Cyclic Antiplatelet peptides with pseudo-bond

The present invention relates to cyclic peptide analogs containing a pseudo-bond, useful as platelet aggregation inhibitors. An example of a compound of this invention includes Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H. These compounds inhibit the binding of fibrinogen to the platelet GPIIb-IIIa integrin receptor which inhibits platelet aggregation and therefore these compounds act as potent antithrombotics.

FIELD OF THE INVENTION 
The present invention relates to conformationally restrained peptide 
analogs as platelet aggregation inhibitors. These compounds inhibit the 
binding of fibrinogen to the platelet GPIIb-IIIa integrin receptor which 
inhibits platelet aggregation and therefore these compounds act as potent 
antithrombotics. 
BACKGROUND OF THE INVENTION 
Platelets occur in whole blood and are an integral component of thrombus 
formation and blood coagulation. Glycoprotein IIb-IIIa, a member of the 
integrin superfamily, is found on the platelet surface and participates in 
platelet function by interacting with proteins such as fibrinogen, which 
contain the amino acid sequence Arg-Gly-Asp. Various factors activate the 
GPIIb-IIIa receptor allowing interaction with fibrinogen and stimulating 
platelet aggregation and thrombus formation. A compound which blocks the 
interaction of GPIIb-IIIa with Arg-Gly-Asp containing peptides such as 
fibrinogen would antagonize platelet activation by any stimulus and would 
be an important anti-thrombotic agent. 
Many disease states are characterized by blood vessel occlusion due to 
thrombus formation. Some of these thrombotic diseases are myocardial 
infarction, stroke, pulmonary embolism, deep vein thrombosis, peripheral 
arterial occlusion and coronary artery reocclusion following angioplasty. 
Patients whose blood flows over artificial surfaces are also at risk for 
thrombus formation. An agent which blocks platelet aggregation by 
inhibiting fibrinogen binding to the GPIIb-IIIa receptor should be useful 
in these hyperthrombotic states. 
This invention describes such an agent which is a peptide of varying length 
and contains the Arg-Gly-Asp sequence or an analog thereof and is 
conformationally restrained by cyclization of an amino acid residue 
side-chain onto a backbone (CH.sub.2 NH) amide bond replacement. The 
cyclization strategy described allows the preparation of a linear peptide 
of varying length containing a conformational restraint at the important 
Arg-Gly-Asp sequence. A combination of varying peptide length and 
localized conformational restraint will provide peptides with high 
platelet aggregation inhibiting activity. 
SUMMARY OF THE INVENTION 
Antiplatelet agents consisting of conformationally restrained peptide 
analogs having the following formula 1 
##STR1## 
wherein Y is a fragment --A.sub.1 --A.sub.2 --A.sub.3 --NR.sub.1 R.sub.2 
wherein 
A.sub.1 is a bond or an amino acid selected from the group consisting of 
Ser, Asp, Met, Trp, Phe or Ala; A.sub.2 is a bond or an amino acid 
selected from the group consisting of Pro, Nle, Met, Leu, Asn, Asp, Val, 
Arg or Leu; A.sub.3 is a bond or an amino acid selected from the group 
consisting of Ala, Asp, Pro or Asn and R.sub.1 and R.sub.2 are each 
independently hydrogen, C.sub.1 -C.sub.10 alkyl, benzyl, indolyl, 
pyridinyl, or phenyl optionally substituted with 1 to 3 substituents 
selected from the group consisting of Cl, Br, NO.sub.2, NH.sub.2, OH or 
OCH.sub.3 ; 
Z is a fragment W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein 
A.sub.4 is a bond or an amino acid selected from the group consisting of 
Gly or .beta.Ala; A.sub.5 is a bond or an amino acid selected from the 
group consisting of Arg, Lys, Thr, Ile, Leu, Phe, Asp, Asn or Val; A.sub.6 
is a bond or an amino acid selected from the group consisting of Val, Lys, 
Arg, Asp, Asn or Ala and W is hydrogen, succinyl, C.sub.1 -C.sub.10 acyl, 
C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
wherein m is an integer 1-3, or --(CH.sub.2).sub.p CO.sub.2 H 
wherein p is an integer 1-4; 
X is CONH, CH.sub.2 NH, COCH.sub.2, CH.sub.2 CH.sub.2, --CH.sub.2 O-- or 
--CH.dbd.CH--; 
R is hydrogen, C.sub.1 -C.sub.10 alkyl, benzyl, indolyl, naphthyl, thienyl, 
p-HO-benzyl, p-NO.sub.2 -benzyl, p-Cl-benzyl; and p-NH.sub.2 -benzyl; and 
n is an integer 1-3, 
with the proviso that when either of A.sub.6, A.sub.5 and A.sub.4 are amino 
acids, W is not C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 
H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H, or a pharmaceutically acceptable 
salt thereof. 
These conformationally restrained peptide analogs and their pharmaceutical 
compositions are useful as anti-thrombotic agents. 
DETAILED DESCRIPTION OF THE INVENTION 
The term "C.sub.1 -C.sub.10 alkyl" refers to a straight or branched alkyl 
of from 1 to 10 carbon atoms such as methyl, ethyl, propyl, isopropyl, 
butyl, isobutyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, 
isohexyl, heptyl, octyl, nonyl, or decyl. The term "C.sub.1 -C.sub.10 
acyl" refers to a straight or branched acyl group of from 1-10 carbon 
atoms such as acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, 
octanoyl, nonanoyl, decanoyl and the like. 
The following common abbreviations of the naturally occurring amino acids 
are used throughout this specification: 
Ala--alanine 
Arg--arginine 
Gly--glycine 
Asp--aspartic acid 
Glu--glutamic acid 
Leu--leucine 
Trp--tryptophan 
Ser--serine 
Met--methionine 
Phe--phenylalanine 
Pro--proline 
Nle--norleucine 
Asn--asparagine 
Val--valine 
.beta.Ala--beta alanine 
Lys--lysine 
Ile--isoleucine 
The following common abbreviations of various protecting groups are used 
throughout this specification: 
Boc=t-butyloxycarbonyl 
Bn=benzyl 
Chxl=cyclohexyl 
Tos or Tosyl=p-toluenesulfonyl 
Cbz=carbobenzyloxy 
Ac=acetyl 
Suc=succinyl 
TFA=trifluoroacetic acid 
C.sub.6 H.sub.5 =unsubstituted phenyl 
The .alpha.-amino protecting group employed with each amino acid introduced 
into the peptide sequence may be any such protecting group known in the 
art. Among the classes of--amino protecting groups contemplated are (1) 
acyl type protecting groups such as: formyl, trifluoroacetyl, phthalyl, 
toluenesulfonyl (Tos or tosyl), benzenesulfonyl, nitro-phenylsulfenyl, 
tritylsulfenyl, o-nitrophenoxyacetyl and .alpha.-chlorobutyryl; (2) 
aromatic urethane type protecting groups such as benzyloxycarbonyl and 
substituted benzyloxycarbonyl, such as p-chlorobenzyloxycarbonyl, 
p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 
p-methoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, 
.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl and 
benzhydryloxycarbonyl; (3) aliphatic urethane protecting groups such as 
tert-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, 
isopropyloxycarbonyl, ethoxycarbonyl and allyloxycarbonyl; (4) cycloalkyl 
urethane type protecting groups such as cyclopentyloxycarbonyl, 
adamantyloxycarbonyl and cyclohexyloxycarbonyl; (5) thio urethan type 
protecting groups such as phenylthiocarbonyl; (6) alkyl type protecting 
groups such as triphenylmethyl (trityl) and benzyl; and (7) trialkylsilane 
groups such as trimethylsilane. The preferred .alpha.-amino protecting 
group is tert-butyloxycarbonyl (Boc). 
Other nomenclature designations used to described the conformationally 
restrained peptide derivatives of this invention are .PSI.[CH.sub.2 NH], 
.PSI.[COCH.sub.2 ], .PSI.[CH.sub.2 O],.PSI.[CH.sub.2 CH.sub.2 ] and 
.PSI.[erythro-CH=CH] wherein the symbol ".PSI." designates a modified 
peptide bond. 
The natural amino acids, with the exception of glycine, contain a chiral 
carbon atom. Unless otherwise specifically indicated, the optically active 
amino acids, referred to herein, are of the L-configuration. The 
stereochemistry at the carbon atom bearing the R substituent is either the 
D- or L-configuration. As is customary, the structure of peptides written 
out herein is such that the amino terminal end is on the left side of the 
chain and the carboxy terminal end is on the right side of the chain. 
Certain conformationally restrained peptides of formula 1 are preferred in 
the method of treating hyperthrombotic states. Applicants prefer those 
peptide derivatives of the formula 1 wherein X is CONH, COCH.sub.2 or 
CH.sub.2 CH.sub.2 ; those peptide derivatives wherein Y is benzylamine or 
Asp-NH.sub.2 ; those peptide derivatives wherein n is 2, those peptide 
derivatives wherein R is CH.sub.3, benzyl or p-OH-benzyl and those peptide 
derivatives wherein Z is succinyl, --(CH.sub.2).sub.3 CO.sub.2 H or 
CH.sub.3 CO-Asp-Gly-. 
The peptide derivatives of the formula 1 can form pharmaceutically 
acceptable salts with any non-toxic, organic or inorganic acid. 
Illustrative inorganic acids which form suitable salts include 
hydrochloric, hydrobromic, sulphuric and phosphoric acid and acid metals 
salts such as sodium monohydrogen orthophosphate and potassium hydrogen 
sulfate. Illustrative organic acids which form suitable salts include the 
mono, di and tricarboxylic acids. Illustrative of such acids are, for 
example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, 
fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, 
benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 
2-phenoxybenzoic and sulfonic acids such as methane sulfonic, 
trifluoromethane sulfonic and 2-hydroxyethane sulfonic acid. 
As with any generic group of chemical compounds, certain groups are 
preferred. Applicants prefer those peptide derivatives of formula 1 
wherein Z is H, Ph-(CH.sub.2).sub.3 --, HO.sub.2 C--(CH.sub.2).sub.3 --, 
or Ac-Asp-Gly-, X is --CONH--, --COCH.sub.2 --, or --CH.sub.2 CH.sub.2, Y 
is NHCH.sub.2 Ph or Asp-NH.sub.2, and R is --CH.sub.3, --CH.sub.2 Ph or 
4--OH--CH.sub.2 Ph. 
The conformationally restrained peptides of formula 1 wherein X is CONH can 
be prepared by one of ordinary skill in the art. A general synthetic 
procedure for preparing these compounds is set forth in Scheme A. In 
Scheme A, all substituents are as previously described unless otherwise 
indicated. 
##STR2## 
Scheme A provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is CONH.sub.2. 
In step a, the appropriate N-Boc-amino(O-Bn) acid of structure (1) is 
amidated with the appropriate amine or peptide residue of structure (2) to 
give the corresponding N-Boc-amino(O-Bn) acid amide of structure (3). 
Examples of appropriate N-Boc amino(O-Bn) acid starting materials of 
structure (1) are Boc-Asp(.beta.-Bn) (n=1), Boc-Glu(.delta.-Bn) (n=2) or 
O.sup..epsilon. -Bn-N.sup..alpha. -Boc-aminoadipic acid (n=3). 
For example, the appropriate N-Boc-amino(O-Bn) acid of structure (1) is 
contacted with a molar equivalent of the appropriate amine or peptide 
residue of structure (2), a molar excess of an activating agent such as a 
mixture of 1-hydroxybenzotriazole hydrate and 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The reactants 
are typically contacted in a suitable organic solvent such as methylene 
chloride or tetrahydrofuran. The reactants are typically stirred together 
at room temperature for a period of time ranging from 5-24 hours. The 
N-Boc-amino(O-Bn) acid amide of structure (3) is recovered from the 
reaction zone by extractive procedures as is known in the art. It may be 
purified by chromatography. 
The selection of an appropriate coupling reagent is within the skill of the 
art. Suitable coupling agents are (1) carbodiimides (e.g., 
N,N'-dicyclohexylcarbodiimide; (2) cyanamides (e.g., 
N,N-dibenzylcyanamide); (3) ketenimines; (4) isoxazolium salts (e.g., 
N-ethyl-5-phenyl-isoxazolium-3'-sulfonate; (5) monocyclic nitrogen 
containing heterocyclic amides of aromatic character containing one 
through four nitrogens in the ring such as imidazolides, pyrazolides, and 
1,2,4-triazolides. Specific heterocyclic amides that are useful include 
N,N'-carbonyldiimidazole and N,N-carbonyl-di-1,2,4-triazole; (6) 
alkoxylated acetylene (e.g., ethoxyacetylene); (7) reagents which form a 
mixed anhydride with the carboxyl moiety of the amino acid (e.g., 
ethylchloroformate and isobutylchloroformate) or the symmetrical anhydride 
of the amino acid to be coupled (e.g., Boc-Phe-O-Phe-Boc) and (8) nitrogen 
containing heterocyclic compounds having a hydroxy group on one ring 
nitrogen (e.g., N-hydroxyphthalimide, N-hydroxysuccinimide and 
1-hydroxybenzotriazole). Other activating reagents and their use in 
peptide coupling are described by Kapoor, J. Pharm. Sci., 59, 1-27 1970, 
which is incorporated herein by reference. 
In step b, the N-Boc protecting group of the appropriate N-Boc-amino(O-Bn) 
acid amide of structure (3) is cleaved to give the corresponding 
amino(O-Bn) acid amide salt of structure (4). 
For example, the appropriate N-Boc-amino(O-Bn) acid amide of structure (3) 
is contacted with a suitable acid, such as anhydrous hydrochloric acid or 
trifluoroacetic acid. The reactants are typically contacted in a suitable 
polar organic solvent such as dioxane. The reactants are typically stirred 
together at room temperature for a period of time ranging from 15 minutes 
to 4 hours. The amino(O-Bn) acid amide salt of structure (4) is recovered 
from the reaction zone by evaporation of the solvents. It may be purified 
by chromatography. 
In step c, the appropriate amino(O-Bn) acid amide salt of structure (4) is 
coupled with N-Boc-Asp(.beta.-Chxl) of structure (5) to give the 
corresponding N-Boc-Asp(.beta.-Chxl)-amnio(O-Bn) acid amide of structure 
(6) as described previously in step a. 
