US 6,784,190 B2 · Integrin receptor antagonists

Abstract

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors αvβ3, αvβ5, and/or αvβ6 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, wound healing, viral disease, tumor growth, and metastasis.

A compound of the formula

wherein
Y is selected from the group consisting of
—(CH2)m,
—(CH2)m—O—(CH2)n—,
—(CH2)m—NR4—(CH2)n—,
—(CH2)m—S—(CH2)n—,
—(CH2)m—SO—(CH2)n—,
—(CH2)m—SO2—(CH2)n—,
—(CH2)m—O—(CH2)n—O—(CH2)p—,
—(CH2)m—O—(CH2)n—NR4—(CH2)p—,
—(CH2)m—NR4—(CH2)n—NR4—(CH2)p—,
—(CH2)m—O—(CH2)n—S—(CH2)p—,
—(CH2)m—S—(CH2)n—S—(CH2)p—,
—(CH2)m—NR4—(CH2)n—S—(CH2)p—,
—(CH2)m—NR4—(CH2)n—O—(CH2)p—,
—(CH2)m—S—(CH2)n—O—(CH2)p—, and
—(CH2)m—S—(CH2)n—NR4—(CH2)p—,
wherein any methylene (CH2) carbon atom in Y, other than in R4, can be substituted by one or two R3 substituents;
Z is selected from the group consisting of
—CH2CH2—, and —CH═CH—, wherein either carbon atom can be substituted by one or two R3 substituents;
R1 and R2 are each independently selected from the group consisting of
hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl, C3-8 cycloheteroalkyl, C3-8 cycloalkyl C1-6 alkyl, C3-8 cycloheteroalkyl C1-6 alkyl, aryl, aryl C1-8 alkyl, amino, amino C1-8 alkyl, C1-3 acylamino, C1-3 acylamino C1-8 alkyl, (C1-6 alkyl)pamino, (C1-6 alkyl)pamino C1-8 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl C1-6 alkyl, C1-3 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 alkyl, hydroxycarbonyl-C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, C1-6 alkyloxy-C1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C1-8 alkyl-S(O)p, (C1-8 alkyl)paminocarbonyl, C1-8 alkyloxycarbonylamino, (C1-8 alkyl)paminocarbonyloxy, (aryl C1-8 alkyl)pamino, (aryl)pamino, aryl C1-8 alkylsulfonylamino, and C1-8 alkylsulfonylamino;
or two R1 substituents, when on the same carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group;
each R3 is independently selected from the group consisting of
hydrogen,
aryl,
C1-10 alkyl,
aryl-(CH2)r—O—(CH2)s—,
aryl-(CH2)rS(O)p—(CH2)s—,
aryl-(CH2)r—C(O)—(CH2)s—,
aryl-(CH2)r—C(O)—N(R4)—(CH2)s—,
aryl-(CH2)r—N(R4)—C(O)—(CH2)s—,
aryl-(CH2)r—N(R4)—(CH2)s—,
halogen,
hydroxyl,
oxo,
trifluoromethyl,
C1-8 alkylcarbonylamino,
aryl C1-5 alkoxy,
C1-5 alkoxycarbonyl,
(C1-8 alkyl)paminocarbonyl,
C1-6 alkylcarbonyloxy,
C3-8 cycloalkyl,
(C1-6 alkyl)pamino,
amino C1-6 alkyl,
arylaminocarbonyl,
aryl C1-5 alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl C1-6 alkyl,
hydroxycarbonyl,
hydroxycarbonyl C1-6 alkyl,
HC≡C—(CH2)t—,
C1-6 alkyl-C≡C—(CH2)t—,
C3-7 cycloalkyl-C≡C—(CH2)t—,
aryl-C≡C—(CH2)t—,
C1-6 alkylaryl-C≡C—(CH2)t—,
CH2═CH—(CH2)t—,
C1-6 alkyl-CH═CH—(CH2)t—,
C3-7 cycloalkyl-CH═CH—(CH2)t—,
aryl-CH═CH—(CH2)t—,
C1-6 alkylaryl-CH═CH—(CH2)t—,
C1-6 alkyl-SO2—(CH2)t—,
C1-6 alkylaryl-SO2—(CH2)t—,
C1-6 alkoxy,
aryl C1-6 alkoxy,
aryl C1-6 alkyl,
(C1-6 alkyl)pamino C1-6 alkyl,
(aryl)pamino,
(aryl)pamino C1-6 alkyl,
(aryl C1-6 alkyl)pamino,
(aryl C1-6 alkyl)pamino C1-6 alkyl,
arylcarbonyloxy,
aryl C1-6 alkylcarbonyloxy,
(C1-6 alkyl)paminocarbonyloxy,
C1-8 alkylsulfonylamino,
arylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
arylsulfonylamino C1-6 alkyl,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkoxycarbonylamino,
