# US 6,294,549 B1 · Method for eliciting an αvβ5 or dual αvβ3/αvβ5 antagonizing effect

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- Number: US 6,294,549 B1
- Document ID: US6294549B1
- Status: Granted
- Kind: B1
- Application number: 09/120,997
- Filed: 1998-07-23
- Granted: 2001-09-25
- Earliest claimed: 1997-07-23
- Assignees: Merck & Co., Inc.
- Inventors: George D. Hartman; Mark E. Duggan
- Web page: https://patentgrep.com/patent/US6294549B1

## CPC

- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/426: 1,3-Thiazoles
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/497: containing further heterocyclic rings
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

A method for eliciting an αvβ5 or dual αvβ3/αvβ5 antagonizing effect in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of the formula which are useful for inhibiting restenosis, angiogenesis, atherosclerosis, diabetic retinopathy, macular degeneration, inflammation or tumor growth.

## Claims

### Claim 1

A method for inhibiting a condition selected from the group consisting of restenosis, angiogenesis, diabetic retinopathy, inflammation, and tumor growth in a mammal which comprises administering to the mammal a therapeutically effective amount of a compound of the formula:
and pharmaceutically acceptable salts thereof, wherein
X is
a 5- or 6-membered monocyclic aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S and either unsubstituted or substituted with R1 or R2, or
a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S and either unsubstituted or substituted with R1 or R2,
wherein R1 and R2 are independently selected from the group consisting of
hydrogen, F, Cl, Br, I,
C1-10 alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1-8 alkyl,
amino,
amino C1-8 alkyl,
C1-3 acylamino,
C1-3 acylamino C1-8 alkyl,
C1-6 alkylamino,
C1-6 alkylamino C1-8 alkyl,
C1-6 dialkylamino,
C1-6 dialkylamino C1-8 alkyl,
C1-4 alkoxy,
C1-4 alkoxy C1-6 alkyl,
carboxy,
carboxy C1-6 alkyl,
C1-3 alkoxycarbonyl,
C1-3 alkoxycarbonyl C1-6 alkyl,
carboxy C1-6 alkyloxy,
hydroxy, and
hydroxy C1-6 alkyl;
Y is
where Z is O, NR8, or S; and R8 is defined as R1 above;
R3 and R4 are independently
hydrogen,
a five or six membered mono or nine or ten membered polycyclic unsaturated, partially or fully saturated ring system containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen or sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
—(CH2)n-aryl, wherein n=1-4 and aryl is defined as a five or six membered unsaturated or partially saturated monocyclic ring system, or nine or ten membered polycyclic ring system wherein at least one of the rings is unsaturated or partially saturated and each of the other rings is optionally unsaturated, partially saturated or fully saturated, said aryl group containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
halogen,
hydroxyl,
C1-5alkylcarbonylamino,
arylC1-5 alkoxy,
C1-5 alkoxycarbonyl,
aminocarbonyl,
C1-5 alkylaminocarbonyl,
C1-5 alkylcarbonyloxy,
C3-8 cycloalkyl,
oxo,
amino,
C1-3 alkylamino,
aminoC1-3 alkyl,
arylaminocarbonyl,
arylC1-5alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl-C1-4 alkyl,
hydroxycarbonyl,
hydroxycarbonyl C1-5 alkyl,