In step d, the benzyl protecting group of the appropriate 
N-Boc-Asp(.beta.-Chxl)-amino(O-Bn) acid amide of structure (6) is removed 
to give the corresponding N-Boc-Asp(.beta.-Chxl)-amino acid amide of 
structure (7). 
For example, the appropriate N-Boc-Asp(.beta.-Chxl)-amino(O-Bn) acid amide 
of structure (6) is contacted with a catalytic amount of a suitable 
hydrogenation catalyst such as Perlman's catalyst. The reactants are 
typically contacted in a suitable protic organic solvent such as methanol. 
The reactants are typically subjected to hydrogenation at room temperature 
on a Paar Hydrogenation Apparatus for a period of time ranging from 2-24 
hours. The N-Boc-Asp(.beta.-Chxl)-amino acid amide of structure (7) is 
recovered from the reaction zone by filtration and evaporation of the 
solvent. It may be purified by chromatography. 
In step e, the appropriate N-Boc-Asp(.beta.-Chxl)-amino acid amide of 
structure (7) is coupled with oxime resin to give the corresponding 
N-Boc-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (8). 
For example, the appropriate N-Boc-Asp(.beta.-Chxl)-amino acid amide of 
structure (7) is contacted with a molar excess of a suitable coupling 
agent such as 1,3-dicyclohexylcarbodiimide. The reactants are typically 
contacted in a suitable organic solvent such as methylene chloride or 
tetrahydrofuran. The reactants are typically stirred together at room 
temperature for a period of time ranging from 2-24 hours, filtered and 
stirred with a suitable capping mixture such as acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for a period of 
time ranging from 15 minutes to 10 hours. 
The N-Boc-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (8) is 
recovered from the reaction zone by filtration. 
In step f, the N-Boc protecting group of the appropriate 
N-Boc-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (8) is 
cleaved to give the corresponding Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (9). 
For example, the appropriate N-Boc-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (8) is contacted with a suitable acid such as 
trifluoroacetic acid with anisole. The reactants are typically contacted 
in a suitable organic solvent such as methylene chloride. The reactants 
are typically stirred together at room temperature for a period of time 
ranging from 10 minutes to 30 minutes. The Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (9) is recovered from the reaction zone by 
filtration. 
In step g, the appropriate Asp(.beta.-Chxl)-amino acid amide oxime resin of 
structure (9) is coupled with N-Boc-Gly symmetrical anhydride (10) to give 
the corresponding N-Boc-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (11). 
For example, the appropriate Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (9) is contacted with 2.5 molar equivalents of N-Boc-Gly 
symmetrical anhydride (10). The reactants are typically contacted in a 
suitable organic solvent such as dimethylformamide. The reactants are 
typically stirred together at room temperature for a period of time 
ranging from 1-12 hours, filtered and stirred with a suitable capping 
mixture such as acetic anhydride:diisopropylethylamine:dimethylformamide 
(6:2:24) for a period of time ranging from 15 minutes to 10 hour. The 
N-Boc-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (11) 
is recovered from the reaction zone by filtration. 
In step h, the N-Boc protecting group of the appropriate 
N-Boc-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (11) 
is cleaved to give the corresponding Gly-Asp(.beta.-Chxl)-amino acid amide 
oxime resin of structure (12) as described previously in step f. 
In step i, the appropriate Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (12) is coupled with N-Boc-Arg(N.sup.g -Tos) 
symmetrical anhydride (13) to give the corresponding N-Boc-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (14) 
as described previously in step g. 
In step j, the N-Boc protecting group of the appropriate N-Boc-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (14) 
is cleaved to give the corresponding Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (15) 
as described previously in step f. 
In step k, the appropriate Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (15) is coupled with the appropriate D 
or L-N-Boc-NHCHR-aldehyde of structure (16) to give the corresponding 
N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (17). 
For example, the appropriate Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (15) is contacted with 2.5 molar 
equivalents of the appropriate D or L-N-Boc-NHCHR-aldehyde of structure 
(16) and a molar equivalent of sodium cyanoborohydride. The reactants are 
typically stirred together at room temperature for a period of time 
ranging from 1-10 hours. The N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (17) 
is recovered from the reaction zone by filtration and washing with 
solvent. 
In optional step 1, the .PSI.[CH.sub.2 NH] functionality of the appropriate 
N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (17) 
may be alkylated to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (18) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein 
W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as is well known in 
the art, such as reductive alkylation. 
In step m, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (17) 
or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (18) 
wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give the 
corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (19) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds. 
For example, the N-Boc of the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 
NH]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of 
structure (17) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (18) 
wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds is first cleaved to give the 
corresponding intermediate NH.sub.2 CHR-.PSI.[CH.sub.2 NH)-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin or NH.sub.2 
CHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in step f. 
The intermediate NH.sub.2 CHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin or NH.sub.2 
CHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is then cyclized 
and cleaved from the oxime resin by contacting with a suitable dilute 
acid, such as 1% acetic acid in dimethylformamide. The reactants are 
typically shaken together at room temperature for a period of time ranging 
from 2 hours to 2 days. The Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (19) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen or C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds is recovered from the reaction zone 
by evaporation of the solvent. It may be purified by chromatography. 
In optional step n, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of 
structure (19) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be acylated as 
is known in the art to give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of 
structure (20) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 acyl or succinyl and A.sub.6, A.sub.5 and A.sub.4 are 
bonds. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.9 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (19) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen and A.sub.6, 
A.sub.5 and A.sub.4 are bonds may be converted to the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (20) wherein Z' 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen and at least 
one of A.sub.6, A.sub.5 and A.sub.4 is an amino acid by standard peptide 
chemistry as is known in the art. The terminal amino of the peptide side 
chain A.sub.6 --A.sub.5 --A.sub.4 may then be acylated as is known in the 
art to give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of 
structure (20) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 acyl or succinyl and at least one of A.sub.6, A.sub.5 
and A.sub.4 is an amino acid. 
In step o, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (19) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds or the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (20) wherein Z' 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 acyl or succinyl and at least one of A.sub.6, A.sub.5 and 
A.sub.4 is an amino acid are removed to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg-Gly-Asp-amino acid] amide of 
structure (21). 
For example, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (19) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds or the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-amino acid]amide of structure (20) wherein Z' 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 acyl or succinyl and at least one of A.sub.6, A.sub.5 and 
A.sub.4 is an amino acid is contacted with hydrogen fluoride and and a 
suitable scavenger such as anisole. The reactants are typically stirred 
together at 0.degree. C. for a period of time ranging from 20 minutes to 1 
hour. The Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg-Gly-Asp-amino acid]amide of 
structure (21) is recovered from the reaction zone by evaporation of the 
solvent. It may be purified by chromatography. 
Starting materials for use in Scheme A are readily available to one of 
ordinary skill in the art. For example, oxime resin is described in J. 
Org. Chem., 45 1295-1300 1980.

The following examples present typical syntheses as described in Scheme A. 
These examples are understood to be illustrative only and are not intended 
to limit the scope of the present invention in any way. As used herein, 
the following terms have the indicated meanings: "g" refers to grams; 
"mmol" refers to millimoles; "mL" refers to milliliters; "bp" refers to 
boiling point; "mp" refers to melting point; ".degree.C." refers to 
degrees Celsius; "mm Hg" refers to millimeters of mercury; ".mu.L" refers 
to microliters; ".mu.g" refers to micrograms; and ".mu.M" refers to 
micromolar. 
EXAMPLE 1 
MDL-101,429KM 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 
CO.sub.2 H-SEQ ID NO: 1 
##STR3## 
Step a Boc-Glu(.delta.-Bn)(NHBn) 
Dissolve Boc-Glu(.delta.-Bn) (6.68 g, 19.8 mmol) in dichloromethane (40 mL) 
and add 1-hydroxybenzotriazole hydrate (3.4 g, 25.2 mmol), 
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (4.2 g, 21.9 
mmol) and benzylamine (2.2 mL, 20 mmol). Stir at room temperature 
overnight and dilute with ethyl acetate (250 mL). Wash with 0.5N 
hydrochloric acid (3.times.80 mL), saturated sodium hydrogen carbonate 
(3.times.80 mL) and saturated sodium chloride (80 mL). Dry (MgSO.sub.4), 
filter and evaporate the solvent in vacuo to give the title compound as a 
white crystalline solid (8.19 g, 97%). 
Step b 
Glu(.delta.-Bn)(NHBn) hydrochloride 
Dissolve Boc-Glu(.delta.-Bn)(NHBn) (8.19 g, 19.2 mmol) in a solution of 4N 
hydrochloric acid in dioxane (40 mL). Stir at room temperature for 30 
minutes and evaporate the solvent in vacuo to give the title compound as a 
brittle foam. 
Step c 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)(NHBn) 
Dissolve Glu(.delta.-Bn)(NHBn) hydrochloride (19.2 mmol) in 
dimethylformamide (50 mL) and add 1-hydroxybenzotriazole hydrate (3.27 g, 
21 mmol), Boc-Asp(.beta.-Chxl) (6.04 g, 19.2 mmol), triethylamine (4.7 mL) 
and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (4.08 g, 
21.3 mmol). Stir at room temperature overnight and dilute with ethyl 
acetate (300 mL). Wash with 0.5N hydrochloric acid (3.times.125 mL), 
saturated sodium hydrogen carbonate (3.times.100 mL), water (150 mL) and 
saturated sodium chloride (150 mL). Dry (MgSO.sub.4), filter and evaporate 
the solvent in vacuo to give the title compound as a white crystalline 
solid (11.57 g, 97%). 
Step d 
Boc-Asp(.beta.-Chxl)-Glu(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)(NHBn) (11.57 g, 18.6 mmol) in 
methanol (200 mL) and add Perlman's catalyst (200 mg). Hydrogenate on a 
Paar Hydrogenation Apparatus for 4 hours, filter through Celite filter aid 
and evaporate the solvent in vacuo to give the title compound as a brittle 
glass foam (10 g, 100%). 
Step e 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(NHBn) (10 g, 18.6 mmol) in methylene 
chloride (140 mL). Add oxime resin (21 g, 0.69 meq/g, 14.5 mmol) and a 
0.5M solution of 1,3-dicyclohexylcarbodiimide in methylene chloride (42 
mL, 21 mmol) and mix on a rotary evaporator for 20 hours. Filter, wash 
with dimethylformamide (2.times.200 mL), methylene chloride (200 mL), 
methanol (3.times.200 mL) and methylene chloride (3.times.200 mL). Suspend 
in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter and wash with dimethylformamide (2.times.200 mL), methanol 
(3.times.200 mL) and methylene chloride (3.times.200 mL). Dry in vacuo to 
give the title compound (26.3 g). 
Step f 
Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) 
Briefly wash Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (5.2 g, 2 
mmol) with 50 mL of a solution of 25% trifluoroactic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroactic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step g 
Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) 
Mix Boc-Gly (2.1 g, 12 mmol), methylene chloride (12 mL) and add a 0.5M 
solution of 1,3-dicyclohexylcarbodiimide in methylene chloride (12 mL, 6 
mmol). Stir at room temperature for 1 hour, filter and use the resulting 
Boc-Gly symmetrical anhydride as a solution. 
Add Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) to the solution of 
Boc-Gly symmetrical anhydride. Stir at room temperature for 2 hours, 
filter and wash with dimethylformamide (2.times.50 mL). Suspend in a 
capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter, wash with dimethylformamide (3.times.50 mL), isopropanol 
(3.times.50 mL) and methylene chloride (2.times.50 mL). Dry in vacuo to 
give the title compound (5.15 g). 
Step h 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) 
Briefly wash Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (5.15 
g) with 50 mL of a solution of 25% trifluoroactic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroactic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step i 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 2 
Suspend N.sup..alpha. -Boc-Arg(N.sup.g -Tos) (6.43 g, 15 mmol) in methylene 
chloride (15 mL) and add a 0.5M solution of 1,3-dicyclohexylcarbodiimide 
in methylene chloride (15 mL, 7.5 mmol) and dimethylformamide (4 mL). Stir 
at room temperature for 1 hour, filter and use the resulting N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos) symmetrical anhydride as a solution. 
Add Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) to the solution of 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos) symmetrical anhydride. Shake at room 
temperature for 3 hours, filter and wash with dimethylformamide 
(2.times.50 mL) and methylene chloride. Dry in vacuo to give the title 
compound (6.11 g). 
Step j 
Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ 
ID NO: 3 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)(SEQ ID NO: 2) 
(6.11 g) with 50 mL of a solution of 25% trifluoroactic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound (6 g). 
Step k 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 4 
Dissolve Boc-Ala (1.89 g, 10 mmol) in anhydrous tetrahydrofuran (30 mL) and 
add 1,1'-carbonyldiimidazole (1.8 g, 11 mmol). Stir for 30 minutes and add 
a solution of N,O-dimethylhydroxylamine hydrochloride (1.44 g, 15 mmol) in 
dimethylformamide (10 mL) and diisopropylethylamine (2.6 mL). Stir at room 
temperature overnight and dilute with ethyl acetate (150 mL). Wash with 
0.5N hydrochloric acid (3.times.50 mL), saturated sodium hydrogen 
carbonate (3.times.50 mL) and saturated sodium chloride (50 mL). Dry 
(MgSO.sub.4), filter and evaporate the solvent in vacuo to give 
Boc-Ala(NCH.sub.3 (OCH.sub.3)) as a white crystalline solid (1.95 g, 84%); 
mp 148-149.degree. C. 
Anal. Calcd for C.sub.10 H.sub.20 N.sub.2 O.sub.4 : C, 51.71; H, 8.68; N, 
12.06; Found: C, 52.07; H, 8.87; N, 12.00. 