C1-8 alkoxycarbonylamino C1-8 alkyl,
aryloxycarbonylamino C1-8 alkyl,
aryl C1-8 alkoxycarbonylamino,
aryl C1-8 alkoxycarbonylamino C1-8 alkyl,
C1-8 alkylcarbonylamino,
C1-8 alkylcarbonylamino C1-6 alkyl,
arylcarbonylamino C1-6 alkyl,
aryl C1-6 alkylcarbonylamino,
aryl C1-6 alkylcarbonylamino C1-6 alkyl,
aminocarbonylamino C1-6 alkyl,
(C1-8 alkyl)paminocarbonylamino,
(C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
(aryl)paminocarbonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonylamino,
(aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
aminosulfonylamino C1-6 alkyl,
(C1-8 alkyl)paminosulfonylamino,
(C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
(aryl)paminosulfonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminosulfonylamino,
(aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6 alkyl,
arylsulfonyl C1-6 alkyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6 alkyl,
C1-6 alkylcarbonyl,
C1-6 alkylcarbonyl C1-6 alkyl,
arylcarbonyl C1-6 alkyl,
aryl C1-6 alkylcarbonyl,
aryl C1-6 alkylcarbonyl C1-6 alkyl,
C1-6 alkylthiocarbonylamino,
C1-6 alkylthiocarbonylamino C1-6 alkyl,
arylthiocarbonylamino C1-6 alkyl,
aryl C1-6 alkylthiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,
(C1-8 alkyl)paminocarbonyl C1-6 alkyl,
(aryl)paminocarbonyl C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonyl, and
(aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl;
or two R3 substituents, when on the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group or a cyclopropyl group,
wherein any of the alkyl groups of R3 are either unsubstituted or substituted with one to three R1 substituents, and provided that each R3 is selected such that in the resultant compound the carbon atom or atoms to which R3 is attached is itself attached to no more than one heteroatom;
each R4 is independently selected from the group consisting of
hydrogen,
aryl,
aminocarbonyl,
C3-8 cycloalkyl,
amino C1-6 alkyl,
(aryl)paminocarbonyl,
(aryl C1-5 alkyl)paminocarbonyl,
hydroxycarbonyl C1-6 alkyl,
C1-8 alkyl,
aryl C1-6 alkyl,
(C1-6 alkyl)pamino C2-6 alkyl,
(aryl C1-6 alkyl)pamino C2-6 alkyl,
C1-8 alkylsulfonyl,
C1-8 alkoxycarbonyl,
aryloxycarbonyl,
aryl C1-8 alkoxycarbonyl,
C1-8 alkylcarbonyl,
arylcarbonyl,
aryl C1-6 alkylcarbonyl,
(C1-8 alkyl)paminocarbonyl,
aminosulfonyl,
C1-8 alkylaminosulfonyl,
(aryl)paminosulfonyl,
(aryl C1-8 alkyl)paminosulfonyl,
arylsulfonyl,
arylC1-6 alkylsulfonyl,
C1-6 alkylthiocarbonyl,
arylthiocarbonyl, and
aryl C1-6 alkylthiocarbonyl,
wherein any of the alkyl groups of R4 are either unsubstituted or substituted with one to three R1 substituents;
R5 and R6 are each independently selected from the group consisting of
hydrogen,
C1-10 alkyl,
aryl,
aryl-(CH2)r—O—(CH2)s—,
aryl-(CH2)rS(O)p—(CH2)s—,
aryl-(CH2)r—C(O)—(CH2)s—,
aryl-(CH2)r—C(O)—N(R4)—(CH2)s—,
aryl-(CH2)r—N(R4)—C(O)—(CH2)s—,
aryl-(CH2)r—N(R4)—(CH2)s—,
halogen,
hydroxyl,
C1-8 alkylcarbonylamino,
aryl C1-5 alkoxy,
C1-5 alkoxycarbonyl,
(C1-8 alkyl)paminocarbonyl,
C1-6 alkylcarbonyloxy,
C3-8 cycloalkyl,
(C1-6 alkyl)pamino,
amino C1-6 alkyl,
arylaminocarbonyl,
aryl C1-5 alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl C1-6 alkyl,
hydroxycarbonyl,
hydroxycarbonyl C1-6 alkyl,
