 
X. 
Collagen, the major structural protein of mammals, is an essential 
component of the matrix of many tissues, for example, cartilage, bone, 
tendon and skin. Interstitial collagenases are very specific matrix 
metalloproteases which cleave collagen to give two fragments which 
spontaneously denature at physiological temperatures and therefore become 
susceptible to cleavage by less specific enzymes. As cleavage by the 
collagenase results in the loss of structural integrity of the target 
tissue, it is essentially an irreversible process and therefore a good 
target for therapeutic intervention. 
In addition to interstitial collagenases, the matrix metalloprotease family 
of enzymes include two distinct, but highly related, gelatinases: a 72-kDa 
enzyme secreted by fibroblasts and a 92-kDa enzyme released by mononuclear 
phagocytes. These gelatinases are capable of degrading gelatins (denatured 
collagens), native collagen types IV and V, fibronectin and insoluble 
elastin. 
The matrix metalloprotease family also includes stromelysins 1 and 2, which 
are capable of cleaving a broad range of matrix substrates, including 
laminin, fibronectin, proteoglycans and collagen types IV and IX in their 
non-helical domains. 
Matrilysin (putative metalloprotease or PUMP) is a recently described 
member of the matrix metalloprotease family. Matrilysin is capable of 
degrading a wide range of matrix substrates including proteoglycans, 
gelatins, fibronectin, elastin, and laminin. Its expression has been 
documented in mononuclear phagocytes, rat uterine explants and 
sporadically in tumors. 
Inhibitors of matrix metalloproteases are considered to provide useful 
treatments for arthritic diseases, bone resorption disease (such as 
osteoporosis), the enhanced collagen destruction associated with diabetes, 
periodontal disease, corneal ulceration, ulceration of the skin, and tumor 
metastasis. For example, the design and potential use of collagenase 
inhibitors is described in J. Enzyme Inhibition (1987), Vol. 2, pp. 1-22, 
and in Drug News & Prospectives (1990), Vol. 3, No. 8, pp. 453-458. Matrix 
metalloprotease inhibitors are also the subject of various patents and 
patent applications, for example, U.S. Pat. Nos. 5,189,178 (Galardy) and 
5,183,900 (Galardy), European Published Patent Applications 0 438 223 
(Beecham) and 0 276 436 (F. Hoffmann-La Roche), Patent Cooperation Treaty 
International Applications 92/21360 (Merck), 92/06966 (Beecham) and 
92/09563 (Glycomed). 
SUMMARY OF THE INVENTION 
The invention provides new compounds which are useful as inhibitors of 
matrix metalloproteases, particularly interstitial collagenases, and which 
are effective in treating disease states characterized by excessive 
activity of matrix metalloproteases. 
Accordingly, one aspect of the invention is directed to compounds of 
formula (I) as a single stereoisomer or as a mixture of stereoisomers: 
##STR2## 
wherein: m is 2, 3, 4, 5, or 6; and 
n is 0, 1, 2, 3, or 4; such that: 
when m is 2, 3 or 4; n is 1, 2, 3, or 4; and 
A is --CH.sub.2 --, --O--, or --N(R.sup.11)--, where R.sup.11 is hydrogen 
or alkyl; 
R.sup.1 is 
a) --CH.sub.2 --R.sup.4 where R.sup.4 is mercapto, acetylthio, carboxy, 
aminocarbonyl, N-hydroxyformylamino, alkoxycarbonyl, aryloxycarbonyl, 
aralkoxycarbonyl, benzyloxyaminocarbonyl, or 
##STR3## 
in which R.sup.6 is optionally substituted aryl, wherein the aryl group 
is quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl; 
b) --CH(R.sup.7)--R.sup.8 where R.sup.7 is alkyl, hydroxy, amino, 
alkylamino, arylamino, alkylsulphonylamino, aralkylsulphonylamino, 
alkoxycarbonyl, aminocarbonyl, aralkyl or carboxy; or R.sup.7 is 
--CH.sub.2 NHR, where R is hydrogen, alkyl, aryl, 2-benzoxazole, 
--SO.sub.2 R.sup.a, --SO.sub.2 NHR.sup.a, --SO.sub.2 OR.sup.a, 
--C(O)R.sup.a --C(O)NHR.sup.a, --C(O)OR.sup.a, where R.sup.a is alkyl, 
trifluoromethyl, aryl, aralkyl, aralkenyl or arylcarbonylaminoalkylaryl; 
and R.sup.8 is carboxy, hydroxyaminocarbonyl, alkoxycarbonyl or 
aralkoxycarbonyl; or 
c) --NH--CH(R.sup.9)--R.sup.10 where R.sup.9 is hydrogen, alkyl or aralkyl, 
and R.sup.10 is carboxy, alkoxycarbonyl or aralkoxycarbonyl, phosphonyl, 
dialkylphosphonyl, or methoxyphosphonyl; 
R.sup.2 is alkyl, alkenyl, trifluoromethylalkyl, cycloalkyl, 
cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aralkoxyalkyl, aryl, 
aryloxyalkyl or aralkyl; and 
R.sup.3 is hydrogen, hydroxy, halo, alkyl, alkoxy or aralkoxy; 
when n is 0; m is 4, 5 or 6; and 
A is --CH(R.sup.12)-- where R.sup.12 is carboxy, alkoxycarbonyl or 
optionally substituted carbamoyl; and 
R.sup.1, R.sup.2 and R.sup.3 are as defined above; 
or a pharmaceutically acceptable salt thereof. 
Another aspect of the invention is directed to methods of inhibiting matrix 
metalloprotease activity in a mammal, which methods comprise administering 
to the mammal in need thereof a therapeutically effective amount of a 
compound of formula (I), or a pharmaceutically acceptable salt thereof. 
Another aspect of the invention is directed to pharmaceutical compositions 
useful in inhibiting matrix metalloprotease activity in a mammal, which 
composition comprises a therapeutically effective amount of a compound of 
formula (I), or a pharmaceutically acceptable salt thereof; and a 
pharmaceutically acceptable excipient. 
A further aspect of the invention relates to the methods of preparation for 
a compound of formula (I). 
DETAILED DESCRIPTION OF THE INVENTION 
Definitions 
As used in the specification and appended claims, unless specified to the 
contrary, the following terms have the meaning indicated: 
"BOC" refers to t-butoxycarbonyl. 
"CBZ" refers to benzyloxycarbonyl (carbobenzyloxy). 
"DMF" refers to N,N-dimethylformamide. 
"EDCI" refers to N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide. 
"HOBT" refers to 1-hydroxybenzotriazole. 
"EtOAc" refers to ethyl acetate. 
"THF" refers to tetrahydrofuran. 
"DCC" refers to 1,3-dicyclohexyl carbodiimide. 
"DMAP" refers to 4-dimethylaminopyridine. 
"Pht" refers to phthalimide. 
"Acetylthio" refers to the radical --SC(O)CH.sub.3. 
"Halo" refers to bromo, chloro or fluoro. 
"Alkyl" refers to a straight or branched chain monovalent radical 
consisting solely of carbon and hydrogen, having from one to six carbon 
atoms and containing no unsaturation, e.g., methyl, ethyl, n-propyl, 
2-methylpropyl (iso-butyl), 1-methylethyl (iso-propyl), 1,1-dimethylethyl 
(t-butyl), and the like. 
"Alkenyl" refers to a straight or branched chain radical containing at 
least one unsaturated bond, e.g., ethenyl, pent-4-enyl and the like. 
"Lower alkyl" refers to a straight or branched chain containing one to four 
carbon atoms. 
"Alkylamino" refers to a radical of the formula --NHR.sub.a wherein R.sub.a 
is alkyl as defined above, e.g. methylamino, ethylamino, n-propylamino, 
and the like. 
"Alkylene" as used herein means a branched or unbranched saturated divalent 
hydrocarbon radical containing 1 to 6 carbon atoms, such as methylene, 
ethylene, propylene, 2-methylpropylene, 1,2-dimethylpropylene, hexylene, 
and the like. 
"Alkoxy" refers to a radical of the formula --OR.sub.a wherein R.sub.a is 
alkyl as defined above, e.g., methoxy, ethoxy, n-propoxy, i-propoxy, 
1-methylethoxy, n-butoxy, t-butoxy, and the like which is optionally 
substituted with hydroxy, alkoxy, aryl, amino, alkylamino, dialkylamino, 
dialkylaminocarbonyl or N-methylpiperidin-3-yl. 
"Aminocarbonyl" refers to a radical of the formula --C(O)--NH.sub.2 where 
the amino group may be optionally substituted with one or two of the 
groups selected from a group consisting of hydroxy, aralkyl, aralkoxy, 
alkylaminoalkyl and dialkylaminoalkyl, such as hydroxyaminocarbonyl. 
"Aryl" refers to a monovalent unsaturated aromatic carbocyclic radical 
having one or two rings, such as phenyl, naphthyl, indanyl or biphenyl, or 
to a monovalent unsaturated aromatic heterocyclic radical such as 
quinolyl, dihydroisoxazolyl, furanyl, imidazolyl, pyridyl, phthalimido, or 
thienyl optionally substituted with aryl as defined herein. Aryl can 
optionally be mono-, di- or tri-substituted independently with halo, 
hydroxy, lower alkyl, alkoxy, trifluoromethyl, aryloxy, amino, aryl, 
acetamido, and/or cyano. e.g., 6-nitroquinol-2-yl, 6-fluoroquinol-2-yl, 
6-hydroxyquinol-2-yl, 6-methoxyquinol-2-yl, 6-nitronaphth-1-yl, 
6-chloronaphth-1-yl, 6-hydroxynaphth-1-yl, 6-methoxynaphth-1-yl, 
6-nitronaphth-2-yl, 6-chloronaphth-2-yl, 6-hydroxynaphth-2-yl, 
6-methoxynaphth-2-yl, 6-nitrophenyl, 6-chlorophenyl, 6-hydroxyphenyl, 
6-methoxyphenyl, biphenyl, 3-methylpyridyl, 4-ethylpyridyl, 
4-chlorophenyl, 4-phenoxyphenyl, 2-pyrrolidin-1-yl-ethoxy-phenyl, 
4-cyanophenyl, naphthalen-2-yl, 4-hydroxy-3-methyl-phenyl and the like. 
"Aryloxy" refers to a radical of the formula --OR.sub.b wherein R.sub.b is 
aryl as defined above, e.g., phenoxy, quinol-2-yloxy, naphth-1-yloxy, or 
naphth-2-yloxy, and the like. 
"Aralkyl" refers to a radical of the formula --R.sub.c R.sub.b wherein 
R.sub.c is alkylene as defined above and R.sub.b is aryl as defined above, 
e.g., benzyl, phenylethylene, 3-phenylpropyl, and the like. 
"Aralkoxy" refers to a radical of the formula --OR.sub.c R.sub.b wherein 
R.sub.c is alkylene as defined above and R.sub.b is aryl as defined above, 
e.g., benzyloxy, 3-naphth-2-ylpropoxy, and the like. 
"Alkoxycarbonyl" refers to a radical of the formula --C(O)OR.sub.b wherein 
R.sub.b is alkyl as defined above, or R.sub.b is a saturated carbocyclic 
ring containing one or more heteroatoms e.g., methoxycarbonyl, 
ethoxycarbonyl, t-butoxycarbonyl, N-methylpiperid-4-yl-oxycarbonyl, and 
the like. 
"Aralkoxycarbonyl" refers to a radical of the formula --C(O)R.sub.d wherein 
R.sub.d is aralkoxy as defined above, e.g., benzyloxycarbonyl, 
naphthyl-2-ylethoxycarbonyl, and the like. 
"Benzyloxyaminocarbonyl refers to the radical of the formula 
--C(O)NHOCH.sub.2 Ph wherein Ph is phenyl. 
"Carbamoyl" refers to the radical --C(O)NH.sub.2. 
"Carboxy" refers to the radical --C(O)OH. 
"Cycloalkyl" refers to a monovalent saturated carbocyclic radical 
containing no unsaturation and having from three to six carbon atoms, e.g. 
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. 
"Cycloalkylalkyl" refers to a radical of the formula --(CH.sub.2).sub.p 
R.sub.c where R.sub.c is cycloalkyl as defined above and p is an integer 
of 1-6, e.g. cyclopentylpropyl, cyclopropylmethyl, cyclobutylmethyl, 
cyclohexylbutyl. 
"Dialkylamino" refers to a radical of the formula --NR.sub.f R.sub.g where 
R.sub.f and R.sub.g are independently alkyl as defined above or R.sub.f 
and R.sub.g together form a ring, for example, morpholinyl, piperidinyl or 
pyrrolindinyl, and the like. 
"Hydroxyamino" refers to the radical --NHOH. 
"Hydroxyaminocarbonyl" refers to the radical --C(O)NHOH. 
"N-hydroxyformylamino" refers to the radical --N(OH)C(O)H. 
"Mercapto" refers to the radical --SH. 
"Sulfonyl" refers to the radical .dbd.S(O).sub.2 
"Phosphonyl" refers to the radical --PO(OH).sub.2 
"Optional" or "optionally" means that the subsequently described event of 
circumstances may or may not occur, and that the description includes 
instances where said event or circumstance occurs and instances in which 
it does not. For example, "optionally substituted quinol-2-yl" means that 
the quinol-2-yl radical may or may not be substituted and that the 
description includes both substituted quinol-2-yl radicals and quinol-2-yl 
radicals having no substitution. 
"Optionally substituted carbamoyl" refers to a carbamoyl radical optionally 
substituted on the nitrogen atom by one or more substituents selected from 
the group consisting of alkyl, mono- and di-alkylaminoalkyl, and aralkyl. 
"Amino-protecting group" as used herein refers to those organic groups 
intended to protect nitrogen atoms against undesirable reactions during 
synthetic procedures, and includes, but is not limited to, benzyl, acyl, 
acetyl, benzyloxycarbonyl (carbobenzyloxy), p-methoxybenzyloxycarbonyl, 
p-nitrobenzyloxycarbonyl, t-butoxycarbonyl, and the like. 
"Pharmaceutically acceptable salt" includes both pharmaceutically 
acceptable acid and base addition salts. 
"Pharmaceutically acceptable acid addition salt" refers to those salts 
which retain the biological effectiveness and properties of the free 
bases, which are not biologically or otherwise undesirable, and which are 
formed with inorganic acids such as hydrochloric acid, hydrobromic acid, 
sulfuric acid, nitric acid, phosphoric acid and the like, and organic 
acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, 
oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, 
tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, 
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, 
salicylic acid, and the like. 
"Pharmaceutically acceptable base addition salt" refers to those salts 
which retain the biological effectiveness and properties of the free 
acids, which are not biologically or otherwise undesirable. These salts 
are prepared from addition of an inorganic base or an organic base to the 
free acid. Salts derived from inorganic bases include, but are not limited 
to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, 
zinc, copper, manganese, aluminum salts and the like. Preferred inorganic 
salts are the ammonium, sodium, potassium, calcium, and magnesium salts. 
Salts derived from organic bases include, but are not limited to, salts of 
primary, secondary, and tertiary amines, substituted amines including 
naturally occurring substituted amines, cyclic amines and basic ion 
exchange resins, such as isopropylamine, trimethylamine, diethylamine, 
triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 
2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, 
histidine, caffeine, procaine, hydrabamine, choline, betaine, 
ethylenediamine, glucosamine, methylglucamine, theobromine, purines, 
piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like 
Particularly preferred organic bases are isopropylamine, diethylamine, 
ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. 
"Mammal" includes humans and all domestic and wild animals, including, 
without limitation, cattle, horses, swine, sheep, goats, dogs, cats, and 
the like. 
"Therapeutically effective amount" refers to that amount of a compound of 
formula (I) which, when administered to a mammal in need thereof, is 
sufficient to effect treatment, as defined below, for disease-states 
alleviated by the inhibition of matrix metalloprotease activity, 
particularly interstitial collagenase activity. The amount of a compound 
of formula (I) which constitutes a "therapeutically effective amount" will 
vary depending on the compound, the disease-state and its severity, and 
the mammal to be treated, but can be determined routinely by one of 
ordinary skill in the art having regard to his own knowledge and to this 
disclosure. 
"Treating" or "treatment" as used herein cover the treatment of a disease 
state in a mammal, particularly in a human, which disease state is 
alleviated by the inhibition of matrix metalloprotease activity, 
particularly interstitial collagenase activity, and the like; and include: 
(i) preventing the disease-state from occurring in a mammal, in particular, 
when such mammal is predisposed to the disease state but has not yet been 
diagnosed as having it; 
(ii) inhibiting the disease-state, i.e., arresting its development; or 
(iii) relieving the disease-state, i.e., causing regression of the disease 
state. 
"Isomers" are different compounds that have the same molecular formula. 
"Stereoisomers" are isomers that differ only in the way the atoms are 
arranged in space. 
"Enantiomers" are a pair of stereoisomers that are non-superimposable 
mirror images of each other. A 1:1 mixture of a pair of enantiomers is a 
"racemic" mixture. 
"Diastereoisomers" are stereoisomers which are not mirror-images of each 
other. 
The nomenclature used herein is basically a modified form of I.U.P.A.C. 
nomenclature wherein compounds of the invention are named as derivatives 
of phosphinic or alkanoic acids having a tricylo substituent. The 
compounds of formula (I) have at least two asymmetric carbon atoms in 
their structure; i.e. at the point of attachment of the R.sup.2 
substituent and the indolylmethyl group. The compounds of formula (I) and 
their pharmaceutically acceptable salts may therefore exist as single 
enantiomers, racemates, diastereoisomers, and as mixtures of enantiomers 
and diastereomers. All such single stereoisomers, racemates, 
diasteroisomers, and mixtures thereof, are intended to be within the scope 
of this invention. 
When naming the single stereoisomers of compounds of formula (I) an 
absolute descriptor, R or S, may be assigned to the chiral carbon atoms 
therein according to the "Sequence Rule" procedure of Cahn, Ingold and 
Prelog. 
For example, the following compound of formula (I) wherein n is 2; m is 3; 
A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
--C(O)NHOH; R.sup.2 is 2-methylpropyl and R.sup.3 is hydrogen, i.e., the 
compound of the following formula: 
##STR4## 
is named herein as 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide. 
Another example is the following compound of formula (I) wherein m is 2; n 
is 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
carboxy; R.sup.2 is 3-(4-pyridinyl)-propyl; and R.sup.3 is hydrogen, i.e., 
the compound of the following formula: 
##STR5## 
which is named (3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic 
acid. 
Utility and Administration 
A. Utility 
The compounds of formula (I) are useful in inhibiting mammalian matrix 
metalloproteases, particularly mammalian interstitial collagenases, 
thereby preventing the degradation of collagen within the mammal. The 
compounds are therefore useful in treating disease states which are 
associated with increased activity of matrix metalloproteases, 
particularly increased activity of interstitial collagenase, such as 
arthritis and osteoarthritis, tumor metastasis, periodontal disease and 
corneal ulcerations. See, e.g., Arthritis and Rheumatism (1993), Vol. 36, 
No. 2, pp. 181-189; Arthritis and Rheumatism (1991), Vol. 34, No. 9, pp. 
1073-1075; Seminars in Arthritis and Rheumatism (1990), Vol. 19, No. 4, 
Supplement 1 (February), pp. 16-20; Drugs of the Future (1990), Vol. 15, 
No. 5, pp. 495-508; and J. Enzyme Inhibition (1987), Vol. 2, pp. 1-22. 
B. Testing 
The ability of the compounds of formula (I) to inhibit matrix 
metalloprotease activity, particularly interstitial collagenase activity, 
may be demonstrated by a variety of in vitro and ex vivo assays known to 
those of ordinary skill in the art. For example, the activity of the 
individual metalloprotease may be demonstrated in the in vitro assay 
described in Anal. Biochem. (1985), Vol. 147, p. 437, or modifications 
thereof. Physiological effects of the inhibition of matrix 
metalloproteases may be demonstrated by the ex vivo bovine cartilage 
explant assay described in Methods of Enzymology (1987), Vol. 144, pp. 
412-419, or modifications thereof; or by the ex vivo rat fetal long bone 
assay described in Proc. Natl. Acad. Sci. USA (1988), Vol. 85, pp. 
8761-8765, or modifications thereof, or in J. Clin. Invest. (1965), Vol. 
44, pp. 103-116, or modifications thereof. 
The ability to inhibit activity of collagenase-1, -2 and -3, stromelysin-1, 
gelatinases A an B, and matrilysin may be demonstrated by the assays as 
described in the MMP Enzymatic Assay in FEBS, 296, 263 (1992) or 
modifications thereof. The ability of the compounds of formula (I) to 
inhibit MMP mediated processes in vivo may be tested using the 
interleukin-1 stimulated cartilage explant assay and cartilage plug 
implantation assay. 
C. General Administration 
Administration of the compounds of formula (I), or their pharmaceutically 
acceptable salts, in pure form or in an appropriate pharmaceutical 
composition, can be carried out via any of the accepted modes of 
administration or agents for serving similar utilities. Thus, 
administration can be, for example, orally, nasally, parenterally, 
topically, transdermally, or rectally, in the form of solid, semi-solid, 
lyophilized powder, or liquid dosage forms, such as for example, tablets, 
suppositories, pills, soft elastic and hard gelatin capsules, powders, 
solutions, suspensions, or aerosols, or the like, preferably in unit 
dosage forms suitable for simple administration of precise dosages. The 
compositions will include a conventional pharmaceutical carrier or 
excipient and a compound of formula (I) as the/an active agent, and, in 
addition, may include other medicinal agents, pharmaceutical agents, 
carriers, adjuvants, etc. 
Generally, depending on the intended mode of administration, the 
pharmaceutically acceptable compositions will contain about 1% to about 
99% by weight of a compound(s) of formula (I), or a pharmaceutically 
acceptable salt thereof, and 99% to 1% by weight of a suitable 
pharmaceutical excipient. Preferably, the composition will be about 5% to 
75% by weight of a compound(s) of formula (I), or a pharmaceutically 
acceptable salt thereof, with the rest being suitable pharmaceutical 
excipients. 
The preferred route of administration is oral, using a convenient daily 
dosage regimen which can be adjusted according to the degree of severity 
of the disease-state to be treated. For such oral administration, a 
pharmaceutically acceptable composition containing a compound(s) of 
formula (I), or a pharmaceutically acceptable salt thereof, is formed by 
the incorporation of any of the normally employed excipients, such as, for 
example, pharmaceutical grades of mannitol, lactose, starch, 
pregelatinized starch, magnesium stearate, sodium saccharine, talcum, 
cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl 
gallate, and the like. Such compositions take the form of solutions, 
suspensions, tablets, pills, capsules, powders, sustained release 
formulations and the like. 
Preferably such compositions will take the form of capsule, caplet or 
tablet and therefore will also contain a diluent such as lactose, sucrose, 
dicalcium phosphate, and the like; a disintegrant such as croscarmellose 
sodium or derivatives thereof; a lubricant such as magnesium stearate and 
the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, 
gelatin, cellulose ether derivatives, and the like. 
The compounds of formula (I), or their pharmaceutically acceptable salts, 
may also be formulated into a suppository using, for example, about 0.5% 
to about 50% active ingredient disposed in a carrier that slowly dissolves 
within the body, e.g., polyoxyethylene glycols and polyethylene glycols 
(PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%). 
Liquid pharmaceutically administrable compositions can, for example, be 
prepared by dissolving, dispersing, etc., a compound(s) of formula (I) 
(about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, 
and optional pharmaceutical adjuvants in a carrier, such as, for example, 
water, saline, aqueous dextrose, glycerol, ethanol and the like, to 
thereby form a solution or suspension. 
If desired, a pharmaceutical composition of the invention may also contain 
minor amounts of auxiliary substances such as wetting or emulsifying 
agents, pH buffering agents, antioxidants, and the like, such as, for 
example, citric acid, sorbitan monolaurate, triethanolamine oleate, 
butylated hydroxytoluene, etc. 
Actual methods of preparing such dosage forms are known, or will be 
apparent, to those skilled in this art; for example, see Remington's 
Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 
1990). The composition to be administered will, in any event, contain a 
therapeutically effective amount of a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, for treatment of a disease-state 
alleviated by the inhibition of matrix metalloprotease in accordance with 
the teachings of this invention. 
The compounds of formula (I), or their pharmaceutically acceptable salts, 
are administered in a therapeutically effective amount which will vary 
depending upon a variety of factors including the activity of the specific 
compound employed, the metabolic stability and length of action of the 
compound, the age, body weight, general health, sex, diet, mode and time 
of administration, rate of excretion, drug combination, the severity of 
the particular disease-state, and the host undergoing therapy. Generally, 
a therapeutically effective daily dose is from about 0.14 mg to about 14.3 
mg/kg of body weight per day of a compound of formula (I), or a 
pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to 
about 10 mg/kg of body weight per day; and most preferably, from about 1.4 
mg to about 7.2 mg/kg of body weight per day. For example, for 
administration to a 70 kg person, the dosage range would be from about 10 
mg to about 1.0 gram per day of a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, preferably from about 50 mg to 
about 700 mg per day, and most preferably from about 100 mg to about 500 
mg per day. 
PREFERRED EMBODIMENTS 
One preferred class of the compounds of formula (I) are those where n is 1, 
2 or 3, m is 3, and A is --CH.sub.2 --. 