C1-6alkyl, either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl, C1-5alkylcarbonylamino, arylC1-5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylaminocarbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, aminoC1-3 alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonyl-C1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C1-5 alkyl, provided that the carbon atom to which R3 and R4 are attached bears only one heteroatom,
—(CH2)mC≡CH,
—(CH2)mC≡C—C1-6 alkyl,
—(CH2)mC≡C—C3-7cycloalkyl,
—(CH2)mC≡C— aryl,
—(CH2)mC≡C—C1-6 alkyl aryl,
—(CH2)mCH═CH2,
—(CH2)mCH═CH C1-6 alkyl,
—(CH2)mCH═CH—C3-7cycloalkyl,
—(CH2)mCH═CH aryl,
—(CH2)mCH═CH C1-6 alkyl aryl,
—(CH2)mSO2C1-6 alkyl, or
—(CH2)mSO2C1-6 alkylaryl;
R5 is
hydrogen,
fluorine,
C1-8 alkyl,
hydroxyl,
hydroxy C1-6 alkyl,
carboxy,
carboxy C1-6 alkyl,
C1-6 alkyloxy;
C3-8 cycloalkyl,
aryl C1-6 alkyloxy,
aryl,
aryl C1-6 alkyl,
C1-6 alkylcarbonyloxy,
amino,
C1-6 alkylamino,
amino C1-6 alkyl,
C1-6 alkylamino C1-6 alkyl,
aryl amino,
aryl amino C1-6 alkyl,
aryl C1-6 alkylamino,
aryl C1-6 alkylamino C1-6 alkyl,
aryl carbonyloxy,
aryl C1-6 alkylcarbonyloxy,
C1-6 dialkylamino,
C1-6 dialkylamino C1-6 alkyl,
C1-6 alkylaminocarbonyloxy,
C1-8 alkylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
aryl sulfonylamino C1-6 alkyl,
aryl sulfonylamino,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkyloxycarbonylamino,
C1-8 alkyloxycarbonylamino C1-8 alkyl,
aryl C1-8 alkyloxycarbonylamino,
aryl oxycarbonylamino,
aryl oxycarbonylamino C1-8 alkyl,
aryl C1-8 alkyloxycarbonylamino C1-8 alkyl,
C1-8 alkylcarbonylamino,
C1-8 alkylcarbonylamino C1-6 alkyl,
aryl carbonylamino C1-6 alkyl,
aryl carbonylamino,
aryl C1-6 alkylcarbonylamino,
aryl C1-6 alkylcarbonylamino C1-6 alkyl,
C1-8 alkylaminocarbonylamino,
aminocarbonylamino,
aminocarbonylamino C1-6 alkyl,
C1-8 alkylaminocarbonylamino C1-6 alkyl,
aryl aminocarbonylamino C1-6 alkyl,
aryl aminocarbonylamino,
aryl C1-8 alkylaminocarbonylamino,
aryl C1-8 alkylaminocarbonylamino C1-6 alkyl,
aminosulfonylamino C1-6 alkyl,
aminosulfonylamino,
C1-8 alkylaminosulfonylamino,
C1-8 alkylaminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6alkyl,
aryl sulfonyl,
aryl sulfonyl C1-6alkyl,
aryl alkylsulfonyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6alkyl,
C1-6 alkylcarbonyl,
C1-6 alkylcarbonyl C1-6 alkyl,
aryl carbonyl C1-6alkyl,
aryl carbonyl,
aryl C1-6 alkylcarbonyl,
aryl C1-6 alkylcarbonyl C1-6alkyl,
C1-6 alkylthiocarbonylamino,
C1-6 alkylthiocarbonylamino C1-6 alkyl,
aryl thiocarbonylanmino C1-6 alkyl,
aryl thiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,
aminocarbonyl C1-6 alkyl,
aminocarbonyl,
C1-8 alkylaminocarbonyl,
C1-8 alkylaminocarbonyl C1-6 alkyl,
aryl aminocarbonyl C1-6 alkyl,
aryl aminocarbonyl,
aryl C1-8 alkylaminocarbonyl,
aryl C1-8 alkylaminocarbonyl C1-6 alkyl,
wherein alkyl groups and aryl groups are optionally unsubstituted or substituted with one or more substituents selected from R1 and R2; and
R6, R7, and R9 are independently
hydrogen,
C1-8 alkyl,
aryl,
aryl C1-8 alkyl,
hydroxy,
C1-8 alkyloxy,
aryloxy,
aryl C1-6 alkyloxy,
C1-8 alkylcarbonyloxy C1-4 alkyloxy,
aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy,
C1-8 alkylaminocarbonylmethyleneoxy, or
C1-8 dialkylaminocarbonylmethyleneoxy,
and wherein m and n are integers 0-6.

