US 5,635,477 AGranted

Cyclic compounds useful as inhibitors of platelet glycoprotein IIB/IIIA

AssigneeThe DuPont Merck Pharmaceutical Company

InventorsWilliam F. Degrado, Sharon A. Jackson, Shaker A. Mousa, Anju Parthasarathy, Michael Sworin, Maria Rafalski

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Abstract

This invention relates to novel cyclic compounds containing carbocyclic ring systems useful as antagonists of the platelet glycoprotein IIb/IIIa complex, to pharmaceutical compositions containing such cyclic compounds, with or without other therapeutic agents, and to methods of using these compounds, with or without other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of other thromboembolic disorders. This invention also relates to methods of using the cyclic compounds of the invention in combination with anti-coagulants such as warfarin or heparin, or additional anti-platelet agents such as aspirin, piroxicam or ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or argatroban, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof, for the treatment of thromboembolic disorders. A representative compound of the invention is cyclo(D-Val-(.sup..alpha. N-methyl Arg)-Gly-Asp-(3-aminomethylbenzoic acid).

Claims22

Dependent claims

A compound of the formula (I):

##STR171## or a pharmaceutically acceptable salt form thereof wherein:
R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl or phenyl (C.sub.1 -C.sub.4)alkyl;
R.sup.2 is H or methyl;
R.sup.10 is H, halogen, C.sub.1 -C.sub.8 alkyl, phenyl or C.sub.1 -C.sub.4 alkoxy;
n is 0-2;
n' is 0-1;
J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-phenylGly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro, .beta.-Ala, D-Tyr, D-Ser, NMeGly, D-cyclohexylGly, D-cyclohexylmethylGly, D-norvaline, D-2-aminobutyric acid, D-2-aminopentanoic acid, Gly, N.sup..epsilon. -p-azidobenzoyl-D-Lys, N.sup..epsilon. -p-benzoylbenzoyl-D-Lys, N.sup..epsilon. -tryptophanyl-D-Lys, N.sup..epsilon. -o-benzylbenzoyl-D-Lys, N.sup..epsilon. -p-acetobenzoyl-D-Lys, N.sup..epsilon. -dansyl-D-Lys, N.sup..epsilon. -t-butoxycarbonylglycyl-D-Lys, N.sup..epsilon. -glycyl-D-Lys, N.sup..epsilon. -p-benzoylbenzoylglycyl-D-Lys, N.sup..epsilon. -p-phenylbenzoyl-D-Lys, N.sup..epsilon. -m-benzoylbenzoyl-D-Lys, or N.sup..epsilon. -o-benzoylbenzoyl-D-Lys;
K is .alpha.NMeArg, N.sup..delta.,N.sup..alpha. -diMe-N.sup..delta. -guanidinylOrn, N.sup..alpha. -MeLys or N.sup..epsilon.,N.sup..alpha. -diMeLys;
L is Gly;
M is selected from Asp, .beta.-MeAsp, NMeAsp,
Asp-(methylcarbonyloxymethyl ester),
Asp-(ethylcarbonyloxymethyl ester),
Asp-(t-butylcarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(1-(methylcarbonyloxy)ethyl ester),
Asp-(1-(ethylcarbonyloxy)ethyl ester),
Asp-(1-(t-butylcarbonyloxy)ethyl ester),
Asp-(1-(cyclohexylcarbonyloxy)ethyl ester),
Asp-(i-propyloxycarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(t-butyloxycarbonyloxymethyl ester),
Asp-(1-(i-propyloxycarbonyloxy)ethyl ester),
Asp-(1-(cyclohexyloxycarbonyloxy)ethyl ester),
Asp-(1-(t-butyloxycarbonyloxy)ethyl ester),
Asp-(dimethylaminoethyl ester),
Asp-(diethylaminoethyl ester),
Asp-((1,3-dioxa-5-methyl-cyclopenten-2-one-4-yl)methyl ester),
Asp-((5-(t-butyl)-1,3-dioxa-cyclopenten-2-one-4-yl)methyl ester),
Asp-((1,3-dioxa-5-phenyl-cyclopenten-2-one-4-yl)methyl ester), or
Asp-(1-(2-(2-methoxypropyl)carbonyloxy)ethyl ester).

27 more elements

A compound of formula (II):

