Claims for Patent: 6,472,403

Summary for Patent: 6,472,403

Title:	.alpha.V integrin receptor antagonists
Abstract:	The present invention relates to novel imidazolidinone derivatives thereof, their synthesis, and their use as .alpha.v integrin receptor antagonists. More particularly, the compounds of the present invention are antagonists of the integrin receptors .alpha.v.beta.3 and/or .alpha.v.beta.5 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.
Inventor(s):	Duggan; Mark E. (Schwenksville, PA), Halczenko; Wasyl (Lansdale, PA), Hutchinson; John H. (Philadelphia, PA), Li; Aiwen (Audubon, PA), Meissner; Robert S. (Schwenksville, PA), Perkins; James J. (Churchville, PA), Steele; Thomas G. (Schwenksville, PA), Wang; Jiabing (Chalfont, PA), Patane; Michael A. (Billerica, MA)
Assignee:	Merck & Co., Inc. (Rahway, NJ)
Application Number:	09/766,148
Patent Claims:	1. A compound of the Formula (I) ##STR25## or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of ##STR26## each R.sup.1 is independently hydrogen or C.sub.1-3 alkyl and each non-aromatic ring carbon atom is unsubstituted or independently substituted with one or two R.sup.2 substituents and each aromatic ring carbon atom is unsubstituted or independently substituted with one R.sup.2 substituent selected from the group consisting of C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloheteroalkyl, C.sub.3-8 cycloalkyl-C.sub.1-6 alkyl, C.sub.3-8 cycloheteroalkyl-C.sub.1-6 alkyl, aryl, aryl-C.sub.1-6 alkyl, amino-C.sub.1-6 alkyl, C.sub.1-3 acylamino, C.sub.1-3 acylamino-C.sub.1-6 alkyl, amino, (C.sub.1-6 alkyl).sub.1-2 amino, C.sub.3-6 cycloalkyl-C.sub.0-2 amino, (C.sub.1-6 alkyl).sub.1-2 amino-C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-4 alkoxy-C.sub.1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C.sub.1-6 alkyl, C.sub.1-3 alkoxycarbonyl, C.sub.1-3 alkoxycarbonyl-C.sub.1-6 alkyl, hydroxy, hydroxy-C.sub.1-6 alkyl, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoroethoxy, C.sub.1-8 alkyl-S(O).sub.0-2, (C.sub.1-8 alkyl).sub.0-2 aminocarbonyl, C.sub.1-8 alkyloxycarbonylamino, (C.sub.1-8 alkyl).sub.1-2 aminocarbonyloxy, (aryl).sub.1-2 amino, aryl-C.sub.1-3 alkylsulfonylamino, and C.sub.1-8 alkylsulfonylamino; or two R.sup.2 substituents, when on the same non-aromatic carbon atom, are taken together with the carbon atom to which they are attached to form a carbonyl group; or two R.sup.2 substituents, together with the carbon atom to which they are attached, join to form a 3- to 6-membered saturated spiro-carbocyclic ring; R.sup.4 is aryl wherein the aryl group is selected from the group consisting of (1) phenyl, (2) naphthyl, (3) pyridyl, (4) furyl, (5) thienyl, (6) pyrrolyl, (7) oxazolyl, (8) thiazolyl, (9) imidazolyl, (10) pyrazolyl, (11) isoxazolyl, (12) isothiazolyl, (13) pyrimidinyl, (14) quinolyl, (15) isoquinolyl, (16) benzimidazolyl, (17) benzofuryl, (18) benzothienyl, (19) indolyl, (20) benzthiazolyl, (21) benzoxazolyl, (22) dihydrobenzofuryl, (23) benzo(1,3)dioxolanyl, and (24) benzo(1,4)dioxanyl; and mono, di, and tri-substituted aryl wherein the substituents are independently hydrogen, hydroxy, hydroxy-C.sub.1-6 alkyl, halogen, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, aryl, aryl C.sub.1-3 alkyl, amino, amino C.sub.1-6 alkyl, C.sub.1-3 acylamino, C.sub.1-3 acylamino-C.sub.1-6 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, C.sub.1-6 alkylamino-C.sub.1-6 alkyl, di(C.sub.1-6)alkylamino-C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxy-C.sub.1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C.sub.1-6 alkyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-3 alkoxycarbonyl-C.sub.1-6 alkyl, C.sub.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.sub.1-3 alkyl; and R.sup.3 is hydrogen or C.sub.1-3 alkyl. 2. The compound of claim 1 wherein R.sup.4 is mono- or di-substituted phenyl, pyridyl, quinolyl, pyrimidinyl, pyrazolyl, or dihydrobenzofuryl; wherein the substituents are independently hydrogen, hydroxy, hydroxy-C.sub.1-6 alkyl, halogen, C.sub.1-8 alkyl, C.sub.3-8 cycloalkyl, aryl, aryl C.sub.1-3 alkyl, amino, amino-C.sub.1-6 alkyl, C.sub.1-3 acylamino, C.sub.1-3 acylamino-C.sub.1-6 alkyl, C.sub.1-6 alkylamino, di(C.sub.1-6)alkylamino, C.sub.1-6 alkylamino C.sub.1-6 alkyl, di(C.sub.1-6)alkylamino-C.sub.1-6 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkoxy-C.sub.1-6 alkyl, hydroxycarbonyl, hydroxycarbonyl-C.sub.1-6 alkyl, C.sub.1-5 alkoxycarbonyl, C.sub.1-3 alkoxycarbonyl C.sub.1-6 alkyl, C.sub.