Dissolve Boc-Ala(NCH.sub.3 (OCH.sub.3)) (1.16 g, 5 mmol) in anhydrous 
tetrahydrofuran (40 mL) and cool in an ice bath. Add a 1M solution of 
lithium aluminum hyride in tetrahydrofuran (3.1 mL) and stir for 40 
minutes at 5.degree. C. Quench with an aqueous solution of sodium hydrogen 
sulfate (0.75 g in 15 mL) and dilute with water (150 mL). Extract into 
ethyl acetate (3.times.40 mL), dry (MgSO.sub.4) and evaporate the solvent 
in vacuo to give Boc-Ala-al as a white crystalline solid. 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)(SEQ ID NO: 3) 
(1.5 g, 0.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours 
and filter. Wash with dimethylformamide (3.times.20 mL), methylene 
chloride (3.times.20 mL) and collect by filtration to give the title 
compound (1.42 g). 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 5 
Treat Boc-Ala.PSI.[CH.sub.2 NH-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 4) 
(5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 
25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound (269 mg, 68%). 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 
CO.sub.2 H-SEQ ID NO: 1 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](.alpha.-NHBn) (SEQ ID NO: 5) (269 
mg) in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. 
Allow the solvent to evaporate and extract into 30% aqueous acetic acid. 
Lyophillize to give the title compound (232 mg) and purify by Reverse 
phase-HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the title 
compound (34.2 mg). 
FAB MS: 604.2 (M+H.).sup.+ 
AAA: Asp, 0.98; Glu, 1.02; Gly, 0.86. 
EXAMPLE 2 
Cyclo[Ala.PSI.[(CH.sub.2 N(CO(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 6 
##STR4## 
Optional step n Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 7 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 5) (0.5 mmol) in 
dimethylformamide (10 mL) and add diisopropylethylamine (0.44 mL) and 
succinic anhydride (250 mg, 2.5 mmol). Shake for 4 hours, filter, wash 
with dimethylformamide and dry in vacuo to give the title compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 6 
Suspend Cyclo(Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 
7) (183 mg) in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. 
C. Allow the solvent to evaporate and extract into 30% aqueous acetic 
acid. Lyophillize to give the title compound (139 mg). Purify by reverse 
phase HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the title 
compound. 
EXAMPLE 3 
MDL 100,187 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 8 
##STR5## 
Optional step 1 Boc-Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 9 
Suspend Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 4) 
(0.5 mmol) in 1% acetic acid in dimethylformamide (10 mL). Add succinic 
semialdehyde (1.6 mL, 15% in water) and sodium cyanohydride (100 mg). 
Shake for 4 hours, filter, wash with dimethylformamide and dichloromethane 
and dry in vacuo to give the title compound. 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 10 
Treat Boc-Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 9) 
(0.5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 
25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
4 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound (408 mg, %). 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 8 
Suspend Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg(N.sup.g 
-TOS)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 10) (408 mg) in 
hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the 
solvent to evaporate and extract into 30% aqueous acetic acid. Lyophillize 
to give the title compound (329 mg) and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound 
(32.7 mg). 
(M+H).sup.+ =690.4 
AAA: Asp, 1.04; Glu, 1.05; Gly, 0.91; 61.8% peptide 
EXAMPLE 4 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 
Ph)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 
11 
##STR6## 
Optional Step 1 Boc-Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 Ph)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 12 
Suspend Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 4) 
(0.5 mmol) in 1% acetic acid in dimethylformamide (10 mL). Add 
dihydrocinnamaldehyde (0.33 mL, 336 mg) and sodium cyanohydride (100 mg). 
Shake for 4 hours, filter, wash with dimethylformamide and methylene 
chloride. Dry in vacuo to give the title compound. 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 Ph)]-Arq(N.sup.g 
-Tos)-Gly-Asp-(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 13 
Treat Boc-Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 Ph)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 12) 
(0.5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 
25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
4 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound (176 mg). 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 
Ph)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 
11 
Suspend Cyclo[Ala.PSI.[CH.sub.2 N((CH.sub.2).sub.3 Ph)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 13) (176 mg) in 
hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the 
solvent to evaporate and extract into 30% aqueous acetic acid. Lyophillize 
to give the title compound and purify by Reverse phase-HPLC (aqueous 
trifluoroacetic acid/acetonitrile) to give the title compound. 
(M+H).sup.+ =722.5 
AAA: Asp, 1.01; Glu, 1.03; Gly, 0.96; 57.5% peptide 
EXAMPLE 5 
Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 
Ph)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 
14 
##STR7## 
Optional Step n Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 
Ph)]-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 
15 
Mix hydrocinnamic acid (751 mg, 5 mmol), methylene chloride (12 mL) and add 
a 1M solution of 1,3-dicyclohexylcarbodiimide in 1-methyl-2-pyrrolidinone 
(2.5 mL) along with methylene chloride (5 mL). Stir at room temperature 
for 1 hour and filter to give a solution of hydrocinnamic acid symmetrical 
anhydride. 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 5) (0.5 mmol) in 
the solution of hydrocinnamic acid symmetrical anhydride. Add 
diisopropylethylamine (0.44 mL) and shake for 4 hours. Filter, wash with 
dimethylformamide and methylene chloride. Dry in vacuo to give the title 
compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 
Ph)]-Arg-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 
14 
Suspend Cyclo[Ala.PSI.[CH.sub.2 N(CO(CH.sub.2).sub.2 Ph)]-Arg(N.sup.g 
-Tos)-Gly-Asp(.delta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 15) (0.5 mmol) 
in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow 
the solvent to evaporate and extract into 30% aqueous acetic acid. 
Lyophillize to give the title compound and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound. 
EXAMPLE 6 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu](LeuNHBn).cndot.CF.sub.3 CO.sub.2 H 
##STR8## 
Step a Boc-Glu(.delta.-Bn)(LeuNHBn) 
Dissolve Boc-Leu(NHBn) (1.60 g, 5 mmol) in a solution of 4N hydrochloric 
acid in dioxane (10 mL). Stir at room temperature for 30 minutes and 
evaporate the solvent in vacuo to give Leu(NHBn).cndot.hydrochloride. 
Dissolve Boc-Glu(.delta.-Bn) (1.60 g, 5 mmol) in dichloromethane (10 mL) 
and add 1-hydroxybenzotriazole hydrate (0.84 g, 5.5 mmol), 
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.05 g, 5.5 
mmol), Leu(NHBn).cndot.hydrochloride (5 mmol) and diisopropylethylamine 
(1.36 mL, mmol). Stir at room temperature overnight and dilute with ethyl 
acetate (200 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a white crystalline solid (2.5 g, 
93%). 
MS (CI/CH.sub.4) 540 (M+H.sup.+) 
Step b 
Glu(.delta.-Bn)-Leu(NHBn) hydrochloride 
Dissolve Boc-Glu(.delta.-Bn)-Leu(NHBn) (2.5 g) in a solution of 4N 
hydrochloric acid in dioxane (10 mL). Stir at room temperature for 30 
minutes and evaporate the solvent in vacuo to give the title compound. 
Step c 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Leu(NHBn) 
Dissolve Glu(.delta.-Bn)-Leu(NHBn) hydrochloride (4.6 mmol) in 
dimethylformamide (10 mL) and add 1-hydroxybenzotriazole hydrate (0.78 g, 
5.06 mmol), Boc-Asp(.beta.-Chxl) (1.46 g, 4.6 mmol), diisopropylethylamine 
(1.34 mL) and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride 
(0.98 g, 5.06 mmol). Stir at room temperature overnight and dilute with 
ethyl acetate (150 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a solid (3.27 g, 96%). 
MS (CI/CH.sub.4) 737 (M+H.sup.+) 
Step d 
Boc-Asp(.beta.-Chxl)-Glu-Leu(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Leu(NHBn) (18.6 mmol) in 
methanol (200 mL) and add Perlman's catalyst (200 mg). Hydrogenate on a 
Paar Hydrogenation Apparatus for 4 hours, filter through Celite filter aid 
and evaporate the solvent in vacuo to give the title compound. 
Step e 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu-Leu(NHBn) (18.6 mmol) in methylene 
chloride (140 mL). Add oxime resin (21 g, 0.69 meq/g, 14.5 mmol) and a 
0.5M solution of 1,3-dicyclohexylcarbodiimide in methylene chloride (42 
mL, 21 mmol) and mix on a rotary evaporator for 20 hours. Filter, wash 
with dimethylformamide (2.times.200 mL), methylene chloride (200 mL), 
methanol (3.times.200 mL) and methylene chloride (3.times.200 mL). Suspend 
in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter and wash with dimethylformamide (2.times.200 mL), methanol 
(3.times.200 mL) and methylene chloride (3.times.200 mL). Dry in vacuo to 
give the title compound. 
Step f 
Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) 
Briefly wash Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) (2 
mmol) with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step g 
Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn)-SEQ ID NO: 16 
Add Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) to a solution of 
Boc-Gly symmetrical anhydride. Stir at room temperature for 2 hours, 
filter and wash with dimethylformamide (2.times.50 mL). Suspend in a 
capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter, wash with dimethylformamide (3.times.50 mL), isopropanol 
(3.times.50 mL) and methylene chloride (2.times.50 mL). Dry in vacuo to 
give the title compound. 
Step h 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn)-SEQ ID NO: 17 
Briefly wash Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) 
(SEQ ID NO: 16) (0.5 mmol) with 50 mL of a solution of 25% trifluoroacetic 
acid in methylene chloride with 1% anisole and filter. Treat with 50 mL of 
a solution of 25% trifluoroacetic acid in methylene chloride with 1% 
anisole, stir for 25 minutes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with 50 mL of a 
solution of 1% diisopropylethylamine in methylene chloride and filter to 
give the title compound. 
Step i 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Leu(NHBn)-SEQ ID NO: 18 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos) symmetrical anhydride (7.5 
mmol) in dimethylformamide (40 mL) and add 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) (SEQ ID NO: 17) 
(0.5 mmol). Shake at room temperature for 3 hours, filter and wash with 
dimethylformamide (2.times.50 mL) and methylene chloride. Dry in vacuo to 
give the title compound. 
Step j 
Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Leu(NHBn)-SEQ ID NO: 19 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos)-Gly-Asp(.alpha.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) (SEQ ID NO: 
18) (0.5 mmol) with 50 mL of a solution of 25% trifluoroacetic acid in 
methylene chloride with 1% anisole and filter. Treat with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% 
anisole, stir for 25 minutes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with 50 mL of a 
solution of 1% diisopropylethylamine in methylene chloride and filter to 
give the title compound. 
Step k 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn)-SEQ ID NO: 
20 
Dissolve Boc-Ala-al (5mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g 
-Tos)-Gly-Asp(.delta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) (SEQ ID NO: 
19) (0.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and 
filter. Wash with dimethylformamide (3.times.20 mL), methylene chloride 
(3.times.20 mL) and evaporate the solvent in vacuo to give the title 
compound. 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.Glu]-Leu(NHBn) 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Leu(NHBn) (SEQ ID NO: 
20) (0.5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) 
for 25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.CF.sub.3 CO.sub.2 H 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Leu(NHBn) (269 mg) in hydrogen 
fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the solvent to 
evaporate and extract into 30% aqueous acetic acid. Lyophillize to give 
the title compound (232 mg) and purify by Reverse phase-HPLC (aqueous 
trifluoroacetic acid/acetonitrile) to give the title compound. 
EXAMPLE 7 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Trp(NHBn).cndot.CF.sub.3 CO.sub.2 H 
##STR9## 
Step a Boc-Glu(.delta.-Bn)-Trp(NHBn) 
Dissolve Boc-Trp(NHBn) (1.97 g, 5 mmol) in a solution of 4N hydrochloric 
acid in dioxane (10 mL). Stir at room temperature for 30 minutes and 
evaporate the solvent in vacuo to give Trp(NHBn).cndot.hydrochloride. 
Dissolve Boc-Glu(.delta.Bn) (1.60 g, 5 mmol) in dichloromethane (10 mL) and 
add 1-hydroxybenzotriazole hydrate (0.84 g, 5.5 mmol), 
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.05 g, 5.5 
mmol), Trp(NHBn).cndot.hydrochloride (5 mmol) and diisopropylethylamine 
(1.36 mL, mmol). Stir at room temperature overnight and dilute with ethyl 
acetate (200 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a solid (3.11 g, 100%). 
MS (CI/CH.sub.4) 613 (M+H.sup.+) 
Step b 
Glu(.delta.-Bn)-Trp(NHBn) hydrochloride 
Dissolve Boc-Glu(.delta.-Bn)-Trp(NHBn) (3.11 g) in a solution of 4N 
hydrochloric acid in dioxane (10 mL). Stir at room temperature for 30 
minutes and evaporate the solvent innvacuo to give the title compound. 
Step c 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Trp(NHBn) 
Dissolve Glu(.delta.-Bn)-Trp(NHBn) hydrochloride (5 mmol) in 
dimethylformamide (10 mL) and add 1-hydroxybenzotriazole hydrate (0.84 g, 
5.5 mmol), Boc-Asp(.beta.-Chxl) (1.58 g, 5 mmol), diisopropylethylamine 
(1.46 mL) and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride 
(1.05 g, 5.5 mmol). Stir at room temperature overnight and dilute with 
ethyl acetate (150 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a solid (3.77 g, 93%). 
MS (CI/CH.sub.4) 810 (M+H.sup.+) 
Step d 
Boc-Asp(.beta.-Chxl)-Glu-Trp(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Trp(NHBn) (18.6 mmol) in 
methanol (200 mL) and add Perlman's catalyst (200 mg). Hydrogenate on a 
Paar Hydrogenation Apparatus for 4 hours, filter through Celite filter aid 
and evaporate the solvent in vacuo to give the title compound. 
Step e 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu-Trp(NHBn) (18.6 mmol) in methylene 
chloride (140 mL). Add oxime resin (21 g, 0.69 meq/g, 14.5 mmol) and a 
0.5M solution of 1,3-dicyclohexylcarbodiimide in methylene chloride (42 
mL, 21 mmol) and mix on a rotary evaporator for 20 hours. Filter, wash 
with dimethylformamide (2.times.200 mL), methylene chloride (200 mL), 
methanol (3.times.200 mL) and methylene chloride (3.times.200 mL). Suspend 
in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter and wash with dimethylformamide (2.times.200 mL), methanol 
(3.times.200 mL) and methylene chloride (3.times.200 mL). Dry in vacuo to 
give the title compound. 
Step f 
Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) 
Briefly wash Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (2 
mmol) with 50 mL of a solution of 25% trifluoroactic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroactic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride 
(50mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step g 
Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn)-SEQ ID NO: 21 
Add Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (0.5 mmol) to a 
solution of Boc-Gly symmetrical anhydride. Stir at room temperature for 2 
hours, filter and wash with dimethylformamide (2.times.50 mL). Suspend in 
a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2;24) for 30 minutes. 