A preferred subclass of compounds of this class are those compounds where n 
is 1 or 2, where R.sup.1 is --CH.sub.2 --R.sup.4 and R.sup.3 is hydrogen, 
especially where R.sup.2 is 2-methylpropyl, biphenylpropyl, 
thien-2-yl-ethyl, cyclopentyl, cyclopropylmethyl, or cyclopentylmethyl; 
and R.sup.4 is acetylthio, mercapto, carboxy, alkoxycarbonyl, 
N-hydroxyaminocarbonyl, or N-hydroxyformylamino. 
A preferred subgroup of compounds of this group are those compounds wherein 
R.sup.2 is 2-methylpropyl or cyclopentylmethyl, and R.sup.4 is acetylthio, 
mercapto, carboxy, N-hydroxyaminocarbonyl, or N-hydroxyformylamino. 
Another preferred subgroup included those compounds wherein R.sup.1 is 
##STR6## 
where R.sup.6 is optionally substituted aryl, wherein the aryl group is 
quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl. A preferred 
subclass of compounds of this class are those compounds wherein R.sup.6 is 
quinol-2-yl. 
Another preferred subgroup of compounds are those compounds wherein R.sup.1 
is --CH(R.sup.7)--R.sup.8 where R.sup.7 is --CH.sub.2 NHR, especially 
where R is hydrogen, R.sup.2 is 2-methylpropyl or cyclopentylmethyl, 
R.sup.3 is hydrogen, and R.sup.8 is carboxy. Particularly preferred are 
those compounds where R is methoxycarbonyl, methanesulfonyl, or 
ethylureido. 
Another preferred subgroup of compounds are those compounds wherein R.sup.1 
is --CH(R.sup.7)--R.sup.8 where R.sup.7 is alkyl, alkoxycarbonyl or 
carboxy; and R.sup.2 is 2-methylpropyl or cyclopentylmethyl; R.sup.3 is 
hydrogen; and R.sup.8 is carboxy or hydroxyaminocarbonyl. Particularly 
preferred are those compounds wherein R.sup.7 is methoxycarbonyl. 
Another preferred subgroup of compounds are those compounds wherein R.sup.1 
is --NH--CH(R.sup.9)--R.sup.10 where R.sup.9 is hydrogen, alkyl or 
aralkyl; and R.sup.10 is carboxy, alkoxycarbonyl or aralkoxycarbonyl. 
Another preferred class of compounds are those compounds wherein n is 2 or 
3; m is 4; A is --N(R.sup.11)-- where R.sup.11 is hydrogen or alkyl; 
R.sup.2 is alkyl; and R.sup.3 is hydrogen. A preferred subclass of 
compounds of this class are those compounds wherein n is 2, R.sup.2 is 
2-methylpropyl, and R.sup.11 is methyl. 
Another preferred class of compounds are those compounds wherein m and n 
are both 2; A is oxygen; R.sup.4 is carboxy or hydroxyaminocarbonyl; and 
R.sup.2 is aryl, aralkyl or aralkoxyalkyl. 
Presently, the most preferred compounds of formula (I) are the following: 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide; 
(3R,9S)-N-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; 
(3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid; 
(3R,9S)-4-cyclopentyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(3R,9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid and its 
methyl or ethyl ester; 
(3R,9S)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexano 
ic acid; 
(3R,9S)-4-(3-methoxy-4,5(R,S)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatric 
yclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-butanoic acid; 
(3R,9S)-4-(3-hydroxy-4,5(R,S)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatric 
yclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-butanoic acid; 
(3R,9S)-4-(3-bromo-4,5(R,S)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatricyc 
lo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-butanoic acid; 
(2S,3R,9S)-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!-octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(2R,3R,9S)-2-(ethoxycarbonylamino-methyl-5-methyl-3-(8-oxo-1,7-diazatricycl 
o9.6.1.0.sup.12,17 
!-octdeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(2R,3R,9S)-2-(methanesulfonamidomethyl)-4-cyclopentyl-3-(8-oxo-1,7-diazatri 
cyclo9.6.1.0.sup.12,17 !octadeca-11 (18),12(17) 
13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13 
,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)pentanamide; 
(10S)-4-methyl-2-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)pentyl(quinolin-2-ylt 
hiomethyl)phosphinic acid; 
(10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup. 
13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)pentanamide; 
(3R,10S)-N-hydroxy-5-methyl-2-methoxycarbonyl-3-(9-oxo-1,8-diazatricyclo-1 
0.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14, 
16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid ethyl 
ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
1-(2-dimethylaminoethyl)amide; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
1-methylpiperidin-4-yl ester; 
(3R,10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)propionic acid; 
(3R,10S)-4-cyclopropyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; 
(3R,10S)-6-(biphenyl-4-yl)-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!-nonadeca12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 !nonadeca-12 
(19),13(18),14,16-tetraen-10-ylcarbamoyl)-5-(thiophen-2-yl)pentanoic acid; 
(3R,10S)-2-(aminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup. 
13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-N-hydroxy-N-formylamino-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1 
.0.sup.13,18 !nonadeca12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid; 
(3R,10S)-2-(methoxycarbonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-6-pyridin-4-yl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(methanesulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo1 
0.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(3-ethylureidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1 
.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid; 
(3RS,10S)-N-hydroxy-N-formyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.s 
up.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexylamine; 
(2S,3R,9S)-N-hydroxy-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0. 
sup.12,17 !octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; 
(3R,9S)-5-methyl-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-3-cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12 
,17 !octadeca-11(18),12,14,16-tetraen-9-yl)succinamic acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid; 
(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-pentanoic acid; 
(3R,9S)-5-(4-chloro-phenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-pentanoic acid ethyl 
ester; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid 
ethyl ester; 
(3R,9S)-6-(4-hydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R.9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic 
acid; 
(3R,9S)-6-4-(3-hydroxy-propoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazotricyclo9 
.6.1.0 12l!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-5-(4-phenoxy-phenyl)-pent 
anoic acid; 
(3R,9S)-6-4-(2-hydroxy-ethoxy)-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9. 
6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-4-(2-pyrrolidin-1-yl-e 
thoxy)-phenyl!-hexanoic acid; 
(3R,9S)-6-(4-methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-6-4-(2-methoxy-ethoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazatricyclo9. 
6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-5-phenyl-pentanoic acid; 
(3R,9S)-3-(-oxo-4-oxa-1,7-diaza-tricyclo 9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-phenyl-hexanoic acid; 
(3R,9S)-6-(3-hydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-4-(3-piperidin-1-yl-pr 
opoxy)-phenyl!-hexanoic acid; 
(3R,9S)-6-4-(3-dimethylamino-propoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazatric 
yclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-6-4-(2-dimethylamino-ethoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazatricy 
clo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-6-(4-cyano-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-6-naphthalen-2-yl-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12,1 
7 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-(4-pyrrol-1-yl-phenyl)- 
hexanoic acid; 
(3R,9S)-6-(4-hydroxy-3-methyl-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6. 
1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid; 
(3R,9S)-6-(4-benzyloxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup 
.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-6-4-(4-aminobutoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1. 
0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-5-(4-methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-pentanoic acid; 
(3R,9S)-6-(4-amino-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-4-(pyridin-4-ylmethoxy 
)-phenyl!-hexanoic acid; 
(3R,9S)-6-(4-acetylamino-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.s 
up.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid; 
and 
(3R,9S)-6-4-(3-hydroxy-propoxy)-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9 
.6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid ethyl ester. 
Preparation of Compounds of Formula (I) 
Compounds of formula (I) are peptide derivatives which can be prepared from 
the constituent a-amino acid derivative. Standard methods for the 
formation of peptide bonds are further illustrated by M. Bodanszky et al., 
The Practice of Peptide Synthesis (1984), Springer-Verlag; M. Bodanszky, 
Principles of Peptide Synthesis (1984), Springer-Verlag; J. P. Greenstein 
et al., Chemistry of the Amino Acids (1961), Vol. 1-3, John Wiley and Sons 
Inc.; G. R. Pettit, Synthetic Peptides (1970), Vol. 1-2, Van Nostrand 
Reinhold Company. 
Amide couplings used to form the compounds of formula (I) are generally 
performed by the carbodiimide method with reagents such as 
dicyclohexylcarbodiimide or 
N'-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide (EDCI) in the presence of 
1-hydroxybenzotriazole (HOBT) in an inert solvent such as 
dimethylformamide (DMF). Other methods of forming the amide or peptide 
bond include, but not limited to synthetic routes via an acid chloride, 
acyl azide, mixed anhydride or activated ester such as nitrophenyl ester. 
Typically, solution phase amide couplings with or without peptide 
fragments are performed. 
The selection of protecting groups for the terminal amino or carboxy groups 
of compounds used in the preparation of the compounds of formula (I) is 
dictated in part by the particular amide or peptide coupling conditions, 
and in part by the amino acid and/or peptide components involved in the 
coupling. Amino-protecting groups commonly used include those which are 
well-known in the art, for example, benzyloxycarbonyl (carbobenzyloxy), 
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl 
(BOC), and the like. It is preferred to use either BOC or 
benzyloxycarbonyl (CBZ) as the protecting group for the a-amino group 
because of the relative ease of its removal by mild acids, e.g., by 
trifluoroacetic acid (TFA) or hydrochloric acid in ethyl acetate; or by 
catalytic hydrogenation. 
The individual stereoisomers of compounds of formula (I) may be separated 
from each other by methods known to those of ordinary skill in the art, 
e.g., where R.sup.1 is carboxy, by separation (e.g. fractional 
crystallization, chromatography, and/or by the methods disclosed herein) 
of the diastereomeric salts formed by the reaction of a compound of 
formula (I) with an optically active base, at temperatures between 
0.degree. C. and the reflux temperature of the solvent employed for 
fractional crystallization. Exemplary of such optically active bases are 
brucine, strychnine, quinine, quinidine, cinchonidine, ephedrine, 
.alpha.-methylbenzylamine, and the like. 
Combinations of substituents and/or variables in the compounds of formula 
(I) are permissible only if such combinations result in stable compounds. 
A. Preparation of Intermediates: Compounds of Formula (J) 
Compounds of formula (J): 
##STR7## 
where R.sup.3 is as defined in the Summary of the Invention, and p is 5, 
6, 7 or 8, are useful for the preparation of compounds of formula (I). 
Compounds of formula (J) are prepared as shown in Reaction Scheme 1 below; 
R.sup.3 and p are as defined, BOC is t-butoxycarbonyl, and R.sup.13 is 
hydrogen, mesyl or tosyl. 
##STR8## 
Compounds of formulae (B) and (F) are commercially available, e.g., from 
Karl Industries, Inc. or Sigma, respectively, or may be prepared by 
methods known to those skilled in the art. 
In general, compounds of formula (J) are prepared by first esterifying an 
alcohol of formula (B) with acetic anhydride in the presence of a base, 
preferably pyridine, to form a compound of formula (C), which is then 
reduced in the presence of acetic anhydride to form a compound of formula 
(D). The compound of formula (D) is hydrolyzed under acidic conditions, 
preferably hydrochloric acid, to form a compound of formula (E), which is 
then coupled with a compound of formula (F) under standard peptide 
coupling conditions, for example, with EDCI in the presence of HOBT in 
DMF, to form a compound of formula (G) wherein R.sup.13 is hydroxy. This 
compound may then be treated with either tosyl chloride or mesyl chloride 
to form a compound of formula (G) wherein R.sup.13 is mesyl or tosyl. 
Cyclization of the tosylates so formed with an excess of NaH in an inert 
solvent, preferably THF, under high dilution at room temperature yields 
the compounds of formula (H). Alternatively, the cyclization of the 
tosylates so formed with concentrated sodium hydroxide in an inert 
solvent, preferably CH.sub.2 Cl.sub.2, in the presence of a phase transfer 
catalyst, preferably tetra(n-butyl)ammonium hydrogen sulfate, yields the 
compound of formula (H). The protecting group on the compounds of formula 
(H) is removed under mild acidic conditions, preferably in the presence of 
trifluoroacetic acid, to yield compounds of formula (J). 
B. Preparation of Compounds of Formulae (Ia), (Ib), (Ic) and (Id) 
Compounds of formula (Ia) are compounds of formula (I) where n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is alkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention. 
Compounds of formula (Ib) are compounds of formula (I) where n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is carboxy; and R.sup.2 and R.sup.3 are as defined in the Summary 
of the Invention. 
Compounds of formula (Ic) are compounds of formula (I) where n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is benzyloxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined 
in the Summary of the Invention. 
Compounds of formula (Id) are compounds of formula (I) where n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is hydroxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined in 
the Summary of the Invention. 
Compounds of formula (Ia), (Ib), (Ic) and (Id) are prepared as shown in 
Reaction Scheme 2 below, where p is 5, 6, 7 or 8; R.sup.14 is alkyl or 
benzyl; R.sup.7a is hydrogen or alkoxycarbonyl; and R.sup.2 and R.sup.3 
are as defined in the Summary of the Invention. 
##STR9## 
Compounds of formula (K) are prepared by methods described herein or may 
be prepared by methods known to those of ordinary skill in the art. 
In general, compounds of formulae (Ia), (Ib) and (Ic) are prepared by first 
coupling a compound of formula (J) with a compound of formula (K) under 
standard peptide coupling conditions to form a compound of formula (Ia). 
The protecting group in the compound of formula (Ia) is then removed under 
mild acidic conditions to yield a compound of formula (Ib). 
A compound of formula (Ib) is then coupled with O-benzylhydroxylamine under 
standard peptide coupling conditions to yield a compound of formula (Ic). 
The benzyl protecting group in the compound of formula (Ic) is then 
removed under catalytic hydrogenation conditions to yield a compound of 
formula (Id). 
C. Preparation of Compounds of Formula (Ie) and (If) 
Compounds of formula (Ie) are compounds of formula (I) wherein n is 1, 2, 
or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 
where R.sup.4 is acetylthio; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention. 
Compounds of formula (If) are compounds of formula (I) wherein n is 1, 2, 
or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 
where R.sup.4 is mercapto; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention. 
Compounds of formulae (Ie) and (If) are prepared as shown in the following 
Reaction Scheme 3 where R.sup.2 and R.sup.3 are as defined above and p is 
5, 6, 7 or 8: 
##STR10## 
Compounds of formula (M) are commercially available or may be prepared by 
methods known to those skilled in the art. 
In general, compounds of formulae (Ie) and (If) are prepared by first 
coupling a compound of formula (M) with a compound of formula (J) under 
standard peptide coupling conditions to yield a compound of formula (Ie). 
Treatment of compounds of formula (Ie) with concentrated NH.sub.4 OH in 
methanol yields the corresponding compounds of formula (If). 
D. Preparation of Compounds of Formula (K) and Individual Stereoisomers 
Thereof 
Compounds of formula (K): 
##STR11## 
wherein R.sup.14 is alkyl or benzyl and R.sup.7a is hydrogen, 
alkoxycarbonyl, hydroxycarbamoyl, carboxy or optionally substituted 
carbamoyl, are used in the preparation of compounds of formula (I). 
Individual stereoisomers of compounds of formula (K) are used in the 
preparation of the corresponding stereoisomer of compounds of formula (I). 
In particular, compounds of following formula (Ka): 
##STR12## 
wherein R.sup.7a is hydrogen, is a stereoisomer of a compound of formula 
(K) that has an R configuration. Compounds of formula (Ka) are prepared as 
shown in the following Reaction Scheme 4 wherein R.sup.2 is as defined 
above: 
##STR13## 
In a similar manner, but substituting D-(-)-2,10-camphor sultam for 
L-(+)-2,10-camphor sultam, the corresponding individual stereoisomers in 
the S configuration are prepared. 
Compounds of formula (HH) are commercially available or may be prepared 
according to methods known to those of ordinary skill in the art, for 
example, by the method described in Example 11 below. L-(+)-2,10-Camphor 
sultam and D-(-)-2,10-camphor sultam are commercially available, for 
example, from Aldrich. 
In general, compounds of formula (Ka) are prepared by first condensing a 
compound of formula (HH) with L-(+)-2,10-camphor sultam to form a compound 
of formula (N). Using NaHMDS to generate the anion for 1 hour, the 
reaction is quenched with the t-butylbromoacetate to form the 
corresponding ester of formula (Q). The camphor group is then removed 
under basic conditions to yield an individual stereoisomer of a compound 
of formula (Ka) wherein the carbon to which the R.sup.2 substituent is 
attached is in the R configuration. 
Alternatively, compounds of formula (Ka) may be prepared according to the 
following Reaction Scheme 4A. 
##STR14## 
A compound of formula (HH) is first condensed with 
4S-phenylmethyloxazolidinone under standard conditions to give the 
corresponding compound of formula (aa). An approximately equimolar amount 
of sodium hexamethyldisilazide is added to a compound of formula (aa) in 
an inert solvent such as THF. The reaction takes place at -70.degree. C. 
to -95.degree. C., for about 15 minutes. t-Butylbromoacetate is added in 
excess to this mixture and the solution is stirred for about 2 hours at 
-90.degree. C. to -60.degree. C. to yield predominantly a single 
stereoisomer of formula (bb), which is purified by standard organic 
chemistry procedures. The oxazolidinone group of a compound of formula 
(bb) is removed under basic conditions to yield an individual stereoisomer 
of formula (Ka). 
Compounds of formula (Kb): 
##STR15## 
wherein R.sup.7c is alkoxycarbonyl, may be prepared as shown in the 
following Reaction Scheme 5 wherein R.sup.2 and R.sup.7c are as defined 
above: 
##STR16## 
Compounds of formula (R) and (T) are commercially available or may be 
prepared according to methods known to those skilled in the art. 
In general, compounds of formula (Kb) are prepared by first treating a 
compound of formula (R) with isobutene and a catalytic amount of 
concentrated H.sub.2 SO.sub.4 in methylene chloride followed by 
distillation to yield a t-butyl ester of formula (S). The compound of 
formula (S) is then reacted with a compound of formula (T) in the presence 
of potassium t-butoxide to yield the compound of formula (U). Hydrolysis 
of the compound of formula (U) under acidic conditions, preferably with 
trifluoroacetic acid at room temperature, yields the compound of formula 
(Kb) where R.sup.7c is alkoxycarbonyl. 
Compounds of formula (K) where R.sup.7a is carboxy may be prepared from 
compounds of formula (Kb) where R.sup.7c is alkoxycarbonyl by methods 
known to those of ordinary skill in the art, e.g. hydrolysis. 
In addition to the above described methods of preparing isomers of formula 
(K), compounds of formula (K) wherein R.sup.7a is alkyl may be prepared by 
treating a compound of formula (K) wherein R.sup.7a is hydrogen in an 
aprotic solvent, for example, THF, in the presence of NaN(TMS).sub.2 with 
an haloalkane, preferably iodomethane, to yield a compound of formula (K) 
wherein R.sup.7a is alkyl. 
E. Preparation of Compounds of Formula (Ig) 
Compounds of formula (Ig) are compounds of formula (I) wherein n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is 
##STR17## 
in which R.sup.6 is optionally substituted aryl, wherein the aryl group is 
quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl; R.sup.2 is alkyl 
and R.sup.3 is hydrogen. Compounds of formula (Ig) are prepared as shown 
in the following Reaction Scheme 6 wherein p is 5, 6, 7 or 8; R.sup.2, 
R.sup.3 and R.sup.6 are as defined above and R.sup.12a is mesyl or tosyl: 
##STR18## 
where Et represents ethyl. 
Compounds of formula (W) may be prepared according to methods known to 
those of ordinary skill in the art or may be prepared according to the 
method described in Example 19 below. Compounds of formula (Z) are 
commercially available or may be prepared according to methods known to 
those of ordinary skill in the art. 
In general, compounds of formula (Ig) are prepared by first treating a 
compound of formula (W) with formamide to form a compound of formula (X). 
The compound of formula (X) is then treated with tosyl or mesyl chloride 
under basic conditions to form a compound of formula (Y). The compound of 
formula (Y) is then reacted with a salt of a compound of formula (Z) 
(preferably the sodium salt formed from the reaction of the compound of 
formula (Z) with sodium hydride) to form a compound of formula (AA). The 
compound of formula (AA) is then hydrolyzed under basic conditions to form 
a compound of formula (BB). The compound of formula (BB) is then coupled 
with a compound of formula (J) under standard peptide conditions, 
preferably with 1,1'-carbonyldiimidazole, to form a compound of formula 
(Ig). 
F. Preparation of Compounds of Formulae (Ih), (Ii) and (Ij) 
Compounds of formulae (Ih), (Ii) and (Ij) are compounds of formula (Ib), 
formula (Ic) and formula (Id), respectively, as described above in Section 
B, wherein the indole ring is completely saturated. They are prepared as 
shown in the following Reaction Scheme 7 wherein R.sup.2 and R.sup.3 are 
as defined in the Summary of the Invention, R.sup.7a is hydrogen and p is 
5, 6, 7 or 8: 
##STR19## 
In general, compounds of formulae (Ih), (Ii) and (Ij) are prepared by first 
reducing a compound of formula (Ib) under catalytic hydrogenation 
conditions to form a compound of formula (Ih). The compound of formula 
(Ih) is then reacted with O-benzylhydroxylamine under standard peptide 
coupling conditions to yield a compound of formula (Ii). The benzyl 
protecting group is then removed from the compound of formula (Ii) under 
catalytic hydrogenation conditions to yield a compound of formula (Ij). 
G. Preparation of Compounds of Formulae (Ik), (Il), (Im) and (In) 
Compounds of formula (Ik) are compounds of formula (I) with an allylic 
bond, wherein n is 2 or 3; m is 4; A is --NR.sup.11 where R.sup.11 is 
hydrogen or alkyl; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
t-butoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention. 
Compounds of formula (Il) are compounds of formula (I) with an allylic 
bond, wherein n is 2 or 3; m is 4; A is --NR.sup.11 where R.sup.11 is 
hydrogen or alkyl; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
carboxy; and R.sup.2 and R.sup.3 are as defined in the Summary of the 
Invention. 
Compounds of formula (Im) are compounds of formula (I) with an allylic 
bond, wherein n is 2 or 3; m is 4; A is --NR.sup.11 where R.sup.11 is 
hydrogen or alkyl; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
benzyloxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention. 
Compounds of formula (In) are compounds of formula (I) where n is 2 or 3; m 
is 4; A is --NR.sup.11 where R.sup.11 is hydrogen or alkyl; R.sup.1 is 
--CH.sub.2 --R.sup.4 where R.sup.4 is hydroxyaminocarbonyl; and R.sup.2 
and R.sup.3 are as defined in the Summary of the Invention. 
Compounds of formula (Ik), (Il), (Im) and (In) are prepared as shown in the 
following Reaction Scheme 8 where n is 2 or 3; R.sup.2, R.sup.3 and 
R.sup.11 are as defined above; R.sup.14 is alkyl or benzyl; R.sup.7a is 
hydrogen; and BOC is t-butoxycarbonyl: 
##STR20## 
Compounds of formula (F) are prepared by methods known to those of ordinary 
skill in the art or by the methods described herein. 
In general, compounds of formulae (Ik), (Il), (Im) and (In) are prepared by 
first reacting a compound of formula (F) with a diaminealkane or 
mono-alkyl substituted diaminealkane under standard peptide coupling 
conditions, for example, with HOBT and EDCI, in an inert solvent, for 
example, DMF, to form a compound of formula (DD). The compound of formula 
(DD) is then reacted with trans-1,4-dichlorobut-2-ene under basic 
conditions to form a compound of formula (EE). The amino-protecting group 
of the compound of formula (EE) is then removed under mild acidic 
conditions, preferably with trifluoroacetic acid, to form a compound of 
formula (FF). 
The compound of formula (FF) is then coupled with a compound of formula (K) 
under standard peptide coupling conditions, for example, with HOBt and 
EDCI, to form a compound of formula (Ik). The protecting group of the 
compound of formula (Ik) is then removed under mildly acidic conditions, 
for example, with trifluoroacetic acid, to yield a compound of formula 
(Il). The compound of formula (Il) is then treated with 
O-benzylhydroxylamine under standard peptide coupling conditions to yield 
a compound of formula (Im). The protecting group of formula (Im) is then 
removed under catalytic hydrogenation conditions to yield a compound of 
formula (In). 
H. Preparation of Compounds of Formulae (Io) and (Ip) 
Compounds of formula (Io) are compounds of formula (I) wherein n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --NH--CH(R.sup.9)--R.sup.10 
where R.sup.9 is hydrogen, alkyl or aralkyl, and R.sup.10 is 
aralkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention. 
Compounds of formula (Ip) are compounds of formula (I) wherein n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --NH--CH(R.sup.9)--R.sup.10 
where R.sup.9 is hydrogen, alkyl or aralkyl, and R.sup.10 is carboxy; and 
R.sup.2 and R.sup.3 are as defined in the Summary of the Invention. 
Compounds of formulae (Io) and (Ip) are prepared as shown in the following 
Reaction Scheme 9 wherein p is 5, 6, 7 or 8; and R.sup.2, R.sup.3 and 
R.sup.9 are as defined above: 
##STR21## 
Compounds of formula (JJ) are prepared by methods known to those of 
ordinary skill in the art or by the method described in Example 36 below. 
