Alpha v integrin receptor antagonists
The present invention relates to novel chain-fluorinated alkanoic acid derivatives thereof, their synthesis, and their use as αv integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors αvβ3 and/or αvβ5 and are useful for inhibiting bone resorption, treating and preventing osteoporosis, and inhibiting vascular restenosis, diabetic retinopathy, macular degeneration, angiogenesis, atherosclerosis, inflammation, inflammatory arthritis, viral disease, cancer, and metastatic tumor growth.
1. A compound of the Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
X is
wherein each non-aromatic ring carbon atom is unsubstituted or independently substituted with one or two R 1 substituents and each aromatic ring carbon atom is unsubstituted or independently substituted with one R 1 substituent selected from the group consisting of
C 1-8 alkyl, C 3-8 cycloalkyl, C 3-8 cycloheteroalkyl, C 3-8 cycloalkyl-C 1-6 alkyl, C 3-8 cycloheteroalkyl-C 1-6 alkyl, aryl, aryl-C 1-6 alkyl, amino, amino-C 1-6 alkyl, C 1-3 acylamino, C 1-3 acylamino-C 1-6 alkyl, (C 1-6 alkyl) 1-2 amino, C 3-6 cycloalkyl-C 0-2 alkylamino, (C 1-6 alkyl) 1-2 amino-C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkoxy-C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C 1-6 alkyl, C 1-3 alkoxycarbonyl, C 1-3 alkoxycarbonyl-C 1-6 alkyl, hydroxy, hydroxy-C 1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C 1-8 alkyl-S(O) 0-2 , (C 1-8 alkyl) 0-2 aminocarbonyl, C 1-8 alkyloxycarbonylamino, (C 1-8 alkyl) 1-2 aminocarbonyloxy, (aryl C 1-3 alkyl) 1-2 amino, (aryl) 1-2 amino, aryl-C 1-3 alkylsulfonylamino, and C 1-8 alkylsulfonylamino;
or two R 1 substituents, when on the same non-aromatic carbon atom, are taken together with the carbon atom to which they are attached to form acarbonyl group, or two R 1 substituents, together with the non-aromatic carbon atoms to which they are attached, join to form a 4- to 6-membered saturated or unsaturated carbocyclic ring;
R 2 is hydrogen or C 1-4 alkyl;
R 3 is fluoro and R 4 is hydrogen or R 3 is hydrogen and R 4 is fluoro;
R 5 is aryl wherein the aryl group is selected from the group consisting of
(1) phenyl,
(2) naphthyl,
(3) pyridinyl,
(4) fliryl,
(5) thienyl,
(6) pyrrolyl,
(7) oxazolyl,
(8) thiazolyl,
(9) imidazolyl,
(10) pyrazolyl,
(11) isoxazolyl,
(12) isothiazolyl,
(13) pyrimidinyl,
(14) pyrazinyl,
(15) pyridazinyl,
(16) quinolyl,
(17) isoquinolyl,
(18) benzimidazolyl,
(19) benzofuryl,
(20) benzothienyl,
(21) indolyl,
(22) benzthiazolyl,
(23) benzoxazolyl,
(24) dihydrobenzofuryl,
(25) benzo(1,3)dioxolanyl, and
(26) benzo(1,4)dioxanyl;
and mono, di, and tri-substituted aryl wherein aryl is as defined above and the substituents are independently hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aryl C 1-3 alkyl, amino, amino C 1-6 alkyl, C 1-3 acylamino, C 1-3 acylamino-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 1-6 alkylamino-C 1-6 alkyl, di(C 1-6 )alkylamino-C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkoxy-C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C 1-6 alkyl, C 1-5 alkoxycarbonyl, C 1-3 alkoxycarbonyl-C 1-6 alkyl, C 1-5 alkylcarbonyloxy, cyano, tnifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, or nitro; or two adjacent substituents together with the carbon atoms to which they are attached join to form a five- or six-membered saturated or unsaturated ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, whose ring carbon atoms may be substituted with oxo or C 1-3 alkyl; and
R 6 is hydrogen or C 1-3 alkyl.