### Claim 2 (depends on 1)

A method of claim 1 wherein the compound has the formula:
and pharmaceutically acceptable salts thereof, wherein
X is
wherein n is 2-4, and n′ is 2 or 3, and
wherein R1 and R2 are independently selected from the group
consisting of
hydrogen, F, Cl, Br, I,
C1-10 alkyl,
C3-8 cycloalkYl,
aryl,
aryl C1-8 alkyl,
amino,
amino C1-8 alkyl,
C1-3 acylamino,
C1-3 acylamino C1-8 alkyl,
C1-6 alkylamino,
C1-6 alkylamino C1-8 alkyl,
C1-6 dialkylamino,
C1-6 dialkylamino C1-8 alkyl,
C1-4 alkoxy,
C1-4 alkoxy C1-6 alkyl,
carboxy,
carboxy C1-6 alkyl,
C1-3 alkoxycarbonyl,
C1-3 alkoxycarbonyl C1-6 alkyl,
carboxy C1-6 alkyloxy,
hydroxy, and
hydroxy C1-6 alkyl.

### Claim 3 (depends on 2)

A method of claim 2 wherein the compound has the formula
and pharmaceutically acceptable salts thereof, wherein
X is
wherein n′ is 2 or 3, and
Y is
where Z is O, NR8, or S; and R8 is defined as R1.

### Claim 4 (depends on 3)

A method of claim 3 wherein the compound has the formula
and pharmaceutically acceptable salts thereof, wherein
X is
wherein R1 and R2 are independently selected from the group consisting of
hydrogen or
amino,
amino C1-8 alkyl;
Y is
R8 is hydrogen or aryl C0-8 alkyl;
R3 is
hydrogen,
a six membered monocyclic unsaturated, partially or fully saturated ring system, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
—(CH2)n-aryl, wherein n=1-4 and aryl is defined as a six membered monocyclic unsaturated or partially saturated ring system, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
C3-8 cycloalkyl, or
C1-6alkyl, either unsubstituted or substituted, with C3-8 cycloalkyl;
R4 is
hydrogen,
—(CH2)n-aryl, wherein n=0-4 and aryl is defined as a six membered monocyclic unsaturated or partially saturated ring or a nine or ten membered polycyclic ring system wherein at least one of the rings is unsaturated or partially saturated and each of the other rings is optionally unsaturated, partially saturated or fully saturated, said aryl group either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonylC0-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
C1-6alkyl, or
—(CH2)0-4 C≡CH;
R5 is
hydrogen,
aryl sulfonylamino C1-6 alkyl,
aryl sulfonylamino,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
aryl sulfonylamino C1-6 alkyl,
aryl sulfonylamino,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
minosulfonylamino C1-6 alkyl,
aminosulfonylamino,
C1-8 alkylaminosulfonylamino,
C1-8 alkylaminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6alkyl,
aryl sulfonyl C1-6alkyl,
aryl sulfonyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6alkyl,
wherein alkyl groups and aryl groups may be unsubstituted or substituted with one or more substituents selected from R1 or R2; and
R6 is
hydrogen,
C1-8 alkyl, or
aryl,
aryl C1-8 alkyl.

### Claim 5 (depends on 4)

A method of claim 4 wherein the compound has the formula
and pharmaceutically acceptable salts thereof, wherein
X is
Y is
R3 is
hydrogen,
methyl,
R4 is
hydrogen,
methyl,
R5 is
hydrogen, or
R6 is
hydrogen,
methyl,
ethyl, or
t-butyl.

