TETRAHYDRONAPHTHYRIDINEPENTANAMIDE INTEGRIN ANTAGONISTS2-Substituted-4-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentanamido)butanoic acids are disclosed. These compounds selectively inhibit alphaVbeta3 without activating the alphaVbeta3 receptor. Theyare useful for treating osteoporosis, acute myelogenous leukemia, sickle cell disease, focal segmental glomerulosclerosis, fibrosis, supravalvular aortic stenosis associated with Williams syndrome, tumors expressing alphaVbeta3, tumor metastasis, bone resorption, T-cell lymphoma, retinal disease, age-related macular degeneration, diabetic retinitis, and herpes simplex virus infection. They may also be used for inhibiting tumor angiogenesis.The compound of following formula:wherein,r1it is hydrogen or (c1-c6) alkyl；r2it is hydrogen or (c1-c6) alkyl；r3selected from-nhc (=o) r4,-nhc (=o) nhr5,-nhc (=o) or5,-nhso2r6,-nhr7, aryl and heterocycle；institute it states aryl or heterocycle optionally to be replaced by 1-3 substituent group, the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1-c6) halogenated alkyl, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1-c6) oxa alkyl, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, acetoxyl group, nitro, amino, (c1-c6) alkyl amino, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulfonyl-amino, (c1-c6) alkyl asia sulphur acyl group, (c1-c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl；r4it is selected from(a) heterocycle optionally replaced by 1-3 substituent group, the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1- c6) halogenated alkyl, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1- c6) oxa alkyl, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, acetoxyl group, nitro, amino, (c1-c6) alkyl amino, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulfonyl-amino, (c1-c6) alkyl sulfenyl base, (c1-c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl；(b)(c1-c10) alkyl；(c) phenyl replaced by 1-3 substituent group, the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1-c6) halogen substituted alkyl, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1-c6) oxygen miscellaneous alkyl, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, acetoxyl group, nitro, amino, (c1-c6) alkyl ammonia base, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulfonyl-amino, (c1-c6) alkyl sulphinyl, (c1-c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl；(d) hydroxyl (c1-c10) alkyl；(e)(c1-c10) oxa alkyl；r5selected from (c1-c10) alkyl, (c1-c6) oxa alkyl, (c1-c10) fluoro alkyl, aryl, heteroaryl and benzyl；the virtue base, heteroaryl or benzyl are optionally replaced by 1-3 substituent group, and the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1-c6) halogenated alkyl, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1-c6) oxa alkyl, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, acetoxyl group, nitro, amino, (c1-c6) alkyl amino, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulfonyl-amino, (c1-c6) alkyl asia sulphur acyl group, (c1-c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl；r6selected from (c1-c10) alkyl, oxa- (c1-c10) alkyl, (c1-c10) oxa alkyl, heteroaryl and aryl；the aryl or heteroaryl is optionally replaced by 1-3 substituent group, and the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1-c6) alkyl halide base, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1-c6) oxa- alkane base, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, acetoxyl group, nitro, amino, (c1-c6) alkyl amino, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulfonyl-amino, (c1-c6) alkyl sulphinyl, (c1- c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl；r7selected from heteroaryl and aryl；the aryl or heteroaryl are optionally replaced by 1-3 substituent group, and the substituent group is independently selected from (c1-c10) alkyl, halogen, (c1-c6) halogenated alkyl, (c1-c6) acyl group, hydroxyl (c1-c6) low alkyl group, benzenesulfonyl, hydroxyl, halogenated (c1-c6) alkoxy, (c1-c6) oxa alkyl, carboxyl, (c1-c6) alkoxy carbonyl, formamido, cyano, second acyloxy, nitro, amino, (c1-c6) alkyl amino, two (c1-c6) alkyl amino, (c1-c6) alkyl sulfenyl, (c1-c6) alkyl sulphur acylamino-, (c1-c6) alkyl sulphinyl, (c1-c6) alkyl sulphonyl, heterocycle and (c1-c10) oxyl, andr10and r11independently selected from hydrogen and fluorine.
테트라하이드로나프티리딘펜탄아미드 인테그린 길항물질2-치환된-4-(5-(5,6,7,8-테트라하이드로-1,8-나프티리딘-2-일)펜탄아미도 부탄산을 개시한다. 상기 화합물은 αVβ3 수용체의 활성화 없이 αVβ3를 선택적으로 억제한다. 상기는 골다공증, 급성 골수성 백혈병, 겸상적혈구병, 국소 분절성 사구체경화증, 섬유증, 윌리엄스 증후군과 관련된 대동맥 판상부 협착증, αVβ3 발현 종양, 종양 전이, 골흡수, T-세포 림프종, 망막병, 연령-관련 황반변성, 당뇨성 망막염, 및 단순포진 바이러스 감염의 치료에 유용하다. 상기는 또한 종양 혈관형성의 억제에 사용될 수 있다.하기 화학식의 화합물화학식 [이미지]상기 식에서,R1은 수소 또는 (C1-C6)하이드로카빌이고;R2는 수소 또는 (C1-C6)하이드로카빌이고;R3은 -NHC(=O)R4; -NHC(=O)NHR5; -NHC(=O)OR5; -NHSO2R6; -NHR7; 아릴 및 헤테로사이클릴 중에서 선택되고; 상기 아릴 또는 헤테로사이클릴은 (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 임의로 치환되며;R4는 (a) (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 임의로 치환된 헤테로사이클릴;(b) (C1-C10)하이드로카빌;(c) (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 치환된 페닐;(d) 하이드록시(C1-C10)알킬;(e) (C1-C10)옥사알킬중에서 선택되고;R5는 (C1-C10)하이드로카빌; (C1-C6)옥사알킬; (C1-C10)플루오로하이드로카빌; 아릴, 헤테로아릴 및 벤질 중에서 선택되고; 상기 아릴, 헤테로아릴 또는 벤질은 (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 임의로 치환되며;R6은 (C1-C10)하이드로카빌; 옥소(C1-C10)하이드로카빌; (C1-C10)옥사알킬; 헤테로아릴; 및 아릴 중에서 선택되고; 상기 아릴 또는 헤테로아릴은 (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 임의로 치환되며;R7은 헤테로아릴; 및 아릴 중에서 선택되고; 상기 아릴 또는 헤테로아릴은 (C1-C10)하이드로카빌, 할로겐, (C1-C6)할로알킬, (C1-C6)아실, 하이드록시(C1-C6)저급알킬, 벤젠설포닐, 하이드록시, 할로(C1-C6)알콕시, (C1-C6)옥사알킬, 카복시, (C1-C6)알콕시카보닐, 카복스아미도, 시아노, 아세톡시, 니트로, 아미노, (C1-C6)알킬아미노, 디(C1-C6)알킬아미노, (C1-C6)알킬티오, (C1-C6)알킬설포닐아미노, (C1-C6)알킬설피닐, (C1-C6)알킬설포닐, 헤테로사이클릴, 및 (C1-C10)하이드로카빌옥시 중에서 독립적으로 선택된 1 내지 3개의 치환체로 임의로 치환되며;R10 및 R11은 수소 및 플루오로 중에서 독립적으로 선택된다.