Filter, wash with dimethylformamide (3.times.50 mL), isopropanol 
(3.times.50 mL) and methylene chloride (2.times.50 mL). Dry in vacuo to 
give the title compound. 
Step h 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn)-SEQ ID NO: 22 
Briefly wash Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) 
(SEQ ID NO: 21) (0.5 mmol) with 50 mL of a solution of 25% trifluoroacetic 
acid in methylene chloride with 1% anisole and filter. Treat with 50 mL of 
a solution of 25% trifluoroacetic acid in methylene chloride with 1% 
anisole, stir for 25 minutes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with 50 mL of a 
solution of 1% diisopropylethylamine in methylene chloride and filter to 
give the title compound. 
Step i 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Trp(NHBn)-SEQ ID NO: 23 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos) symmetrical anhydride (7.5 
mmol) in dimethylformamide (40 mL) and add 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (SEQ ID NO: 22). 
Shake at room temperature for 3 hours, filter and wash with 
dimethylformamide (2.times.50 mL) and methylene chloride. Dry in vacuo to 
give the title compound. 
Step j 
Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Trp(NHBn)-SEQ ID NO: 24 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (SEQ ID NO: 
23) (0.5 mmol) with 50 mL of a solution of 25% trifluoroacetic acid in 
methylene chloride with 1% anisole and filter. Treat with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% 
anisole, stir for 25 minutes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with 50 mL of a 
solution of 1% diisopropylethylamine in methylene chloride and filter to 
give the title compound. 
Step k 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn)-SEQ ID NO: 
25 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (SEQ ID NO: 
24) (0.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and 
filter. Wash with dimethylformamide (3.times.20 mL), methylene chloride 
(3.times.20 mL) and evaporate the solvent in vacuo to give the title 
compound. 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Trp(NHBn) 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Trp(NHBn) (SEQ ID NO: 
25) (0.5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) 
for 25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Trp(NHBn).cndot.CF.sub.3 CO.sub.2 H 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Trp(NHBn) (269 mg) in hydrogen 
fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the solvent to 
evaporate and extract into 30% aqueous acetic acid. Lyophillize to give 
the title compound (232 mg) and purify by Reverse phase-HPLC (aqueous 
trifluoroacetic acid/acetonitrile) to give the title compound. 
EXAMPLE 8 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Arg(NHBn).cndot.CF.sub.3 CO.sub.2 H 
##STR10## 
Step a Boc-Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos)(NHBn) (2.59 g, 5 mmol) in a 
solution of 4N hydrochloric acid in dioxane (10 mL). Stir at room 
temperature for 30 minutes and evaporate the solvent in vacuo to give 
Arg(N.sup.g -Tos)(NHBn).cndot.hydrochloride. Dissolve Boc-Glu(.delta.-Bn) 
(1.60 g, 5 mmol) in dichloromethane (10 mL) and add 1-hydroxybenzotriazole 
hydrate (0.84 g, 5.5 mmol), 1-(3-dimethylaminopropyl)3-ethylcarbodiimide 
hydrochloride (1.05 g, 5.5 mmol), Arg(N.sup.g 
-Tos)(NHBn).cndot.hydrochloride (5 mmol) and diisopropylethylamine (1.36 
mL, mmol). Stir at room temperature overnight and dilute with ethyl 
acetate (200 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a solid (2.95 g, 80%). 
MS (Neg Ion CI/CH.sub.4) 735 (M-H).sup.- 
Step b 
Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) hydrochloride 
Dissolve Boc-Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) (2.95 g) in a solution 
of 4N hydrochloric acid in dioxane (10 mL). Stir at room temperature for 
30 minutes and evaporate the solvent in vacuo to give the title compound. 
Step c 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) 
Dissolve Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) hydrochloride (4 mmol) in 
dimethylformamide (10 mL) and add 1-hydroxybenzotriazole hydrate (0.67 g, 
4.4 mmol), Boc-Asp(.beta.-Chxl) (1.26 g, 4 mmol), diisopropylethylamine 
(1.12 mL) and 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride 
(0.84 g, 4.4 mmol). Stir at room temperature overnight and dilute with 
ethyl acetate (150 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), 
saturated sodium hydrogen carbonate (3.times.50 mL) and saturated sodium 
chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in 
vacuo to give the title compound as a solid (1.21 g, 32%). 
MS (FAB CI/CH.sub.4) 943.5 (M+H.sup.+) 
Step d 
Boc-AsP(.beta.-Chxl)-Glu-Arg(N.sup.g -Tos)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Arg(N.sup.g -Tos)(NHBn) (18.6 
mmol) in methanol (200 mL) and add Perlman's catalyst (200 mg). 
Hydrogenate on a Paar Hydrogenation Apparatus for 4 hours, filter through 
Celite filter aid and evaporate the solvent in vacuo to give the title 
compound. 
Step e 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g -Tos)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu-Arg(N.sup.g -Tos)(NHBn) (18.6 mmol) in 
methylene chloride (140 mL). Add oxime resin (21 g, 0.69 meq/g, 14.5 mmol) 
and a 0.5M solution of 1,3-dicyclohexylcarbodiimide in methylene chloride 
(42 mL, 21 mmol) and mix on a rotary evaporator for 20 hours. Filter, wash 
with dimethylformamide (2.times.200 mL), methylene chloride (200 mL), 
methanol (3.times.200 mL) and methylene chloride (3.times.200 mL). Suspend 
in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter and wash with dimethylformamide (2.times.200 mL), methanol 
(3.times.200 mL) and methylene chloride (3.times.200 mL). Dry in vacuo to 
give the title compound. 
Step f 
Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g -Tos)(NHBn) 
Briefly wash Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn) (2 mmol) with 50 mL of a solution of 25% trifluoroacetic acid 
in methylene chloride with 1% anisole and filter. Treat with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% 
anisole, stir for 25 minutes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with 50 mL of a 
solution of 1% diisopropylethylamine in methylene chloride and filter to 
give the title compound. 
Step g 
Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn)-SEQ ID NO: 26 
Add Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g -Tos)(NHBn) (0.5 
mmol) to a solution of Boc-Gly symmetrical anhydride (0.5 mmol). Stir at 
room temperature for 2 hours, filter and wash with dimethylformamide 
(2.times.50 mL). Suspend in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter, wash with dimethylformamide (3.times.50 mL), isopropanol 
(3.times.50 mL) and methylene chloride (2.times.50 mL). Dry in vacuo to 
give the title compound. 
Step h 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g -Tos)(NHBn)-SEQ 
ID NO: 27 
Briefly wash Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn) (SEQ ID NO: 26) (0.5 mmol) with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole and filter. 
Treat with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole, stir for 25 minutes and filter. Briefly wash 
three times with methylene chloride (50 mL) and filter. Briefly wash three 
times with isopropanol (50 mL) and filter. Briefly wash two times with 50 
mL of a solution of 1% diisopropylethylamine in methylene chloride and 
filter to give the title compound. 
Step i 
Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Arg(N.sup.g -Tos)(NHBn)-SEQ ID NO: 28 
Dissolve N.alpha.-Boc-Arg(N.sup.g -Tos) symmetrical anhydride (7.5 mmol) in 
dimethylformamide (40 mL) and add Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Arg(N.sup.g -Tos)(NHBn) (SEQ ID NO: 27). Shake at room temperature 
for 3 hours, filter and wash with dimethylformamide (2.times.50 mL) and 
methylene chloride. Dry in vacuo to give the title compound. 
Step j 
Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn)-SEQ ID NO: 29 
Briefly wash Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Arg(N.sup.g -Tos)(NHBn) (SEQ ID NO: 28) (0.5 mmol) with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% anisole 
and filter. Treat with 50 mL of a solution of 25% trifluoroacetic acid in 
methylene chloride with 1% anisole, stir for 25 minutes and filter. 
Briefly wash three times with methylene chloride (50 mL) and filter. 
Briefly wash three times with isopropanol (50 mL) and filter. Briefly wash 
two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step k 
Boc-Ala.PSI.[CH.sub.2 NH]-Ar(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn)-SEQ ID NO: 30 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn) (SEQ ID NO: 29) (0.5 mmol) and sodium cyanoborohydride (150 
mg). Shake for 2 hours and filter. Wash with dimethylformamide (3.times.20 
mL), methylene chloride (3.times.20 mL) and evaporate the solvent in vacuo 
to give the title compound. 
Step m 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Arg(N.sup.g -Tos)(NHBn) 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Arg(N.sup.g 
-Tos)(NHBn) (SEQ ID NO: 30) (0.5 mmol) with 25% trifluoroacetic acid in 
methylene chloride (25 mL) for 25 minutes. Wash with methylene chloride 
(3.times.20 mL), isopropanol (3.times.20 mL), methylene chloride (20 mL), 
1% diisopropylethylamine in methylene chloride (2.times.25 mL) and 
methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Arg(NHBn).cndot.CF.sub.3 CO.sub.2 H 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Arg(N.sup.g -Tos)(NHBn) (269 mg) 
in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow 
the solvent to evaporate and extract into 30% aqueous acetic acid. 
Lyophillize to give the title compound (232 mg) and purify by Reverse 
phase-HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the title 
compound. 
EXAMPLE 9 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Asp(NHBn).cndot.CF.sub.3 CO.sub.2 H 
##STR11## 
Step a Boc-Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)(NHBn) (2.02 g, 5 mmol) in a solution of 4N 
hydrochloric acid in dioxane (10 mL). Stir at room temperature for 30 
minutes and evaporate the solvent in vacuo to give 
Asp(.beta.-Chxl)(NHBn).cndot.hydrochloride. 
Dissolve Boc-Glu(.delta.-Bn) (1.60 g, 5 mmol) in dichloromethane (10 mL) 
and add 1-hydroxybenzotriazole hydrate (0.84 g, 5.5 mmol), 
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.05 g, 5.5 
mmol), Asp(.beta.-Chxl)(NHBn).cndot.hydrochloride (5 mmol) and 
diisopropylethylamine (1.36 mL, mmol). Stir at room temperature overnight 
and dilute with ethyl acetate (200 mL). Wash with 0.5N hydrochloric acid 
(3.times.50 mL), saturated sodium hydrogen carbonate (3.times.50 mL) and 
saturated sodium chloride (50 mL). Dry (MgSO.sub.4), filter and evaporate 
the solvent in vacuo to give the title compound as a solid (3.05 g, 98%). 
MS (CI/CH.sub.4) 624 (M+H)+ 
Step b 
Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) hydrochloride 
Dissolve Boc-Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) (3.05 g, 4.89 mmol) in 
a solution of 4N hydrochloric acid in dioxane (10 mL). Stir at room 
temperature for 30 minutes and evaporate the solvent in vacuo to give the 
title compound. 
Step c 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) 
Dissolve Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) hydrochloride (4.89 mmol) 
in dimethylformamide (10 mL) and add 1-hydroxybenzotriazole hydrate (0.82 
g, 5.38 mmol), Boc-Asp(.beta.-Chxl) (1.54 g, 4.89 mmol), 
diisopropylethylamine (1.39 mL) and 
1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (1.03 g, 5.38 
mmol). Stir at room temperature overnight and dilute with ethyl acetate 
(150 mL). Wash with 0.5N hydrochloric acid (3.times.50 mL), saturated 
sodium hydrogen carbonate (3.times.50 mL) and saturated sodium chloride 
(50 mL). Dry (MgSO.sub.4), filter and evaporate the solvent in vacuo to 
give the title compound as a solid. 
MS (CI/CH.sub.4) 821 (M+H.sup.+) 
Step d 
Boc-Asp(.beta.-Chxl)-Glu-Asp(.beta.-Chxl)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu(.delta.-Bn)-Asp(.beta.-Chxl)(NHBn) (18.6 
mmol) in methanol (200 mL) and add Perlman's catalyst (200 mg). 
Hydrogenate on a Paar Hydrogenation Apparatus for 4 hours, filter through 
Celite filter aid and evaporate the solvent in vacuo to give the title 
compound. 
Step e 
Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) 
Dissolve Boc-Asp(.beta.-Chxl)-Glu-Asp(.beta.-Chxl)(NHBn) (18.6 mmol) in 
methylene chloride (140 mL). Add oxime resin (21 g, 0.69meq/g, 14.5 mmol) 
and a 0.5M solution of 1,3-dicyclohexylcarbodiimide in methylene chloride 
(42 mL, 21 mmol) and mix on a rotary evaporator for 20 hours. Filter, wash 
with dimethylformamide (2.times.200 mL), methylene chloride (200 mL), 
methanol (3.times.200 mL) and methylene chloride (3.times.200 mL). Suspend 
in a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter and wash with dimethylformamide (2.times.200 mL), methanol 
(3.times.200 mL) and methylene chloride (3.times.200 mL). Dry in vacuo to 
give the title compound. 
Step f 
Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) 
Briefly wash Boc-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn) (2 mmol) with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole and filter. 
Treat with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole, stir for 25 minutes and filter. Briefly wash 
three times with methylene chloride (50 mL) and filter. Briefly wash three 
times with isopropanol (50 mL) and filter. Briefly wash two times with 50 
mL of a solution of 1% diisopropylethylamine in methylene chloride and 
filter to give the title compound. 
Step g 
Boc-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn)-SEQ ID NO: 31 
Add Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) to a 
solution of Boc-Gly symmetrical anhydride. Stir at room temperature for 2 
hours, filter and wash with dimethylformamide (2.times.50 mL). Suspend in 
a capping mixture of acetic 
anhydride:diisopropylethylamine:dimethylformamide (6:2:24) for 30 minutes. 
Filter, wash with dimethylformamide (3.times.50 mL), isopropanol 
(3.times.50 mL) and methylene chloride (2.times.50 mL). Dry in vacuo to 
give the title compound. 
Step h 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn)-SEQ ID 
NO: 32 
Briefly wash Boc-Gly-Asp(5-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn) (SEQ ID NO: 31) (0.5 mmol) with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% anisole 
and filter. Treat with 50 mL of a solution of 25% trifluoroacetic acid in 
methylene chloride with 1% anisole, stir for 25 minutes and filter. 
Briefly wash three times with methylene chloride (50 mL) and filter. 