### Claim 6 (depends on 5)

A method of claim 5 wherein the compound is selected from the group consisting of
4-(2-Aminothiazol-4-yl)butanoyl-glycyl-2(S)-phenylsulfonamido-β-alanine t-butyl ester,
4-(2-Aminothiazol-4-yl)butanoyl-glycyl-2(S)-phenylsulfonamido-β-alanine,
4-(2-Aminothiazol-4-yl)butanoyl-glycyl-3(R)-(2-phenethyl)-β-alanine methyl ester,
4-(2-Aminothiazol-4-yl)butanoyl-glycyl-3(R)-(2-phenethyl)-β-alanine,
5-(2-Pyridylamino)pentanoylglycyl-2(S)-phenylsulfonamido-β-alanine ethyl ester,
5-(2-Pyridylamino)pentanoylglycyl-2(S)-phenylsulfonamido-β-alanine,
4-(2-Amino-pyridin-6-yl)butanoyl-sarcosine-3(R)-[(2-indol-3-yl)ethyl]-β-alanine ethyl ester,
4-(2-Aminopyridin-6-yl)butanoyl-sarcosine-3(R)-[(2-indol-3-yl)ethyl]-β-alanine,
4-(2-Aminopyridin-6-yl)butanoyl-glycyl-2(S)-phenylsulfonamido-β-alanine t-butyl ester,
4-(2-Aminopyridin-6-yl)butanoyl-glycyl-2(S)-phenylsulfonamido-β-alanine,
4-(Pyridin-4-yl)butanoyl-sarcosine-3(R)-[2-(indol-3-yl)ethyl]-β-alanine ethyl ester,
4-(Pyridin-4-yl)butanoyl-sarcosine-3(R)-[2-(indol-3-yl)ethyl]-β-alanine,
4-(2-Bocamino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-(2-phenethyl)-β-alanine ethyl ester,
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-(2-phenethyl)-β-alanine ethyl ester,
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-(2-phenethyl)-β-alanine,
4-(2-Boc-amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-[(2-indol-3-yl)ethyl]-β-alanine,
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-[(2-indol-3-yl)ethyl]-β-alanine,
4-(2-Bocamino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-methyl-β-alanine ethyl ester,
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-methyl-β-alanine ethyl ester,
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-methyl-β-alanine,
4-(Pyzidin-4-yl)butanoyl-N-(2-phenylethyl)glycyl-3(R)-(2-phenethyl)-β-alanine ethyl ester,
4-(Pyridin-4-yl)butanoyl-N-(2-phenyl)glycyl-3(R)-(2-phenethyl)-β-alanine,
b 4-(2-BOC-Aminopyridin-4-yl)butanoyl-N-(2-phenethyl)glycyl-3(R)-methyl-β-alanine,
