Isoprenyl transferase inhibitorsPeptidomimetic compounds useful in the treatment of Ras-associated human cancers, and other conditions mediated by farnesylated or geranylgeranylated proteins; and synthetic intermediates thereof.Following formula: compound or its pharmacologically acceptable salt: wherein: r 1be h, nhr 8or nr 8r 9, r herein 8be h, c 1-6alkyl, c 1-6acyl group, c 2-14alkoxy carbonyl or any other amido protecting group, r 9be c 1-6alkyl, c 1-6acyl group or c 2-14carbalkoxy; perhaps, when with r 7when linking to each other, be one and contain the difunctionality organic moiety that is less than 50 carbon atoms; r 2be h, c 1-8alkyl, (c 6-40aryl) (c 0-6or (c alkyl), 3-10heteroaryl) (c 0-6alkyl); r 3be h, c 1-6alkyl or (c 6-40aryl) (c 0-6alkyl); r 4be c 3-16cycloalkyl, (c 3-16heterocyclic radical)-(c 0-6alkyl), (c 6-12aryl) (c 0-6alkyl), (c 3-16heteroaryl) (c 0-6alkyl), r 5(ch-) (c=o) r 6, r 5(ch-) (c=s) r 6, r 5(ch-) (ch 2) r 6, r 5(ch 2-), or any other amino protecting group, r herein 5be c 1-6alkyl, (c 3-10heterocyclic radical) (c 0-6alkyl), (c 3-10heteroaryl) (c 1-6alkyl), methylol ,-(ch 2) n-a-(ch 2) m-ch 3,-(ch 2) n(c=o) nh 2, or-(ch 2) n(c=o) nh (ch 2) mch 3(a is o, s, so or so herein 2, n be 0,1,2 or 3 and m be 0,1 or 2), or any other naturally occurring amino acid side chain; and r 6be h, nh 2, nhoh, c 3-16heterocyclic radical, c 3-16heteroaryl, nhr 10, nr 10r 11, or 12, nr 10or 11, or nhor 13, or any other carboxy protective group, each r herein 10and r 11be c independently of one another 1-6alkyl, (c 3-16heterocyclic radical) (c 0-6alkyl), c 2-14acyl-oxygen carbonyl, (c 3-16heteroaryl) (c 0-6alkyl) or any other amino protecting group, r 12be h, c 1-6alkyl, (c 1-12acyl group) oxygen (c 1-12alkyl), (c 1-12alkyl) oxygen (c 1-12or c alkyl), 2-14carbalkoxy, or any other hydroxyl-or carboxyl-protecting group, and r 13be hydrogen, c 1-6alkyl or (c 6-40aryl) (c 0-6alkyl); x is=o ,=s, or two h that independent key connects; y is selected from following five formulas: r herein 14be h, halogen, hydroxyl, c 1-6alkyl, c 2-6alkenyl, c 2-6alkynyl, c 1-12alkoxyl group, c 1-6acyloxy, c 1-6acyl group, c 6-41aryl, c 3-40heterocyclic radical, c 3-40heteroaryl, c 1-12alkylsulfonyloxy, c 1-12haloalkyl sulfonyloxy, c 6-40aryl-sulfonyl oxygen or c 6-41aryloxy; r herein 15be h, halogen, hydroxyl, c 1-6alkyl, c 2-6alkenyl, c 2-6alkynyl, c 1-12alkoxyl group, c 1-6acyloxy, c 1-6acyl group, c 6-41aryl, c 3-40heterocyclic radical, c 3-40heteroaryl, c 1-12alkylsulfonyloxy, c 1-12haloalkyl sulfonyloxy, c 6-40aryl-sulfonyl oxygen or c 6-41aryloxy; r herein 16be h, halogen, hydroxyl, c 1-6alkyl, c 2-6alkenyl, c 2-6alkynyl, c 1-12alkoxyl group, c 1-6acyloxy, c 1-6acyl group, c 6-41aryl, c 3-40heterocyclic radical, c 3-40heteroaryl, c 1-12alkylsulfonyloxy, c 1-12haloalkyl sulfonyloxy, c 6-40aryl-sulfonyl oxygen, perhaps c 6-41aryloxy; r herein 17be hydrogen, c 1-8alkyl, (c 6-40aryl) (c 0-6alkyl), (c 3-10heteroaryl) (c 0-6alkyl), perhaps (c 3-10heterocyclic radical) (c 0-6alkyl); with r herein 18be hydrogen, c 1-8alkyl, (c 6-40aryl) (c 0-6alkyl), (c 3-10heterocyclic radical) (c 0-6alkyl), perhaps (c 3-10heteroaryl) (c 0-6alkyl) and z be o, s, so, so 2, or nr 19, r herein 19be h, c 1-6alkyl, c 1-6acyl group, (c 6-40aryl) (c 0-6alkyl), c 3-10heterocyclic radical, c 3-10heteroaryl, (c 3-10heteroaryl) (c 0-6or c alkyl), 2-14carbalkoxy; perhaps r wherein 18and nr 19link to each other and form a dual functional c 6-40aryl, difunctionality c 3-12heterocyclic radical or dual functional c 3-12heteroaryl; and r 7be the organic moiety that is lower than 50 carbon atoms, perhaps, when with r 1when linking to each other, be a difunctionality organic moiety that is less than 50 carbon atoms.