Briefly wash three times with isopropanol (50 mL) and filter. Briefly wash 
two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step i 
Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn)-SEQ ID NO: 33 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos) symmetrical anhydride (7.5 
mmol) in dimethylformamide (40 mL) and add 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) (SEQ 
ID NO: 32). Shake at room temperature for 3 hours, filter and wash with 
dimethylformamide (2.times.50 mL) and methylene chloride. Dry in vacuo to 
give the title compound. 
Step i 
Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn)-SEQ ID NO: 34 
Briefly wash Boc-Arg(N.sup.g -Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn) (SEQ ID NO: 33) (0.5 mmol) with 50 mL of a 
solution of 25% trifluoroacetic acid in methylene chloride with 1% anisole 
and filter. Treat with 50 mL of a solution of 25% trifluoroacetic acid in 
methylene chloride with 1% anisole, stir for 25 minutes and filter. 
Briefly wash three times with methylene chloride (50 mL) and filter. 
Briefly wash three times with isopropanol (50 mL) and filter. Briefly wash 
two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step k 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)-Asp(.beta.-Chxl)(NHBn)-SEQ ID NO: 35 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimetylformamide (10 mL). Add Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) 
(SEQ ID NO: 34) (0.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 
2 hours and filter. Wash with dimethylformamide (3.times.20 mL), methylene 
chloride (3.times.20 mL) and evaporate the solvent in vacuo to give the 
title compound. 
Step m 
Cyclo(Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Asp(.beta.-Chxl)(NHBn) 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)-Asp(.beta.-Chxl)(NHBn) 
(SEQ ID NO: 35) (0.5 mmol) with 25% trifluoroacetic acid in methylene 
chloride (25 mL) for 25 minutes. Wash with methylene chloride (3.times.20 
mL), isopropanol (3.times.20 mL), methylene chloride (20 mL), 1% 
diisopropylethylamine in methylene chloride (2.times.25 mL) and methylene 
chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step o 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Asp(NHBn).cndot.CF.sub.3 CO.sub.2 H 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos)-Gly-Asp(.beta.-Chxl)-.delta.-Glu]-Asp(.beta.-Chxl)(NHBn) (0.5 mmol) 
in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow 
the solvent to evaporate and extract into 30% aqueous acetic acid. 
Lyophillize to give the title compound and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound. 
The following compounds can be prepared by analogous procedures to those 
described above in Examples 1-9: 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 
N-Gly-Asp-Ac]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[Phe.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 
N-Gly-Asp-Ac]-Arg-Gly-Asp-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 
NH]-Arg-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA. 
The conformationally restrained peptide analogs of formula 1 wherein X is 
CH.sub.2 NH can be prepared by one of ordinary skill in the art. A general 
synthetic procedure for preparing these compounds is set forth in Scheme 
B. In Scheme B, all substituents are as previously described unless 
otherwise indicated. 
##STR12## 
Scheme B provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is CH.sub.2 NH. 
In step a, the appropriate Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (12) is coupled with N-Boc-N.sup.g -Tos argininal (22) 
to give the corresponding N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
NH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (23). 
For example, the appropriate Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (12) is contacted with a molar equivalent of 
N-Boc-N.sup.g -Tos argininal (22) and a molar equivalent of sodium 
cyanoborohydride. The reactants are typically contacted in a suitable 
acidic organic solvent mixture such as 1% acetic acid in 
dimethylformamide. The reactants are typically shaken together at room 
temperature for a period of time ranging from 1-5 hours. The 
N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 NH]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (23) is recovered from the reaction zone by 
filtration and washing with solvent. 
In step b, the Gly.PSI.[CH.sub.2 NH] functionality of the appropriate 
N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 NH]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (23) is protected to give the corresponding 
N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (24). 
For example, the appropriate N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
NH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (23) is 
contacted with 2.5 molar equivalents of benzyl chloroformate and three 
molar equivalents of a base, such as triethylamine. The reactants are 
typically contacted in a suitable organic solvent such as methylene 
chloride. The reactants are typically stirred together at room temperature 
for a period of time ranging from 15 minutes to 10 hours. The 
N-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (24) is recovered from the reaction 
zone by filtration. 
In step c, the N-Boc protecting group of the appropriate N-Boc-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (24) is cleaved to give the corresponding Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (25) as described previously in Scheme A, step f. 
In step d, the appropriate Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (25) 
is coupled with the appropriate D or L-Boc-NHCHR-aldehyde of structure 
(16) to give the corresponding Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (26) as described previously in Scheme A, step k. 
In optional step e, the N-Boc-NHCHR-.PSI.[CH.sub.2 NH] functionality of the 
appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (26) 
may be alkylated to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (27) wherein Z" is W--A.sub.6 
--A.sub.5 --A.sub.4 -- wherein W is C.sub.1 -C.sub.10 alkyl, 
--(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H 
wherein m is an integer 1-3 and p is an integer 1-4 and A.sub.6, A.sub.5 
and A.sub.4 are bonds as described previously in Scheme A, optional step 
1. 
In step f, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (26) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (27) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (28) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A4 are bonds as described previously 
in Scheme A, step m. 
In optional step g, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid] amide of structure (28) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 
-- wherein W is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be 
acylated to give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid] amide of structure (29) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 
-- wherein W is C.sub.1 -C.sub.10 acyl or succinyl as described previously 
in Scheme A, optional step n. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (28) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be converted to 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (29) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid by standard peptide chemistry as is known in the art. The terminal 
amino of the peptide side chain A6--A5--A4 may then be acylated as is 
known in the art to give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 N-Cbz]-Gly-Asp(.beta.-Chxl)-amino 
acid] amide of structure (29) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 
-- wherein W is C.sub.1 -C.sub.10 acyl or succinyl and at least one of 
A.sub.6, A.sub.5 and A.sub.4 is an amino acid. 
In step h, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (28) wherein Z" 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 alkyl --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds or the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-amino acid]amide] of structure (29) wherein Z' 
is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 
-C.sub.10 acyl or succinyl and at least one of A.sub.6, A.sub.5 and 
A.sub.4 is an amino acid are removed to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg.PSI.[CH.sub.2 NH]-Gly-Asp-amino acid] 
amide of structure (30) as described previously in Scheme A, step o. 
Starting materials for use in Scheme B are readily available to one of 
ordinary skill in the art. For example, N-Boc-N.sup.g -Tos argininal is 
described by J. M. Maraganore, J. W. Fenton and T. Kline, PCT 
International Publication Number WO 91/02750, Mar. 7, 1991. 
The following examples present typical syntheses as described in Scheme B. 
These examples are understood to be illustrative only and are not intended 
to limit the scope of the present invention in any way. 
EXAMPLE 10 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 36 
##STR13## 
Step a N.sup..alpha. -Boc-Arg(N.sup.g -Tos).cndot.[CH.sub.2 
NH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 37 
Dissolve N.sup..alpha. -Boc-Ng-Tos argininal (5 mmol) in a solution of 1% 
acetic acid in dimethylformamide (10 mL). Add 
Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (0.5 mmol) and sodium 
cyanoborohydride (150 mg). Shake for 2 hours and filter. Wash with 
dimethylformamide (3.times.20 mL), methylene chloride (3.times.20 mL) and 
recover the title compound by filtration. 
Step b 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)- SEQ ID NO: 38 
Dissolve benzyl chloroformate (5 mmol) in methylene chloride (7 mL) and add 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
NH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 37) 
(1.0 mmol) followed by triethylamine (0.26 mL, 2.0 mmol). Stir at room 
temperature for 30 minutes, wash with dimethylformamide (3.times.20 mL), 
methylene chloride (3.times.20 mL) and recover the title compound by 
filtration. 
Step c 
Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 39 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 38) 
(0.5 mmol) with 50 mL of a solution of 25% trifluoroactic acid in 
methylene chloride with 1% anisole and filter. Treat with 50 mL of a 
solution of 25% trifluoroactic acid in methylene chloride with 1% anisole, 
stir for 25 minutes and filter. Briefly wash three times with methylene 
chloride (50 mL) and filter. Briefly wash three times with isopropanol (50 
mL) and filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step d 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N(Cbz)]-Gly-Asp(.delta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 40 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 39) 
(0.50.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and 
filter. Wash with dimethylformamide (3.times.20 mL), methylene chloride 
(3.times.20 mL) and recover the title compound by filtration. 
Step f 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.delta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 41 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N(Cbz)]-Gly-Asp(.delta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 
40) (0.5 mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) 
for 25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step h 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 36 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N-Cbz]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 41) (269 mg) in 
hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the 
solvent to evaporate and extract into 30% aqueous acetic acid. Lyophillize 
to give the title compound (232 mg) and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound. 
EXAMPLE 11 
Cyclo[Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 42 
##STR14## 
Optional Step e Boc-Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N(Cbz)]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 43 
Suspend Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N(Cbz)]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 
40) (5 mmol) in methanol (distilled from Mg) (50 mL) and add formaldehyde 
(0.405 mL of a 37% solution in water, 5 mmol), sodium cyanoborohydride 
(0.62 g, 5 mmol) and 1 drop of 1% bromocresol green in methanol. Maintain 
the pH of the reaction with 1N hydrochloric acid in methanol until the 
indicator no longer changes and filter. Briefly wash three times with 
methylene chloride (50 mL) and filter. Briefly wash three times with 
isopropanol (50 mL) and filter. Briefly wash two times with methylene 
chloride and filter to give the title compound. 
Step f 
Cyclo[Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N(Cbz)]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 44 
Treat Boc-Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
N(Cbz)]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 
43) (5 mmol) with 25% triflouroacetic acid in methylene chloride (25 mL) 
for 25 minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step h 
Cyclo[Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 42 
Suspend Cyclo[Ala.PSI.[CH.sub.2 N(CH.sub.3)]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 N(Cbz)]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ 
ID NO: 44) (269 mg) in hydrogen fluoride and anisole. Stir for 1 hour at 
0.degree. C. Allow the solvent to evaporate and extract into 30% aqueous 
acetic acid. Lyophillize to give the title compound (232 mg) and purify by 
Reverse phase-HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the 
title compound. 
The following compounds can be prepared by analogous procedure to those 
described above in Example 10-11: 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gyl-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 NH]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).PSI.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu.cndot.-Leu(NHBn)]TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 NH]-Gyl-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Gyl-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 NH]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
NH]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA. 
The conformationally restrained peptide analogs of formula 1 wherein X is 
CH.dbd.CH can be prepared by one of ordinary skill in the art. A general 
synthetic procedure for preparing these compounds is set forth in Scheme 
C. In Scheme C, all substituents are as previously described unless 
otherwise indicated. 
##STR15## 
Scheme C provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is CH.dbd.CH. 
In step a, N-Boc-N.sup.g -Tos argininal (22) is coupled under Wittig 
conditions with (3-trimethylsilyl-2-propynyl)triphenylphosphonium bromide 
(31) to give 
E-8-(tosylquanidino)-5-(t-butyloxycarbonylamino)-3-ene-trimethylsilyloctyn 
e (32). 
For example, (3-trimethylsilyl-2-propynyl)triphenylphosphonium bromide (31) 
is first contacted with a molar equivalent of a suitable base such as 
n-butyllithium. The reactants are typically contacted in a suitable 
anhydrous solvent such as tetrahydrofuran. 
The reactants are typically stirred together for a period of time ranging 
from 5 minutes to 2 hours and at a temperature range of from -78.degree. 
to 0.degree. C. The resulting intermediate yield is then contacted with a 
molar equivalent of N-Boc-N.sup.g -Tos argininal (22). The reactants are 
typically stirred together for a period of time ranging from 2-24 hours 
and at a temperature range of from 0.degree. C. to room temperature. The 
E-8-(tosylquanidino)-5-(t-butyloxycarbonylamino)-3-ene-trimethylsilyloctyn 
e (32) is recovered from the reaction zone by extractive methods as is 
known in the art. It may be purified by chromatography. 
In step b, 
E-8-(tosylquanidino)-5-(t-butyloxycarbonylamino)-3-ene-trimethylsilyloctyn 
e (32) is oxidized to give N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly (33). 
For example, 
E-8-(tosylquanidino)-5-(t-butyloxycarbonylamino)-3-ene-trimethylsilyloctyn 
e (32) is first contacted with 2 molar equivalents of a reducing agent such 
as dicyclohexylborane. The reactants are typically contacted in a suitable 
organic solvent such as tetrahydrofuran. The reactants are typically 
stirred together at room temperature for a period of time ranging from 
2-24 hours. The resulting borane complex is then contacted with a molar 
excess of appropriate oxidizing agent such as a mixture of aqueous sodium 
hydroxide/hydrogen perioxide. The reactants are typically stirred together 
for a period of time ranging from 1 minute to 1 hour and at a temperature 
range of from -20.degree. to 0.degree. C. The N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly (33) is recovered from the 
reaction zone by exctractive methods as is known in the art. It may be 
purified by chromatography. 
In step c, N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly (33) 
is coupled with the appropriate Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (9) to give the corresponding N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (34). 
For example, N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly 
(33) is contacted with two molar equivalents of the appropriate 
Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (9), two molar 
equivalents of an activating agent such as a mixture of 
1-hydroxybenzotriazole hydrate and 
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and a suitable 
non-nucleophilic base such as triethylamine or diisopropylethylamine. The 
reactants are typically contacted in a suitable organic solvent such as 
methylene chloride or tetrahydrofuran. The reactants are typically stirred 
together at room temperature for a period of time ranging from 5-24 hours. 
The N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (34) is recovered from the reaction zone by filtration. 
In step d, the N-Boc protecting group of the appropriate N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (34) is cleaved to give the corresponding 
Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide 
oxime resin of structure (35) as described previously in Scheme A, step f. 
In step e, the appropriate Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (35) is coupled with the appropriate D or 
L-N-Boc-NHCHR-aldehyde of structure (16) to give the corresponding 
N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (36) as described previously in Scheme A, step k. 
In optional step f, the N-Boc-NHCHR-.PSI.[CH.sub.2 NH]functionality of the 
appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (36) may be alkylated to give the corresponding 
N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (37) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein 
W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in Scheme A, optional step l. 
In step g, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (36) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (37) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein 
W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (38) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in Scheme A, step m. 