4-(2-Aminopyridin-4-yl)butanoyl-N-(2-phenethyl)glycyl-3(R)-methyl-β-alanine,
4-(Pyridyloxy)butyrate-N-(2-phenethyl)glycyl-3(R)-2-phenethyl-β-alanine ethyl ester,
4-(Pyridyloxy)butyrate-N-(2-phenethyl)glycyl-3(R)-2-phenethyl-β-alanine,
3-[(N-Methyl)-N-(4-pyridyl)]aminopropionyl-sarcosine-3(R)-(2-phenethyl)-β-alanine ethyl ester,
3-[(N-Methyl)-N-(4-pyridyl)]aminopropionyl-sarcosine-3(R)-(2-phienethyl)-β-alanine,
N—{N′-3-(4-t-Butoxycarbonyl-1-piperizinyl)benzoyl)glycyl}-3(R)-methyl-β-alanine benzyl ester,
N—[N′-[3-(1-Piperazinyl)benzoyl]glycyl]-3(R)-methyl-β-alanine,
N—[N′-[3-(4-t-Butoxycarbonyl-1-piperazinyl)benzoyl]glycyl]-3(R)-(2-phenethyl)-β-alanine methyl ester,
N—[N′-[3-(1-Piperazinyl)benzoyl]glycyl]3(R)-(2-phenethyl)-β-alanine,
N—[N′-[3-(4-t-Butoxycarbonyl-1-piperazinyl)benzoyl]-N′-(2-phenethyl)glycyl]-3(R)-(2-phenethyl)-β-alanine methyl ester,
N—[N′-[3-(1-Piperazinyl)benzoyl]-N′-(2-phenethyl)glycyl]-3(R)-(2-phenethyl)-β-alanine,
4-(1,2,3,4-Tetrahydro-1,8-naphithyridin-7-yl)butanol-glycyl-β-alanine t-butyl ester,
4-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)butanoyl-glycyl-β-alanine,
4-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)butanoyl-glycyl-3(S)-pyridin-3-yl-β-alanine ethyl ester,
4-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)butanoyl-glycyl-3(S)pyrdin-3-yl-β-alanine,
Ethyl N-pyridin-4-ylisonipecotyl-N-cyclopropylglycine-3(S)-ethynyl-β-alanine,
N-Pyridin-ylisonipecotyl-N-cyclopropylglycine-3(S)-ethynyl-β-alanine,
Ethyl N-pyridin-4-ylnipecotyl-N-cyclopropylglycine-3(S)-ethynyl-β-alanine,
N-Pyridin-4-ylnipecotyl-N-cydlopropylglycine-3(S)-ethynyl-β-alanine,
4-(1,2,3,4-Tetrahydlro-1,8-naphthyriclin-5-yl)butanoyl-N-(cyclo-propyl)gly-3(S)ethynyl-β-alanine ethyl ester,
4-(1,2,3,4-Tetrahydlro-1,8-naphthyriclin-5-yl)butanoyl-N-(cyclo-propyl)glycyl-3(S)-ethynyl-β-alanine, and
3-{2-[5-(1H-Benzoimidazol-2-yl-amino)-pentanoylamino]-acetylamino}-3(S)-pyridin-3-yl-propionic acid,
and pharmaceutically acceptable salts thereof.