이소프레닐 전이효소 억제제본 발명은 라스-관련 암 및 기타 파네실화 또는 제라닐제라닐화 단백질에 의해 매개되는 상태의 치료에 유용한 펩티도미메틱(peptidomimetics); 및 그의 합성 중간생성물에 관한 것이다.하기 식의 화합물 또는 그의 약제학상 허용가능한 염; [이미지] 상기 식에서, R1은 H, NHR8, 또는 NR8R9이고, 여기서, R8은 H, C1-6알킬, C1-6아실, C2-14알킬옥시카르보닐 또는 임의의 다른 아미노-보호기이며, 그리고 R9는C1-6알킬, C1-6아실, C2-14알킬옥시카르보닐이거나; 또는 R7과 일괄해서, 50탄소원자 미만의 2관능성 유기 부분이며; R2는 H, C1-8알킬, (C6-40아릴), (C0-6알킬) 또는 (C3-10헤테로아릴), (C0-6알킬)이고; R3은 H, C1-6알킬, 또는 (C6-40아릴), (C0-6알킬) 이며; R4는 C3-16시클로알킬, (C3-16헤테로시클릭 래디칼), (C0-6알킬), (C6-12아릴), (C0-6알킬), (C3-16헤테로아릴), (C0-6알킬), R5(CH-)(C=O)-R6, R5(CH-)(C=S)-R6, R5(CH-)(CH2)-R6, 또는 R5(CH2-) 또는 임의의 기타 아미노-보호기이며, 여기서R5는C1-6알킬, (C3-10헤테로시클릭 래디칼), (C0-6알킬), (C3-10헤테로아릴), (C1-6알킬), 하이드록시메틸, -(CH2)n-A-(CH2)m-CH3, -(CH2)n(C=O)NH2, 또는 -(CH2)n(C=O)NH2(CH2)mCH3이거나(여기서, A는 O, S, SO, 또는 SO2이고, n은 0, 1, 2 또는 3이며, m은 0, 1 또는 2이다.) 또는 임의의 다른 자연발생 아미노산의 측쇄이며; 그리고 R6는 H, NH2, NHOH, C3-16헤테로시클릭 래디칼, C3-10헤테로아릴, NHR10, NR10R11, OR12, NR10OR11, NHOR13, 또는 임의의 다른 카르복실-보호기이고, 여기서 R10 및 R11은 각각 독립적으로 C1-6알킬, (C3-16헤테로시클릭 래디칼), (C0-6알킬), C2-14아실옥시카르보닐, (C3-16헤테로아릴), (C0-6알킬) 또는 임의의 다른 아미노-보호기이고; R12는 H, C1-6알킬, (C1-12아실)옥시(C1-12알킬), (C1-12알킬)옥시(C1-12알킬), C2-14알킬옥시카르보닐, 또는 다른 임의의 하이드록실-또는 카르복실-보호기이며, R13은 H, C1-6알킬, (C6-40아릴)(C0-6알킬)이며; X는 =O, =S, 또는 두개의 단일-결합된 H이고; Y는 아래의 다섯개의 식으로부터 선택되며; [이미지] 여기서, R14는 H, 할라이드, 하이드록시, C1-6알킬, C2-6알케닐, C2-6알키닐, C1-12알콕시, C1-12아실옥시, C1-6아실, C6-41아릴, C3-40헤테로시클릭 래디칼, C3-40헤테로아릴, C1-12알킬설포닐옥시, C1-12할로알킬설포닐옥시, C6-40아릴설포닐옥시, 또는 C6-41아릴옥시이고; [이미지] 여기서, R15는 H, 할라이드, 하이드록시, C1-6알킬, C2-6알케닐, C2-6알키닐, C1-12알콕시, C1-6아실옥시, C1-6아실, C6-41아릴, C3-40헤테로시클릭 래디칼, C3-40헤테로아릴, C1-12알킬설포닐옥시, C1-12할로알킬설포닐옥시, C6-40아릴설포닐옥시, 또는 C6-41아릴옥시이며; [이미지] 여기서, R16는 H, 할라이드, 하이드록시, C1-6알킬, C2-6알케닐, C2-6알키닐, C1-12알콕시, C1-6아실옥시, C1-6아실, C6-41아릴, C3-40헤테로시클릭 래디칼, C3-40헤테로아릴, C1-12알킬설포닐옥시, C1-12할로알킬설포닐옥시, C6-40아릴설포닐옥시, 또는 C6-41아릴옥시이고; [이미지] 여기서, R17은 H, C1-8알킬, (C6-40알킬)(C0-6알킬), (C3-10헤테로아릴)(C0-6알킬) 또는 (C3-10헤테로시클릭 래디칼)(C0-6알킬)이며, 그리고 [이미지] 여기서, R18은 H, C1-8알킬, (C6-40알킬)(C0-6알킬), (C3-10헤테로시클릭 래디칼)(C0-6알킬) 또는 (C3-10헤테로아릴)(C0-6알킬)이고; Z는 O, S, SO, SO2 혹은 NR 19 이며, 여기서, R19는 H, C1-6알킬, C1-6아실, (C6-40아릴)(C0-6알킬), C3-10헤테로시클릭 래디칼, C3-10헤테로아릴, (C3-10헤테로아릴)(C0-6알킬), 또는 C2-14알킬옥시카르보닐이거나; 또는 여기서 R18 및 NR19는 일괄해서 2관능성 C6-40아릴, 2관능성 C3-12헤테로시클릭 래디칼 또는 2관능성 C3-12헤테로아릴을 형성하고; 및 R7은 탄소 원자 50 미만의 유기 부분이거나, 또는 R1과 함께 일괄해서 탄소 원자 50 미만의 2관능성 유기 부분이다.