In optional step h, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly--Asp(.beta.-Chxl)-amino 
acid] amide of structure (38) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 
-- wherein W is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly--Asp(.beta.-Chxl)-amino acid] amide of 
structure (39) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 acyl or succinyl and A.sub.6, A.sub.5 and A.sub.4 are 
bonds. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (38) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be converted to 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly--Asp(.beta.-Chxl)-amino acid] amide of 
structure (39) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid by standard peptide chemistry as is known in the art. The terminal 
amino of the peptide side chain A.sub.6 --A.sub.5 --A.sub.4 may then be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (39) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 acyl or succinyl and at least one of A.sub.6, A.sub.5 
and A.sub.4 is an amino acid. 
In step i, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (38) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 alkyl, (CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds or the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (39) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 acyl or succinyl and at least one of 
A.sub.6, A.sub.5 and A.sub.4 is an amino acid are removed to give the 
corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-amino acid] amide of structure (40) as 
described previously in Scheme A, step o. 
Starting materials for use in Scheme C are readily available to one of 
ordinary skill in the art. 
The following example presents a typical synthesis as described above in 
Scheme C. This example is understood to be illustrative only and is not 
intended to limit the scope of the present invention in any way. 
EXAMPLE 12 
Cyclo[Ala.PSI.[CH.sub.2 
NH]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 
CO.sub.2 H-SEQ ID NO: 45 
##STR16## 
Step a 
E-8-(Tosylquanidino)-5-(t-butyloxycarbonylamino)-3-ene-trimethylsilyloctyn 
e 
Dissolve (3-trimethylsilyl-2-propynyl)triphenylphosphonium bromide (24 
mmol) in anhydrous tetrahydrofuran (250 mL), cool to -78.degree. C. and 
place under an argon atmosphere. Add a solution of n-butyllithium in 
hexane (16.3 mL, 26 mmol). Stir at -78.degree. C. for 10 minutes, then 
add, by dropwise addition, a solution of N.sup..alpha. 
-Boc-Arg(N.sup..epsilon. -Tos)-al (20 mmol) in tetrahydrofuran (5 mL). 
Stir for 10 minutes, allow to warm to room temperature, and stir for an 
additional 17 hours. Dilute with saturated ammonium chloride (100 mL), 
wash twice with 10% sodium hydroxide and dry (MgSO.sub.4). Evaporate the 
solvent in vacuo to give the title compound. 
Step b 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly 
Dissolve cyclohexene (9.035 g, 0.11 mol) in tetrahydrofuran (3 mL) and cool 
to -15.degree. C. Slowly add borane (24.1 mL of a 2.3M solution in 
tetrahydrofuran) and stir at -15.degree. C. for 1 hour to give 
dicyclohexylborane (55 mmol). 
Add a 0.degree. C. solution of E-8-(Tosylquanidino)-5-(t-5 
butyloxycarbonylamino)-3-ene-trimethylsilyloctyne (25 mmol) in 
tetrahydrofuran (15 mL) and stir at room temperature until the reaction 
mixture becomes homogeneous. Cool to 0.degree. C., dilute with 3N sodium 
hydroxide (25 mL) and immediately oxidize by adding 30% hydrogen peroxide 
(2 mL). Saturate with potassium carbonate, acidify the aqueous phase with 
1N hydrochloric acid and decant the upper phase. 
Extract the aqueous phase with ethyl ether (2.times.), dry (MgSO.sub.4) and 
evaporate the solvent in vacuo to give the title compound. 
Step c 
N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 46 
Mix Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (10 mmol), 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly (5.3 mmol), 
hydroxybenztriazole (1.65 g, 11 mmol) and 
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.1 g, 11 
mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene 
chloride (20 mL) and stir at room temperature for several hours. Briefly 
wash two times with 5 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step d 
Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 47 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn) (SEQ ID NO: 46) (2 mmol) with 50 mL of a solution of 25% 
trifluoroactic acid in methylene chloride with 1% anisole and filter. 
Treat with 50 mL of a solution of 25% trifluoroactic acid in methylene 
chloride with 1% anisole, stir for 25 minutes and filter. Briefly wash 
three times with methylene chloride (50 mL) and filter. Briefly wash three 
times with isopropanol (50 mL) and filter. Briefly wash two times with 50 
mL of a solution of 1% diisopropylethylamine in methylene chloride and 
filter to give the title compound. 
Step e 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 48 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn) (SEQ ID NO: 47) (0.5 mmol) and sodium cyanoborohydride (150 
mg). Shake for 2 hours and filter. Wash with dimethylformamide (3.times.20 
mL), methylene chloride (3.times.20 mL) and filter to give the title 
compound. 
Step g 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 
49 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn) (SEQ ID NO: 48) (5 mmol) with 25% trifluoroacetic acid in 
methylene chloride (25 mL) for 25 minutes. Wash with methylene chloride 
(3.times.20 mL), isopropanol (3.times.20 mL), methylene chloride (2 mL), 
1% diisopropylethylamine in methylene chloride (2.times.25 mL) and 
methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step i 
Cyclo[Ala.PSI.[CH.sub.2 
NH]Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 
CO.sub.2 H-SEQ ID NO: 45 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID 
NO: 49) (269 mg) in hydrogen fluoride and anisole. Stir for 1 hour at 
0.degree. C. Allow the solvent to evaporate and extract into 30% aqueous 
acetic acid. Lyophillize to give the title compound (232 mg) and purify by 
Reverse phase-HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the 
title compound. 
The following compounds may be prepared by analogous procedures to those 
described above in Example 12: 
Cyclo[D-Phe.PSI.[CH.sub.2 
NH]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[(E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 
N-Gly-Asp-Ac]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.T 
FA; 
Cyclo[D-Phe.PSI.[CH.sub.2 
NH]-Arg.PSI.[[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 
NH]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.(CH.sub.2 
N-Gly-Asp-Ac]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.T 
FA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 
NH]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[E-CH.dbd.CH]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA. 
The conformationally restrained peptides of formula 1 wherein X is CH.sub.2 
CH.sub.2 can be prepared by one of ordinary skill in the art. A general 
synthetic procedure for preparing these compounds is set forth in Scheme 
D. In Scheme D, all substituents are as previously described unless 
otherwise indicated. 
##STR17## 
Scheme D provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is CH.sub.2 CH.sub.2. 
In step a, the olefin functionality of the appropriate N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly (33) is reduced to give the 
corresponding N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly (41). 
For example, the appropriate N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[E-CH.dbd.CH]-Gly (33) is contacted with a catalytic amount with 
a suitable hydrogenation catalyst such as palladium/carbon. The reactants 
are typically contacted in a suitable protic solvent such as methanol. The 
reactants are shaken at room temperature under an atmosphere of hydrogen 
at a pressure range of from 35-50 psi. The N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly (41) is recovered from the reaction 
zone by filtration and evaporation of the solvent. 
In step b, N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly (41) is coupled with the appropriate Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (9) to give the corresponding N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (42) as described previously in Scheme 
C, step c. 
In step c, the N-Boc protecting group of the appropriate N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino 
acid amide oxime resin of structure (42) is cleaved to give the 
corresponding Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (43) as 
described previously in Scheme A, step f. 
In step d, the appropriate Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (43) is 
coupled with the appropriate D or L-N-Boc-NHCHR-aldehyde of structure (16) 
to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (44) as described previously in Scheme A, step k. 
In optional step e, the N-Boc-NHCHR-.PSI.[CH.sub.2 NH] functionality of the 
appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure 
(44) may be alkylated to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (45) 
wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds as described previously in Scheme 
A, optional step l. 
In step f, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (44) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (45) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly--Asp(.beta.-Chxl)-amino acid] amide of 
structure (46) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in Scheme A, step m. 
In optional step g, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (46) wherein Z" is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen and A.sub.6, 
A.sub.5 and A.sub.4 are bonds may be acylated as is known in the art to 
give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (47) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 acyl or succinyl and A.sub.6, A.sub.5 and A.sub.4 are 
bonds. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (46) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be converted to 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (47) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid by standard peptide chemistry as is known in the art. The terminal 
amino of the peptide side chain A.sub.6 --A.sub.5 --A.sub.4 may then be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (47) wherein Z' is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 -C.sub.10 acyl or 
succinyl and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid. 
In step h, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (46) wherein Z" is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 -C.sub.10 
alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H 
wherein m is an integer 1-3 and p is an integer 1-4 and A.sub.6, A.sub.5 
and A.sub.4 are bonds or the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (47) wherein Z' is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 -C.sub.10 
acyl or succinyl and at least one of A.sub.6, A.sub.5 and A.sub.4 is an 
amino acid are removed to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (47) as described 
previously in Scheme A, step o. 
Starting materials for use in Scheme D are readily available to one of 
ordinary skill in the art. 
The following example presents a typical synthesis as described above in 
Scheme D. This example is understood to be illustrative only and is not 
intended to limit the scope of the present invention in any way. 
EXAMPLE 13 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 50 
##STR18## 
Step a N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[E-CH.dbd.CH]-Gly (5.5 
mmol) in methanol (50 mL) and place in a Paar hydrogenation flask. Add 10% 
palladium/C (500 mg). Charge the vessel to 50 psi and shake for 18 hours. 
Filter through Celite and remove the solvent in vacuo to give the title 
compound. 
Step b 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 51 
Mix Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (10 mmol), 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 ]-Gly (10 
mmol), hydroxybenztriazole (1.65 g, 11 mmol) and 
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.1 g, 11 
mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene 
chloride (20 mL) and stir at room temperature for several hours. Briefly 
wash two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step c 
Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 52 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 51) (0.5 
mmol) with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step d 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 53 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 52) (0.5 
mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and filter. 
Wash with dimethylformamide (3.times.2 mL), methylene chloride (3.times.2 
mL) and filter to give the title compound. 
Step f 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 54 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 53) (0.5 
mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 25 
minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step h 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 50 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 54) (269 
mg) in hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. 
Allow the solvent to evaporate and extract into 30% aqueous acetic acid. 
Lyophillize to give the title compound (232 mg) and purify by Reverse 
phase-HPLC (aqueous trifluoroacetic acid/acetonitrile) to give the title 
compound. 
The following compounds can be prepared by analogous procedures to those 
described above in Example 13: 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 CH.sub.2 
]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
CH.sub.2 ]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA. 
The conformationally restrained peptides of formula 1 wherein X is 
COCH.sub.2 can be prepared by one of ordinary skill in the art. A general 
synthetic procedure for preparing these compounds is set forth in Scheme 
E. In Scheme E, all substituents are as previously described unless 
otherwise indicated. 
##STR19## 
Scheme E provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is COCH.sub.2. 
In step a, the appropriate Asp(.beta.-Chxl)-amino acid amide oxime resin of 
structure (9) is coupled with N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-OH (49) to give the corresponding 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (50) as 
described previously in Scheme D, step b. 
In step b, the N-Boc protecting group of the appropriate N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (50) is cleaved to give the corresponding 
Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide 
oxime resin of structure (51) as described previously in Scheme A, step f. 
In step c, the appropriate Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (51) is 
coupled with the appropriate D or L-N-Boc-NHCHR-aldehyde of structure (16) 
to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (52) as described previously in Scheme A, step k. 
In optional step d, the N-Boc-NHCHR-.PSI.[CH.sub.2 NH] functionality of the 
appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (52) may be alkylated to give the corresponding 
N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (53) 
wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 
-C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p 
CO.sub.2 H wherein m is an integer 1-3 and p is an integer 1-4 and 
A.sub.6, A.sub.5 and A.sub.4 are bonds as described previously in Scheme 
A, optional step l. 
In step e, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (52) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (53) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein 
W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (54) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 
or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in Scheme A, step m. 
In optional step f, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino 
acid] amide of structure (54) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 
-- wherein W is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (55) wherein Z' is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 -C.sub.10 acyl or 
succinyl and A.sub.6, A.sub.5 and A.sub.4 are bonds. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (54) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be converted to 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] amide of 
structure (55) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is hydrogen and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid by standard peptide chemistry as is known in the art. The terminal 
amino of the peptide side chain A.sub.6 --A.sub.5 --A.sub.4 may then be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (55) wherein Z' is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 -C.sub.10 acyl or 
succinyl and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino 
acid. 
In step g, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (54) wherein Z" is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 -C.sub.10 
alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H 
wherein m is an integer 1-3 and p is an integer 1-4 and A.sub.6, A.sub.5 
and A.sub.4 are bonds or the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z)]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-amino acid] 
amide of structure (55) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is hydrogen, C.sub.1 -C.sub.10 acyl or succinyl and at least one 
of A.sub.6, A.sub.5 and A.sub.4 is an amino acid are removed to give the 
corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-amino acid] amide of structure (56) as described previously in 
Scheme A, step o. 
Starting materials for use in Scheme E are readily available to one of 
ordinary skill in the art. 
The following example presents a typical sythesis as described in Scheme E. 
This example is understood to be illustrative only and is not intended to 
limit the scope of the present invention in any way. 
EXAMPLE 14 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 55 
##STR20## 
Step a Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 56 
Suspend N.sup..alpha. -Boc-Arg(N.sup.g -Tos) (1.0 mmol) in benzene (4 mL) 
and add N-methylmorpholine (252 mg, 2.5 mmol). Cool to -22.degree. C. and 
add isobutylchloroformate (136 mg, 1.0 mmol). Stir for 20 minutes and 
slowly add to a solution of excess diazomethane (previously prepared from 
8.7 g of nitrosomethylurea and dried for several hours at 0.degree. C. 
over potassium hyroxide pellets). Stir at 0.degree. C. for several hours 
and remove residual benzene and diazomethane on a steam-bath in the hood. 
Evaporate the residual benzene in vacuo to give N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos)-CHN.sub.2. 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CHN.sub.2 in anhydrous ethyl 
ether (5 mL) and treat with a slight excess of hydrochloric acid in 
dioxane. Evaporate the solvent on a steam bath then in vacuo to give 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 Cl. 
Mix N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 Cl (0.485 mmol), 
dimethylformamide (40 mL) and sodium iodide (10 g). Reflux for 8 hours, 
cool and add methylene chloride (40 mL). Filter and evaporate the filtrate 
to a residue. Partition the residue between methylene chloride (2 mL) and 
water (2 mL). Separate the organic phase, dry (MgSO.sub.4) and evaporate 
the solvent in vacuo to give N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 
I. 