### Claim 7 (depends on 6)

A method of claim 6 wherein the salt is selected from the group consisting of
4-(2-Aminothiazol-4-yl)butanoyl-glycyl-3(R)-(2-phenethyl)-β-alanine trifluoroacetate salt,
5-(2-Pyridylamino)pentanoylglycyl-2(S)-phenylsulfonamido-β-alanine trifluoroacetate salt,
N—[N′-[3-(1-Piperazinyl)benzoyl]glycyl]-3(R)-methyl-β-alanine trifluoroacetic acid salt,
N—[N′-[3-(1-Piperazinyl)benzoyl]glycyl]-3(R)-(2-phenethyl)-β-alanine trifluoroacetic acid salt,
N—[N′-[3-(1-Piperazinyl)benzoyl]-N′-(2-phenethyl)glycyl]-3(R)-(2-phenethyl)-β-alanine trifluoroacetic acid salt, and
4-(2-Amino-pyridin-6-yl)butanoyl-N-cyclopropylglycyl-3(R)-(2-phenethyl)-β-alanine ethyl ester hydrochloride.

### Claim 8 (depends on 1)

The method of claim 1 wherein the condition is diabetic retinopathy.

### Claim 9

A composition comprising a carrier suitable for topical ophthamological administration and between about 0.01-5% w/v of a compound of the formula:
and pharmaceutically acceptable salts thereof, wherein
X is
a 5- or 6-membered monocyclic aromatic ring system containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S and either unsubstituted or substituted with R1 or R2, or
a 9- to 10-membered polycyclic ring system, wherein one or more of the rings is aromatic, containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O or S and either unsubstituted or substituted with R1 or R2,
wherein R1 and R2 are independently selected from the group consisting of
hydrogen, F, Cl, Br, I,
C1-10 alkyl,
C3-8 cycloalkyl,
aryl,
aryl C1-8 alkyl,
amino,
amino C1-8 alkyl,
C1-3 acylamino,
C1-3 acylamino C1-8 alkyl,
C1-6 alkylamino,
C1-6 alkylamino C1-8 alkyl,
C1-6 dialkylamino,
C1-6 dialkylamino C1-8 alkyl,
C1-4 alkoxy,
C1-4 alkoxy C1-6 alkyl,
carboxy,
carboxy C1-6 alkyl,
C1-3 alkoxycarbonyl,
C1-3 alkoxycarbonyl C1-6 alkyl,
carboxy C1-6 alkyloxy,
hydroxy, and
hydroxy C1-6 alkyl;
Y is
where Z is O, NR8, or S; and R8 is defined as R1 above;
R3 and R4 are independently
hydrogen,
a five or six membered mono or nine or ten membered polycyclic unsaturated, partially or fully saturated ring system containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfuir, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
—(CH2)n-aryl, wherein n=1-4 and aryl is defined as a five or six membered unsaturated or partially saturated monocyclic ring system, or nine or ten membered polycyclic ring system wherein at least one of the rings is unsaturated or partially saturated and each of the other rings is optionally unsaturated, partially saturated or fully saturated, said aryl group containing 0, 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen and sulfur, either unsubstituted or substituted, with one or more groups selected from hydroxyl, halogen, cyano, trifluoromethyl, C1-3 alkoxy, C1-5 alkylcarbonyloxy, C1-5 alkoxycarbonyl, C1-5 alkyl, aminoC1-5 alkyl, hydroxycarbonyl, hydroxycarbonylC1-5 alkyl, or hydroxycarbonylC1-5 alkoxy,
halogen,
hydroxyl,
C1-5alkylcarbonylamino,
arylC1-5 alkoxy,
C1-5 alkoxycarbonyl,
aminocarbonyl,
C1-5 alkylaminocarbonyl,
C1-5 alkylcarbonyloxy,
C3-8 cycloalkyl,
oxo,
amino,
C1-3 alkylamino,
aminoC1-3 alkyl,
arylaminocarbonyl,
arylC1-5alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl-C1-4 alkyl,
hydroxycarbonyl,
hydroxycarbonyl C1-5 alkyl,