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.sub.1-3 alkyl. 3. The compound of claim 2 wherein R.sup.4 is mono- or di-substituted quinolyl, pyridyl, or pyrimidinyl; wherein the substituents are independently hydrogen, halogen, phenyl, C.sub.1-4 alkyl, C.sub.3-6 cycloalkyl, C.sub.1-3 alkoxy, amino, C.sub.1-3 alkylamino, di(C.sub.1-3) alkylamino, hydroxy, cyano, trifluoromethyl, 1,1,1-trifluoroethyl, trifluoromethoxy, or trifluoroethoxy. 4. The compound of claim 3 wherein R.sup.2 is selected from the group consisting of C.sub.1-4 alkylamino, C.sub.3-6 cycloalkyl-C.sub.0-2 alkylamino cyano, C.sub.1-4 alkyl, cyclopropyl, aryl C.sub.1-3 alkyl, C.sub.1-4 acylamino, C.sub.1-4 alkoxy, C.sub.1-4 alkylthio, aminocarbonyl, (C.sub.1-6 alkyl).sub.1-2 aminocarbonyl, C.sub.1-4 alkoxycarbonyl, trifluoromethyl, and trifluoromethoxy. 5. The compound of claim 4 wherein R.sup.2 is selected from the group consisting of C.sub.1-3 alkylamino, C.sub.3-6 cycloalkylmethylamino, C.sub.1-4 alkyl, cyclopropyl, trifluoromethyl, and trifluoromethoxy. 6. The compound of claim 5 selected from the group consisting of: 3-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno- [1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid; 3(R)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno- [1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid; 3(S)-(6-methoxy-pyridin-3-yl)-3-{2-oxo-3-(5,6,7,8-tetrahydro-5,5-ethyleno- [1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl-propionic acid; 3(S)-(6-Methoxy-pyridin-3-yl)-3-{2-oxo-3-(7(R)-methyl-5,6,7,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid; and 3(S)-(6-Methoxy-pyridin-3-yl)-3-{2-oxo-3-(7(S)-methyl-5,6,7,8-tetrahydro- [1,8]naphthyridin-2-yl)-propyl]-imidazolidin-1-yl}-propionic acid; or a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 8. The composition of claim 7 which further comprises an active ingredient selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cytotoxic/antiproliferative agent, e) a matrix metalloproteinase inhibitor, f) an inhibitor of epidermal-derived, fibroblast-derived, or platelet-derived growth factors, g) an inhibitor of VEGF, h) an antibody to a growth factor or a growth factor receptor, i) an inhibitor of Flk-1/KDR, Flt-1, Tck/Tie-2, or Tie-1, j) a cathepsin K inhibitor, k) a growth hormone secretagogue, l) an inhibitor of osteoclast proton ATPase, m) an inhibitor of urokinase plasminogen activator, n) a tumor-specific antibody-interleukin-2 fusion protein, o) an inhibitor of HMG-CoA reductase, p) a farnesyl transferase inhibitor or a geranylgeranyl transferase inhibitor or a dual farnesyl/geranylgeranyl transferase inhibitor, and q) human parathyroid hormone (hPTH) or hPTH(1-34); and mixtures thereof. 9. The composition of claim 8 wherein said active ingredient is selected from the group consisting of a) an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof, b) an estrogen receptor modulator, c) an androgen receptor modulator, d) a cathepsin K inhibitor, e) an HMG-CoA reductase inhibitor, and f) an inhibitor of osteoclast proton ATPase; and mixtures thereof. 10. The composition of claim 9 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate. 11. A method of treating or preventing osteoporosis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to claim 1. 12. A method of inhibiting a condition selected from the group consisting of bone resorption, restenosis, angiogenesis, biabetic retinopathy, macular degeneration, and inflammatory arthritis, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1. 13. A method of treating or preventing osteoporosis which comprises administering to a mammal in need of such treatment or prevention a therapeutically or prophylactically effective amount of a compound of claim 1 in combination with an effective amount of an organic bisphosphonate or a pharmaceutically acceptable salt or ester thereof. 14. The method of claim 13 wherein said organic bisphosphonate or pharmaceutically acceptable salt or ester thereof is alendronate monosodium trihydrate.

Details for Patent 6,472,403

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2020-01-20
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2020-01-20