HC≡C—(CH2)t—,
C1-6 alkyl-C≡C—(CH2)t—,
C3-7 cycloalkyl-C≡C—(CH2)t—,
aryl-C≡C—(CH2)t—,
C1-6 alkylaryl-C≡C—(CH2)t—,
CH2═CH—(CH2)t—,
C1-6 alkyl-CH═CH—(CH2)t—,
C3-7 cycloalkyl-CH═CH—(CH2)t—,
aryl-CH═CH—(CH2)t—,
C1-6 alkylaryl-CH═CH—(CH2)t—,
C1-6 alkyl-SO2—(CH2)t—,
C1-6 alkylaryl-SO2—(CH2)t—,
C1-6 alkoxy,
aryl C1-6 alkoxy,
aryl C1-6 alkyl,
(C1-6 alkyl)pamino C1-6 alkyl,
(aryl)pamino,
(aryl)pamino C1-6 alkyl,
(aryl C1-6 alkyl)pamino,
(aryl C1-6 alkyl)pamino C1-6 alkyl,
arylcarbonyloxy,
aryl C1-6 alkylcarbonyloxy,
(C1-6 alkyl)paminocarbonyloxy,
C1-8 alkylsulfonylamino,
arylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
arylsulfonylamino C1-6 alkyl,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkoxycarbonylamino,
C1-8 alkoxycarbonylamino C1-8 alkyl,
aryloxycarbonylamino C1-8 alkyl,
aryl C1-8 alkoxycarbonylamino,
aryl C1-8 alkoxycarbonylamino C1-8 alkyl,
C1-8 alkylcarbonylamino,
C1-8 alkylcarbonylamino C1-6 alkyl,
arylcarbonylamino C1-6 alkyl,
aryl C1-6 alkylcarbonylamino,
aryl C1-6 alkylcarbonylamino C1-6 alkyl,
aminocarbonylamino C1-6 alkyl,
(C1-8 alkyl)paminocarbonylamino,
(C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
(aryl)paminocarbonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonylamino,
(aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
aminosulfonylamino C1-6 alkyl,
(C1-8 alkyl)paminosulfonylamino,
(C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
(aryl)paminosulfonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminosulfonylamino,
(aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6 alkyl,
arylsulfonyl C1-6 alkyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6 alkyl,
C1-6 alkylcarbonyl,
C1-6 alkylcarbonyl C1-6 alkyl,
arylcarbonyl C1-6 alkyl,
aryl C1-6 alkylcarbonyl,
aryl C1-6 alkylcarbonyl C1-6 alkyl,
C1-6 alkylthiocarbonylamino,
C1-6 alkylthiocarbonylamino C1-6 alkyl,
arylthiocarbonylamino C1-6 alkyl,
aryl C1-6 alkylthiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,
(C1-8 alkyl)paminocarbonyl C1-6 alkyl,
(aryl)paminocarbonyl C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonyl, and
(aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl;
or R5 and R6 are taken together with the carbon atom to which they are attached to form a carbonyl group,
wherein any of the alkyl groups of R5 or R6 are either unsubstituted or substituted with one to three R1 substituents, and provided that each R5 and R6 are selected such that in the resultant compound the carbon atom to which R5 and R6 are attached is itself attached to no more than one heteroatom;
R7 and R8 are each independently selected from the group consisting of
hydrogen,
C1-10 alkyl,
aryl,
aryl-(CH2)r—O—(CH2)s—,
aryl-(CH2)rS(O)p—(CH2)s—,
aryl-(CH2)r—C(O)—(CH2)s—,
aryl-(CH2)r—C(O)—N(R4)—(CH2)s—,
aryl-(CH2)r—N(R4)—C(O)—(CH2)s—,
aryl-(CH2)r—N(R4)—(CH2)s—,
halogen,
hydroxyl,
C1-8 alkylcarbonylamino,
aryl C1-5 alkoxy,
C1-5 alkoxycarbonyl,
(C1-8 alkyl)paminocarbonyl,
C1-6 alkylcarbonyloxy,
C3-8 cycloalkyl,
(C1-6 alkyl)pamino,
amino C1-6 alkyl,
arylaminocarbonyl,
aryl C1-5 alkylaminocarbonyl,
aminocarbonyl,
aminocarbonyl C1-6 alkyl,
hydroxycarbonyl,
hydroxycarbonyl C1-6 alkyl,
HC≡C—(CH2)t—,
C1-6 alkyl-C≡C—(CH2)t—,
C3-7 cycloalkyl—C≡C—(CH2)t—,
aryl—C≡C—(CH2)t—,