In general, compounds of formulae (Io) and (Ip) are prepared by first 
treating a compound of formula (JJ) with triflic anhydride, followed by 
treatment with a compound of formula (KK) under basic conditions to form a 
compound of formula (LL). The compound of formula (LL) is then hydrolyzed 
under mildly acidic conditions, preferably with trifluoroacetic acid, to 
form a compound of formula (MM). The compound of formula (MM) is then 
coupled with a compound of formula (J) under standard peptide coupling 
conditions to form a compound of formula (Io). The compound of formula 
(Io) is then deprotected to form a compound of formula (Ip). 
I. Preparation of Compounds of Formulae (Iq) and (Ir) 
Compounds of formula (Iq) are compounds of formula (I) wherein n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH(R.sup.7)--R.sup.8, 
where R.sup.7 is --CH.sub.2 NHR, in which R is hydrogen, and R.sup.8 is 
carboxy, benzyloxycarbonyl or alkoxycarbonyl, and R.sup.2 and R.sup.3 are 
as defined in the Summary of the Invention. 
Compounds of formula (Ir) are compounds of formula (I) wherein n is 1, 2 or 
3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH(R.sup.7)--R.sup.8, 
where R.sup.7 is --CH.sub.2 NHR, R.sup.8 is carboxyl, and R, R.sup.2, and 
R.sup.3 are as defined in the summary of the Invention. 
Compounds of formulae (Iq) and (Ir) are prepared as shown in Reaction 
Scheme 10 below. 
##STR22## 
where Pht represents phthalimido. 
##STR23## 
Compounds of formula (J) are prepared by methods shown above. Compounds of 
Formula (NN) are prepared by methods well known to those skilled in the 
art, for example as described in EP 575844. 
In general, compounds of formulae (PP) and (Iq) are prepared by first 
coupling a compound of formula (J) with a compound of formula (NN) under 
standard peptide coupling conditions to form a compound of formula (PP). 
The phthalimido group of the compound of formula (PP) is then converted 
into an amine by standard methods, for example treatment with hydrazine, 
to give a compound of formula (Iq). 
The compound of Formula (Iq) may then be converted into a compound of 
formula (Ir) by reactions well known in the art. For example, reaction of 
a compound of formula (Iq) with an alkylsulfonyl halide in the presence of 
a base, followed by hydrolysis of the product with trifluoroacetic acid, 
gives a compound of formula (Ir) where R is alkylsulfonyl. Similarly, 
reaction of (Iq) with an alkyl, aryl, or arylalkyl chloroformate gives the 
corresponding carbamate, reaction with an acyl halide gives the 
corresponding amide, reaction with an appropriately substituted isocyanate 
gives the corresponding urea, etc. 
J. Preparation of Compounds of Formula (I) where R.sup.1 is --CH.sub.2 
--R.sup.4, in which R.sup.4 is N-hydroxyformylamino 
To prepare compounds of formula (I) where R.sup.1 is --CH.sub.2 --R.sup.4, 
in which R.sup.4 is N-hydroxyformylamino, a compound of formula (J) is 
first reacted, under the peptide coupling conditions described above, with 
a compound of the formula: 
##STR24## 
Such compounds may be prepared as shown in U.S. patent application Ser. No. 
08/343,158, the complete disclosure of which is hereby incorporated by 
reference. 
The product of this coupling reaction is then debenzylated in a manner 
similar to that shown in Reaction Scheme II above, to give a compound of 
formula (I) where R.sup.1 is --CH.sub.2 --R.sup.4, in which R.sup.4 is 
N-hydroxyformylamino. 
R. Preparation of Compounds of Formula (Is), (It) or (Iu) 
Compounds of formula (Is) are compounds of formula (I) wherein m and n are 
both 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
t-butyloxycarbonyl; and ER.sup.2 and R.sup.3 are as defined in the Summary 
of the Invention. 
Compounds of formula (It) are compounds of formula (I) wherein m and n are 
both 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
carboxy; and R.sup.2 and R.sup.3 are as defined in the Summary of the 
Invention. 
Compounds of formula (Iu) are compounds of formula (I) wherein m and n are 
both 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
alkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention. 
Compounds of formula (Is), (It) or (Iu) are prepared as shown in the 
following Reaction Scheme 11. 
##STR25## 
Compounds of formula (Ka) may be prepared as disclosed herein. The 
preparation of compounds of formula (ff) is discussed below. 
In general, compounds of formula (Is) are prepared by first coupling a 
compound of (Ka) with a compound of formula (ff) under standard peptide 
coupling conditions to yield a compound of formula (Is). 
Treatment of compounds of formula (Is) under mild acidic conditions yields 
the corresponding compounds of formula (It). 
Compounds of formula (Is) may also be converted to compounds of formula 
(Iu) wherein R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
alkoxycarbonyl other than t-butylcarbonyl, by methods known in the art. 
Additionally, compounds of formula (I) wherein m and n are 2; A is oxygen; 
R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is hydroxyaminocarbonyl; and 
R.sup.2 and R.sup.3 are as defined in the Summary of the Invention, may be 
prepared following the procedures as described above for the conversion of 
compounds of formula (Id) from compounds of formula (Ic). 
L. Preparation of the Compound of Formula (ff) 
The preparation of the compound of formula (ff) 
##STR26## 
is shown in the following Reaction Scheme 12. 
##STR27## 
Compounds of formulae (kk) and (ll) are commercially available, e.g., from 
Sigma or Aldrich respectively, or may be prepared by methods known to 
those skilled in the art. 
Compounds of formula (ll) dipicted in Reaction Scheme 12 is used for the 
preparation of compounds of formula (I) wherein m and n are both 2. It is 
understood that the process of Reaction Scheme 12 may be carried out with 
any one of the compounds represented by the formula H.sub.2 
N(CH.sub.2).sub.n O(CH.sub.2).sub.m OH in which m and n are as defined in 
the Summary of the Invention. These compounds are either commercially 
available or can be prepared by methods known to those skilled in the art. 
In general, the compound of formula (ff) is prepared by first coupling the 
compound of formula (kk) with the compound of formula (ll) under standard 
peptide coupling conditions, for example, with DCC in the presence of of 
HOBT in DMF, to form the compound of formula (mm). This compound (mm) is 
then treated with tosyl chloride to form a compound of formula (nn). Mesyl 
chloride may also be used instead of tosyl chloride for this reaction. 
Cyclization of the tosylate so formed with an excess of NaH in an inert 
solvent, preferably THF, under high dilution at room temperature yields 
the compound of formula (oo). Alternatively, the cyclization of the 
tosylates so formed with concentrated sodium hydroxide in an inert 
solvent, preferably CH.sub.2 Cl.sub.2, in the presence of a phase transfer 
catalyst, preferably tetra(n-butyl)ammonium hydrogen sulfate, yields the 
compound of formula (oo). The protecting group BOC on the compound of 
formula (oo) is removed under mild acidic conditions, preferably in the 
presence of trifluoroacetic acid, to yield the compound of formula (ff). 
M. Preparation of Compounds of Formula (Iv) 
Compounds of formula (Iv) are compounds of formula (I) wherein m and n are 
both 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 wherein R.sup.4 is 
carboxyl or alkoxycarbonyl; and R.sup.2 is aralkyl in which the alkylene 
chain is --(CH).sub.3 --; and R.sup.3 is as defined in the Summary of the 
Invention. 
Compounds of formula (Iv) are prepared as shown in the following Reaction 
Scheme 13. 
##STR28## 
The Compound of formula (ff) may be prepared as disclosed herein. 
Compounds of formula (gg) may be prepared following Reaction Scheme 4A 
except replacing the compound of (HH) with the corresponding allyl 
compound where the group shown as R.sup.2 in formula (HH) is replaced with 
prop-2-enyl. 
In general, compounds of formula (Iv) are prepared by first coupling a 
compound of (ff) with a compound of formula (gg) under standard peptide 
coupling conditions to yield a compound of formula (hh). 
Addition of aryl of the R.sup.2 group to the allyl chain via arylation of 
compounds of formula (hh) is carried out in the presence of a base and a 
palladium catalyst by adding aryl halide, preferably bromide or iodide, 
and heating the reaction mixture for about 2 to 4 hours, preferably 4 
hours, at about 100.degree. C. to form a compound of formula (ii). 
Catalytic hydrogenation (Pd/C) of an allyl compound of formula (ii) yields 
the corresponding compounds of the formula (Iv'). 
Compounds of formula (Iv') may be converted to the corresponding compounds 
wherein R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is carboxy or other 
alkoxycarbonyl groups following the procedures as described for the 
preparation of compounds of formula (It) and (Iu). 
Alternatively, arylation may be carried out first on compounds of (gg) 
following the procedures as described above, and the resulting compound of 
formula (Ka) is then coupled with the compound of formula (ff). 
N. Preparation of Compounds of Formula (Iw) Compounds of formula (Iw) are 
compounds of formula (I) wherein R.sup.2 is aralkyl in which aryl is 
substituted with an alkoxy group (aryl-O--R"); and m, n, A, R.sup.1 and 
R.sup.3 are as defined in the Summary of the Invention. 
These compounds can be prepared via modification of the substituents on the 
aryl ring such as O-alkylation of the phenol group (i.e., R" is hydrogen). 
Salts of Compounds of Formula (I) 
In addition, all compounds of formula (I) that exist in free base form may 
be converted to their pharmaceutically acceptable salts by treatment with 
the appropriate inorganic or organic acid. Salts of the compounds of 
formula (I) can also be converted to the free base form or to another 
salt. 
In summary, compounds of formula (I) are prepared by: 
1. reacting a compound of formula (K) where R.sup.7a is hydrogen or 
alkoxycarbonyl; R.sup.14 is alkyl or benzyl and R.sup.2 is as defined in 
the Summary of the Invention; with a compound of formula (J) wherein p is 
5, 6, 7 or 8 and R.sup.3 is as defined in the Summary of the Invention; to 
form a compound of formula (I) wherein n is 1, 2, or 3; m is 3 or 4; A is 
--CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
alkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention; or 
2. treating a compound of formula (I) wherein n is 1, 2, or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
alkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention; to form a compound of formula (I) wherein n is 1, 2, or 3; 
m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is carboxy; and R.sup.2 and R.sup.3 are as defined in the Summary 
of the Invention; or 
3. treating a compound of formula (I) wherein n is 1, 2, or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
carboxy; and R.sup.2 and R.sup.3 are as defined in the Summary of the 
Invention; with O-protected hydroxylamine such as O-benzylhydroxylamine to 
form a compound of formula (I) wherein n is 1, 2, or 3; m is 3 or 4; A is 
--CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
benzyloxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention; or 
4. treating a compound of formula (I) wherein n is 1, 2, or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
benzyloxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention; to form a compound of formula (I) wherein n is 
1, 2, or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 -- 
R.sup.4 where R.sup.4 is hydroxyaminocarbonyl; and R.sup.2 and R.sup.3 are 
as defined in the Summary of the Invention; or 
5. reacting a compound of formula (M) wherein R.sup.2 is as defined in the 
Summary of the Invention, with a compound of formula (J) where p is 5, 6, 
7 or 8; and R.sup.3 is hydrogen, to form a compound of formula (I) wherein 
n is 1, 2 or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 
--R.sup.4 where R.sup.4 is acetylthio; and R.sup.2 and R.sup.3 are as 
defined in the Summary of the Invention; or 
6. treating a compound of formula (I) wherein n is 1, 2 or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
acetylthio; and R.sup.2 and R.sup.3 are as defined in the Summary of the 
Invention; to form a compound of formula (I) wherein n is 1, 2 or 3; m is 
3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 
is mercapto; and R.sup.2 and R.sup.3 are as defined in the Summary of the 
Invention; or 
7. reacting a compound of formula (BB) where R.sup.2 is as defined in the 
Summary of the Invention; and R.sup.6 is optionally substituted aryl 
wherein the aryl group is quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl 
or phenyl; with a compound of formula (J) where p is 5, 6, 7 or 8; and 
R.sup.3 is as defined in the Summary of the Invention, to form a compound 
of formula (I) wherein n is 1, 2 or 3; m is 3 or 4; A is --CH.sub.2 --; 
R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
##STR29## 
in which R.sup.6 is optionally substituted aryl, wherein the aryl group 
is quinol-2-yl, naphth-1-yl, naphth-2-yl, pyridyl or phenyl; R.sup.2 and 
R.sup.3 are as defined in the Summary of the Invention; or 
8. treating a compound of formula (Im) where n is 2 or 3; m is 4; 
A is --NR.sup.11 where R.sup.11 is hydrogen or alkyl; R.sup.1 is --CH.sub.2 
--R.sup.4 where R.sup.4 is benzyloxyaminocarbonyl; and R.sup.2 and R.sup.3 
are as defined in the Summary of the Invention; to form a compound of 
formula (I) wherein n is 2 or 3; m is 4; A is --NR.sup.11 where R.sup.11 
is hydrogen or alkyl; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
hydroxyaminocarbonyl; and R.sup.2 and R.sup.3 are as defined in the 
Summary of the Invention; or 
9. reacting a compound of formula (MM) where R.sup.9 is hydrogen, alkyl or 
aralkyl and R.sup.2 is as defined in the Summary of the Invention; with a 
compound of formula (J) where p is 5, 6, 7 or 8 and R.sup.3 is as defined 
in the Summary of the Invention; to form a compound of formula (I) wherein 
n is 1, 2 or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is 
--NH--CH(R.sup.9)--R.sup.10 where R.sup.9 is hydrogen, alkyl or aralkyl, 
and R.sup.10 is aralkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined 
in the Summary of the Invention; or 
10. treating a compound of formula (I) wherein n is 1, 2 or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --NH--CH(R.sup.9)--R.sup.10 where R.sup.9 
is hydrogen, alkyl or aralkyl, and R.sup.10 is aralkoxycarbonyl; and 
R.sup.2 and R.sup.3 are as defined in the Summary of the Invention; to 
form a compound of formula (I) wherein n is 1, 2 or 3; m is 3 or 4; A is 
--CH.sub.2 --; R.sup.1 is --NH--CH(R.sup.9)--R.sup.10 where R.sup.9 is 
hydrogen, alkyl or aralkyl, and R.sup.10 is carboxy; and R.sup.2 and 
R.sup.3 are as defined in the Summary of the Invention; or 
11. treating a compound of formula (PP) wherein p is 5, 6, 7 or 8; 
R.sup.14 is hydroxy, benzyl or alkyl; and R.sup.2 and R.sup.3 are as 
defined in the Summary of the Invention;, to form a compound of formula 
(I) wherein n is 1, 2 or 3; m is 3 or 4; A is --CH.sub.2 --; R.sup.1 is 
--CH(R.sup.7)--R.sup.8 where R.sup.7 is --CH.sub.2 NHR in which R is 
hydrogen and R.sup.8 is carboxy, benzyloxycarbonyl or alkoxycarbonyl; and 
R.sup.2 and R.sup.3 are as defined in the Summary of the Invention; or 
12. treating a compound of formula (I) wherein n is 1, 2 or 3; m is 3 or 4; 
A is --CH.sub.2 --; R.sup.1 is --CH(R.sup.7)--R.sup.8 where R.sup.7 is 
--CH.sub.2 NHR in which R is hydrogen and R.sup.8 is benzyloxycarbonyl or 
alkoxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary of 
the Invention; to form a compound of formula (I) wherein n is 1, 2 or 3; m 
is 3 or 4; A is --CH.sub.2 --; R.sup.1 is --CH(R.sup.7)--R.sup.8 where 
R.sup.7 is --CH.sub.2 NHR in which R is hydrogen and R.sup.8 is carboxy; 
and R.sup.2 and R.sup.3 are as defined in the Summary of the Invention; or 
13. reacting a compound of formula (Ka) wherein R.sup.2 is as defined in 
the Summary of the Invention with a compound of formula (ff) wherein 
R.sup.3 is as defined in the Summary of the Invention; to form a compound 
of formula (I) wherein m and n are both 2; A is oxygen; R.sup.1 is 
--CH.sub.2 --R.sup.4 where R.sup.4 is t-butyloxycarbonyl; and R.sup.2 and 
R.sup.3 are as defined in the Summary of the Invention; or 
14. hydrogenating a compound of formula (ii) wherein R.sup.3 is as defined 
in the Summary of the Invention, to form a compound of formula (I) wherein 
m and n are both 2; A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where 
R.sup.4 is t-butyloxycarbonyl; R.sup.2 is aralkyl (aryl-(CH.sub.2).sub.3 
--); and R.sup.3 is as defined in the Summary of the Invention; or 
15. converting a compound of formula (I) wherein m and n are both 2; A is 
oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is 
t-butyloxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary 
of the Invention; to a compound of formula (I) wherein m and n are both 2; 
A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is carboxy; and 
R.sup.2 and R.sup.3 are as defined in the Summary of the Invention; or 
16. converting a compound of formula (I) wherein m and n are both 2; A is 
oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is carboxy or 
t-butyloxycarbonyl; and R.sup.2 and R.sup.3 are as defined in the Summary 
of the Invention; to a compound of formula (I) wherein m and n are both 2; 
A is oxygen; R.sup.1 is --CH.sub.2 --R.sup.4 where R.sup.4 is an 
alkoxycarbonyl other than t-butyloxycarbonyl; and R.sup.2 and R.sup.3 are 
as defined in the Summary of the Invention; or 
17. converting a compound of formula (I) wherein R.sup.2 is 
hydroxyarylalkyl; and m, n, a, R.sup.1 and R.sup.3 are as defined in the 
Summary of the Invention, to form a compound of formula (I) wherein 
R.sup.2 is alkoxyarylalkyl; and m, n, A, R.sup.1 and R.sup.3 are as 
defined in the Summary of the Invention. 
The following specific examples are provided as a guide to assist in the 
practice of the invention, and are not intended as a limitation on the 
scope of the invention.

EXAMPLE 1 
Compound of formula (E) 
A. 6-Cyano-1-hexanol (7.1 g, 55.8 mmol) was dissolved in 30 mL of acetic 
anhydride under argon atmosphere. To this material was added 5.3 mL (65.4 
mmol) of pyridine dropwise and the mixture was left to stir for 2 hours. 
The contents of the flask were then poured into a beaker containing 50 mL 
of ice water and the material was stirred for 15 minutes. The mixture was 
transferred to a 250 mL separatory funnel and ether (100 mL) was added. 
After shaking the ether phase was isolated and the aqueous phase washed 
twice more with ether (2.times.100 mL). The combined ether phase was 
washed with brine, dried (MgSO.sub.4) and filtered. Evaporation (rotary 
evaporator and vacuum pump) provided 6-cyano-1-acetoxyhexane (the compound 
of formula (C)) which was used immediately in the next step. 
B. 6-Cyano-1-acetoxy-hexane (55.8 mmol) was dissolved in about 100 mL of 
acetic anhydride in a Parr reaction bottle (500 mL capacity). To this was 
added acetic acid (0.5 mL) followed by platinum oxide (100 mg). The flask 
was placed on a R hydrogenator apparatus and charged with hydrogen gas 
(40 psi). The material was shaken for 12 hours, filtered through celite 
(to remove catalyst), charged with fresh platinum oxide (100 mg) and 
hydrogen (40 psi) and left to shake for a further 24 hours. The material 
was filtered through celite and all volatiles were removed under reduced 
pressure (rotary evaporator). The desired 1-acetoxy-7-acetamidoheptane was 
pure enough to use in the next step (11.8 g obtained). 
C. 1-Acetoxy-7-acetamidoheptane (11.8 g, 54.3 mmol) was dissolved in 20 mL 
of methanol in a 200 mL round bottom flask. To this was added 50 mL of 40% 
aqueous hydrochloric acid and the mixture was heated at reflux for 60 
hours. All volatiles were removed under reduced pressure. The desired 
7-amino-1-heptanol was obtained as the crystalline hydrochloride salt, 
m.p. 74.degree.-81.degree. C., MS: 131 (MH.sup.+). 
EXAMPLE 2 
Compounds of formula (G) 
A. N-Methylmorpholine (2.2 mL, 19.7 mmol) was added dropwise at room 
temperature to 7-amino-1-heptanol hydrochloride salt (3.3 g, 19.7 mmol), 
in 50 mL of dry DMF under argon with stirring. After stirring for 5 
minutes the following were added: N-t-butoxycarbonyl-L-tryptophan, (5 g, 
16.45 mmol), 1-hydroxybenzotriazole, (2.52 g, 16.45 mmol) and EDCI 
hydrochloride (4.73 g, 24.7 mmol). The mixture was stirred for 2 hours and 
then the DMF removed under reduced pressure. The residue was taken up in 
cold 2.5% HCl (100 mL) and ethyl acetate (3.times.100 mL) and transferred 
to a separatory funnel. The organic phase was isolated and washed 
consecutively with cold 2.5% HCl (100 mL) and then brine (100 mL). The 
ethyl acetate phase was dried (MgSO.sub.4), filtered and concentrated to 
obtain N-t-butoxycarbonyl-L-tryptophan-(7-hydroxyheptyl)amide; IR (neat): 
3300, 2921, 1685, 1645, 1490, 1356, 1157 cm.sup.-1 ; .sup.1 H NMR (80 MHz, 
CDCl.sub.3): .delta.0.98-1.62 (m, 10H, --(CH.sub.2).sub.5 --), 1.45 (s, 
9H, t-butyl), 2.86-3.32 (m, 4H,CH--CH.sub.2, HN--CH.sub.2), 3.68 (t, 2H, 
J=5.6 Hz, --CH.sub.2 OH), 4.22-4.55 (m, 1H, CH), 5.12-5.32 (broad d, 1H, 
NH--CH), 5.65-5.9 (broad t, 1H, NH--CH.sub.2), 6.98-7.92 (m, 5H, ArH), 
8.63 (broad s, indole NH). 
B. A solution of N-t-butoxycarbonyl-L-tryptophan-(7-hydroxyheptyl)amide 
(8.2 g) in 150 mL of anhydrous pyridine was cooled to 0.degree. C. (ice 
bath). Para-toluenesulfonyl chloride (4.7 g) was added to the solution in 
one portion and the cooled mixture was left to stir for 7 hours. The 
reaction was quenched by adding 50 mL of ice water and removing all 
volatiles under reduced pressure. The product, 
N-t-butoxycarbonyl-L-tryptophan-(N'-(7-(4'-methylphen-1-yl)sulfonyloxy)hep 
tyl)amide was isolated by column chromatography on silica gel using 10-40% 
ethyl acetate/hexane as eluant. This material crystallized on standing, 
MS: 572 (MH.sup.+). 
C. Alternatively, to a solution of N-t-butoxycarbonyl-L-tryptophan (5.0 g, 
16.45 mmol), 6-amino-1-hexanol (2.31 g, 19.74 mmol) and 
1-hydroxybenzotriazole.H.sub.2 O (2.52 g, 16.45 mmol) in dry DMF (50 mL) 
at room temperature under argon was added EDCI (4.73 g, 24.68 mmol). After 
stirring overnight, the DMF was removed under high vacuum. The residue was 
partitioned between ethyl acetate (150 mL) and 1N HCl (75 mL). The organic 
layer was further washed with 1N HCl (75 mL), saturated sodium bicarbonate 
solution (2.times.75 mL), and finally with brine (50 mL). The organic 
layer was dried (MgSO.sub.4) and evaporated to dryness to yield 6.45 g 
(97%) N-t-butoxycarbonyl-L-tryptophan-N'-(6-hydroxyhexyl)amide as a white 
foam, MS: 404.3 (M+H).sup.+. The purity of the product was confirmed by 
analytical HPLC. 
D. Proceeding further, to 
N-t-butoxycarbonyl-L-tryptophan-N'-(6-hydroxyhexyl)amide (5.5 g, 13.64 
mmol) in 150 mL dry pyridine at 0.degree. C. under argon was added 3.9 g 
(20.46 mmol) p-toluenesulfonyl chloride. The homogeneous solution was 
stirred at the same temperature overnight. The reaction was quenched with 
25 mL of water and excess pyridine was removed under reduced pressure. The 
residue was dissolved in ethyl acetate (120 mL) and washed with 1N HCl 
(2.times.50 mL), saturated NaHCO.sub.3 solution (50 mL), and brine (50 
mL). The organic layer was dried (MgSO.sub.4) and evaporated to give as a 
pale yellow oil, 
N-t-butoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)hex 
yl)amide (5.77 g, 76%), MS: 558.3 (M+H).sup.+. 