Suspend sodium hydride (1 g, 0.21 mmol) in tetrahydrofuran, place under a 
nitrogen atmosphere and cool to 0.degree. C. Add, by dropwise addition, 
dibenzyl malonate (0.2 mmol). Stir at 0.degree. C. until anion formation 
is complete and add N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 I (0.21 
mmol). Heat at reflux for several hours, cool and pour into water (40 mL). 
Extract with ethyl acetate (3.times.60 mL), dry (MgSO.sub.4) and evaporate 
the solvent in vacuo to give N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 
CH(CO.sub.2 CH.sub.2 Ph).sub.2. 
Mix N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 CH(CO.sub.2 CH.sub.2 
Ph).sub.2 (5.3 mmol) and 10% palladium/carbon (0.5 g) in 95% ethanol (40 
mL). Hydrogenate at room temperature at atmospheric pressure. Filter and 
evaporate the filtrate in vacuo to give N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos)-CH.sub.2 CH(CO.sub.2 H).sub.2. 
Suspend N.sup..alpha. -Boc-Arg(N.sup.g -Tos)-CH.sub.2 CH(CO.sub.2 H).sub.2 
(0.2 mmol) in acetonitrile (80 mL) and treat with copper(I) oxide (1.5 mg, 
0.01 mmol). Heat at reflux for 7 hours. Cool, filter and evaporate the 
solvent in vacuo. Take the residue up in ethyl ether (10 mL) and wash with 
10% hydrochloric acid (2.times.5 mL), water (5 mL) and brine (5 mL). Dry 
(MgSO.sub.4) and evaporate the solvent in vacuo to give N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly. 
Mix Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (10 mmol), 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly (5.3 mmol), 
hydroxybenztriazole (1.65 g, 11 mmol) and 
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.1 g, 11 
mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene 
chloride (20 mL) and stir at room temperature for several hours. Briefly 
wash two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step b 
Arg(N.sup.g -Tos).PSI.[COCH.sub.2 ]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 57 
Briefly wash Boc-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 56) (0.5 
mmol) with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step c 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 58 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 57) (0.5 
mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and filter. 
Wash with dimethylformamide (3.times.2 mL), methylene chloride (3.times.2 
mL) and evaporate the solvent in vacuo to give the title compound. 
Step e 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 59 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 58) (5 
mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 25 
minutes. Wash with methylene chloride (3.times.2 mL), isopropanol 
(3.times.2 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step g 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu](NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 55 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[COCH.sub.2 
]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 59) (269 mg) in 
hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the 
solvent to evaporate and extract into 30% aqueous acetic acid. Lyophillize 
to give the title compound (232 mg) and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound. 
The following compounds may be prepared by analogous procedures to those 
described above in Example 14: 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[COCH.sub.2 
]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[COCH.sub.2 ]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
The conformationally restrained peptides of formula 1 wherein X is CH.sub.2 
O can be prepared by one of ordinary skill in the art. A general synthetic 
procedure for preparing these compounds is set forth in Scheme F. In 
Scheme F, all substituents are as previously described unless otherwise 
indicated. 
##STR21## 
Scheme F provides a general synthetic procedure for preparing the compounds 
of formula 1 wherein X is CH.sub.2 O. 
In step a, N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly (57) 
is coupled with the appropriate Asp(.beta.-Chxl)-amino acid amide oxime 
resin of structure (9) to give the corresponding N.sup..alpha. 
-Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (58) as described previously in Scheme C, 
step c. 
In step b, the N.sup..alpha. -Boc protecting group of the appropriate 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (58) is 
cleaved to give the corresponding Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (59) as 
described previously in Scheme A, step f. 
In step c, the appropriate Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (59) is 
coupled with the appropriate D or L-N-Boc-NHCHR-aldehyde of structure (16) 
to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin 
of structure (60) as described previously in Scheme A, step k. 
In optional step d, the N-Boc-NHCHR-.PSI.[CH.sub.2 NH] functionality of the 
appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of structure (60) may 
be alkylated to give the corresponding N-Boc-NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid 
amide oxime resin of structure (61) wherein Z" is W--A.sub.6 --A.sub.5 
--A.sub.4 -- wherein W is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m 
C.sub.6 H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 
1-3 and p is an integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as 
described previously in Scheme A, optional step l. 
In step e, the appropriate N-Boc-NHCHR-.PSI.[CH.sub.2 NH]-Arg(N.sup.g 
Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of 
structure (60) or N-Boc-NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid amide oxime resin of 
structure (61) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W 
is C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds is cyclized to give 
the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure 
(62) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is 
hydrogen, C.sub.1 -C.sub.10 alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or 
--(CH.sub.2).sub.p CO.sub.2 H wherein m is an integer 1-3 and p is an 
integer 1-4 and A.sub.6, A.sub.5 and A.sub.4 are bonds as described 
previously in Scheme A, step m. 
In optional step f, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] 
amide of structure (62) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is hydrogen and A.sub.6, A.sub.5 and A.sub.4 are bonds may be 
acylated as is known in the art to give the corresponding 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (63) wherein Z' is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is C.sub.1 -C.sub.10 acyl or 
succinyl and A.sub.6, A.sub.5 and A.sub.4 are bonds. 
In addition, the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure 
(62) wherein Z" is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen 
and A.sub.6, A.sub.5 and A.sub.4 are bonds may be converted to the 
corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z')]-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure 
(63) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen 
and at least one of A.sub.6, A.sub.5 and A.sub.4 is an amino acid by 
standard peptide chemistry as is known in the art. The terminal amino of 
the peptide side chain A.sub.6 --A.sub.5 --A.sub.4 may then be acylated as 
is known in the art to give the corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z')]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] 
amide of structure (63) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is C.sub.1 -C.sub.10 acyl or succinyl and at least one of 
A.sub.6, A.sub.5 and A.sub.4 is an amino acid. 
In step g, the protecting groups of the appropriate 
Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z")]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-amino acid] amide of structure (62) wherein Z" is 
W--A.sub.6 --A.sub.5 --A.sub.4 -- wherein W is hydrogen, C.sub.1 -C.sub.10 
alkyl, --(CH.sub.2).sub.m C.sub.6 H.sub.5 or --(CH.sub.2).sub.p CO.sub.2 H 
wherein m is an integer 1-3 and p is an integer 1-4 and A.sub.6, A.sub.5 
and A.sub.4 are bonds or the appropriate Cyclo[NHCHR-.PSI.[CH.sub.2 
N(Z)]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-amino acid] 
amide of structure (63) wherein Z' is W--A.sub.6 --A.sub.5 --A.sub.4 -- 
wherein W is hydrogen, C.sub.1 -C.sub.10 acyl or succinyl and at least one 
of A.sub.6, A.sub.5 and A.sub.4 is an amino acid are removed to give the 
corresponding Cyclo[NHCHR-.PSI.[CH.sub.2 N(Z)]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-amino acid] amide of structure (64) as described previously in 
Scheme A, step o. 
Starting materials for use in Scheme F are readily available to one of 
ordinary skill in the art. 
The following example presents a typical synthesis as described above in 
Scheme F. This example is understood to be illustrative only and is not 
intended to limit the scope of the present invention in any way. 
EXAMPLE 15 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-(NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 60 
##STR22## 
Step a N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 61 
Suspend N.sup..alpha. -Boc-N.sup.g -Tos arginine (10 g) in anhydrous 
tetrahydrofuran (80 mL) and cool to 0-5.degree. C. Add 
1,1'-carbonyldiimidazole (3.61 g) all at once and continue stirring for 20 
minutes. Immerse in a dry ice/acetone bath to maintain a temperature of 
-20.degree. to -30.degree. C. Add, by dropwise addition, a suspension of 
lithium aluminum hydride (1.8 g in 80 mL of tetrahydrofuran) over 45 
minutes. Stir an additional 30 minutes at -20.degree. C., quench with the 
dropwise addition of 2N hydrochloric acid (63 mL) at -10.degree. C. Filter 
and evaporate the solvent in vacuo to give N.sup..alpha. -Boc-N.sup.g -Tos 
argininol. 
Dissolve N.sup..alpha. -Boc-N.sup.g -Tos argininol (70.5 mmol) in acetone 
(500 mL) and treat with potassium carbonate (10.7 g, 77.6 mmol), potassium 
iodide (1.17 g, 7.05 mmol) and ethyl bromoacetate (77.6 mmol). Reflux for 
several hours, cool, filter and evaporate the solvent in vacuo. Purify by 
flash chromatography to give N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly(OEt). 
Dissolve N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly(OEt) (20 
mmol) in methanol (40 mL). Add 1N lithium hydroxide (25 ml, 20 mmol) and 
stir under an argon atmosphere for 3.5 hours. Acidify with 1N hydrochloric 
acid (25 mL), saturate with sodium chloride and extract with ethyl acetate 
(3.times.25 mL). Combine the organic phases, dry (MgSO.sub.4) and 
evaporate the solvent in vacuo to give N.sup..alpha. -Boc-Arg(N.sup.g 
-Tos).PSI.[CH.sub.2 O]-Gly. 
Mix Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (10 mmol), 
N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly (5.3 mmol), 
hydroxybenztriazole (1.65 g, 11 mmol) and 
1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (2.1 g, 11 
mmol). Add a solution of diisopropylethylamine (3.8 mL) in methylene 
chloride (20 mL) and stir at room temperature for several hours. Briefly 
wash two times with 50 mL of a solution of 1% diisopropylethylamine in 
methylene chloride and filter to give the title compound. 
Step b 
Arg(N.sup.g -Tos).PSI.[CH.sub.2 O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime 
resin)(NHBn)-SEQ ID NO: 62 
Briefly wash N.sup..alpha. -Boc-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 61) (2 
mmol) with 50 mL of a solution of 25% trifluoroacetic acid in methylene 
chloride with 1% anisole and filter. Treat with 50 mL of a solution of 25% 
trifluoroacetic acid in methylene chloride with 1% anisole, stir for 25 
minutes and filter. Briefly wash three times with methylene chloride (50 
mL) and filter. Briefly wash three times with isopropanol (50 mL) and 
filter. Briefly wash two times with 50 mL of a solution of 1% 
diisopropylethylamine in methylene chloride and filter to give the title 
compound. 
Step c 
Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn)-SEQ ID NO: 63 
Dissolve Boc-Ala-al (5 mmol) in a solution of 1% acetic acid in 
dimethylformamide (10 mL). Add Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 62) 
(0.5 mmol) and sodium cyanoborohydride (150 mg). Shake for 2 hours and 
filter. Wash with dimethylformamide (3.times.20 mL), methylene chloride 
(3.times.20 mL) and evaporate the solvent in vacuo to give the title 
compound. 
Step e 
Cyclo[(Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn)-SEQ ID NO: 64 
Treat Boc-Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-Glu(.delta.-oxime resin)(NHBn) (SEQ ID NO: 63) (5 
mmol) with 25% trifluoroacetic acid in methylene chloride (25 mL) for 25 
minutes. Wash with methylene chloride (3.times.20 mL), isopropanol 
(3.times.20 mL), methylene chloride (20 mL), 1% diisopropylethylamine in 
methylene chloride (2.times.25 mL) and methylene chloride (25 mL). 
Suspend in a solution of 1% acetic acid in dimethylformamide and shake for 
2 days. Filter and wash with dimethylformamide. Evaporate the solvent in 
vacuo and dissolve the residual oil in acetic acid. Lyophillize to give 
the title compound. 
Step g 
Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-(NHBn).cndot.CF.sub.3 CO.sub.2 H-SEQ ID NO: 60 
Suspend Cyclo[Ala.PSI.[CH.sub.2 NH]-Arg(N.sup.g -Tos).PSI.[CH.sub.2 
O]-Gly-Asp(.beta.-Chxl)-.delta.-Glu](NHBn) (SEQ ID NO: 64) (269 mg) in 
hydrogen fluoride and anisole. Stir for 1 hour at 0.degree. C. Allow the 
solvent to evaporate and extract into 30% aqueous acetic acid. Lyophillize 
to give the title compound (232 mg) and purify by Reverse phase-HPLC 
(aqueous trifluoroacetic acid/acetonitrile) to give the title compound. 
The following compounds may be prepared by analogous procedures to those 
described above in Example 15: 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]--Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 O]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.cndot.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N-Gly-Asp-Ac]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Leu(NHBn).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 NH]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Asp(NH.sub.2).cndot.TFA; 
Cyclo[D-Tyr.PSI.[CH.sub.2 N(C(O)(CH.sub.2).sub.2 CO.sub.2 
H)]-Arg.PSI.[CH.sub.2 O]-Gly-Asp-.delta.-Glu]-Phe(NH.sub.2).cndot.TFA; 
Cyclo[D-Phe.PSI.[CH.sub.2 N((CH.sub.2).sub.3 CO.sub.2 H)]-Arg.PSI.[CH.sub.2 
O]-Gly-Asp-.delta.-Glu]-Trp(NH.sub.2).cndot.TFA. 
The antiplatelet dose of a peptide analog of this invention is from 0.2 
mg/kg to 250 mg/kg of patient body weight per day depending on the 
patient, the severity of the thromobotic condition to be treated and the 
peptide analog selected. The suitable dose for a particular patient can be 
readily determined. Preferably from 1 to 4 daily doses would be 
administered typically with from 5 mg to 100 mg of active compound per 
dose. 
Antiplatelet therapy is indicated for the prevention or recurrence of 
myocardial infarction and stroke, as well as other disease conditions 
associated with platelet aggregation. Those experienced in this field are 
readily aware of the circumstances requiring anticoagulant and 
antiplatelet therapy. The term "patient" used herein is taken to mean 
mammals such as primates, including humans, sheep, horses, cattle, pigs, 
dogs, cats, rats and mice. 
Although some of the peptide derivatives may survive passage through the 
gut following oral administration, applicants prefer non-oral 
administration, for example, subcutaneous, intravenous, intramuscular or 
intraperitoneal; administration by depot injection; by implant 
preparation; by application to the mucous membranes, such as, that of the 
nose, throat and bronchial tubes, for example, in an aerosol can 
containing a peptide derivative of this invention in a spray or dry powder 
form, or transdermally. 