2. The compound of claim 1 wherein R 5 is mono- or di-substituted
phenyl,
pynidinyl,
quinolyl,
pyrimidinyl,
pyrazinyl,
pyrazolyl, or
dihydrobeuzofuryl;
wherein the substituents are independently hydrogen, hydroxy, hydroxy-C 1-6 alkyl, halogen, C 1-8 alkyl, C 3-8 cycloalkyl, aryl, aryl C 1-3 alkyl, amino, amino-C 1-6 alkyl, C 1-3 acylamino, C 1-3 acylamino-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 )alkylamino, C 1-6 alkylamino C 1-6 alkyl, di(C 1-6 )alkylamino-C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkoxy-C 1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C 1-6 alkyl, C 1-5 alkoxycarbonyl, C 1-3 alkoxycarbonyl C 1-6 alkyl, C 1-5 alkylcarbonyloxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, trifluoroethoxy, or nitro; or two adjacent substituents together with the carbon atoms to which they are attached join to form a five- or six-membered saturated or unsaturated ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S, whose ring carbon atoms may be substituted with oxo or C 1-3 alkyl.
3. The compound of claim 2 wherein R 5 is mono- or di-substituted
quinolyl,
pyridinyl, or
pyrimidinyl;
wherein the substituents are independently hydrogen, halogen, phenyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, di(C 1-3 )alkylamino, hydroxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, or trifluoroethoxy.
4. The compound of claim 1 wherein R 1 is selected from the group consisting of
hydrogen,
amino,
C 1-4 alkylamino,
C 3-6 cycloalkyl-C 0-2 alkylamino
cyano,
C 1-4 alkyl,
cyclopropyl,
aryl C 1-3 alkyl,
C 1-3 acylamino,
C 1-4 alkoxy,
C 1-4 alkylthio,
aminocarbonyl,
(C 1-6 alkyl) 1-2 aminocarbonyl,
C 1-3 alkoxycarbonyl,
trifluoromethyl, and
trifluoromethoxy.
5. The compound of claim 4 wherein R 1 is selected from the group consisting of
hydrogen,
amino,
C 1-3 alkylamino,
C 3-6 cycloalkylmethylamino,
C 1-4 alkyl,
cyclopropyl,
trifluoromethyl, and
trifluoromethoxy.
6. The compound of claim 1 wherein X is;
7. The compound of claim 6 wherein R 3 is hydrogen and R 4 is fluoro.
8. The compound of claim 7 wherein R 1 is C 1-4 alkyl or cyclopropyl and R 5 is mono- or di-substituted quinolyl, pyridinyl, or pyrimidinyl, wherein the substituents are independently hydrogen, halogen, phenyl, C 1-4 alkyl, C 3-6 cycloalkyl, C 1-3 alkoxy, amino, C 1-3 alkylamino, di(C 1-3 )alkylamino, hydroxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, or trifluoroethoxy.
9. The compound of claim 8 selected from the group consisting of
5,5-Difluoro-3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)-nonanoic acid;
9-(3-Cyclopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-5,5-difluoro-3-(2-methyl-pyrimidin-5-yl)-nonanoic acid;
9-(3-Cyclopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-5,5-difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-nonanoic acid;
9-(3-Cyclopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-5,5-difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-nonanoic acid;
5,5-Difluoro-3-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid; and
5,5-Difluoro-3(R)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5 H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 selected from the group consisting of
5,5-Difluoro-3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1 ,8]-naphthyridin-2-yl)-nonanoic acid;
9-(3-Cyclopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-5,5-difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-nonanoic acid;
9-(3-Cyclopropyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-5,5-difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(R)-(2-methyl-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
5,5-Difluoro-3(S)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid; and
5,5-Difluoro-3(R)-(2-methoxy-pyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-5H-pyrido[2,3-b]azepin-2-yl)-nonanoic acid;
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. The composition of claim 11 further comprising alendronate monosodium trihydrate.
13. A method of eliciting an αvβ3 integrin receptor antagonizing effect in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1 , wherein the αvβ3 antagonizing effect is the inhibition of bone resorption.
14. A method of treating osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1 .