E. To 5-hydroxytryptophan (3.5 g, available from Sigma) and triethylamine 
(5.6 mL) in water (25 mL) and tetrahydrofuran (50 mL) was added BOC-ON 
(2-(t-butoxy-carbonyloxyimino)-2-phenylacetonitrile). After 2.5 hours, the 
tetrahydrofuran was removed, 10% Na.sub.2 CO.sub.3 (20 mL) was added and 
the mixture was partitioned with ether (50 mL). The aqueous portion was 
further extracted with ether (20 mL) and then acidified with cold 10% HCl 
in a two-phase system containing ethyl acetate (100 mL). The ethyl acetate 
portion was separated and washed with water (30 mL), brine, dried over 
anhydrous MgSO.sub.4 and concentrated to give a syrup. The syrup was 
reacted with 6-amino-1-hexanol in a similar manner as described above in 
Example 1C to yield 
N-t-butoxycarbonyl-L-(5-hydroxy)tryptophan-N'-(6-hydroxyhexyl)amide. Half 
of this product was taken up in 40 mL of DMF and treated with K.sub.2 
CO.sub.3 (5 g) and iodomethane (1.2 g) at room temperature overnight. The 
reaction mixture was then partitioned between water (50 mL) and ethyl 
acetate (80 mL), the organic portion was further washed with water 
(2.times.20 mL), brine, dried over anhydrous MgSO.sub.4 and concentrated 
to an oil. Purification of the product, 
N-t-butoxycarbonyl-L-(5-methoxy)tryptophan-N'-(6-hydroxyhexyl)amide, was 
then done by silica gel chromatography; .sup.1 H NMR: .delta.(CDCl.sub.3) 
0.9-1.6 (m, CH.sub.2, 8H); 1.45 (s, 9H); 2.7-3.3 (m, 5H); 3.6 (t, 2H); 
3.85 (s, 3H); 4.35 (m, 1H); 5.3 (broad d, 1H); 5.85 (broad t, 1H); 
6.75-8.3 (m, 4H); 8.73 (broad s, 1H). 
F. In a similar manner, the following compounds are made: 
N-t-butoxycarbonyl-L-(5-ethoxy)tryptophan-N'-(6-hydroxyhexyl)amide; 
N-t-butoxycarbonyl-L-(5-propoxy)tryptophan-N'-(6-hydroxyhexyl)amide; 
N-t-butoxycarbonyl-L-(5-ethyl)tryptophan-N'-(6-hydroxyhexyl)amide; and 
N-t-butoxycarbonyl-L-(4-methyl)tryptophan-N'-(6-hydroxyhexyl)amide. 
EXAMPLE 3 
Compounds of formula (H) 
A. 
N-t-Butoxycarbonyl-L-tryptophan-(N'-(4'-methylphen-1-yl)sulfonyloxyheptyl) 
amide (6.78 g) was added portion-wise to a solution of NaH (60% in oil, 1.9 
g) in 1.1 liters of anhydrous tetrahydrofuran and left to stir overnight. 
The reaction mixture was concentrated and taken up in water (150 mL) and 
CH.sub.2 Cl.sub.2 (150 mL). The aqueous phase was made slightly acidic 
with 2.5% HCl (pH=3-4) and the organic phase was isolated (3.times.150 mL) 
and washed consecutively with cold 2.5% HCl (150 mL), 5% NaHCO.sub.3 (150 
mL) and brine (150 mL). The organic phase was dried (MgSO.sub.4), filtered 
and concentrated providing a green-yellow semi-solid material. 
Purification by chromatography on silica gel gave 
(11S)-11-N'-(t-butoxycarbonyl)amino-10-oxo-1,9-diaza-tricyclo11.6.1.0.sup 
.14,19 !eicosa-13(20),14(19),15,17-tetraene, m.p. 208.degree.-209.degree. 
C., MS: 400 (M+H).sup.+. 
B. Alternatively, to 
N-t-butoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)hex 
yl)amide (5 g, 8.97 mmol) in one liter of dry THF at 0.degree. C. under 
argon was added 4 equivalents of 60% NaH (1.44 g, 36 mmol) in small 
portions over 10 minutes. The mixture was then stirred at room temperature 
overnight. The resulting yellow mixture was evaporated down to .about.200 
mL and 1 liter of distilled water was added. The mixture was then 
acidified with 1N HCl with vigorously stirring. The yellow precipitate was 
collected by filtration and dried over P.sub.2 O.sub.5 at high vacuum 
overnight. The dry crude product (8 g) was chromatographed on silica-gel 
60, eluted with 30% ethyl acetate in CH.sub.2 Cl.sub.2 to give 1.2 g (35%) 
of 
(10S)-10-N'-(t-butoxycarbonyl)amino-9-oxo-1,8-diaza-tricyclo10.6.1.0.sup. 
13,18 !nonadeca-12(19),13(18),14,16-tetraene as a white powder, MS: 386 
(M+H)+, m.p. 222.degree.-223.degree. C. 
C. Alternatively, to a solution of the 
N-t-butoxycarbonyl-L-tryptophan-(N'-(6-(4'-methylphen-1-yl)sulfonyloxy)hex 
yl)amide (1.21 g, 2.17 mmol) in 45 ml reagent grade methylene chloride were 
added 15 ml of 40% aqueous KOH and 0.3 equivalent of benzyl triethyl 
ammonium chloride (0.65 mmol, 148 mg). The two phase mixture was stirred 
vigorously at room temperature overnight. The organic layer was separated 
and the aqueous layer was extracted with 25 mL methylene chloride. The 
combined organic layer was washed with water (25 mL), dried (MgSO.sub.4), 
and evaporated to dryness. The residue was stirred in 10% ether in pet 
ether at 0.degree. C. for 15 minutes and filtered to give 792 mg (93%) of 
(10S)-10-N'-(t-butoxy-carbonyl)amino-(9-oxo-1,8-diaza-tricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraene as a white powder. 
EXAMPLE 4 
Compounds of formula (J) 
A. 
(11S)-11-N'-(t-Butoxycarbonyl)amino-(10-oxo-1,9-diazatricyclo11.6.1.0.sup 
.14,19 !eicosa-13(20),14(19),15,17-tetraene (850 mg) was dissolved in 5 mL 
of a 10% trifluoroacetic acid in methylene chloride solution and stirred 
for 1 hour. The volatiles were removed under reduced pressure. The residue 
was taken up in CH.sub.2 Cl.sub.2 (40 mL) and 1N NaOH (40 mL) and 
transferred to a separatory funnel. The organic phase was isolated and 
washed with brine, dried (MgSO.sub.4), filtered and concentrated to obtain 
654 mg of (11S)-11-amino-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraene. 
B. Alternatively, 
(10S)-10-N'-(t-butoxycarbonyl)amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup. 
13,18)nonadeca-12(19),13(18),14,16-tetraene (0.5 mmol, 193 mg) was stirred 
in 20% TFA/CH.sub.2 Cl.sub.2 (10 mL) at room temperature for 2 hours. 
Excess of TFA and solvent was removed under reduced pressure. The residue 
was dissolved in ethyl acetate (30 mL) and washed with 1N HCl (25 mL), 
brine (10 mL), and dried (MgSO.sub.4). Evaporation to dryness gave 140 mg 
(quant.) of (10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene as a white foam, m.p. 
157.degree.-160.degree. C., MS: 286.2 (M+H).sup.+. 
EXAMPLE 5 
Compounds of formula (Ia) 
A. To a stirred solution of 
(11S)-11-amino-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraene (654 mg) and racemic 
4-methyl-2-t-butoxycarbonylmethylpentanoic acid (800 mg) in 30 mL of 
anhydrous DMF under argon was added 1-hydroxybenzotriazole (360 mg), 
followed by EDCI (940 mg). The mixture was left to stir overnight and then 
the DMF was removed under reduced pressure. The residue was taken up in a 
mixture of CH.sub.2 Cl.sub.2 (100 mL) and 1.5% cold HCl (100 mL) and 
transferred to a separatory funnel. The organic phase was isolated and 
washed consecutively with 1.5% HCl (100 mL), 5% NaHCO.sub.3 (100 mL) and 
brine (100 mL). The CH.sub.2 Cl.sub.2 phase was dried (MgSO.sub.4), 
filtered and concentrated providing a semicrystalline product, 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl 
ester. The two individual stereoisomers of this compound were separated by 
chromatography on silica gel with ethyl acetate/hexane as eluant. The less 
polar stereoisomer had a melting point of 154.degree.-157.degree. C., 
.alpha.!.sub.D.sup.24 43.9.degree., c=23.8 mg/2 mL CHCl.sub.3, while the 
more polar stereoisomer had a melting point of 168.degree.-171.degree. C., 
.alpha.!.sub.D.sup.24 =-19.1.degree., c=11.86 mg/2 mL CHCl.sub.3. 
B. Alternatively, to a solution of 
(2R)-4-methyl-2-(t-butoxycarbonylmethyl)pentanoic acid as prepared above 
(2.39 g, 10.4 mmol), HOBt.H.sub.2 O (2.5 g, 1 eq.), N-methylmorpholine 
(2.3 mL, 2 eq.), and 
(10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (2.96 g, 1 eq.) in dry DMF (200 mL) 
under argon was added EDCI (3.96 g, 2.0 eq.). The resulting mixture was 
stirred overnight, then the next morning the DMF was removed at 35.degree. 
C. under high vacuum. The residue was partitioned between CH.sub.2 
Cl.sub.2 (150 mL)/water (75 mL), then the organic layer was washed with 
0.5N HCl (2.times.75 mL), saturated NaHCO.sub.3 (2.times.75 mL) and 
finally with brine (1.times.75 mL). After drying the CH.sub.2 Cl.sub.2 
layer over Na.sub.2 SO.sub.4, it was filtered and evaporated to dryness. 
Purification by column chromatography (petroleum ether to 30% ethyl 
acetate/petroleum ether) gave 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester (3.24 g, 62.7%). 
C. In a similar manner, the following compounds of formula (Ia) were 
prepared: 
(3R,10S)-4-phenyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid 
t-butyl ester, MS: 532 (M+H).sup.+ ; 
(3R,10S)-4-cyclohexyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid 
t-butyl ester, MS: 538 (M+H).sup.+ ; 
(3R,10S)-6-phenyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-hexanoic acid 
t-butyl ester, MS: 560 (M+H).sup.+ ; and 
(3R,10S)-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester, MS: 484 (M+H).sup.+ ; 
(3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup 
.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
benzyl ester, MS: 590 (M+H).sup.+ ; 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo(10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid t-butyl 
ester; 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid methyl 
ester; MS: 496 (M+H).sup.+ ; 
(3R,10S)-4-cyclopropyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid t-butyl 
ester; 
(3R,9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid ethyl 
ester; 
(3R,9S)-6-pyridin-4-yl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid ethyl 
ester; 
(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-yl-carbamoyl)pentanoic acid ethyl 
ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanoic acid 
t-butyl ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanoic acid ethyl 
ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanoic acid 
isopropyl ester; 
(3R,10S)-5-methyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl 
ester; 
(3R,10S)-4-cyclopentyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13 
,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid 
ethyl ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanoic acid 
t-butyl ester; and 
(3R,10S)-4-cyclopentyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13 
,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid 
isopropyl ester. 
Similarly, the following compound was prepared: 
(3RS,10S)-N-benzyloxy-N-formyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0 
.sup.13,18 !nonadeca-12(19),13(18),14,16-teraen-10-ylcarbamoyl)hexylamine. 
D. Alternatively the following methyl esters may be prepared from the 
corresponding t-butyl ester under the conditions as described in Example 
56: 
(3R,9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid methyl 
ester; 
(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18) 12(17),13,15-tetraen-9-yl-carbamoyl)pentanoic acid methyl 
ester; and 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanoic acid methyl 
ester. 
E. Alternatively, to (2R)-4-methyl-2-(t-butoxy-carbonylmethyl)pentanoic 
acid (1 g, 4.34 mmol) in dry THF (100 mL) at -78.degree. C. under argon 
was added NaN(TMS).sub.2 (1.0M in THF, 10.9 mL, 2.5 eq) dropwise and the 
mixture was stirred for 1 hour. Iodomethane (0.33 mL, 1.2 eq) was added 
and the resulting mixture was stirred overnight from -78.degree. C. to 
room temperature. The next day the reaction was quenched with water (100 
mL). After extracting with ether (3.times.100 mL), the aqueous layer was 
combined with ethyl acetate and with stirring was added 4N HCl to pH=2. 
Sodium chloride was also added to saturation and the aqueous layer was 
extracted with ethyl acetate (3.times.100 mL). The combined organic 
extracts were dried over Na.sub.2 SO.sub.4, filtered and concentrated to 
give (2R)-4-methyl-2-((1-methyl-1-t-butoxy-carbonyl)methyl)pentanoic acid 
as a dark brown oil (1 g). To this crude reaction product (500 mg) and 
(10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (399 mg, 0.7 in dry DMF at 
0.degree. C. under argon was added HOBt-H.sub.2 O (1.1 eq, 234 mg), 
followed by EDCI (663 mg, 2.5 eq). The resulting mixture was stirred 
overnight from 0.degree. C. to room temperature. Most of the DMF was 
removed by pump distillation at 65.degree. C. Then, the residue was 
partitioned between CH.sub.2 Cl.sub.2 (150 mL). After washing with 0.5N 
HCl (2.times.75 mL), saturated NaHCO.sub.3 (2.times.75 mL) and brine 
(1.times.75 mL), the organic layer was dried over Na.sub.2 SO.sub.4, 
filtered and evaporated to dryness. The crude material was purified by 
flash column chromatography on silica eluting with 30% ethyl acetate in 
petroleum ether to yield a mixture of three compounds, the two individual 
stereoisomers of 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diaza-tricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
t-butyl ester and 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
t-butyl ester. Further purification provided separation of the three 
compounds; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester (13 mg) as a white solid; 1:1 mixture of the stereoisomers (5 mg) as 
a white solid; and the less polar stereoisomer of 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanoic acid 
t-butyl ester (15 mg); 300 MHz .sup.1 H NMR in CDCL.sub.3 (less polar 
diastereomer): .delta.(-0.2)-(-0.05) (m, 1H); 0.5-0.7 (m, 1H); 0.9 (dd, 
J=4 Hz, J=6.7 Hz, 6H); 1.15 (d, J=8.4 Hz, 3H); 1.18-1.4 (m, 3H); 1.41 (s, 
9H); 1.45-1.73 (m, 4H); 1.75-1.8 (m, 2H); 2.5-2.7 (m, 3H); 2.89 (dd, 
J=10.9 Hz, J=15 Hz, 1H); 3.34-3.5 (m, 2H); 3.95-4.1 (m, 1H); 4.25-4.4 (m, 
1H); 4.72-4.82 (m, 1H); 5.22-5.3 (m, 1H); 6.52 (d, J=7.5 Hz, 1H); 6.91 (s, 
1H); 7.13 (dd, J=6.7 Hz, J=8.4 Hz, 1H); 7.22 (dd, J=5 Hz, J=7.1 Hz, 1H); 
7.34 (d, J=8.4 Hz, 1H); 7.84 (d, J=8.4 Hz, 1H). 
EXAMPLE 6 
Compounds of formula (Ib) 
A. The less polar stereoisomer of 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-yl-carbamoyl)hexanoic acid t-butyl 
ester (300 mg) was covered with 5 mL of a 10% trifluoroacetic 
acid/methylene chloride solution and left to stir. After 2.5 hours, TLC 
indicated that the reaction was complete. All volatiles were removed under 
reduced pressure. The residue was taken up in CH.sub.2 Cl.sub.2 (40 mL) 
and transferred to separatory funnel and washed consecutively with 0.5% 
HCl (40 mL) and brine (40 mL). The organic phase was dried (MgSO.sub.4), 
filtered and concentrated to provide the less polar stereoisomer of 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid. 
B. In a similar manner, the more polar stereoisomer of 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid t-butyl 
ester was hydrolyzed to yield the more polar stereoisomer of 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid. 
C. Alternatively, 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester (3.24 g, 6.5 mmol) was taken up in 95% TFA (aqueous) (30 mL) at 
0.degree. C. and then stirred for 20 minutes. The ice bath was then 
removed and the mixture was stirred for another 1 hour. After 
concentrating it to an oil, the residue was taken up in ethyl acetate (250 
mL) and washed with water (7.times.150 mL). The organic layer was dried 
over Na.sub.2 SO.sub.4, filtered and evaporated to dryness to yield a 
single stereoisomer of 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,1.8 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a 
white powder, 2.83 g (98.4% yield); MS: 442 (M+H).sup.+ 
D. In a similar manner, but replacing 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester with the appropriate compound of formula (Ia), the following 
compounds of formula (Ib) were prepared: 
(3R,10S)-4-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid, MS: 
474 (M-H).sup.- ; 
(3R,10S)-4-cyclohexyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid, MS: 
482 (M+H).sup.+ ; 
(3R,10S)-3-cyclohexyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) propanoic acid, MS: 
468 (M+H).sup.+ ; 
(3R,10S)-6-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS: 
502 (M-H).sup.31 ; 
(3R,10S)-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 !nonadeca-12 
(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS: 426 
(M-H).sup.- ; 
(3R,10S)-2-amino-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS: 
457 (M+H).sup.+ ; 
(3R,10S)-2-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS: 
458 (M+H).sup.+ ; 
(3R,10S)-2-aminomethyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13, 
18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-5-methyl-3-(15-methoxy-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13.18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-carboxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12 (17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid; 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; MS: 
509; 
(3R,10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)propionic acid; MS: 
454; 
(3R,10S)-3-cyclopropyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; MS: 
439; 
(3R,10S)-6-(biphenyl-4-yl)-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; MS: 
579; and 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-5-(thiophen-2-yl)pen 
tanoic acid, MS: 496.3 (M+H).sup.+. 
Similarly prepared is: 
(3R,10S)-4-cyclopropyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; 
(3R,9S)-4-cyclobutyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(3R,9S)-4-(3-methoxy-4,5(RS)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatricy 
clo9.6.1.0.sup.12,17 !octadeca-11(18),12 
(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(3R,9S)-4-(3-hydroxy-4,5(RS)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatricy 
clo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(3R,9S)-4-(3-bromo-4,5(RS)-dihydro-isoxazol-5-yl)-3-(8-oxo-1,7-diazatricycl 
o9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid; 
(3R,9S)-5-(4-chlorophenoxy)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)pentanoic acid; 
(3R,9S)-5-methoxy-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)pentanoic acid; 
(3R,9S)-6-methoxy-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanoic acid; 
(3R,9S)-7-phenyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)heptanoic acid; 
(3R,10S)-3-(15-fluoro-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-5-methyl-hexanoic 
acid; 
(3R,10S)-5-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-pentanoic acid; 
(3R,10S)-3-cyclohexyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-yl)-succinamic acid; 
(3R,10S)-3-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-yl)-succinamic acid; 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-5-methylhex-5-enoic 
acid; 
(3R,10S)-2(R)-aminomethyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-5-methyl-hexanoic 
acid; 
(3R,10S)-3-(15-benzyloxy-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-5-methyl-hexanoic 
acid; 
(3R,10S)-3-(15-hydroxy-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-5-methyl-hexanoic 
acid; 
(3R10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)octanoic acid; 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-7-hydroxyheptanoic 
acid; 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-7-benzyloxyheptanoic 
acid; 
(3R,10S)-4-(3-thiophenyl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid; 
(3R,10S)-6-trifluoromethyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-hexanoic acid; 
(3R,10S)-5-(2-thiophenyl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-pentanoic acid; 
(3R,10S)-7-(4-biphenyloxy)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-heptanoic acid; 
(3R,10S)-7-phenoxy-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-heptanoic acid; 
(3R,10S)-4-(3-furanyl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid; 
(3R,10S)-6-(3-pyridyl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-hexanoic acid; 
(3R,10S)-6-(4-pyridyl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-hexanoic acid; 
(3R,10S)-3-(4-phenylimidazol-1-yl)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup. 
13,18 !nonadeca-11(19),12(18)14,16-tetraen-10-yl)-succinic acid; 
(3R,10S)-4-cyclobutyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid; and 
(3R,10S)-4-benzyloxy-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-11(19),12(18),14,16-tetraen-10-ylcarbamoyl)-butanoic acid. 
E. (3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (183 
mg) was taken up in 40 mL of dry CH.sub.2 Cl.sub.2 and at 0.degree. C. 
ethanol (0.5 mL, 5 eq) was added followed by N,N-dimethylaminopyridine 
(0.1 eq, 5 mg) and finally EDCI (209 mg, 5 eq). The resulting solution was 
stirred from 0.degree. C. to room temperature overnight. Additional 
CH.sub.2 Cl.sub.2 (100 mL) was added and the mixture was washed with 0.5N 
HCl (2.times.50 mL), saturated NaHCO.sub.3 (2.times.50 mL) and finally 
with brine (1.times.50 mL). The organic layer was dried over Na.sub.2 
SO.sub.4, filtered and evaporated to dryness. Recrystallization from ethyl 
acetate and petroleum ether gave 
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid ethyl 
ester as a white solid (Yield: 108 mg, 55%), MS: 470 (M+H).sup.+. 
Similarly prepared was 
(3R,10S)-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid ethyl 
ester; MS: 496 (M+H).sup.+ ; 
(3R,9S)-5-(4-chloro-phenoxy)-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)pentanoic acid 
diethylcarbamoylmethyl ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
indan-5-yl ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
morpholinylethyl ester; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
(1-methyl-4-piperidine ester, MS: 539.51 (M+S.sup.+); and 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
(1-methyl-3-piperidinylmethyl ester. 
F. Alternatively, the less polar stereoisomer of 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester prepared in Example 5D above (15 mg) was taken up in CH.sub.2 
Cl.sub.2 (2.4 mL) and TFA (0.6 mL) and the resulting mixture was stirred 
at room temperature for 4 hrs. The solvent was removed under reduced 
pressure at 35.degree. C. Then ethyl acetate was added and the solution 
was washed with water (3.times.10 mL). The organic layer was dried over 
Na.sub.2 SO.sub.4, filtered and evaporated to dryness. Recrystallization 
from ethyl acetate/petroleum ether gave 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a 
white solid (7 mg), MS: 456.3 (M+H).sup.+. 
G. In a similar manner, the 1:1 mixture of stereoisomers of 
(3R,10S)-2-methyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester (prepared in Example 5D above) (5 mg) was hydrolyzed to yield 3 mg 
of a white solid; 300 MHz .sup.1 H NMR in CDCl.sub.3 : 
.delta.(-0.5)-(-0.3) (m, 1H); 0.6-0.8 (m, 1H); 0.8-1.05 (m, 6H); 1.05-1.22 
(m, 2H); 1.35 (3H, dd, J=9 Hz); 1.4-1.7 (m, 3H); 1.7-1.95 (m, 3H); 
2.3-2.48 (m, 1H); 2.54-2.73 (m, 1H); 2.8-3.0 (m, 2H); 3.38-3.5 (m, 1H); 
3.52-3.72 (m, 1H); 3.8-3.98 (m, 1H); 4.34-4.45 (m, 1H); 4.7-4.84 (m, 1H); 
5.0-5.08 (m, 1H); 6.8 (d, 1H); 7.15-7.25 (m, 1H); 7.25-7.32 (m, 1H); 7.35 
(d, J=8.4 Hz, 1H); 7.88 (d, J=8.4 Hz). 
H. Alternatively, 
(3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
benzyl ester was taken up in ethanol (35 mL, some heating was required) 
and ammonium formate 1642 mg, 3 eq) was added followed by 10% Pd on 
activated charcoal (100 mg). After stirring under argon at room 
temperature for 3 hrs. the reaction was complete. The mixture was 
suction-filtered through a 1 cm bed of celite, then it was concentrated, 
MeOH was added and it was filtered through a plug of cotton. After 
concentrating, CH.sub.2 Cl.sub.2 was added to the residue and it was 
stirred vigorously and then filtered. The filtrate was concentrated and 
recrystallized from ethyl acetate/pet. ether to give 
(3R,10S)-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
as a white solid (yield: 140 mg), MS: 500.3 (M+H).sup.+. 
I. 
(3R,10S)-2-Methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanoic acid 
was taken up in ethanol (25 mL) and then 1N LiOH (0.3 mL, 3 eq) was added 
dropwise. The resulting homogeneous solution was stirred at room 
temperature for 3 hrs. Most of the ethanol was removed under reduced 
pressure at 30.degree. C. Then water (5 mL) and ethyl acetate (30 mL) was 
added and with stirring, 4N HCl was added until pH=2. The ethyl acetate 
layer was further washed with brine, dried over Na.sub.2 SO.sub.4, 
filtered and evaporated to dryness. Purified by reverse phase HPLC to give 
47 mg of 
(3R,10S)-2-carboxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19), 13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, as a 
white solid, MS: 484.5 (M-H).sup.-. 
EXAMPLE 7 
A. The mixture of dibenzylfumarate (5.3 g, 0.018 mol) and 
4-biphenyl-4-yl-1H-imidazole (3.94 g, 0.018 mol) was heated at 
110.degree.-115.degree. C. for 4 hours. The mixture was then taken up in 
ether and washed with 0.05% HCl, 0.01N NaOH and brine, and dried. After 
removal of ether, the crude product obtained was purified by column 
chromagraphy (60% EtOAc/hexanes) to give 5.75 g of 
2-(4-biphenyl-4-yl-imidazol-1-yl)succinic acid dibenzyl ester, MS: 517.3 
(M+H).sup.+. 
In a similar manner, the following compounds were prepared: 
2-(4-phenylimidazol-1-yl)succinic acid dibenzyl ester; 
2-(4-(4-methoxyphenyl)-imidazol-1-yl)succinic acid dibenzyl ester; and 
2-(4-(4-phenoxyphenyl)-imidazol-1-yl)succinic acid dibenzyl ester. 