C1-6 alkylaryl—C≡C—(CH2)t—,
CH2═CH—(CH2)t,
C1-6 alkyl—CH≡C—(CH2)t—,
C3-7 cycloalkyl—CH═CH—(CH2)t—,
aryl-CH═CH—(CH2)t—,
C1-6 alkylaryl-CH═CH—(CH2)t—,
C1-6 alkyl-SO2—(CH2)t—,
C1-6 alkylaryl-SO2—(CH2)t—,
C1-6 alkoxy,
aryl C1-6 alkoxy,
aryl C1-6 alkyl,
(C1-6 alkyl)pamino C1-6 alkyl,
(aryl)pamino,
(aryl)pamino C1-6 alkyl,
(aryl C1-6 alkyl)pamino,
(aryl C1-6 alkyl)pamino C1-6 alkyl,
arylcarbonyloxy,
aryl C1-6 alkylcarbonyloxy,
(C1-6 alkyl)paminocarbonyloxy,
C1-8 alkylsulfonylamino,
arylcarbonylamino,
arylsulfonylamino,
C1-8 alkylsulfonylamino C1-6 alkyl,
arylsulfonylamino C1-6 alkyl,
aryl C1-6 alkylsulfonylamino,
aryl C1-6 alkylsulfonylamino C1-6 alkyl,
C1-8 alkoxycarbonylamino,
C1-8 alkoxycarbonylamino C1-8 alkyl,
aryloxycarbonylamino C1-8 alkyl,
aryl C1-8 alkoxycarbonylamino,
aryl C1-8 alkoxycarbonylamino C1-8 alkyl,
C1-8 alkylcarbonylamino C1-6 alkyl,
arylcarbonylamino C1-6 alkyl,
aryl C1-6 alkylcarbonylamino,
aryl C1-6 alkylcarbonylamino C1-6 alkyl,
aminocarbonylamino C1-6 alkyl,
arylaminocarbonylamino,
(C1-8 alkyl)paminocarbonylamino,
(C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
(aryl)paminocarbonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonylamino,
(aryl C1-8 alkyl)paminocarbonylamino C1-6 alkyl,
aminosulfonylamino C1-6 alkyl,
(C1-8 alkyl)paminosulfonylamino,
(C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
(aryl)paminosulfonylamino C1-6 alkyl,
(aryl C1-8 alkyl)paminosulfonylamino,
(aryl C1-8 alkyl)paminosulfonylamino C1-6 alkyl,
C1-6 alkylsulfonyl,
C1-6 alkylsulfonyl C1-6 alkyl,
arylsulfonyl C1-6 alkyl,
aryl C1-6 alkylsulfonyl,
aryl C1-6 alkylsulfonyl C1-6 alkyl,
C1-6 alkylcarbonyl,
C1-6 alkylcarbonyl C1-6 alkyl,
arylcarbonyl C1-6 alkyl,
aryl C1-6 alkylcarbonyl,
aryl C1-6 alkylcarbonyl C1-6 alkyl,
C1-6 alkylthiocarbonylamino,
C1-6 alkylthiocarbonylamino C1-6 alkyl,
arylthiocarbonylamino C1-6 alkyl,
aryl C1-6 alkylthiocarbonylamino,
aryl C1-6 alkylthiocarbonylamino C1-6 alkyl,
(C1-8 alkyl)paminocarbonyl C1-6 alkyl,
(aryl)paminocarbonyl C1-6 alkyl,
(aryl C1-8 alkyl)paminocarbonyl,
(aryl C1-8 alkyl)paminocarbonyl C1-6 alkyl, and
C7-20 polycyclyl C0-8 alkylsulfonylamino,
wherein any of the alkyl groups of R7 and R8 are either unsubstituted or substituted with one to three R1 substituents, and provided that each R7 and R8 are selected such that in the resultant compound the carbon atom to which R7 and R8 are attached is itself attached to no more than one heteroatom;
R9 is selected from the group consisting of
hydrogen,
C1-8 alkyl,
aryl,
aryl C1-8 alkyl,
C1-8 alkylcarbonyloxy C1-4 alkyl,
aryl C1-8 alkylcarbonyloxy C1-4 alkyl,
C1-8 alkylaminocarbonylmethylene, and
C1-8 dialkylaminocarbonylmethylene;
wherein
each m is independently an integer from 1 to 6;
each n is independently an integer from 0 to 6;
each p is independently an integer from 0 to 2;
each r is independently an integer from 1 to 3;
each s is independently an integer from 0 to 3;
and
each t is independently an integer from 0 to 3;
and the pharmaceutically acceptable salts thereof.

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Integrin receptor antagonists

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Integrin receptor antagonists

Life of this patent

Abstract

Claims23