For parenteral administration the compounds may be administered as 
injectable dosages of a solution or suspension of the compound in a 
physiologically acceptable diluent with a pharmaceutical carrier which can 
be a sterile liquid such as water and oils with or without the addition of 
a surfactant and other pharmaceutically acceptable adjuvants. Illustrative 
of oils which can be employed in these preparations are those of 
petroleum, animal, vegetable, or synthetic origin, for example, peanut 
oil, soybean oil, and mineral oil. In general, water, saline, aqueous 
dextrose and related sugar solutions, ethanol and glycols such as 
propylene glycol or polyethylene glycol are preferred liquid carriers, 
particularly for injectable solutions. 
The compounds can be administered in the form of a depot injection or 
implant preparation which may be formulated in such a manner as to permit 
a sustained release of the active ingredient. The active ingredient can be 
compressed into pellets or small cylinders and implanted subcutaneously or 
intramuscularly as depot injections or implants. Implants may employ inert 
materials such as biodegradable polymers or synthetic silicones, for 
example, Silastic, silicone rubber manufactured by the Dow-Corning 
Corporation. 
The compounds of this invention can also be administered topically. This 
can be accomplished by simply preparing a solution of the compound to be 
administered, preferably using a solvent known to promote transdermal 
absorption such as ethanol or dimethyl sulfoxide (DMSO) with or without 
other excipients. Preferably topical administration will be accomplished 
using a patch either of the reservoir and porous membrane type or of a 
solid matrix variety. 
Some suitable transdermal devices are described in U.S. Pat. Nos. 
3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generally 
contain a backing member which defines one of its face surfaces, an active 
agent permeable adhesive layer defining the other face surface and at 
least one reservoir containing the active agent interposed between the 
face surfaces. Alternatively, the active agent may be contained in a 
plurality of microcapsules distributed throughout the permeable adhesive 
layer. In either case, the active agent is delivered continuously from the 
reservoir or microcapsules through a membrane into the active agent 
permeable adhesive, which is in contact with the skin or mucosa of the 
recipient. If the active agent is absorbed through the skin, a controlled 
and predetermined flow of the active agent is administered to the 
recipient. In the case of microcapsules, the encapsulating agent may also 
function as the membrane. 
In another device for transdermally administering the compounds in 
accordance with the present invention, the pharmaceutically active 
compound is contained in a matrix from which it is delivered in the 
desired gradual, constant and controlled rate. The matrix is permeable to 
the release of the compound through diffusion or microporous flow. The 
release is rate controlling. Such a system, which requires no membrane is 
described in U.S. Pat. No. 3,921,636. At least two types of release are 
possible in these systems. Release by diffusion occurs when the matrix is 
non-porous. The pharmaceutically effective compound dissolves in and 
diffuses through the matrix itself. Release by microporous flow occurs 
when the pharmaceutically effective compound is transported through a 
liquid phase in the pores of the matrix. 
The efficacy of the compounds of this invention to act as antithrombotic 
and antiplatelet aggregation agents can be demonstrated using standard art 
recognized tests. Applicants have determined the relevant activities for 
the representative compounds of Table I by the procedures outlined in 
Example 16 and the results are tabulated in Table II. 
TABLE I 
______________________________________ 
COMPOUNDS EVALUATED FOR ANTIPLATELET AND 
ANTITHROMBOTIC ACTIVITY 
##STR23## 
Test Compound # 
Z 
______________________________________ 
I H 
II HOC(.dbd.O)(CH.sub.2).sub.3 -- 
III H.sub.2 N(CH.sub.2).sub.2 C(.dbd.O)-- 
IV C.sub.6 H.sub.5 --(CH.sub.2).sub.3 -- 
______________________________________ 
TABLE II 
__________________________________________________________________________ 
ANTIPLATELET AND ANTITHROMBOTIC ACTIVITY OF VARIOUS FORMULA 
I COMPOUNDS 
.sup.125 I-Fibrinogen 
Platelet Aggregation 
GPIIbIIIa (Fibrogen 
Cyclic Flow 
Test Binding to Platelets 
ADP Induced 
ELISA Reduction 
Compound # 
IC.sub.50 (.mu.M) 
IC.sub.50 (.mu.M) 
IC.sub.50 (.mu.M) 
mg/min 
__________________________________________________________________________ 
I 2.4 -- 0.20 0.3 
II 1.2 -- 0.54 0.01 
III 2.4 49.2 3.0 0.1 
IV 0.27 6.4 0.3 0.3 
__________________________________________________________________________ 
EXAMPLE 16 
Determination of antiplatelet and antithrombotic activity 
Experimental Animals 
Male Sprague-Dawley rats (300-400 gm) purchased from Harlan Sprague Dawley, 
Inc., (Indianapolis, Ind. 46229) were used in these studies. 
Blood Sampling 
Blood samples were drawn into plastic syringes containing 3.8% trisodium 
citrate (1:10, V:V). Plasma was prepared by centrifugation at 
2,000.times.g for 10 min. Venous blood for in vitro studies was collected 
from healthy, drug free, male volunteers. 
Coagulation Assays 
Activated partial thromboplastin time (aPTT) determinations were carried 
out using the reagents and methods of Dade Diagnostics, Inc., (Aguada, 
Puerto Rico 00602). Thrombin clotting times were determined by incubating 
0.1 ml of rat plasma at 37.degree. C. with 0.1 ml of 0.1M Tris buffer, pH 
7.5 for 30 seconds. Coagulation was started with 0.1 ml of bovine thrombin 
(Sigma Diagnostics, St. Louis, Mo. 63178) solution (12 NIH units/ml). All 
clotting times were measured semiautomatically using a MLA-Electra 750, 
MLA, Inc. (Pleasantville, N.Y. 10570). The concentration required for 
doubling the clotting time (ID.sub.2) was calculated using simple linear 
regression. 
Platelet Aggregation In Vitro 
Human platelet rich plasma (PRP) was prepared by centrifugation at 
200.times.g for 10 min. at room temperature. Platelet poor plasma (PPP) 
was prepared by centrifugation at 2000.times.g for 10 min. PRP was exposed 
only to plastic laboratory ware. All experiments were completed within 3 
hr of blood collection. Platelet aggregation was measured photometrically 
using a Chrono-log dual channel aggregometer (Chrono-log Corp., 
Haverstown, Pa. 19083). One hundred percent light transmission was defined 
with autologus PPP. Percent maximal change in light transmission was 
determined from PRP following addition of ADP (1 .mu.M) or thrombin. 
Thrombin (0.2-2.0 Units/ml)-induced platelet aggregation was concentration 
dependent and the half-maximal concentration used for inhibition studies. 
MDL 102,530 was incubated with PRP (0.45 ml) for 30 sec prior to the 
addition of ADP or thrombin. Aggregation was measured in a total volume of 
0.5 ml. Inhibitory responses were expressed s percent inhibition when 
compared to a control value. The concentration resulting in 50% inhibition 
of aggregation (IC.sub.50) was calculated by simple linear regression. 
Preparation of Human Platelets 
Human blood was collected by venipuncture in tubes containing one-tenth 
volume of acid-citrate-dextrose as an anticoagulant. Platelet-rich plasma 
was prepared by centrifugation of the blood for 10 min at 500 g at room 
temperature. The platelet-rich plasma was decanted and one-tenth volume of 
acid-citrate-dextrose was added followed by centrifugation at 1000 g at 
room temperature for 10 min to sediment the platelets. The platelets were 
suspended in two ml modified Tyrode's buffer (2 M NaCl, 0.5 M dextrose, 
0.2 M NaHCO.sub.3, 0.1 M KCl, 0.1 M MgCl.sub.2, 0.1 M NaH.sub.2 PO.sub.4 
and 0.1 M HEPES, pH 7.3) containing 0.35% bovine serum albumin and then 
filtered on a 50 ml column of Sepharose 2B (Pharmacia) equilibrated with 
Tyrode's buffer. Finally, the platelets were counted in an automated 
hematology analyzer. 
Platelet Aggregation In Vivo in Anesthetized Dogs 
In open-chest anesthetized dogs, left anterior descending coronary arterial 
(LAD) blood flow, aortic blood pressure, heart rate and EKG were recorded. 
In the presence of a critical stenosis and endothelial damage of the LAD, 
LAD coronary arterial flow showed a slow and progressive decrease to near 
zero followed by a sudden return to near control level which is referred 
to as a cyclic flow reduction (CFR). Cyclic flow reductions are known to 
be caused by platelet thrombi formation followed by their dissemination. 
The antithrombotic activity of these compounds were evaluated in this 
model by their abilities to abolish CFRs. 
Fibrinogen Iodination 
Human low solubility fibrinogen (Kabi) was prepared as described previously 
(Lipinska et al., 1974). For .sup.125 I labeling, fibrinogen (1 mg) was 
incubated with three Iodo-Beads (Pierce Chemical Co.) and 1 mCi of 
Na.sup.125 I for 15 min after with .sup.125 I-fibrinogen was separated 
from free radioactivity by filtration through a PD-10 column (Pharmacia). 
The specific activity was approximately 1-5.times.10.sup.17 CPM/mol 
fibrinogen. 
Fibrinogen Binding Assay 
Binding of fibrinogen to human platelets was performed as described by Plow 
and Ginsberg (1981). Binding assays contained, in a volume of 0.2 ml, 
1-2.times.10.sup.7 platelets, 0.1 .mu.M .sup.125 I-fibrinogen, 2 mM 
CaCl.sub.2 and 0.1 U/ml thrombin or various concentrations of activator 
peptides as a stimulus. Incubations were carried out in 1.2 ml Eppendorf 
microcentrifuge tubes at room temperature for 30 min and then duplicate 75 
.mu.l aliquots were layered onto 0.4 ml of 20% sucrose in Tyrode's buffer 
containing 1% bovine serum albumin and platelets were sedimented by 
centrifugation at 10,000 g for 5 min in a Beckman microcentrifuge. Tips of 
the centrifuge tubes were amputated and bound .sup.125 I-fibrinogen was 
measured in a gamma counter (LKB/Pharmacia). Nonspecifically bound 
radioactivity was determined in incubations in which activators were 
excluded and these values were 1-5% of those obtained with thrombin 
activation. 
GPIIbIIIa Enzyme-Linked Immunoassay 
Low solubility fibrinogen, prepared as described by Lipinska et al., J. 
Lab. Clin. Med., 84, 509-516 (1974) (human, KABI) was immobolized at 5 
.mu.g/well on Immunolon 2-96 well plates (inculated overnight at 4.degree. 
to bind to the wells). The wells were blocked with 0.5% bovine serum 
albumin in buffer A (20 nM Tris-HCl, pH 7.5, 2 mM CaCl.sub.2, 120 mM CaCl, 
and 0.02% NaN.sub.3) for two hours at room temperature. All subsequent 
steps were carried out at room temperature. The wells were washed three 
times with buffer A plus 0.5% Tween 20 (BioRad). Purified GPIIbIIIa (2 
.mu.g/well) plus synthetic peptides supplements at the indicated 
concentrations were conincubated for 90 to 120 min with immobilized 
fibrinogen. The wells were washed as above, then the anti-GPIIbIIIa 
monoclonal antibody, CD41a, was added to each well and incubated for 60 
min. After another three washes, goat anti-mouse horseradish peroxidase 
conjugate was added to each well (60 min). The wells were washed three 
times with buffer A plus detergent, followed by two washes with buffer A 
minus detergent. The peroxidase substrate, 3,3',5,5'-tetramethylbenzidine 
(Kirkegaard and Perry Laboratories, Inc.) was added to the wells for color 
development. The reaction was stopped with 0.3N H.sub.2 SO.sub.4, and 
absorbances were measured at 450 mn using a microplate reader (Multiscan 
II, Flow-Titertek). 
GPIIbIIIa Purification 
GPIIbIIIa was purified from human platelets as described by Fitzgerald, et 
al., Anal. Biochem., 151, 169-177 (1985), except that the final gel 
purification step was performed with an HW55 size exclusion column 
(Waters, Advanced Protein Purification System), instead of Sephacryl 
S-300. The protein, greater than 90% pure as assessed by SDS 
polyacrylamide gel electrophoresis, was stored at -80.degree. C. in small 
aliquots. 
__________________________________________________________________________ 
# SEQUENCE LISTING 
- (1) GENERAL INFORMATION: 
- (iii) NUMBER OF SEQUENCES: 64 
- (2) INFORMATION FOR SEQ ID NO:1: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: 
- Xaa Arg Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:2: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: 
- Xaa Gly Xaa Xaa 
- (2) INFORMATION FOR SEQ ID NO:3: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:4: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:5: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:6: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: 
- Xaa Arg Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:7: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:8: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: 
- Xaa Arg Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:9: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:10: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:11: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11: 
- Xaa Arg Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:12: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:13: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:14: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14: 
- Xaa Arg Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:15: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:16: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16: 
- Xaa Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:17: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17: 
- Gly Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:18: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:19: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:20: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 6 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20: 
- Xaa Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:21: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: 
- Xaa Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:22: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: 
- Gly Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:23: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:24: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:25: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 6 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25: 
- Xaa Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:26: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26: 
- Xaa Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:27: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: 
- Gly Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:28: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:29: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:30: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 6 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30: 
- Xaa Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:31: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31: 
- Xaa Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:32: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32: 
- Gly Xaa Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:33: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:34: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34: 
- Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:35: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 6 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35: 
- Xaa Xaa Gly Xaa Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:36: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:37: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:38: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:39: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:40: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:41: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:42: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:43: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:44: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:45: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:46: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:47: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:48: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:49: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:50: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:51: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:52: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:53: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:54: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:55: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:56: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:57: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:58: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:59: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:60: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60: 
- Xaa Xaa Gly Asp Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:61: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:62: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 4 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62: 
- Xaa Gly Xaa Xaa 
1 
- (2) INFORMATION FOR SEQ ID NO:63: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: linear 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
- (2) INFORMATION FOR SEQ ID NO:64: 
- (i) SEQUENCE CHARACTERISTICS: 
#acids (A) LENGTH: 5 amino 
(B) TYPE: amino acid 
(D) TOPOLOGY: circular 
- (ii) MOLECULE TYPE: peptide 
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64: 
- Xaa Xaa Gly Xaa Xaa 
1 5 
__________________________________________________________________________