B. A suspension of 2-(4-biphenyl-4-yl-imidazol-1-yl)succinic acid dibenzyl 
ester (551 mg) in 10 mL of H.sub.2 O was refluxed overnight, and cooled to 
room temperature. The aqueous layer was removed and the remaining solids 
were dried on a lyophilizer to give 
2-(4-biphenyl-4-yl)-imidazol-1-ylsuccinic acid 4-benzyl ester (437 mg), 
MS: 426 (M.sup.+). 
In a similar manner, the following compounds were prepared: 
2-(4-phenyl-imidazol-1-yl)succinic acid 4-benzyl ester; 
2-(4-(4-methoxyphenyl)-imidazol-1-yl)succinic acid 4-benzyl ester; and 
2-(4-(4-phenoxyphenyl)-imidazol-1-yl)succinic acid 4-benzyl ester. 
C. A mixture of 2-(4-biphenyl-4-yl-imidazol-1-yl)succinic acid 4-benzyl 
ester (450 mg, 1.05 mmol), 
(10S)-10-amino-9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (284 mg, 0.95 mmol), EDCI (302 mg, 
1.5 mmol), HOBT (142 mg, 1.05 mmol), N-methylmorpholine (0.14 mL) and DMAP 
(50 mg) in DMF (10 mL) was stirred at room temperature overnight. The 
solution was diluted with 100 mL of EtOAc and washed with brine and 
saturated NaHCO.sub.3 and dried. The crude product obtained after removal 
of solvents was purified by column chromagraphy to give 
(3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo10. 
6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid 
benzyl ester. 
In a similar manner, the following compounds were prepared: 
(3RS,10S)-3-(4-phenyl-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid benzyl 
ester; 
(3RS,10S)-3-(4-(4-methoxyphenyl)-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid benzyl ester; and 
(3RS,10S)-3-(4-(4-phenoxyphenyl)-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid benzyl ester. 
D. A solution of 
(3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo10 
.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid benzyl ester (190 mg) in THF/EtOH (5/1, 20 mL) was hydrogenated with 
10% Pd/C (170 mg) for 8 hours until TLC indicated that the starting 
compound was consumed. The solution was filtered through a pad of Celite. 
The filtrate was evaporated and recrystallized (THF/EtOAc) to give 147 mg 
of 
(3RS,10S)-3-(4-biphenyl-4-yl-imidazol-1-yl)-N-(9-oxo-1,8-diaza-tricyclo10 
.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid, melting point: 222.degree.-226.degree. C., MS: 604.2 (M+H).sup.+. 
In a similar manner, the following compounds were prepared: 
(3RS,10S)-3-(4-phenyl-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid, 
melting point: 184.degree.-187.degree. C., MS: 528.3 (M+H).sup.+ ; 
(3RS,10S)-3-(4-(4-methoxyphenyl)-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid; melting point: 186.degree.-190.degree. C., MS: 558.3 (M+H).sup.+ ; 
(3RS,10S)-3-(4-(4-phenoxyphenyl)-imidazol-1-yl)-N-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic 
acid, MS: 620.12 (M+H).sup.+ ; and 
(3RS,10S)-3-(3-phenyl-pyrazol-1-yl)-N-(9-oxo-1,8-diazatricyclo10.6.1.0.sup 
.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl-succinamic acid, MS: 
568.4 (M+H).sup.+. 
EXAMPLE 8 
A. The carboxylic acids prepared according to Example 6 may be further 
converted to the corresponding amides by reacting the acids with 
appropriate amines in the presence of coupling agents such as EDCI and 
HOBT. These methods are well known to those skilled in the art. 
Accordingly the following compounds are prepared: 
(3RS,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 !nonadeca-12(19), 
13(18),14,16-tetraen-10-ylcarbamoyl)5-methylhexanamide; and 
(3RS,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 !nonadeca-12(19), 
13(18),14,16-tetraen-10-ylcarbamoyl)5-methyl-N-(N,N-dimethylaminoethyl)hex 
anamide, MS: 512.49 (M+H).sup.+. 
B. According to the procedure as described in U.S. Pat. No. 4,412,994, the 
following compound is prepared: 
(3R,10S)-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 !nonadeca-12(19), 
13(18),14,16-tetraen-10-ylcarbamoyl)-5-methyl-N-hydroxy-N-morpholinylmethy 
lhexanamide. 
EXAMPLE 9 
Compounds of formula (Ic) 
A. A solution of the less polar stereoisomer of 
(11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid (210 mg) 
and 5-hydroxybenzotriazole monohydrate (109 mg) in anhydrous DMF (20 mL) 
under argon was cooled to 0.degree. C. (ice bath). To this mixture was 
added EDCI (282 mg) and stirring was continued for 0.5 hours. 
O-benzylhydroxylamine (0.27 mL) was added to the solution and the reaction 
mixture was left to warm to room temperature overnight. All volatiles were 
removed under reduced pressure. The residue was taken up in CH.sub.2 
Cl.sub.2 (100 mL) and 20% HCl (100 mL) and transferred to a separatory 
funnel. The organic phase was isolated and the aqueous phase washed 
(2.times.100 mL) with CH.sub.2 Cl.sub.2. The organic materials were then 
washed consecutively with 5% NaHCO.sub.3, brine, dried (MgSO.sub.4), 
filtered and concentrated to provide 
(11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl) hexanamide as a 
crystalline product. The product was further purified by column 
chromatography on silica gel followed by crystallization from hot ethyl 
acetate/CH.sub.2 Cl.sub.2, to provide the more polar stereoisomer of the 
compound having a melting point at 232.degree.-233.degree. C. m.p., and 
the less polar stereoisomer of the compound having a melting point at 
251.degree.-253.degree. C. 
B. Alternatively, to a solution of 
(3R,10S)-5-methyl-3-(9-oxo-,1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (2.5 g, 
5.82 mmol), HOBt.H.sub.2 O (0.89 g, 1 eq.) and O-benzyl hydroxylamine (2.2 
mL, 3 eq.) in DMF (200 mL) at 0.degree. C. was added EDCI (2.77 g, 2.5 
eq.). The resulting mixture was then stirred overnight. DMF was removed by 
pump distillation at 65.degree. C. To the residue was then added methanol 
(14 mL) followed by ether (140 mL). With stirring at 0.degree. C., 0.5N 
HCl (140 mL) was added, followed by petroleum ether (140 mL). The mixture 
was stirred at 0.degree. C. for 15 minutes, then the white solid was 
suction filtered and subsequently washed with water (100 mL) followed by 
1:1 ether/petroleum ether (100 mL). Drying under vacuum (P.sub.2 O.sub.5) 
for 3 hours gave 
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,1 
8 !-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide as a 
white solid (2.7 g, 84.9%). 
C. In a similar manner, but replacing 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid with 
the appropriately substituted compound of formula (Ib) the following 
compounds of formula (Ic) were prepared: 
(3R,10S)-N-benzyloxy-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide, MS: 605.3 
(M+H).sup.+ ; 
(3R,10S)-N-benzyloxy-6-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide, MS: 609 
(M+H).sup.+ ; 
(3R,10S)-N-benzyloxy-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide, MS: 533 
(M+H).sup.+. 
D. In a similar manner, but replacing O-benzyl hydroxylamine with 
2-dimethylaminoethylamine or 1-methyl-4-hydroxypiperidine, the following 
derivatives of formula (I) were prepared: 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
1-(2-dimethylaminoethyl)amide, MS: 512.49 (M+H).sup.+ ; 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
1-methylpiperidin-4-yl ester, MS: 539.51 (M+H).sup.+ ; 
EXAMPLE 10 
Compounds of formula (Id) 
A. To a solution of the more polar stereoisomer of 
(11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide (90 mg) in 
ethanol/tetrahydrofuran (350 mL; 2:1) was added 10% palladium on charcoal 
(30 mg). The material was stirred with a constant stream of hydrogen gas 
bubbling through it. After 3 hours TLC (10% CH.sub.3 OH/CH.sub.2 Cl.sub.2) 
showed the reaction was complete. The material was filtered through a bed 
of celite (3.times.) and concentrated under reduced pressure to an almost 
dry residue. Methylene chloride (15 mL) was added and the material was 
again concentrated under reduced pressure until almost dried and then 
repeated. To the residue was added 3-4 drops of methanol followed by 
methylene chloride (15 mL). The material was stirred with cooling (ice 
bath) and ether (5 mL) and then hexane (2 mL) was added. A crystalline 
material slowly emerged and was collected by filtration to yield 50 mg of 
the more polar stereoisomer of 
(11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide, m.p. 
197.degree.-201.degree. C., .alpha.!.sub.D.sup.23 =-85.1.degree. (3.5 
mg/1.0 mL DMSO). 
B. In a similar manner, but replacing the more polar stereoisomer of 
(11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-11.6.1.0.sup.14,19 
!-eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide with the 
less polar, the less polar stereoisomer of 
(11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide was made, 
m.p. 212.degree.-216.degree. C., .alpha.!.sub.D.sup.23 38.5.degree. (4.7 
mg/ 1.0 mL CH.sub.3 OH). 
C. Alternatively, 
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,1 
8 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide (1.0 g, 
1.83 mmol) was taken up in a solution of 20% THF in ethanol (500 mL) and 
then Pd on activated charcoal (200 mg) was added portionwise. The 
resulting slurry was stirred as H.sub.2 gas was gently bubbled through the 
solution. After 4 hours, the reaction mixture was suction filtered through 
a bed of celite (1.5 cm), and the filtrate was concentrated and then taken 
up in methanol (30 mL) and filtered through a plug of cotton. 
Recrystallization from methanol/ethyl acetate/ether/petroleum ether gave 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl-carbamoyl)hexanamide (768 mg, 
92%), MS: 455 (M-H).sup.-. 
D. In a similar manner, but replacing 
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,1 
8 !nonadeca-12(19),13(18), 14,16-tetraen-10-ylcarbamoyl)hexanamide with the 
appropriate compound of formula (Ic), the following compounds of formula 
(Id) were prepared: 
(3R,10S)-N-hydroxy-2-methoxycarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10 
.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide, MS: 515 
(M+H).sup.+ ; 
(3R,10S)-N-hydroxy-6-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide, MS: 517 
(M-H).sup.- ; 
(3R,10S)-N-hydroxy-2-aminocarbonyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6 
.1.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) 
hexanamide, MS: 483 (MH.sup.+)--H.sub.2 O; 
(3R,10S)-N-hydroxy-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl) hexanamide, MS: 443 
(MH.sup.+); 
(3R,9S)-N-hydroxy-5-methyl-3-(8-oxo-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; and 
(2S,3R,9S)-N-hydroxy-2-hydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0. 
sup.12,17 !octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; 
(3RS,10S)-N-hydroxy-N-formyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.s 
up.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexylamine, 
MS: 455 (M-H).sup.- ; 
(3R,9S)-N-hydroxy-6-pyridin-4-yl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; 
(3R,9S)-N-hydroxy-2-hydroxy-5-methyl-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)hexanamide; 
(3R,10S)-N-hydroxy-5-methyl-3-(15-methoxy-9-oxo-1,8-diazatricyclo10.6.1.0. 
sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10S)-N-hydroxy-2-acetyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.su 
p.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10S)-N-hydroxy-6-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10S)-N-hydroxy-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10S)-N-hydroxy-5-phenyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)pentanamide; 
(3S,10R)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10RS)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
(3R,10RS)-N-hydroxy-5-methyl-3-(15-fluoro-9-oxo-1,8-diazatricyclo10.6.1.0. 
sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide; 
and 
(3R,10S)-N-hydroxy-2-aminocarbonyl-5-methyl-3-(15-fluoro-9-oxo-1,8-diazatri 
cyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide. 
EXAMPLE 11 
Compounds of formula (Ie) 
A. To a solution of 4-methyl-2-acetylthiomethylpentanoic acid (612 mg, 3 
mmol), (10S)-10-amino-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (427 mg, 1.5 mmol), and 
HOBt.H.sub.2 O (230 mg, 1.5 mmol) in dry DMF (30 mL) under argon at room 
temperature was added EDCI (863 mg, 4.5 mmol) in one portion. After 
stirring overnight, DMF was removed at 30.degree. C. under high vacuum to 
give a yellowish semi-solid. It was dissolved in ethyl acetate (50 mL), 
washed with 1N HCl (30 mL), 5% NaHCO.sub.3 solution (30 mL) and finally 
brine (30 mL). The organic layer was dried (MgSO.sub.4) and evaporated to 
dryness. The resulting pale yellow-oil was stirred in 50% ether-pet. ether 
(40 mL) to yield 600 mg (85%) of 
(10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup 
.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as 1:1 
stereoisomeric mixture. The stereoisomeric mixture was separated in flash 
column chromatography (LPS-2), eluted with 20% ethyl acetate in pet. ether 
to give the less polar stereoisomer, m.p. 226.degree. C., and the more 
polar stereoisomer, m.p. 220.degree. C. 
EXAMPLE 12 
Compounds of formula (If) 
A. To a solution of the less polar stereoisomer of 
(10S)-2-acetylthiomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo10.6.1.0.sup. 
13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide (50 mg, 0.106 
mmol) in 10 mL of methanol at 0.degree. C. under argon was added 0.5 mL 
concentrated NH.sub.4 OH. The reaction mixture was stirred from 0.degree. 
C. (ice-bath was removed after addition of NH.sub.4 OH) to room 
temperature and further stored at room temperature for 1 hour. Excess 
methanol was removed under reduced pressure to give a white solid residue. 
The residue was partitioned between ethyl acetate (30 mL) and 0.1 NHCl (15 
mL). The organic layer was washed with brine (15 mL), dried (MgSO.sub.4), 
and evaporated to dryness. The solid residue was stirred in 50% ether/pet. 
ether and filtered to yield the more polar stereoisomer of 
(10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13 
,18 !nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide as a white 
powder, 41 mg (90%) m.p. 224.degree. C. 
EXAMPLE 13 
Compounds of formula (HH) 
A. To 4-methylpentanoic acid (25 g, 0.215 mmol) in a 25.degree. C. water 
bath, thionyl chloride (20.4 mL, 1.3 g) was slowly added. Then the mixture 
was heated at 50.degree. C. under argon for 3 hours (until the evolution 
of gas had stopped). The crude reaction mixture was distilled at 
atmospheric pressure to give 4-methylpentanoyl chloride (25.3 g, 87.3%), 
b.p. 143.degree. C. 
B. In a similar manner, but replacing 4-methylpentanoic acid with 
5-phenylpentanoic acid (5 g), 5-phenylpentanoyl chloride was prepared (4.4 
g), as a colorless liquid, b.p. 91.degree.-93.degree. C. 
EXAMPLE 14 
Compounds of formula (N) 
A. To a suspension of 60% NaH (836 mg, 1.5 eq.) in toluene (200 mL) at room 
temperature under argon was added L-(+)-2,10-camphorsultam (3.0 g, 3.9 
mmol) portion-wise. The mixture was stirred vigorously at room temperature 
for one hour. Then 4-methylpentanoyl chloride was carefully added dropwise 
to the solution at 0.degree. C. After stirring the reaction at room 
temperature for 3 hours, the reaction was quenched with 10 mL of water, 
and 70 mL of ether was added. The reaction mixture was first washed with 
0.5N HCl (2.times.50 mL), then 5% K.sub.2 CO.sub.3 (3.times.50 mL) and 
finally with brine (1.times.50 mL). The organic layer was dried over 
MgSO.sub.4, filtered and evaporated to dryness. Purification by column 
chromatography (1:6 ethyl acetate/petroleum ether as eluant) gave 
N-4-methylpentanoyl-L-(+)-2,10-camphor sultam (3.39 g, 78%). 
B. In a similar manner, but replacing 4-methylpentanoyl chloride with the 
appropriate chloride, the following compounds of formula (N) were 
prepared: 
N-3-phenylpropanoyl-L-(+)-2,10-camphor sultam, MS: 347 (M.sup.+); 
N-5-phenylpentanoyl-L-(+)-2,10-camphor sultam, MS: 375 M.sup.+ ; 
N-pentanoyl-L-(+)-2,10-camphor sultam, MS: 300 (M+H).sup.+. 
EXAMPLE 15 
Compounds of formula (Q) 
A. To a solution of N-4-methylpentanoyl-L-(+)-2,10-camphor sultam (3.39 g, 
10.8 mmol) in 75 mL of dry THF at -78.degree. C. under argon was added 
NaN(TMS).sub.2 (1.0M in THF, 11.34 mL, 1.05 eq.) dropwise over five 
minutes. After stirring at -78.degree. C. for 1 hour, 
hexamethylphosphoramide (5 mL) was added to the mixture, followed by 
t-butylbromoacetate (5.2 ml, 3 eq), then 400 mg of tetra n-butyl ammonium 
iodide was added in one portion. The resulting solution was kept at 
-78.degree. C. under argon overnight. The next morning, the reaction was 
quenched with water (100 mL), and then it was extracted with ether 
(3.times.100 mL). The combined ether layers were washed with brine, then 
dried over Na.sub.2 SO.sub.4, filtered and concentrated. Purification by 
column chromatography (5:95 ethyl acetate/petroleum ether to 10:90 ethyl 
acetate/petroleum ether as eluant) gave 
N-(4-methyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam 
(4 g, 86.5%). 
B. In a similar manner, but replacing 
N-4-methylpentanoyl-L-(+)-2,10-camphor sultam with the appropriate 
compound of formula (N), the following compounds of formula (Q) were 
prepared: 
N-(3-phenyl-2-t-butoxycarbonylmethyl)propanoyl-L-(+)-2,10-camphor sultam, 
MS: 461 (M.sup.+); 
N-(5-phenyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam, 
MS: 490 (M+H).sup.+ ; 
N-(2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam, MS: 414 
(M+H).sup.+. 
EXAMPLE 16 
Compounds of formula (Ka) 
A. To a stirred solution of 
N-(4-methyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam 
(5.45 g, 12.7 mmol) in 50% aqueous THF (150 mL) at 0.degree. C. under 
argon was added LiOH.H.sub.2 O crystals (2.14 g, 4 eq.) followed by 30% 
H.sub.2 O.sub.2 (11.5 mL). Then the ice-bath was removed and the resulting 
emulsion was stirred for 3 hours before it had turned clear. Most of the 
THF was removed under reduced pressure at 35.degree. C. Then CH.sub.2 
Cl.sub.2 (150 mL) was added and with stirring 4N HCl was added to pH=2. 
After adding NaCl, the aqueous layer was further extracted with CH.sub.2 
Cl.sub.2 (3.times.150 mL). The CH.sub.2 Cl.sub.2 was removed under reduced 
pressure at 35.degree. C. and then the residue was taken up in ethyl 
acetate (150 mL). This solution was then extracted with 5% K.sub.2 
CO.sub.3 (3.times.50 mL) and the combined extracts were washed with ether 
(50 mL). Then CH.sub.2 Cl.sub.2 was added to the aqueous layer and with 
stirring with NaCl, the aqueous layer was extracted with CH.sub.2 Cl.sub.2 
(3.times.70 mL) and the combined extracts were dried over Na.sub.2 
SO.sub.4, filtered and concentrated to give 
(2R)-4-methyl-2-t-butoxycarbonylmethyl-pentanoic acid as a colorless oil 
(2.95 g, quantitative yield). 
B. In a similar manner, but replacing 
N-(4-methyl-2-t-butoxycarbonylmethyl)pentanoyl-L-(+)-2,10-camphor sultam 
with the appropriate compound of formula (Q), the following compounds of 
formula (Ka) were prepared: 
(2R)-3-phenyl-2-t-butoxycarbonylmethyl-propanoic acid, MS: 265 (M+H).sup.+ 
; 
(2R)-5-phenyl-2-t-butoxycarbonylmethyl-pentanoic acid, MS: 293 (M+H).sup.+ 
; 
(2R)-2-t-butoxycarbonylmethyl-pentanoic acid, (colorless oil, 1.09 g). 
C. (2R)-3-Phenyl-2-t-butoxycarbonylmethyl-propanoic acid (55 mg) was taken 
up in glacial acetic acid (20 mL) and PtO.sub.2 (25 mg) was added in 
acetic acid. Then the beaker was placed in a Parr bomb, it was evacuated 
and charged with 100 psi of H.sub.2. After stirring for 3 days, the 
mixture was suction filtered through a 1 cm bed of celite. The filtrate 
was then concentrated to a yellow oil, 
(2R)-3-cyclohexyl-2-t-butoxycarbonylmethyl-propanoic acid (56 mg), MS: 269 
(M-H).sup.-. 
EXAMPLE 17 
Compound of formula (R) 
To a solution of D-leucine (50 g, 0.381 mol) in 570 mL of 3N HBr (aq) at 
0.degree. C. was added sodium nitrite (42 g, 1.6 eq) portion-wise over 1 
hour and 15 minutes. The reaction was further stirred for 3 hrs at 
0.degree. C. then it was extracted with ether (1000 mL). After washing the 
ether layer with water (2.times.500 mL) it was dried over MgSO.sub.4 and 
concentrated. The red syrup was then co-evaporated with chloroform 
(3.times.200 mL) to remove the color and then it was pumped to give 
(2R)-2-bromo-4-methylpentanoic acid, as a colorless oil with a constant 
weight of 71.3 g. 
EXAMPLE 18 
Compound of formula (S) 
Into dichloromethane (80 mL) was condensed isobutene to double the volume 
(at -50.degree. C. CHCl.sub.3 /dry ice). To this solution was added 
(2R)-2-bromo-4-methylpentanoic acid (28 g, 143.6 mmol) and maintaining the 
temperature between -40.degree. and -50.degree. C. concentrated sulphuric 
acid (1 mL) was added dropwise. The reaction was then allowed to warm to 
room temperature over 20 hours. The solution was then concentrated before 
adding additional methylene chloride (300 mL) which was subsequently 
washed with saturated NaHCO.sub.3 (2.times.100 mL) followed by water 
(2.times.100 mL). After drying over Na.sub.2 SO.sub.4, the organic layer 
was filtered and concentrated to give a yellow oil. The material was 
distilled to give 23 g of (2R)-2-bromo-4-methylpentanoic acid t-butyl 
ester as a clear colorless oil. 
EXAMPLE 19 
Compound of formula (U) 
To benzyl methyl malonate (2.13 mL, 1 eq) and potassium-t-butoxide (1.36 g, 
1 eq) in dry DMF (100 mL) at 0.degree. C. was added 
(2R)-2-bromo-4-methylpentanoic acid t-butyl ester (2.89 g, 11.5 mmol) in 
50 mL of DMF dropwise over a period of 1 hr. The resulting solution was 
then stirred at 0.degree. C. for 3 days. Then the reaction mixture was 
partitioned between ether (150 mL) and saturated ammonium chloride (80 
mL). The resulting mixture was suction filtered through celite and the two 
phases were separated. Then the aqueous layer was further extracted with 
ether (3.times.100 mL) and the combined ether extracts were washed with 
water (6.times.100 mL). After drying over MgSO.sub.4, the organic layer 
was filtered and evaporated to dryness. Purification by flash 
column-chromatography (eluting with 4:96 ethyl acetate/petroleum ether) 
gave 
(2R)-2-(1-methoxy-carbonyl-1-benzyloxycarbonyl)methyl!-4-methylpentanoic 
acid t-butyl ester (2.55 g) as a clear colorless oil, MS: 322 
(M-acetone).sup.+. 
EXAMPLE 20 
Compound of formula (Kb) 
(2R)-2-(1-Methoxycarbonyl-1-benzyloxycarbonyl)-methyl!-4-methylpentanoic 
acid t-butyl ester was taken up in 5 mL of 80% TFA (eq) at room 
temperature and stirred for 1.5 hrs by TLC. The reaction was only 30% 
complete so additional TFA (10 mL) was added. Within 1/2 hour, the 
reaction was complete. The TFA was removed under high vacuum at 45.degree. 
C. and the residue was taken up in ethyl acetate and washed with water 
(5.times.30 mL). After drying over Na.sub.2 SO.sub.4, the ethyl acetate 
layer was filtered, concentrated and pumped to yield 
(2R)-2-(1-methoxycarbonyl-1-benzyloxycarbonyl)methyl!-4-methylpentanoic 
acid, as a solid (1.68 g), MS: 322 (M.sup.+). 
EXAMPLE 21 
Compound of formula (W) 
Crystalline phosphinic acid (8.4 g, 0.13 mol) was stirred in neat 
triethylorthoformate (22 mL, 0.20 ml) for 90 minutes at room temperature. 
This was then transferred via cannula to a stirred solution of 
ethylisobutylacrylate (8 g, 0.036 mol) and tetramethylguanidine (4.5 mL, 
0.036 mol) that had been cooled to 0.degree. C. for 10 minutes. The ice 
bath was removed and the reaction stirred for 4 hours. The mixture was 
diluted with 200 ml of diethyl ether and the solution washed with 1N HCl 
(100 ml), water (4.times.100 ml) brine (100 ml), and dried over magnesium 
sulfate. Evaporation under reduced pressure yielded 8.15 g of 
2-(ethoxy)phosphinoylmethyl-4-methylpentanoic acid ethyl ester as a 
slightly yellow colored oil, MS: 349 (M-H.sub.2 O).sup.+. 