##STR172## or a pharmaceutically acceptable salt thereof wherein:
R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl or phenyl(C.sub.1 -C.sub.4)alkyl;
R.sup.2 is H or methyl;
R.sup.10 is H, halogen, C.sub.1 -C.sub.8 alkyl, phenyl or C.sub.1 -C.sub.4 alkoxy;
alternatively, when R.sup.10 is para to the carbonyl, R.sup.10 and R.sup.1 may be taken together to form --CH.sub.2 --CH.sub.2 --CH.sub.2 -- thereby to form a six-membered fused ring;
n is 0-1;
J is D-Ala, D-Val, D-Ile, D-Leu, D-Nle, D-phenylGly, D-Phe, D-Lys, D-Orn, D-Met, D-Pro, .beta.-Ala, D-Tyr, D-Ser, NMeGly, D-cyclohexylGly, D-cyclohexylmethylGly, D-norvaline, D-2-aminobutyric acid, D-2-aminopentanoic acid, N.sup..epsilon. -p-azidobenzoyl-D-Lys, N.sup..epsilon. -p-benzoylbenzoyl-D-Lys, N.sup..epsilon. -tryptophanyl-D-Lys, N.sup..epsilon. -o-benzylbenzoyl-D-Lys, N.sup..epsilon. -p-acetobenzoyl-D-Lys, N.sup..epsilon. -dansyl-D-Lys, N.sup..epsilon. -t-butoxycarbonylglycyl-D-Lys, N.sup..epsilon. -glycyl-D-Lys, N.sup..epsilon. -p-benzoylbenzoylglycyl-D-Lys, N.sup..epsilon. -p-phenylbenzoyl-D-Lys, N.sup..epsilon. -m-benzoylbenzoyl-D-Lys, N.sup..epsilon. -o-benzoylbenzoyl-D-Lys;
K is .alpha.NMeArg, N.sup..delta., N.sup..alpha. -diMe-N.sup..delta. -guanidinylOrn, N.sup..alpha. -MeLys or N.sup..epsilon.,N.sup..alpha. -diMeLys;
L is Gly;
and
M is Asp, .beta.-MeAsp, NMeAsp,
Asp-(methylcarbonyloxymethyl ester),
Asp-(ethylcarbonyloxymethyl ester),
Asp-(t-butylcarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(1-(methylcarbonyloxy)ethyl ester),
Asp-(1-(ethylcarbonyloxy)ethyl ester),
Asp-(1-(t-butylcarbonyloxy)ethyl ester),
Asp-(1-(cyclohexylcarbonyloxy)ethyl ester),
Asp-(i-propyloxycarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(t-butyloxycarbonyloxymethyl ester),
Asp-(1-(i-propyloxycarbonyloxy)ethyl ester),
Asp-(1-(cyclohexyloxycarbonyloxy)ethyl ester),
Asp-(1-(t-butyloxycarbonyloxy)ethyl ester),
Asp-(dimethylaminoethyl ester),
Asp-(diethylaminoethyl ester),
Asp-((1,3-dioxa-5-methyl-cyclopenten-2-one-4-yl)methyl ester),
Asp-((5-(t-butyl)-1,3-dioxa-cyclopenten-2-one-4-yl)methyl ester),
Asp-((1,3-dioxa-5-phenyl-cyclopenten-2-one-4-yl)methyl ester), or
Asp-(1-(2-(2-methoxypropyl)carbonyloxy)ethyl ester).

28 more elements

A compound of Formula (I):

##STR175## or a pharmaceutically acceptable salt form thereof wherein:
R.sup.1 is H, C.sub.1 -C.sub.4 alkyl, phenyl, benzyl or phenyl(C.sub.1 -C.sub.4)alkyl;
R.sup.2 is H or methyl;
R.sup.10 is H, halogen, C.sub.1 -C.sub.8 alkyl, phenyl or C.sub.1 -C.sub.4 alkoxy;
n is 0-2;
n' is 0-1;
J is Ala, Val, Ile, Leu, Nle, phenylGly, Phe, Lys, Orn, Met, Pro, .beta.-Ala, Tyr, Ser, NMeGly, cyclohexylGly, cyclohexylmethylGly, norvaline, 2-aminobutyric acid, 2-aminopentanoic acid, Gly, Cys, S-benzyl-Cys, S-methyl-Cys, Asp, Glu, 2-amino-2-methylpropionic acid, His, 1-allo-isoleucine, Ash, Gln, Thr, Trp, or O-methyl-Tyr;
K is Arg, N.sup..delta. -Me-N.sup..delta. -guanidinylOrn, p-aminomethylPhe, p-guanidinylPhe, Lys or N.sup..epsilon. -MeLys;
L is Gly;
M is Asp, .beta.-MeAsp, NMeAsp,
Asp-(methylcarbonyloxymethyl ester),
Asp-(ethylcarbonyloxymethyl ester),
Asp-(t-butylcarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(1-(methylcarbonyloxy)ethyl ester),
Asp-(1-(ethylcarbonyloxy)ethyl ester),
Asp-(1-(t-butylcarbonyloxy)ethyl ester),
Asp-(1-(cyclohexylcarbonyloxy)ethyl ester),
Asp-(i-propyloxycarbonyloxymethyl ester),
Asp-(cyclohexylcarbonyloxymethyl ester),
Asp-(t-butyloxycarbonyloxymethyl ester),
Asp-(1-(i-propyloxycarbonyloxy)ethyl ester),
Asp-(1-(cyclohexyloxycarbonyloxy)ethyl ester),
Asp-(1-(t-butyloxycarbonyloxy)ethyl ester),
Asp-(dimethylaminoethyl ester),
Asp-(diethylaminoethyl ester),
Asp-((1,3-dioxa-5-methyl-cyclopenten-2-one-4-yl)methyl ester),
Asp-((5-(t-butyl)-1,3-dioxa-cyclopenten-2-one-4-yl)methyl ester),
Asp-((1,3-dioxa-5-phenyl-cyclopenten-2-one-4-yl)methyl ester), or
Asp-(1-(2-(2-methoxypropyl)carbonyloxy)ethyl ester).

27 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/461,611Filed 5 Jun 1995 · continuation
Priority: 30 Sep 1991
Granted: 3 Jun 1997
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07K 14/75
Blood coagulation or fibrinolysis factors: fibrinogen
C07K 7/56
With at least one abnormal peptide link in the ring: the cyclisation not occurring through 2,4-diamino-butanoic acid
A61K 38/00
Medicinal preparations containing peptides
C07K
Peptides