C1-6alkyl, either unsubstituted or substituted, with one or more groups selected from halogen, hydroxyl, C1-5alkylcarbonylamino, arylCl5 alkoxy, C1-5 alkoxycarbonyl, aminocarbonyl, C1-5 alkylaminocarbonyl, C1-5 alkylcarbonyloxy, C3-8 cycloalkyl, oxo, amino, C1-3 alkylamino, aminoC1-3 alkyl, arylaminocarbonyl, arylC1-5alkylaminocarbonyl, aminocarbonyl, aminocarbonyl-C1-4 alkyl, hydroxycarbonyl, or hydroxycarbonyl C1-5 alkyl, provided that the carbon atom to which R3 and R4 are attached bears only one heteroatom,
—(CH2)mC≡CH,
—(CH2)mC≡C—C1-6 alkyl,
—(CH2)mC≡C—C3-7cycloalkyl,
—(CH2)mC≡C— aryl,
—(CH2)mC≡C—C1-6 alkyl aryl,
—(CH2)mCH═CH2,
—(CH2)mCH═CH C1-6 alkyl,
—(CH2)mCH═CH—C3-7cycloalkyl,
—(CH2)mCH═CH aryl,
—(CH2)mCH═CH C1-6 alkyl aryl,
—(CH2)mSO2C1-6 alkyl, or
—(CH2)mSO2C1-6 alkylaryl;
R5 is
hydrogen,
fluorine,
C1-8 alkyl,
hydroxyl,
hydroxy C1-6 alkyl,
carboxy,
carboxy C1-6 alkyl,
C1-6 alkyloxy,
C3-8 cycloalkyl,
aryl C1-6 alkyloxy,
aryl,
aryl C1-6 alkyl,
C1-6 alkylcarbonyloxy,
amino,
C1-6 alkylamino,
amino C1-6 alkyl,
C1-6 alkylamino C1-6 alkyl,
aryl amino,
aryl amino C1-6 alkyl,
aryl C1-6 alkylamino,
aryl C1-6 alkylamino C1-6 alkyl,
aryl carbonyloxy,
aryl C1-6 alkylcarbonyloxy,
C1-6 dialkylamino,
C1-6 dialkylamino C1-6 alkyl,
C1-6 alkylaminocarbonyloxy,
C1-8 alkylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
aryl sulfonylamino C1-6 alkyl,
aryl sulfonylamino,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkyloxycarbonylamino,
C1-8 alkyloxycarbonylamino C1-8 alkyl,
aryl C1-8 alkyloxycarbonylamino,
aryl oxycarbonylamino,
aryl oxycarbonylamino C1-8 alkyl,
aryl C1-8 alkyloxycarbonylamino C1-8 alkyl,
C1-8 alkylcarbonylamino,
C1-8 alkylcarbonylamino C1-6 alkyl,
aryl carbonylamino C1-6 alkyl,
aryl carbonylamino,
aryl C1-6 alkylcarbonylamino,
aryl C1-6 alkylcarbonylamino C1-6 alkyl,
C1-8 alkylaminocarbonylamino,
aminocarbonylamino,
aminocarbonylamino C1-6 alkyl,
C1-8 alkylaminocarbonylamino C1-6 alkyl,
aryl aminocarbonylamino C1-6 alkyl,
aryl aminocarbonylamino,
aryl C1-8 alkylaminocarbonylamino,
aryl C1-8 alkylaminocarbonylamino C1-6 alkyl,
aminosulfonylamino C1-6 alkyl,
aminosulfonylamino,
C1-8 alkylaminosulfonylamino,
C1-8 alkylaminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino C1-6 alkyl,
aryl aminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino,
aryl C1-8 alkylaminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6alkyl,
aryl sulfonyl,
aryl sulfonyl C1-6alkyl,
aryl alkylsulfonyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6alkyl,
C1-6 alkylcarbonyl,
C1-6 alkylcarbonyl C1-6 alkyl,
aryl carbonyl C1-6alkyl,
aryl carbonyl,
aryl C1-6 alkylcarbonyl,
aryl C1-6 alkylcarbonyl C1-6alkyl,
C1-6 alkylthiocarbonylamino,
C1-6 alkylthiocarbonylamino C1-6 alkyl,
aryl thiocarbonylamino C1-6 alkyl,
aryl thiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,
aminocarbonyl C1-6 alkyl,
aminocarbonyl,
C1-8 alkylaminocarbonyl,
C1-8 alkylaminocarbonyl C1-6 alkyl,
aryl aminocarbonyl C1-6 alkyl,
aryl aminocarbonyl,
aryl C1-8 alkylaminocarbonyl,
aryl C1-8 alkylaminocarbonyl C1-6 alkyl,
wherein alkyl groups and aryl groups are optionally unsubstituted or substituted with one or more substituents selected from R1 and R2; and
R6, R7, and R9 are independently
hydrogen,
C1-8 alkyl,
aryl,
aryl C1-8 alkyl,
hydroxy,
C1-8 alkyloxy,
aryloxy,
aryl C1-6 alkyloxy,
C1-8 alkylcarbonyloxy C1-4 alkyloxy,
aryl C1-8 alkylcarbonyloxy C1-4 alkyloxy,
C1-8 alkylaminocarbonylmethyleneoxy, or
C1-8 dialkylaminocarbonylmethyleneoxy,
and wherein m and n are integers 0-6.

### Claim 10 (depends on 9)

A method for inhibiting diabetic retinopathy in a patient comprising topically applying to the patient's eye a therapeutically effective amount of the composition of claim 9.