EXAMPLE 22 
Compound of formula (X) 
Crude 2-(ethoxy)phosphinoylmethyl-4-methylpentanoic acid ethyl ester (26 g) 
was dissolved in 600 mL THF/CH.sub.2 Cl.sub.2 (50/50) and cooled to 
0.degree. C. Diisopropyl-ethylamine (32 mL) and 90.8 mL of 
bis-(trimethylsilyl) acetamide were then added to the solution and the 
resulting mixture was stirred for 20 minutes before paraformaldehyde (5.5 
g) was added. The solution was brought to room temperature and heated at 
37.degree. C. for 18 hours. The solvent was removed by evaporation, and 
the resulting oil dissolved in 200 mL ethyl acetate. The solution was 
washed with 50 mL of 1N HCl (2.times.), 50 mL of brine (2.times.), dried 
over MgSO.sub.4, filtered and evaporated to yield 19.3 g of 2-(ethoxy) 
(hydroxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl ester as a 
faintly yellow oil, MS: 281 (MH.sup.+). 
EXAMPLE 23 
Compounds of formula (Y) 
A. 2-(Ethoxy) (hydroxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl 
ester (5 g) was dissolved in 20 mL of CH.sub.2 Cl.sub.2 and cooled to 
-20.degree. C. (in duplicate). Methanesulfonyl chloride (1.5 mL) and 
triethylamine (3.0 mL) were added to solution dropwise. After 15 minutes 
the bath was removed and the reaction left at room temperature for 3% 
hours. Each solution was then washed with 10 mL cold 2% HCl, 10 mL 
NaHCO.sub.3 (sat), 10 mL brine, dried with MgSO.sub.4, filtered and 
evaporated to yield 12.8 g (combined yield) of 2-(ethoxy) 
(methane-sulfonyloxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl 
ester. 
B. In a similar manner, but replacing methanesulfonyl chloride with 
p-toluenesulfonyl chloride, 2-(ethoxy) 
(p-toluenesulfonyloxymethyl)phosphinoylmethyl-4-methylpentanoic acid ethyl 
ester is prepared. 
EXAMPLE 24 
Compounds of formula (AA) 
Sodium hydride (1.52 g, (60%)) and 6 g of 2-quinoline thiol were stirred 
together at 0.degree. C. in 50 mL DMF. After the initial H.sub.2 evolution 
had subsided, the mixture was stirred at room temperature for 21/2 hours. 
The mixture was then cooled to 0.degree. C. and 2-(ethoxy) 
(methanesulfonyloxymethyl)phosphinoyl-methyl-4-methylpentanoic acid ethyl 
ester (12.8 g) in 10 mL DMF was added via cannula and the resulting 
mixture was then stirred for 18 hours, slowly warming to room temperature. 
The DMP was removed by evaporation, the residue dissolved in 50 mL ethyl 
acetate and washed with 50 mL H.sub.2 O (2.times.), brine (50 mL), dried 
with MgSO.sub.4 and evaporated to a yellow semi-solid. Purification by 
flash chromatography using 10% ethyl acetate/hexane to 80% ethyl 
acetate/hexane for the elution yielded 10 g of 2-(ethoxy) 
(quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl 
ester (Rf 0.35 80% ethyl acetate/hexane), MS: 424 (MH.sup.+). 
B. In a similar manner, but replacing 2-quinolinethiol with 
1-naphthalenethiol, 2-naphthalenethiol or thiophenol, the following 
compounds of formula (AA) are prepared: 
2-(ethoxy) (naphth-1-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid 
ethyl ester; 
2-(ethoxy) (naphth-2-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid 
ethyl ester; and 
2-(ethoxy) (phenylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid 
ethyl ester. 
EXAMPLE 25 
Compounds of formula (BB) 
A. 2-(Ethoxy) 
(quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid ethyl 
ester (4.5 g) was dissolved in 100 mL THF and 12.5 mL of 2N NaOH was added 
together with enough methanol to make the solution homogeneous. After 18 
hours the THF was removed by evaporation, the residue diluted with 50 mL 
H.sub.2 O and washed with 50 mL ethyl acetate. The aqueous phase was then 
acidified to pH 4, and the product extracted with 50 mL ethyl acetate 
(2.times.). The ethyl acetate was washed with 20 mL brine, dried with 
MgSO.sub.4 and evaporated to yield 3.8 g of 2-(hydroxy) 
(quinolin-2-ylthiomethyl)-phosphinoyl-methyl-4-methylpentanoic acid as a 
yellow oil, MS: 368 (MH.sup.+). 
B. In a similar manner the following compounds of formula (BB) are 
prepared: 
2-(hydroxy) (naphth-1-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic 
acid; 
2-(hydroxy) (naphth-2-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic 
acid; and 
2-(hydroxy) (phenylthiomethyl)phosphinoyl-methyl-4-methylpentanoic acid. 
EXAMPLE 26 
Resolution of a compound of formula (BB) 
2-(Hydroxy) (quinolin-2-ylthiomethyl)phosphinoyl-methyl-4-methylpentanoic 
acid (5.3 g) was dissolved in 50 mL of warm ethanol (abs) and 4.2 g of 
(-)-cinchonidine was added. After 30 minutes at room temperature the salt 
began to precipitate out. The flask was covered in foil and allowed to 
stand for 2 days. The salt was then removed by suction filtration, and the 
filtrate evaporated to a yellow foam. The salt and the filtrate were each 
dissolved in 100 mL ethyl acetate and washed successively with 1% HCl to 
remove the cinchonidine while keeping the pH above 4. Both solutions were 
each dried over MgSO.sub.4 and evaporated to yield 2.4 g of a single 
stereoisomer, .alpha.!.sub.D.sup.24 =+10.68.degree. (9.73 mg in methanol 
(2 mL)) and 2.5 g of the other single stereoisomer, .alpha.!.sub.D.sup.24 
=-8.70.degree. (9.88 mg in methanol (2 mL)). 
EXAMPLE 27 
Compound of formula (Ig) 
A single stereoisomer of 2-(hydroxy) 
(quinolin-2-ylthiomethyl)phosphinoylmethyl-4-methylpentanoic acid (300 mg, 
0.81 mmol) and 1,1'-carbonyldiimidazole (174 mg, 1.0 mmol) were stirred at 
0.degree. C. in 6 mL THF for 11/2 hours. 
(10S)-10-Amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (270 mg, 0.95 mmol) was added to 
the solution and the resulting mixture was allowed to warm to room 
temperature and then stirred for 18 hours. The THF was removed by 
evaporation and the residue dissolved in 60 mL ethyl acetate. The ethyl 
acetate was washed with 10 mL H.sub.2 O, 10 mL brine, dried with 
MgSO.sub.4 and evaporated to yield 
(10S)-4-methyl-2-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19) 
13(18)14,16-tetraen-10-ylcarbamoyl)pentyl!(quinolin-2-ylthiomethyl)phosphi 
nic acid as a yellow oil. Purification was carried out by reverse phase 
HPLC using a gradient of acetonitrile and 50 mm NH.sub.4 OAc buffer as the 
eluents. The more polar stereoisomer was isolated (30 mg) at 41% 
acetonitrile, and the less polar stereoisomer (10 mg) at 43% acetonitrile. 
The fractions were lyophilized to off-white powders, MS: 635 (MH.sup.+). 
EXAMPLE 28 
Compound of formula (Ih) 
(3R,10S)-5-Methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid (200 
mg, 0.45 mmol) was dissolved in 10 mL of glacial acetic acid and was 
hydrogenated at 100 psi H.sub.2 pressure in the presence of Pt.sub.2 O (60 
mg) in a Parr reactor at room temperature for 15 hrs. Argon gas was 
bubbled into the reaction mixture for 15 mins. and the catalyst (Pt.sub.2 
O) was filtered off (through a cone of celite). The clear filtrate was 
evaporated to dryness and further co-evaporated with toluene twice to give 
quantitative yield of 
(3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadecan-10-ylcarbamoyl)hexanoic acid as a white solid. MS: 448 
(M-H).sup.31 . 
EXAMPLE 29 
Compound of formula (Ii) 
To (3R,10S)-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadecanylcarbamoyl)hexanoic acid and O-benzylhydroxylamine (5 eq, 2.25 
mmol, 277 mg) in 10 mL of dry DMF at room temperature were added 
1-hydroxybenzo-triazole.H.sub.2 O (2 eq, 0.9 mmol, 122 mg) and EDCI (5 eq, 
2.25 mmol, 431 mg). The resulting clear reaction mixture was stirred at 
room temperature overnight. The solvent was removed under high vacuum at 
room temperature and the residue was partitioned between ethyl acetate (15 
mL) and 1N HCl (15 mL). The ethyl acetate layer was further extracted with 
1N HCl (15 mL). The combined aqueous extract was basified with 4N NaOH to 
pH 10 and was saturated with NaCl and extracted with CH.sub.2 Cl.sub.2 
(3.times.15 ml). The combined CH.sub.2 Cl.sub.2 extract was dried 
(MgSO.sub.4), filtered, and evaporated to dryness to give a semi-solid. 
The semi-solid was stirred in ether (10 mL) at 0.degree. C. for 30 minutes 
and filtered to yield 85 mg (34%) of 
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,1 
8 !nonadecanylcarbamoyl)hexanamide, as a white powder, MS: 555 (M+H).sup.+. 
EXAMPLE 30 
Compound of formula (Ij) 
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadecan-10-ylcarbamoyl)hexanamide (75 mg, 0.135 mmol) was hydrogenated 
at 1 atm H.sub.2 pressure in absolute ethanol (5 mL) in the presence of 
10% Pd-C (35 mg) for 2 hours. Argon gas was bubbled into the reaction 
mixture for 10 minutes and the reaction mixture was filtered through a 
cone of celite. The catalyst on celite was further washed with 5 mL of 
ethanol. The combined filtrate was evaporated to dryness to afford a solid 
residue. The solid was stirred in 10 mL of 5% MeOH in ether at 0.degree. 
C. for 30 mins and filtered to yield 57 mg (91%) of 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadecan-10-ylcarbamoyl) hexanamide, as an off-white powder, MS: 465 
(M+H).sup.+. 
EXAMPLE 31 
Compound of formula (DD) 
To N-t-butoxycarbonyltryptophan (3 mmol, 914 mg) and N-methylethanediamine 
(3.6 mmol, 0.27 g, 0.32 mL) in dry DMF (15 mL) were added 
1-hydroxybenzotriazole.H.sub.2 O (3 mmol, 459 mg) and EDCI (4.5 mmol, 863 
mg). The mixture was stirred at room temperature overnight under argon and 
excess of the solvent (DMF) was removed under high vacuum at 35.degree. C. 
The residue was dissolved in ethyl acetate (40 mL) and the adduct was 
extracted into 1N HCl (3.times.25 mL). The combined aqueous extract was 
basified with solid K.sub.2 CO.sub.3 and extracted with ethyl acetate 
(3.times.25 mL). The combined organic extract was washed with brine (30 
mL) and dried (MgSO.sub.4). Evaporation to dryness yielded 920 mg (85%) 
HPLC pure product, 
N'-t-butoxycarbonyltrytophan-N-((methyl)aminoethyl)-amide as a white foam. 
EXAMPLE 32 
Compound of formula (EE) 
To a vigorously stirred solution of 
N'-t-butoxycarbonyl-trytophan-N-((methyl)aminoethyl)-amide (2 g, 5.55 
mmol) and trans-1,4-dichlorobut-2-ene (8.32 mmol, 1.04 g, 0.88 mL) in 
methylene chloride (15 mL) and 40% KOH (50 mL) was added 0.3 equivalents 
of benzyltriethyl ammonium chloride (1.66 mmol, 378 mg). After stirring at 
room temperature overnight, the yellowish organic layer was separated and 
the aqueous layer further extracted with 30 mL of CH.sub.2 Cl.sub.2. The 
combined methylene chloride extract was washed with brine and dried 
(MgSO.sub.4). The residue was dissolved in 10 mL of MeOH and at 0.degree. 
C. will stirring 50 mL of ether was added. The resulting yellow solid was 
filtered off. The filtrate was evaporated to dryness to give 1.12 g HPLC 
pure product, 
11-N'-(t-butoxycarbonyl)amino-10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1. 
0.sup.14,19 !eicosa-3(4),13(20),14(19),15,17-pentane as a pale yellow 
powder, MS: 413 (M+H).sup.+. 
EXAMPLE 33 
Compound of formula (FF) 
11-N'-(t-Butoxycarbonyl)amino-10-oxo-1,6,9-triaza-6-methyl-tricyclo11.6.1. 
0.sup.14,19 !eicosa-3(4),13(20),14(19),15,17-pentaene (414 mg, 1 mmol) was 
stirred in 40% TFA in CH.sub.2 Cl.sub.2 (10 mL) at room temperature for 1 
hr. Excess of TFA and solvent were removed under reduced pressure. The 
residue was dissolved in methylene chloride (30 mL) and washed with 5% 
K.sub.2 CO.sub.3 solution (2.times.15 ml) and brine (15 mL). The organic 
layer was dried (MgSO.sub.4) and evaporated to give 240 mg (76%) of pale 
yellow foam, 
11-amino-10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1.0.sup.14,19 
!eicosa-3(4),13(20),14(19),15,17-pentane, MS: 313 (M+H).sup.+. 
EXAMPLE 34 
Compounds of formula (Ik) 
11-Amino-10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1.0.sup.14,19 
!eicosa-3(4),13(20),14(19),15,17-pentaene (161 mg, 0.7 mmol) and 
(2R)-4-methyl-2-t-butoxycarbonylmethylpentanoic acid (220 mg, 0.7 mmol) 
was stirred in dry DMF (15 mL) in the presence of HOBt (0.7 mmol). EDCI 
(1.4 mmol, 268 mg), and N-methyl morpholine (1.4 mmol, 0.15 mL) under 
argon at room temperature overnight. Excess of DMF was removed under 
reduced pressure. The residue was dissolved in methylene chloride (30 mL) 
and washed with water (30 mL). The aqueous wash was extracted with 
CH.sub.2 Cl.sub.2 (30 mL). The combined methylene extract was dried (Mg 
SO.sub.4) and evaporated to give a light brown oil. The light brown oil 
was purified reverse-phase HPLC (C.sub.18 column; CH.sub.3 CN-50 MM 
NH.sub.4 OH.sub.2 gradient). The desired fraction was lyophilized to give 
148 mg (40%) of 
(3R,11S)-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo-11.6.1.0.sup.14 
,19 !eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl)hexanoic acid 
t-butyl ester as a pale yellow powder, MS: 525.2 (M+H).sup.+. 
EXAMPLE 35 
Compound of formula (Il) 
(3R,11S)-5-Methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1.0.sup.14,1 
9 !eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl)hexanoic acid 
t-butyl ester (0.228 mmol, 120 mg) was stirred in 20% TFA in CH.sub.2 
Cl.sub.2 (5 mL) at room temperature for 1 hr. Excess solvent was removed 
under reduced pressure (rotary evaporator at 30.degree. C.) to give the 
crude acid, 
(3R,11S)-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo-11.6.1.0.sup.14 
,19 !eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl)hexanoic acid, 
as a light brown oil. Purification by reverse-phase HPLC, eluted with 
CH.sub.3 CN--NH.sub.4 OAc buffer under gradient conditions yielded 90 mg 
(75%) of the acid as pale yellow powder, MS: 469.1 (M+H).sup.+. 
EXAMPLE 36 
Compound of formula (Im) 
(3R,11S)-5-Methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1.0.sup.14,1 
9 !eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl)hexanoic acid and 
O-benzylhydroxylamine. (5 eq, 2.5 mmol, 308 mg) were stirred in dry DMF 
(30 mL) in the presence of HOBt (2 eq, 1 mmol, 135 mg), EDCI (5 eq, 2.5 
mmol, 479 mg), and N-methylmorpholine (10 eq, 5 mmol, 0.55 mL) at room 
temperature under argon for 15 hours. The solvent was removed under high 
vacuum at room temperature. The residue was dissolved in distilled water 
(35 mL) and was extracted with 10% ethyl acetate in pet. ether to remove 
less polar impurities. The expected product was then extracted from the 
aqueous layer with CH.sub.2 Cl.sub.2 (2.times.35 mL). The organic extract 
was washed with brine (25 mL), dried (MgSO.sub.4) and evaporated to give a 
yellow oil (330 mg). The crude product was purified on reverse-phase HPLC 
(CH.sub.3 CN--NH.sub.4 OAc buffer; gradient) and lyophilized to yield 175 
mg (61%) of 
(3R,11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyl-tricyclo11. 
6.1.0.sup.14,19 !eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl) 
hexanamide as an off-white powder, MS: 572 (M-H).sup.-. 
EXAMPLE 37 
Compound of formula (In) 
A mixture of 
(3R,11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo-11. 
6.1.0.sup.14,19 
!eicosa-3(4),13(20),14(19),15,17-pentaen-11-ylcarbamoyl)hexanamide (40 mg, 
0.07 mmol) and 10% Pd-C (10 mg) was stirred in a solution of 3% HCOOH in 
ethanol (5 mL) at room temperature for 1 hour. The mixture was filtered 
through a cone of celite and concentrated in vacuo. To the solid residue 
in 1 mL of 50% AcOH/MeOH with stirring was added 5 mL of ether in one 
portion. The off-white powder was then collected by filtration to give 26 
mg (68%) of 
(3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1,6,9-triaza-6-methyltricyclo11.6.1 
.0.sup.14,19 !eicosa-3(4),13(20), 
14(19),15,17-pentaen-11-ylcarbamoyl)hexanamide, MS: 488.5 (MH.sup.+). 
The following compound was similarly prepared: 
(2S,3R,9S)-(N,2)-dihydroxy-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup. 
12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)hexanamide. 
EXAMPLE 38 
Compounds of formula (JJ) 
A. To a solution of (.+-.)-2-hydroxybutanoic acid, sodium salt (2.54 g, 
20.1 mmol) in dry DMF (30 mL) was added benzyl bromide (2.9 mL, 1.2 eq) 
and anhydrous KI (330 mg, 0.1 eq). The suspension was heated at 
100.degree. C. for 24 hours and the DMF was distilled off under reduced 
pressure. The residue was taken up in ether, washed with water and 
saturated Na.sub.2 S.sub.2 O.sub.3, dried (MgSO.sub.4), and concentrated. 
Distillation of the residual oil afforded 3.7 g (95%) of benzyl 
(.+-.)-2-hydroxybutanoate as a colorless oil, b.p. 95.degree. C. (0.45 
Torr). 
B. Alternatively, to a cold (0.degree. C.) suspension of NaH (3.8 g of a 
60% weight dispersion in mineral oil, 95.0 mmol) in THF (50 mL) was added 
a solution of glycolic acid (7.2 g, 95 mmol) in THF (50 mL) dropwise via 
cannula. The resulting solution was warmed to 25.degree. C. and 
concentrated in vacuo. The resulting salt was suspended in DMF (100 mL) 
and treated with KI (1.57 g, 0.1 eq) and benzyl bromide (12.3 mL, 1.1 eq). 
The mixture was heated at 100.degree. C. for 23 hours under argon and the 
DMF was evaporated. The residue was dissolved in ether and washed with 
water, saturated Na.sub.2 S.sub.2 O.sub.3, and brine, and dried over 
MgSO.sub.4. Distillation afforded benzyl glycolate (8.5 g, 54%) as a 
colorless oil, b.p. 85.degree.-87.degree. C. (0.5 Torr). 
EXAMPLE 39 
Compounds of formula (LL) 
A. To a cold (0.degree. C.) solution of benzyl (.+-.)-2-hydroxybutanoate 
(1.75 g, 9.01 mmol) in CH.sub.2 Cl.sub.2 (50 mL) was added 2,6-lutidine 
(1.2 mL, 1.1 eq) followed by triflic anhydride (1.7 mL, 1.1 eq) dropwise. 
After 10 minutes, a solution of L-leucine t-butyl ester (1.7 g, 1 eq) and 
diisopropylethylamine (1.7 mL, 1.1 eq) in CH.sub.2 Cl.sub.2 (30 mL) was 
added dropwise at 0.degree. C. The solution was warmed to 25.degree. C. 
for 36 hours, diluted with CH.sub.2 Cl.sub.2, and washed with saturated 
NaHCO.sub.3 (50 mL). After drying (Na.sub.2 SO.sub.4) and concentration in 
vacuo, the residual oil was flash chromatographed (silica, 5% ethyl 
acetate/hexanes) to separate diastereomers. The less polar diastereomer, 
(1R)-N-(2-benzyloxycarbonyl)propyl-L-leucine t-butyl ester (R.sub.f 0.22, 
5% ethyl acetate/hexanes), and the more polar diastereomer, 
(1S)-N-(2-benzyloxycarbonyl)propyl-L-leucine t-butyl ester (R.sub.f 0.13), 
were further purified individually by HPLC (5% ethyl acetate/hexanes) to 
afford 1.1 g of the more polar diastereomer and 0.78 g of the less polar 
diastereomer, MS(FAB): 364 (MH.sup.+). 
B. In a similar manner, from benzyl glycolate (379 mg, 2.7 mmol), L-leucine 
t-butyl ester (435 mg, 2.7 mmol), 2,6-lutidine (0.35 mL, 2.8 mmol), 
diisopropylethylamine (0.53 mL, 0.28 mmol), and triflic anhydride (0.51 
mL, 2.8 mmol) there was obtained 383 mg (50%) of 
N-benzyloxycarbonyl-methyl-L-leucine t-butyl ester as a colorless oil, 
MS(FAB): 336 (MH.sup.+). 
EXAMPLE 40 
Compounds of formula (Io) 
A. To a solution of (1S)-N-(2-benzyloxycarbonyl)propyl-L-leucine 
t-butyl-ester (143 mg, 0.393 mmol) in CH.sub.2 Cl.sub.2 (3 mL) at 
0.degree. C. was added TFA (0.5 mL). The solution was stirred at 
25.degree. C. for 4 hours and then concentrated in vacuo to yield the salt 
of (1S)-N-(2-benzyloxycarbonyl)propyl-L-leucine (compound of formula 
(MM)), which was then dissolved in DMF (3 mL) with 
(10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (124 mg, 1.1 eq) and HOBT (80 mg, 
1.5 eq). After cooling to 0.degree. C., N-methylmorpholine (60 mL, 1.5 eq) 
and EDCI (113 mg, 1.5 eq) were added. After 18 hours at 25.degree. C., the 
reaction mixture was diluted with 10 mL of ethyl acetate, washed with 
saturated NaHCO.sub.3 (3.times.10 ml) and water (2.times.10 mL), dried 
(Na.sub.2 SO.sub.4), and concentrated. The residue was flash 
chromatographed (silica, 1% MeOH/CH.sub.2 Cl.sub.2) and fractions with 
R.sub.f 0.5 (5% MeOH/CH.sub.2 Cl.sub.2) were collected. Reverse phase HPLC 
afforded 
(2R,1'S,10S)-2-N-(1-benzyloxycarbonyl)-propylamino!-4-methyl-N-(9-oxo-1,8 
-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl) pentanamide (46 mg), MS(FAB): 
575 (MH.sup.+) 
B. In a similar manner, but substituting 
(1R)-N-(2-benzyloxycarbonyl)propyl-L-leucine t-butyl ester (270 mg) for 
(1S)-N-(2-benzyloxycarbonyl)propyl-L-leucine t-butyl ester, there was 
obtained 
(2R,1'R,10S)-2-(N-(1-benzyloxycarbonyl)propylamino!-4-methyl-N-(9-oxo-1,8- 
diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide, (175 mg), 
MS(FAB): 575 (MH.sup.+). 
EXAMPLE 41 
Compounds of formula (Ip) 
A. To a solution of 
(2R,1'S,10S)-2-N-(1-benzyloxycarbonyl)propylamino!-4-methyl-N-(9-oxo-1,8- 
diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide (46 mg) in 
THF/MeOH (1:1, 2 mL) under argon was added 1M barium hydroxide (0.3 mL). 
After 24 hours at 25.degree. C., CO.sub.2 was passed over the solution and 
the resulting precipitate of barium carbonate was filtered off. The 
solvents were removed under reduced pressure and the aqueous residue was 
adjusted to pH 5.5 with 1M HCl. After removing the water, reverse phase 
HPLC afforded 
(2R,1'S,10S)-2-(N'-(1-Carboxy)propylamino!-4-methyl-N-(9-oxo-1,8-diazatric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide, as a white solid, 
MS(FAB): 483 (M-H).sup.-. 
In a similar manner were prepared: 
(2RS,10S)-2-Carboxymethylamino!-2-cyclohexyl-N-(9-oxo-1,8-diazatricyclo10 
.6.1.013,18!nonadeca-12(19),13(18),14,16-tetraen-10-yl)acetanamide, 497 
(M+H).sup.+. 
(2RS,10S)-2-Carboxymethylamino!-3-methyl-N-(9-oxo-1,8-diazatricyclo10.6.1 
.013,18!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentamide, 471 
(M+H).sup.+. 
(2RS,10S)-2-Phosphonylmethylamino!-4-methyl-N-(9-oxo-1,8-diazatricyclo10. 
6.1.013,18!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentamide 
B. In a similar manner, from 
(2R,1'R,10S)-2-N'-(1-benzyloxycarbonyl)propylamino!-4-methyl-N-(9-oxo-1,8 
-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide, 
(2R,1'S,10S)-2-N'-(1-carboxy)propylamino!-4-methyl-N-(9-oxo-1,8-diazatric 
yclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-yl)pentanamide (16 mg) was 
obtained, MS(FAB): 483(M-H).sup.31 . 
C. Proceeding as in the preparation of compound of formula (Io) above, from 
N-(benzyloxycarbonyl)methyl!-L-leucine t-butyl ester (156 mg, 0.465 
mmol), HOBT (94 mg, 1.5 eq), EDCI (134 mg, 1.5 eq), N-methyl-morpholine 
(77 .mu.L), and (10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (133 mg, 1 eq) there obtained the 
crude benzyl ester after flash chromatography (3% MeOH/CH.sub.2 Cl.sub.2). 
The crude benzyl ester was dissolved in THF/MeOH (1:1, 6 mL) and 
hydrolyzed with 1M barium hydroxide (0.9 mL) overnight. Carbon dioxide was 
passed over the solution and the resulting precipitate was filtered off. 
The filtrate was concentrated and the aqueous residue was adjusted to pH 
5.5 with 1M HCl. Reverse phase HPLC afforded 
(2R,10S)-N'-(carboxymethyl)-amino-4-methyl-N-(9-oxo-1,8-diazatricyclo10.6 
.1.0.sup.13,18 !nonadeca-12(19), 13(18),14,16-tetraen-10-yl)pentanamide (17 
mg) as a white solid, MS(FAB): 457 (MH.sup.+). 
EXAMPLE 42 
Compounds of formula (6) 
4-Methyl-2-Methylenepentanoic Acid 
A. To neat ethyl isobutylmalonate (25 g, 0,13 mol) at 0.degree. was slowly 
added ice cold diethylamine (15.1 mL, 0.15 mol). After stirring for 15 
min, formalin (11,1 mL 37% aqueous formaldehyde) was added dropwise. The 
mixture was allowed to stir at 25.degree. for 3 days. The reaction mixture 
was then treated with a solution of 20 g of K.sub.2 CO.sub.3 in 40 mL of 
water and extracted with ether (2.times.100 mL). The ether extracts were 
combined, washed with brine, dried over MgSO.sub.4 and concentrated under 
reduced pressure at 20.degree.. The crude product, ethyl 
4-methyl-2-methylenepentanoate containing some ether, was dissolved in 
absolute ethanol (250 mL) and treated with acetonitrile (250 mL), 1M LiOH 
(9.7 g in 250 mL of water, 0.23 mol). After stirring overnight, the 
organic solvents were evaporated under reduced pressure and the aqueous 
residue was extracted with ethyl acetate (2.times.150 mL). The combined 
extracts were washed with brine, dried over MgSO.sub.4 and concentrated 
under reduced pressure to afford 10.5 g of 4-methyl-2-methylenepentanoic 
acid as a colorless oil. 
B. In a similar manner, the following compounds of formula (Gd) are 
prepared: 
4-Phenyl-2-methylenebutanoic acid; 
3-Cyclohexyl-2-methylenepropanoic acid; 
5-Phenyl-2-methylenepentanoic acid; 
2-Methylenepentanoic acid; and 
3,3-dimethyl-2-methylenebutanoic acid. 
EXAMPLE 43 
Compound of formula (Id) 
(Reverse Hydroxamate) 
A. A solution of 4-methyl-2-methylenepentanoic acid (3.5 g) and 
O-benzylhydroxylamine were heated at 120.degree. for 8 h. The reaction 
mixture was then partitioned between 50 mL of 1.0N NaOH and 50 mL of 
diethyl ether. The aqueous portion was separated, acidified to pH 3 with 
10% HCl and washed with 50 mL of ether. Ion exchange chromatography 
(Dowex-50W) eluting with 20% pyridine/water gave 
2-(benzyloxyaminomethyl)-4-methylpentanoic acid. 
300 MHz .sup.1 H NMR in CDCl.sub.3 : .delta.0.9-1.0 (dd, 6H,CH.sub.3); 
1,25-1,35 (m, 1H, CH); 1,6-1,75 (m, 2H, CH.sub.2); 2.8-2.9 (m, 1H, 
C.sub..alpha. --H); 3.0-3.2 (AB.sub.q, 2H, CH.sub.2 N); 4.7-4.75 
(AB.sub.q, 2H, CH.sub.2 O); 7.3-7.4 (m, 5H, Ph). 
B. Formylation of 2-(benzyloxyaminomethyl)-4-methylpentanoic acid was 
carried out in dichloromethane with formic acid/acetic anhydride to give 
N-formyl-2-(benzyloxyaminomethyl)-4-methylpentanoic acid. Coupling with a 
compound of formula (J): To 
N-formyl-2-(benzyloxyaminomethyl)-4-methylpentanoic acid (175 mg) and (J) 
(230 mg) in 5% pyridine/dichloromethane (30 mL) was added 
4-dimethylaminopyridine (DMPA) (200 mg) and 
1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI) at 
room temperature. The reaction mixture was stirred for 8 h and then 
concentrated, partitioned between 30 mL of ethyl acetate and 30 mL of 20% 
HCl. The organic portion was washed with water (20 mL), 5% NaHCO.sub.3 (20 
mL) and brine, dried over MgSO.sub.4 and concentrated. Purification on 
silica gel, eluting with 50% ethyl acetate/hexane gave the product as a 
mixture of two isomers. Hydrogenolysis in methanol over 10% Pd/C afforded 
(2RS, 10S)-2-N-formyl, 
N-hydroxyaminomethyl!-4-methyl-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19)13(18),14,6-tetraen-10-yl!pentamide, as a mixture of 2 
isomers, MS 455 (M-H).sup.-, (Compound 6). 
In a similar manner were prepared: 
(2RS, 
10S)-2-iso-propoxycarbonylmethyl!-4-methyl-(9-oxo-1,8-diazatricyclo10.6. 
1.0.sup.13,18 !nonadeca-12(19)13(18),14,6-tetraen-10-yl!pentamide, MS 455 
(M+H).sup.+. 
(2RS, 
10S)-2-morpholinocarbethoxymethyl!-4-methyl-(9-oxo-1,8-diazatricyclo10.6 
.1.0.sup.13,18 !nonadeca-12(19)13(18),14,6-tetraen-10-yl!pentamide, MS 555 
(M+H).sup.+. 
EXAMPLE 44 
Compound of Formula (Iq) 
A. Preparation of Formula (PP) 
To a mixture of 2-(phthalimid-2-ylmethyl)-3(R)-isobutylsuccinic acid 
t-butyl ester (3.4 g), N-methylmorpholine (1.92 ml), 
1-hydroxybenzotriazole (1.3 g)-and 
(10S)-10-amino-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraene (2.49 g) in dry DMF (200 mL) at 
0.degree. C. under argon was added EDCI (3.34 g). The resulting mixture 
was stirred overnight, allowing the mixture to rise to ambient 
temperature, and the solvent then removed at 45.degree. C. under high 
vacuum. The residue was stirred vigorously with a mixture of ethyl acetate 
(300 mL) and 0.5N hydrochloric acid (150 ml). The organic layer was washed 
with 0.5N HCl (2.times.150 ml), saturated NaHCO.sub.3 (2.times.150 ml) and 
finally with brine (1.times.150 ml). After drying the organic layer over 
MgSO.sub.4, it was filtered and evaporated to dryness. Purification of the 
residue by flash column chromatography (10% ethyl acetate/methylene 
chloride) gave 
(3R,10S)-2-(phthalimid-2-ylmethyl)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10 
.6.1.0.sup.13.18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester (4.81 g). This compound was obtained as 2.96 g of a less polar 
diasteroisomer, 1.05 g of a more polar diasteroisomer, and 0.8 g of a 
mixture of the two. 
B. Preparation of Formula (Iq) 
To a solution of the less polar isomer of the compound of formula (PP) 
prepared in 42A (2.96 g) in methanol (50 ml) and methylene chloride (50 
ml) at room temperature was added hydrazine (2.8 ml). The mixture was 
stirred overnight, then a further 200 ml of methylene chloride and 300 ml 
of methanol added, followed by silica gel. The solvent was then removed 
under reduced pressure, and the residue of silica gel on which the 
material was adsorbed was loaded onto a silica gel column and flash 
chromatographed. Elution with 4% methanol/methylene chloride gave 2.01 g 
of (3R,10S)-2-(aminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0. 
sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid t-butyl ester (4.81 g). 
C. Hydrolysis of the ester with trifluoroacetic acid as shown below gave 
(3R,10S)-2-(aminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.1 
3,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
471 (MH.sup.+). 
EXAMPLE 45 
Compound of Formula (Ir) 
A. To a solution of 
(3R,10S)-2-(aminomethyl)-s-methyl-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup 
.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid 
t-butyl ester (363 mg) and triethylamine (0.54 ml) in dry methylene 
chloride (20 ml) at 0.degree. C. was added methanesulfonyl chloride (77 
.mu.ml). The resulting mixture was stirred for 2 hours, allowing the 
mixture to rise to ambient temperature, then methylene chloride (100 ml) 
and 0.5N hydrochloric acid (50 ml) added, stirring vigorously. The aqueous 
layer was further extracted with methylene chloride (2.times.75 ml), then 
the combined organic layers washed with brine (100 ml). After drying the 
organic layer over MgSO.sub.4, it was filtered and evaporated to dryness. 
Purification of the residue by flash column chromatography (20-30% ethyl 
acetate/methylene chloride) gave 
(3R,10S)-2-(methylsulfonamidoaminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid t-butyl 
ester as a white solid (211 mg). 
B. To a solution of the compound obtained in A (180 mg) in methylene 
chloride (4 ml) at 0.degree. C. was added trifluoroacetic acid (2 ml). The 
resulting mixture was stirred for 5 hours, allowing the mixture to rise to 
ambient temperature. The solvent was removed under reduced pressure, ethyl 
acetate was added to the residue, and the solution washed with water 
(7.times.30 ml). After drying the organic layer over MgSO.sub.4, it was 
filtered and evaporated to dryness. Crystallization of the residue from 
methanol/ethyl acetate/hexanes gave 
(3R,10S)-2-(methylsulfonamidoaminomethyl)-5-methyl-3-(9-oxo-1,8-diaza-tric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid as a 
white solid (129 mg). 
C. In a similar manner, the following compounds of formula (Ir) were 
prepared: 
(3R,10S)-2-(methoxycarbonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 !nonadeca-12(19),13(18),14, 
16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 527.5 (M-H.sup.+); 
(3R,10S)-2-(ethoxycarbonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
541.5 (M-H.sup.+); 
(3R,10S)-2-(methanesulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo1 
0.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
549.2 (M-H.sup.+); 
(3R,10S)-2-(ethanesulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10 
.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 563 
(M-H.sup.+); 
(3R,10S)-2-(trifluoromethanesulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazat 
ricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
603.3 (M-H.sup.+); 
(3R,10S)-2-(phenylsulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10 
.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
611.1 (M-H.sup.+); 
(3R,10S)-2-(benzylsulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10 
.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
625.2 (M-H.sup.+); 
(3R,10S)-2-(5-(2-pyridyl)thiophen-2-ylsulfonamidomethyl!-5-methyl-3-(9-oxo- 
1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
692.4 (M-H.sup.+); 
(3R,10S)-2-(thien-2-ylsulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricycl 
o10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
617.5 (M-H.sup.+); 
(3R,10S)-2-(2-phenylvinylsulfonamidomethyl)-5-methyl-3-(9-oxo-1,8-diazatric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS 
637.6 (M-H.sup.+); 
(3R,10S)-2-(1-azanaphthyridin-8-ylsulfonamidomethyl)-5-methyl-3-(9-oxo-1,8- 
diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-hexanoic acid, MS 
549.2 (M-H.sup.+); 
(3R,10S)-2-(3-ethylureidomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1 
.0.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid, MS 542.34 (M-H.sup.+); and 
(3R,10S)-2-(acetylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0 
.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid, MS 512 (M-H.sup.+); 
(3R,10S)-2-(8-quinolinesulfonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(5-benzoylaminomethyl-thien-2-yl)sulfonylaminomethyl-5-methyl-3- 
(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(N-methyl-imidazol-2-ylsulfonylaminomethyl)-5-methyl-3-(9-oxo-1, 
8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid, MS: 
612.7 (M-H).sup.- ; 
(3R,10S)-2-(5-pyridin-2-yl-thien-2-ylsulfonylaminomethyl)-5-methyl-3-(9-oxo 
-1,8-diazatricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(benzylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0 
.sup.13,18 !nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic 
acid; 
(3R,10S)-2-(phthalimid-2-ylmethyl-4-cyclopentyl-3-(9-oxo-1,8-diazatricyclo 
10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; 
(3R,10S)-2-(N-phthalimid-2-ylmethyl-5-methyl-3-(9-oxo-1,8-diazatricyclo10. 
6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid; 
(3R,10S)-2-(methanesulfonylaminomethyl)-4-cyclopentyl-3-(9-oxo-1,8-diazatri 
cyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)butanoic acid; and 
(3R,10S)-2-(phenylethylsulfonylaminomethyl)-5-methyl-3-(9-oxo-1,8-diazatric 
yclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanoic acid. 
Similarly prepared is: 
(3R,9S)-2-(methanesulfonamidomethyl)-4-cyclopentyl-3-(8-oxo-1,7-diazatricyc 
lo9.6.1.0.sup.12,17 
!octadeca-11(18),12(17),13,15-tetraen-9-ylcarbamoyl)butanoic acid. 
EXAMPLE 46 
Compound of formula (mm) 
To a solution of N-t-butoxycarbonyl-L-tryptophan, (128 g, 0.42 mol), 
2-(2-aminoethoxy)ethanol (46.42 g, 0.44 mol), 1-hydroxybenzotriazole (60.0 
g, 0.44 mol) in 700 mL of DMF at 0.degree. C. was added DCC (100 g, 0.48 
mol). After stirring at 0.degree. C. for 15 minutes, the mixture was 
stirred at room temperature overnight. The white solids were filtered and 
washed with EtOAc. The filtrate was concentrated under reduced pressure. 
The residue was taken up in ether and a small amount of EtOAc, washed with 
it HCl (3.times.500 mL), saturated NaHCO.sub.3 (3.times.500 mL), and brine 
(3.times.500 mL). The organic layer was dried (MgSO.sub.4), filtered and 
concentrated to give 
2-(S)-t-butoxycarbonylamino-N-2-(2-hydroxy-ethoxy)ethyl!-3-(1H-indol-3-yl 
)-propionamide, 150 g (yield 91%), MS: 392.2 (M+H).sup.+. 
EXAMPLE 47 
Compound of formula (nn) 
To the compound obtained from Example 46 (50 g, 0.128mol), and 
N,N-dimethylpyridine (200 mg, 1%) in 250 mL of 
triethylamine/dichloromethane (1/4) at 0.degree. C. was added 29 g(0.15 
mol) of p-toluenesulfonyl chloride. The mixture was stirred at 0.degree. 
C. for 4 hours. The solvent was removed at 0.degree. C. under reduced 
pressure. The residue was taken up in EtOAc and 1N HCl, and transferred to 
a separatory funnel. The organic layer was isolated and washed with 2% HCl 
repeatedly until the pH of the aqueous layer was about 2, and with 
saturated NaHCO.sub.3 and brine, the organic phase was dried, and 
evaporated to give 60 g (86%) of 
2-(S)-t-butoxycarbonylamino-2-N-12-(2-4'-methylphenylsulfonyloxy)-ethoxy)e 
thyl!-3-(1H-indol-3-yl)-propionamide, MS: 545 (M.sup.+). 
EXAMPLE 48 
Compound of formula (oo) 
To the compound obtained from Example 47 (30 g, 0.055 mol) in CH.sub.2 
Cl.sub.2 (700 mL) added 50% NaOH (200 mL) and tetra-n-butylammonium 
hydrogen sulfate (20.54 g, 0.06 mol). The mixture was stirred vigorously 
at room temperature for 1 hour. The mixture was then transferred to a 
separatory funnel. The organic phase was isolated and washed with brine, 
and dried. After removing solvent, the crude product was further purified 
by column chromatography (5% acetone/EtOAc) and then recrystallized from 
ether/hexanes to give 4.4 g (21%) of 
t-butoxy-carbonylamino-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-8-one, MS: 374 (M+H).sup.+, melting 
point 177.5.degree.-178.degree. C., .alpha.!.sub.D =-0.852 (MeOH, c=0.983 
g/100 mL). 
EXAMPLE 49 
Compound of formula (ff) 
To the compound obtained from Example 48 (15 g, 0.04 mol) at 0.degree. C. 
added 40% TFA/CH.sub.2 Cl.sub.2 (50 mL). The mixture was stirred at room 
temperature for 3.5 hours. The solvents were removed under reduced 
pressure. To the remaining residue added toluene (50 mL), and the solvent 
was again removed. This sequence was repeated twice. The residue was dried 
in vacuo overnight, and partitioned between EtOAc/1N NaOH. The two layers 
were separated. The aqueous layer was extracted with EtOAc (3.times.100 
mL), and the combined EtOAc phase was washed with 1N NaOH (3.times.100 mL) 
and brine (1.times.100 mL). The solvent was dried (MgSO.sub.4) and 
evaporated to give 11 g(100%) of 
9-(S)-amino-4-oxa-1,7-diaza-tricycloc9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-8-one. 
EXAMPLE 50 
Compound of formula (gg) 
A. To 4-pentenoic acid (28 g, 0.28 mol) in 1L of dry THF at -78.degree. C. 
was added Et.sub.3 N (52.6 mL, 0.38 mol). Pivaloyl chloride (42.5 mL, 0.32 
mol) was added dropwise. After the addition was completed, the reaction 
mixture was warmed to 0.degree. C. and stirred for an additional hour at 
0.degree. C., and then cooled to -78.degree. C. 
In a separate flask, S-4-benzyl-2-oxazolidinone (43 g, 0.24 mol) in dry THF 
(1 L) at -78.degree. C. added triphenylmethane (20mg) as an indicator. A 
solution of n-Buli in hexane (1.6M) was added dropwise until a yellow 
color persisted. The solution was stirred for another 30 minutes. This 
solution was then slowly transferred to the above just formed mixed 
anhydride, and stirred for one hour. The reaction was quenched with 500 mL 
of dilute NH.sub.4 Cl solution. THF was removed and the remaining solution 
was extracted with ether (3.times.500 mL). The combined ether extracts 
were dried over MgSO.sub.4 and concentrated to give 64.9 g of 
(S)-4-benzyl-3-pent-4-enoyl-oxazolidin-2-one, MS: 259 (M.sup.+). 
B. To (S)-4-benzyl-3-pent-4-enol-oxazolidin-2-one (64.9 g, 0.25 mol) in dry 
THF (700 mL) at -78.degree. C. was added sodium bis(trimethylsilyl)amide 
in THF (1.0M, 275mL, 0.28mol) dropwise. After stirring for an additional 
hour at -78.degree. C., t-butylbromoacetate (44.3 mL, 0.30mol) was added 
dropwise. The is mixture was stirred for 4 hours at -78.degree. C., and 
was then quenched with dilute NH.sub.4 Cl solution (200 mL). After removal 
of THF, the aqueous layer was extracted with ether (3.times.300 mL). The 
ether layers were washed with brine (200 mL), dried and evaporated to give 
109.7g of crude product. After column chromatography purification (5% 
acetone/hexanes), 41.3 g of pure 
(R)-3-(S-4-benzyl-2-oxo-oxazolidine-3-carbonyl)hex-5-enoic acid tert-butyl 
ester was obtained, MS: 373 (M.sup.+). 
C. To (R)-3-(S-4-benzyl-2-oxo-oxazolidine-3-carbonyl)-hex-5-enoic acid 
tert-butyl ester (25 g, 0.067mol) in 300 mL of THF/water (1/1) at 
0.degree. C. was added lithium hydroxide (11.25 g, 0.268 mol) and hydrogen 
peroxide (30%, 31.1 mL, 0.268 mol). After stirring at 0.degree. C. for 20 
minutes, the reaction mixture was stirred at room temperature for 2 hours. 
THF was removed, and the remaining solution was acidified to pH 2, 
saturated with NaCl, and extracted with EtOAc (2.times.150 mL). The 
combined EtOAc extracts were extracted with 10% K.sub.2 CO.sub.3 
(4.times.30 mL). The combined K.sub.2 CO.sub.3 layers were washed with 
Et.sub.2 O (2.times.100 mL). To the remaining KCO.sub.3 solution, added 
EtOAc (200 mL) and the solution was acidified to pH 2 at 0.degree. C. 
After saturated with NaCl, the two layers were separated. The aqueous 
layer was extracted with EtOAc (3.times.100 mL). The combined EtOAc 
solution was dried and evaporated to give pure 2-(R)-allyl-succinic acid 
4-t-butyl ester, MS: 215 (M+H.sup.+). 
EXAMPLE 51 
Compound of formula (hh) 
To a solution of 2-(R)-allyl-succinic acid 4-t-butyl ester (5 g, 0.00234 
mol), 9-(S)-amino-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-8-one (6,38 g, 0.00234mol) in 50 mL DMF 
added HOBT (3.47 g, 0.026 mol), DMAP (80 mg), N-methylmorpholine (2.84 g, 
0.028 mol), and EDCI (6.69 g, 0.035 mol). The mixture was stirred at room 
temperature overnight. The reaction mixture was diluted with EtOAc (300 
mL) and washed with brine (2.times.100 mL), saturated NaHCO.sub.3 
(2.times.100 mL) and brine (1.times.100 mL), and dried (MgSO.sub.4). 
Removal of the solvents gave 9 g of crude product. Column chromatographic 
purification (50% EtOAc/CH.sub.2 Cl.sub.2) gave 7.5 g of pure 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-hex-5-enoic acid t-butyl 
ester, MS: 469(M.sup.+). 
EXAMPLE 52 
Compound of formula (ii) 
The compound obtained from Example 51 (1.5 g, 3.2 mmol), m-iodophenol 
(0.70g, 3.2 mmol), NaHCO.sub.3 (0.672 g, 8 mmol), n-tetrabutylammonium 
chloride (0.89 g, 3.2 mmole) and Pd(OAc).sub.2 (72 mg) in 10 mL DMF was 
heated for 15 minutes at 90.degree. C. The solution was diluted with 50 mL 
EtOAc, and washed with brine (4.times.25mL), dried and evaporated. The 
crude product was purified by column chromatography (50% EtOAc/CH.sub.2 
Cl.sub.2) to give 1.5 g of 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-(3-hydroxyphenyl)-hex-5 
-enoic acid t-butyl ester, MS: 562.4 (M+H).sup.+. 
EXAMPLE 53 
Compounds of formula (Iv') 
The compound obtained from Example 52 (1.5 g) in 4 mL EtOH was hydrogenated 
with 1.4 g Pd/C (10l) for 12 hours. The solution was filtered through a 
pad of Celite, washed with EtOH (10 mL). The filtrate was evaporated to 
give 1.34 g (89%) of 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-(3-hydroxyphenyl)-hexan 
oic acid t-butyl ester, MS: 564.2 (M+H).sup.+. 
EXAMPLE 54 
Compounds of formula (Iv) 
The compound obtained from Example 53 (1.34 g, 0.0024 mol) and thioanisole 
(2.58 g, 0.024 mol) in 15 mL 30% TFA/CH.sub.2 Cl.sub.2 were stirred at 
room temperature for 1.5 hours. The solvents were removed. Toluene (50 mL) 
was added to the remaining residue, and then removed under reduced 
pressure. The procedure was repeated several times to remove any remaining 
TFA. The remaining solid residue was stirred in hot EtOAc (10 mL) for 10 
minutes, cooled to room temperature and filtered and washed with ether to 
give 400 mg of pure 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-6-(3-hydroxyphenyl)-hexa 
noic acid, MS: 508.2 (M+H).sup.+. 
Following the procedures as described in Examples 51-54, the following 
compounds are similarly prepared: 
(3R,9S)-6-(4-hydroxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 
562.2 (M-H.sup.-); 
(3R,9S)-6-(4-methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 
520.1 (M.sup.+); 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-6-4-(3-piperidin-1-yl-p 
ropoxy)phenyl!-hexanoic acid, MS: 631.1 (M-H.sup.-); 
(3R,9S)-6-4-(3-dimethylamino-propoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diaza-tri 
cyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 591.1 
(M-H.sup.-); 
(3R,9S)-6-(4-(2-dimethylamino-ethoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diaza-tric 
yclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 577.1 
(M-H.sup.-); 
(3R,9S)-6-(4-cyano-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 
515.1 (M-H.sup.-); 
(3R,9S)-6-naphthalen-2-yl-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12,1 
7 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 
542.3 (M+H+); 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-6-(4-pyrrol-1-yl-phenyl) 
-hexanoic acid, MS: 557 (M+H).sup.+ ; 
(3R,9S)-6-(4-hydroxy-3-methyl-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6. 
1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic 
acid, MS: 522.3 (M+H.sup.+); 
(3R,9S)-6-(4-amino-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, MS: 
505.1 (M-H.sup.-); 
(3R,9S)-6-(4-acetylamino-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.s 
up.12,17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic acid, 
MS: 547.8 (M-H.sup.-); 
(3R,9S)-6-4-(2-hydroxy-ethoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazatricyclo9. 
6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-hexanoic 
acid, MS: 550.1 (M-H.sup.-); and 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-yl-carbamoyl)-6-4-(2-pyrrolidin-1-yl- 
ethoxy)-phenyl!-hexanoic acid, MS: 605.5 (M+H.sup.+). 
EXAMPLE 55 
Compounds of formulae (Is) & (It) 
A. To a solution of 2-(R)-isobutyl-succinic acid 4-t-butyl ester (317 mg, 
1.45 mmol), 9-amino-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-8-one (330 mg, 1.21 mmol) in 30 mL DMF 
added HOBT (163 mg, 1.2 mmol), DMAP (50 mg), N-methylmorpholine (0.16 mL, 
1.45 mmol), and EDCI (348 mg, 1.8 mmol). The mixture was stirred at room 
temperature overnight. After removal of DMF under reduced pressure, the 
residue was taken up in EtOAc (60 mL) and brine (20 mL). The organic layer 
was washed with brine (2.times.50 mL) and saturated NaHCO.sub.3 
(2.times.50 mL) and dried. After evaporation of the solvent, the crude 
product thus obtained was purified on column chromatograph (30-50% 
EtOAc/CH.sub.2 Cl.sub.2) to give 466 mg of pure 
(3R,9S)-5-methyl-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-hexanoic acid t-butyl 
ester. 
B. The t-butyl ester compound obtained from the above step (460 mg, 0.9 
mmol) was stirred in 15mL of a trifluoroacetic acid/methylene chloride 
solution at room temperature overnight. The solvents were removed. 
Methylene chloride was added to the remaining residue, and then removed. 
This procedure was separated several times to remove any remaining TFA. 
The resulting residue was crystallized from EtOAc/CH.sub.2 Cl.sub.2 
/hexanes (4:1:3) to give 100 mg of 
(3R,9S)-5-methyl-3-(8-oxo-1,7-diazatricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid, melting 
point, 193.degree.-194.degree. C. 
Similarly prepared are the following compounds: 
(3R,9S)-3-cyclobutylmethyl-N-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.12, 
17 !octadeca-11(18)12,14,16-tetraen-9-yl)-succinamic acid, MS: 456.2 
(M+H).sup.+ ; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid, 
MS: 493 (M.sup.+); 
(3R,9S)-5-(4-chloro-phenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-pentanoic acid, MS: 
526.3 (M-H.sup.-); 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-6-pyridin-4-yl-hexanoic 
acid, melting point, 190.degree.-193.degree. C.; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-5-phenyl-pentanoic acid, 
MS: 478.3 (M+H).sup.+ ; 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-6-phenyl-hexanoic acid, 
MS: 492.3 (M+H).sup.+ ; and 
(3R,9S)-5-(4-methoxy-phenyl)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18)12,14,16-tetraen-9-yl carbamoyl)-pentanoic acid, MS: 
508 (M+H).sup.+. 
EXAMPLE 56 
Compounds of formula (Iu) 
(3R,9S)-6-4-(3-hydroxy-propoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diazatricyclo9 
.6.1.0.sup.12,17 !octadeca-11(18) 12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid t-butyl ester (1.56 g, 2.5 mmol) was dissolved in 50 mL EtOH 
saturated with HCl. The mixture was stirred at room temperature overnight. 
The solvent was then removed, and the crude product was purified by column 
chromatography (50% EtOAc/methylene chloride-80% EtOAc/methylene chloride) 
to give 0.88 g (59%) of pure 
(3R,9S)-6-4-(3-hydroxy-propoxy)-phenyl!-3-(8-oxo-4-oxa-1,7-diaza-tricyclo 
9.6.1.0.sup.12,17 !octadeca-11(18)12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid ethyl ester, MS: 594.0 (M+H).sup.+. 
Similarly prepared are the following compounds: 
(3R,9S)-5-(4-chloro-phenoxy)-3-(8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18)12,14,16-tetraen-9-ylcarbamoyl)-pentanoic acid ethyl 
ester, MS:556.3 (M+); and 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18)12,14,16-tetraen-9-ylcarbamoyl)-5-phenoxy-pentanoic acid 
ethyl ester, MS:521 (M.sup.+). 
EXAMPLE 57 
Compounds of formula (Iw) 
A. To 
(3R,9S)-6-4-hydroxyphenyl!-3-8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup.1 
2,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid t-butyl 
ester (1.0 g, 1.72 mmol) in DMF (20 mL) at 0.degree. C. was added 
3-iodopropanol(363mg, 1.95 mmol) and cesium carbonate (636 mg, 1.95 mmol). 
The mixture was then stirred at room temperature for 2.5 hours. DMF was 
removed under reduced pressure. The remaining residue was taken up in 
EtOAc (70 mL) and brine (40 mL). The EtOAc layer was washed with brine and 
dried (MgSO,). Removal of solvents to give pure 
(3R,9S)-6-4-(3-hydroxy-propoxy)-phenyl!-3-8-oxo-4-oxa-1,7-diazatricyclo 
9.6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid t-butyl ester (1.1 g, 100%), MS: 622.4 (M+H.sup.+). 
B. The compound obtained from the above step was then converted to the 
corresponding acid compound, 
(3R,9S)-6-4-(3-hydroxypropoxy)-phenyl!-3-8-oxo-4-oxa-1,7-diaza-tricyclo 
9.6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid, following the procedure as described in Example 55B. The resulting 
compound had MS: 564.9 (M-H.sup.-) and 566.1 (M+H.sup.+). 
Similarly prepared are the following compounds: 
(3R,9S)-6-4-(2-methoxy-ethoxy)-phenyl!-3-8-oxo-4-oxa-1,7-diazatricyclo9. 
6.1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid, MS: 564.2 (M-H.sup.-); 
(3R,9S)-6-4-benzyloxy-phenyl!-3-8-oxo-4-oxa-1,7-diazatricyclo9.6.1.0.sup 
.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid, MS: 
598.3 (M+H+); 
(3R,9S)-6-4-(4-amino-butoxy)-phenyl!-3-8-oxo-4-oxa-1,7-diazatricyclo9.6. 
1.0.sup.12,17 !octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid, MS: 579.3 (M+H.sup.+); and 
(3R,9S)-3-8-oxo-4-oxa-1,7-diaza-tricyclo 9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-4-(pyridin-4-ylmethoxy 
)-phenyl!hexanoic acid, MS: 599.2 (M+H.sup.+), melting point, 
169.5.degree.-171.2.degree. C. 
EXAMPLE 58 
Compounds of Formula (I) wherein m and n are 2; A is oxygen; R.sup.1 is 
--CH.sub.2 --R.sup.4 where R.sup.4 is hydroxyaminocarbonyl 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl)-hexanoic 
acid was coupled with O-benzylhydroxyamine according to the procedure 
described in Example 36 to give 
(3R,9S)-N-benzyloxy-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl)-hexanamid 
e. Following the procedure described in Example 37, this compound was 
further converted to 
(3R,9S)-N-hydroxy-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl)-hexanamid 
e, MS: 506 (M+H).sup.+ ; melting point: 224.degree.-225.degree. C. 
EXAMPLE 59 
Salts of Compounds of Formula (I) 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12 
(17),13,15-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic acid was 
converted to the corresponding trifluoroacetic acid salt by stirring the 
compound in 15% trifluoroacetic acid/methylene chloride for 10 minutes. 
The solvents were removed. Methylene chloride was added to the residue. 
The solvent was then removed. This procedure was repeated several times to 
remove any trace of trifluoroacetic acid. The product obtained has melting 
point of 158.degree.-160.degree. C. 
Similarly prepared are the following compounds: 
(3R,9S)-3-(8-oxo-1,7-diaza-tricyclo 9.6.1.0.sup.12,17 !octadeca-11(18),12 
(17),13,15-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic acid 
trifluoroacetate salt; 
(3R,10S)-3-(9-oxo-1,8-diaza-tricyclo10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-6-pyridin-3-yl-hexan 
oic acid trifluoroacetate salt; and 
(3R,10S)-3-(9-oxo-1,8-diaza-tricyclo 10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)-6-pyridin-4-yl-hexan 
oic acid trifluoroacetate salt. 
EXAMPLE 60 
Conversion of Salts of Compounds of Formula (I) to the Corresponding Free 
Base 
(3R,9S)-Ethyl-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoate 
hydrochloride salt was stirred in CH.sub.2 Cl.sub.2 /saturated Na.sub.2 
CO.sub.3 for 10 minutes. The organic layer was separated, dried, and 
evaporated. The crude product was crystallized from CH.sub.2 Cl.sub.2 
/hexanes to give 
(3R,9S)-ethyl-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoate, 
melting point 203.degree.-205.degree. C. 
EXAMPLE 61 
This example illustrates the preparation of representative pharmaceutical 
compositions for oral administration containing a compound of formula (I), 
or a pharmaceutically acceptable salt thereof, e.g., 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo10.6.1.0.sup.13,18 
!-nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide: 
______________________________________ 
A. Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
20.0% 
Lactose 79.5% 
Magnesium stearate 
0.5% 
______________________________________ 
The above ingredients are mixed and dispensed into hard-shell gelatin 
capsules containing 100 mg each, one capsule would approximate a total 
daily dosage. 
______________________________________ 
B. Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
20.0% 
Magnesium stearate 
0.9% 
Starch 8.6% 
Lactose 79.6% 
PVP (polyvinylpyrrolidine) 
0.9% 
______________________________________ 
The above ingredients with the exception of the magnesium stearate are 
combined and granulated using water as a granulating liquid. The 
formulation is then dried, mixed with the magnesium stearate and formed 
into tablets with an appropriate tableting machine. 
______________________________________ 
C. Ingredients 
______________________________________ 
Compound of formula (I) 
0.1 g 
Propylene glycol 
20.0 g 
Polyethylene glycol 400 
20.0 g 
Polysorbate 80 1.0 g 
Water q.s. 100 
mL 
______________________________________ 
The compound of formula (I) is dissolved in propylene glycol, polyethylene 
glycol 400 and polysorbate 80. A sufficient quantity of water is then 
added with stirring to provide 100 mL of the solution which is filtered 
and bottled. 
______________________________________ 
D. Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
20.0% 
Peanut Oil 78.0% 
Span 60 2.0% 
______________________________________ 
The above ingredients are melted, mixed and filled into soft elastic 
capsules. 
EXAMPLE 62 
This example illustrates the preparation of a representative pharmaceutical 
formulation for parenteral administration containing a compound of formula 
(I), or a pharmaceutically acceptable salt thereof, e.g., 
(3R,11S)-N-hydroxy-5-methyl-3-(0-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide: 
______________________________________ 
Ingredients 
______________________________________ 
Compound of formula (I) 
0.02 g 
Propylene glycol 20.0 g 
Polyethylene glycol 400 
20.0 g 
Polysorbate 80 1.0 g 
0.9% Saline solution q.s. 100 
mL 
______________________________________ 
The compound of formula (I) is dissolved in propylene glycol, polyethylene 
glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline 
solution is then added with stirring to provide 100 mL of the I.V. 
solution which is filtered through a 0.2 A membrane filter and packaged 
under sterile conditions. 
EXAMPLE 63 
This example illustrates the preparation of a representative pharmaceutical 
composition in suppository form containing a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, e.g., 
(10S)-2-mercaptomethyl-4-methyl-N-(9-oxo-1,8-diazatricyclo-10.6.1.013,18! 
nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)pentanamide: 
______________________________________ 
Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
1.0% 
Polyethylene glycol 1000 
74.5% 
Polyethylene glycol 4000 
24.5% 
______________________________________ 
The ingredients are melted together and mixed on a steam bath, and poured 
into molds containing 2.5 g total weight. 
EXAMPLE 64 
This example illustrates the preparation of a representative pharmaceutical 
formulation for insufflation containing a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, e.g., 
(10S)-4-methyl-2-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18), 
14,16-tetraen-10-ylcarbamoyl)pentyl-(quinolin-2-ylthiomethyl)phosphinic 
acid: 
______________________________________ 
Ingredients % wt./wt. 
______________________________________ 
Micronized compound of formula (I) 
1.0% 
Micronized lactose 99.0% 
______________________________________ 
The ingredients are milled, mixed, and packaged in an insufflator equipped 
with a dosing pump. 
EXAMPLE 65 
This example illustrates the preparation of a representative pharmaceutical 
formulation in nebulized form containing a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, e.g., 
(3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diazatricyclo-10.6.1.0.sup.13,18 
!nonadeca-12(19),13(18),14,16-tetraen-10-ylcarbamoyl)hexanamide: 
______________________________________ 
Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
0.005% 
Water 89.995% 
Ethanol 10.000% 
______________________________________ 
The compound of formula (I) is dissolved in ethanol and blended with water. 
The formulation is then packaged in a nebulizer equipped with a dosing 
pump. 
EXAMPLE 66 
This example illustrates the preparation of a representative pharmaceutical 
formulation in aerosol form containing a compound of formula (I), or a 
pharmaceutically acceptable salt thereof, e.g., 
(3R,11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo11.6.1.0.sup.14,19 
!eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide: 
______________________________________ 
Ingredients % wt./wt. 
______________________________________ 
Compound of formula (I) 
0.10% 
Propellant 11/12 98.90% 
Oleic acid 1.00% 
______________________________________ 
The compound of formula (I) is dispersed in oleic acid and the propellants. 
The resulting mixture is then poured into an aerosol container fitted with 
a metering valve. 
EXAMPLE 67 
In vitro assay 
Fibroblast type I collagenase was purified from the serum-free culture 
medium of GM0010A cells, stimulated with PMA, by heparin and 
zinc-chelating sepharose columns followed by FPLC (MONO S column). The 
enzyme was activated by incubation with trypsin. 
Type IV collagenase was purified from the serum-containing culture medium 
of fibroblast (GM0010A) cells by zinc-chelating and gelatin-sepharose 
columns, followed by FPLC (MONO S column). The enzyme was shown to be 
homogeneous by SDS-PAGE. The enzyme was activated by incubation with 1 
mmol APMA for 1 hr at 35.degree.-37.degree. C. 
Compounds of formula (I) were dissolved in DMSO and added to a cuvette 
containing 0.2 .mu.g Type I or 0.03 .mu.g Type IV collagenase in 1 ml TC 
buffer (20 mM Tris, 5mM CaCl.sub.2, pH 7.5) (2% DMSO final concentration). 
The concentrations of the compounds of formula (I) were chosen such that 
there was at least one data point for every 20% change in activity. Enzyme 
and compounds were permitted to pre-incubate 3 min at 37.degree. C. To 
initiate the reaction, N-(7-dimethylamino-4-methyl)coumarinyl ("DACM") 
(Sigma) and thiopeptide (Ac-Pro-Leu-Gly-S-"Leu"-Leu-Gly-OEt, Bachem 
Bioscience Inc.) were added to 20 .mu.M each. The fluorescence was 
recorded with excitation and emission wavelengths of 395 and 485 nm, 
respectively. Each data point is the average of duplicate experiments. At 
least six data points, expressed as change in fluorescence per minute 
versus compound concentration were analyzed using the IC.sub.50 fit in the 
program, Enzfitter. 
Compounds of formula (I) exhibited the ability to inhibit the collagenases 
when tested in this assay. 
EXAMPLE 68 
In vitro assay 
This assay determines if the compounds of formula (I) inhibit the release 
of .sup.35 S-labelled glycosaminoglycans (GAG's) from cartilage explants. 
Small cartilage explants (3 mm diameter) were prepared from freshly 
sacrificed bovine knee joints and labeled with .sup.35 SO.sub.4. .sup.35 
S-labelled glycosaminoglycans (GAG's) are released into the culture medium 
in response to the addition of rhIL-1-alpha, which induces the expression 
of chondrocyte matrix metalloproteases (MMP's), including stromelysin and 
collagenase. The percent inhibition of labeled GAG's was corrected for 
spontaneous release in the absence of rhlL-1-alpha. Results for each group 
represent the mean .+-. the S.E.M. for five explants. 
Compounds of formula (I), when tested in this assay, displayed the ability 
to inhibit the release of .sup.35 S-labelled GAG's from cartilage 
explants. 
EXAMPLE 69 
In vitro assay 
An in vitro fetal rat long bone model was used to study the anti-bone 
resorptive effect of the compounds of formula (I). Bovine PTH was used to 
induce bone resorption in vitro. The bone resorptive effects were 
expressed by the amounts of .sup.45 Ca released from the .sup.45 Ca 
pre-labelled fetal rat long bones into the culture medium. The inhibitory 
effect of the compounds of formula (I) against bovine PTH induced bone 
resorption was expressed as mean percent inhibition.+-.sem. 
.sup.45 Ca-prelabelled fetal rat long bones (from forearms) were dissected 
and cultured in Linbro dishes at 37.degree. C. overnight BGJb medium, 
supplemented with 1 mg/ml BSA. There were five pairs of bones in each 
group. The compounds of formula (I) were dissolved in ethanol first, then 
diluted to various concentrations and added simultaneously with Bovine PTH 
(1-34) at 1.times.10.sup.8 M on Day 1. The ethanol concentrations in the 
compound solutions were less than 0.05% which did not interfere with the 
assay. The assay was terminated on Day 6 with one media change on Day 3. 
At the end of each medium change, the .sup.45 Ca present in the culture 
medium was counted. The remaining bones were digested with 0.1N HCl and 
the .sup.45 Ca presented in the bone digest was also counted. The results 
are expressed as % of the total .sup.45 Ca released from each pair of 
bones. Bovine PTH at 1.times.10.sup.-8 M induces bone resorption to the 
maximum level which is set as 100% and this concentration was used as 
standard. The level of base line bone resorption in the presence of medium 
only was set as 0%. All compound-treated groups were compared with bovine 
PTH (1-34) at 1.times.10.sup.-8 M. The concentration at which a compound 
inhibited bone resorption by 50% was defined as IC.sub.50. 
The compounds of formula (Ia) exhibited the ability to inhibit bovine 
PTH-induced bone resorption in this assay. 
EXAMPLE 70 
In vitro Assay 
A. Isolation of MMPs for Assays 
The catalytic domain of human collagenase-l was expressed as a fusion 
protein with ubiquitin in E. Coli (Gehring, E. R. et al., J. Biol. Chem., 
270, 22507, (1995)). After purification of the fusion protein, the 
fibroblast collagenase-1 catalytic domain was released by treatment with 1 
mM of aminophenylmercuric acetate (APMA) for 1 hour at 37.degree. C. and 
purified by zinc chelate chromatography. 
Human collagenase-2 and gelatinase B were isolated in active form from 
buffy coats (Mookhtiar, K. A. et al., Biochemistry, 29, 10620, (1990)). 
The propeptide and catalytic domain portion of human collagenase-3 was 
expressed in E. Coli as an N-terminal fusion protein with ubiquitin. After 
purification, the catalytic domain was obtained by treatment with 1 mM 
APMA for 1 hour at 37.degree. C., and purified by zinc chelate 
chromatography. 
Rat collagenase-3 was purified in active form from the culture media of 
uterine smooth muscle cells (Roswit, W. T. et al., Arch. Biochem. 
Biophys., 225, 285-295 (1983)). 
The catalytic and fibronectin-like portion of human progelatinase A was 
expressed as a fusion protein with ubiquitin in E. Coli. Assays were 
carried out on autolytically activated material. Rat progelatinase A was 
purified from the culture media of interleukin-1 stimulated keratinocytes 
and activated by treatment with 1 mM APMA for 1 hour at 37.degree. C., and 
subsequently dialyzed to remove excess APMA. Human prostromelysin-1 was 
purified from the culture medium of synovial fibroblasts by affinity 
chromatography using an immobilized monoclonal antibody. The zymogen was 
activated by treatment with trypain (1.5 .mu.g/ml) for 1 hour at 
23.degree. C. to give a mixture of 45 and 28 kD species. The catalytic 
domain of human stromelysin was prepared by expression and purification of 
prostromelysin-1 from E. Coli and activated with 1 mM APMA for I hour at 
37.degree. C., followed by dialysis. Rat prostromelysin-1was expressed in 
Chinese Hamster Ovary cells and purified from the culture media. It was 
activated by 1 mM APMA for 1 hour at 37.degree. C., followed by dialysis. 
Human promatrilysin was expressed and purified from Chinese Hamster Ovary 
cells (Barnett, J. et al., Prot. Expres. Pur., 5, 27, (1994)). The zymogen 
was activated by treatment with 1 mM APMA for 1 hour at 37.degree. C., and 
purified by zinc chelate chromatography. 
Compounds of formula (I) exhibited the ability to inhibit the collagenases 
when tested in this assay. 
B. In Vitro Assay Procedure 
Assays were performed in assay buffer (50 mM Tricine pH 7.5, 200 mM sodium 
chloride, 10 mM calcium chloride, 0.005% Brij-35) containing 2.5% methyl 
sulfoxide (DMSO) once the substrate and inhibitor were diluted into it. 
Stock solutions of inhibitors were prepared in 100% DMSO. Stock solutions 
of the substrate were prepared in 100% DMSO at a concentration of 2 mM. 
The assay method was based on the hydrolysis of 
MCA-Pro-Leu-Gly-Leu-DPA-Ala-Arg-NH.sub.2 (Bachem, Inc.) at 37.degree. C. 
(Knight, C. G. et al., FEBS, 296, 263-266 (1992)). The fluoroscence 
changes were monitored with a Perkin-Elmer LS-50B fluorimeter using an 
excitation wavelength of 328 nm and an emission wavelength of 393 nm. The 
substrate concentration, S!, used in the assays was 10 .mu.M. The 
inhibitor was diluted into the assays from solution in 100% DMSO and 
controls substituted an equal volume of DMSO so that the final DMSO 
concentration from inhibitor and substrate dilutions in all assays was 
2.5%. The inhibition results are expressed as the inhibitor concentration 
that produced 50% inhibition (IC.sub.50) of the activity in the control 
(non-inhibited) reaction. 
______________________________________ 
Compound 
IC.sub.50 
______________________________________ 
A 8.8 nM 
B 4.2 nM 
C 0.7 nM 
D 3.9 nM 
E 4.8 nM 
F 0.9 nM 
______________________________________ 
A: (3R,9S)3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic 
acid 
B: (3R,9S)3-(8-oxo-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca11(18),12(17),13,15-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexano 
c acid 
C: 
(3R,9S)6-4(2-methoxy-ethoxy)phenyl3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6. 
.0.sup.12,17 !octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid 
D: 
(3R,9S)6-(4-methoxy-phenyl3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.1 
,17 !octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic acid 
E: 
(3R,9S)6-4(2-hydroxy-ethoxy)-phenyl3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6 
1.0.sup.12,17 !octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic aci 
F: 
(3R,9S)6-4(3-hydroxy-propoxy)-phenyl3-(8-oxo-4-oxa-1,7-diaza-tricyclo9. 
.1.0.sup.12,17 !octadeca11(18),12,14,16-tetraen-9-ylcarbamoyl)-hexanoic 
acid 
Example 71 
In Vitro Assay 
This assay determines the ability of the compounds of formula (I) to 
inhibit the degradation of the collagen matrix (as judged by release of 
hydroxyproline), and proteoglycan (as judged by the release of .sup.35 
S-labelled glycosaminoglycans) from cartilage explants. 
Small cartilage explants (3mm diameter) were prepared from freshly 
sacrificed bovine knee joints and labelled with .sup.35 SO.sub.4. .sup.35 
S-labelled glycosaminoglycans (GAG's) and collagen fragments are released 
into the culture medium in response to the addition of rhIL-1-alpha, which 
induces the expression of chondrocyte matrix metalloproteases (MMP's), 
including stromelysin and collagenase. The percent inhibition of 
hydroxyproline and GAG's released was corrected for spontaneous release in 
the absence of rhIL-1-alpha. 
Compounds of formula (I), when tested in this assay, displayed the ability 
to inhibit the release of both collagen fragments and .sup.35 S-labelled 
GAG's from cartilage explants. 
EXAMPLE 72 
In Vitro Assay 
The cartilage plug implantation assay measures the destruction of the 
collagen matrix of a cartilage plug implanted in a rat (Bishop, J. et al., 
J. Pharm. Tox. Methods, 30, 19, (1993)). 
Previously frozen bovine nasal cartilage plugs weighing approximately 20 mg 
were embedded in polyvinyl sponges impregnated with Mycobacterium 
tuberculosis and implanted subcutaneously in female Lewis rats. Dosing was 
begun 9 days after implantation and plugs were harvested about one week 
later. The plugs were weighed, hydrolyzed, and the hydroxyproline content 
measured. Efficacy was determined by the comparison of the 
compound-treated groups with vehicle treated controls. 
The compounds of formula (I) exhibited the ability to inhibit the 
degradation of the cartilage plugs in this assay. 
EXAMPLE 73 
Toxicity 
Female rats were administered oral doses of 75 and 200 mg/Kg/day of 
(3R,9S)-3-(8-oxo-4-oxa-1,7-diaza-tricyclo9.6.1.0.sup.12,17 
!octadeca-11(18),12,14,16-tetraen-9-ylcarbamoyl)-6-pyridin-4-yl-hexanoic 
acid for 10 days. No treatment related pathological changes were present 
at either of the doses given.