4-MERCAPTOPYRROLIDINE DERIVATIVES AS FARNESYL TRANSFERASE INHIBITORSPharmaceutical compositions comprising an inhibitor of ras farnesylation of formula (I) wherein, R1 is for example H and further values as defined in the specification; R2 is for example H and further values as defined in the specification; R3 is for example H or a substituent having values as defined in the specification; p is 0-3 in which R3 values can be the same or different; L is a linking moiety for example -CO-NH2- and further values as defined in the specification; A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms where the heteroatoms are independently selected from O, N and S; or a -S-S- dimer thereof when R2=H; or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier. A particular use is cancer therapy.A pharmaceutical composition comprising an inhibitor of ras famesylation ofFormula IFormula I wherein:R is selected from H: -CMalkyl: -Cj_3alkylene-Ph optionally mono or di-substituted onPh with substituents selected from CMalkyl. halogen. OH. C1.4a.koxy. C * .4alkanoyl.Cι _4alkanoyloxy. amino, C1_4alkylam.no. di(Cι_4alkyl)amino. Cι .4alkanoylamino. nitro, cyano. carboxy, carbamoyl, C * _4alkoxycarbonyl. thiol. C ] _4alkylsulfanyl.C].4alkylsulfιnyl,Cι.4alkylsulfonyl and sulfonamido; -CO-C1.4a.kyl; -CO-0-Cι.4alkyl;-CO-O-C2-4alkenyl; -CO-O-(CH2)nPh optionally substituted on Ph as defined for substitution on Ph in R1 = -Ci-3alkylene-Ph in this claim 1 and n=0-4;-C]_4alkylene-CONR4R5 where R4 & R5 are independently selected from H. CMalkyl; and -C  _4alkylene-COOR6 where R6 is selected from H. C  _4alkyl:R is selected from H; -CMalkyl: -Cι_3alkylene-Ph optionally substituted on Ph as defined for substitution on Ph in R1 = -C 1.3 alky lene-Ph in this claim 1: -COC* _4alkyl: and -COOCι_4alkyl;R3 is selected from H; OH: CN: CF3; NO2: -C1.4 alkyl: -C * .4alkylene-R7 where R7 is selected from phenyl, naphthyl. and a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O.N and S and any aryl ring in R is optionally substituted as defined for substitution on the Ph group in R = -C 1.3 alky lene-Ph in claim 1 : R7: C2-4alkenyl; halogen: -(CH2)nCOOR8 where n= 0-3 and R8 represents H. Cι_4alkyl. C2-4alkenyl: -CONR9R10 where R9 and R10 independently represent H.Cι_4alkyl. C2-4alkenyl, -O-Cι.4alkyl. -O-C2-4alkenyl. or -C,. alkylenePh optionally substituted as defined for this group for R1 in this claim 1 :-CON(R )OR] where R1 ' and R independently represent H. C ι_4alkyl and C2_4alkenyl: a group of Formula II. -CONR13-CHR14-COOR17 . where R13 is H or C Malkyl. R17 is H orICj.galkyl. R is selected from the side chain of a lipophilic amino acid. carbamoylC alkyl. N.-(monoC!_4alkyl)carbamoylCι_4alkyl and N-(diC,. 4alkyl)carbamoylC alkyl. the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid: a lactone of formulaCMalkyl monosubstituted on carbon with =N-OH; a group of Formula -X-R where X is selected from O. CO. CH2- S. SO. SO2 and R15 is selected from CMalkyl, phenyl, naphthyl. a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O.N and S and any aryl ring in R is optionally substituted as defined for the Ph group in R' = -C 1 _3alkylene-Ph in this claim 1 ;p is 0-3 in which RJ values can be the same or different;L is a linking moiety selected from the following groups written from left to right in Formula I:-CO-NR16- where R16 is selected from H, C1.4a.kyl. C 1 _4alkylene-Z, -CO-Cι_4alkylene-Z. -CO-Cι_6alkyl. -COZ. and Z, and Z is selected from -O-C1.4a.kyl, phenyl, naphthyl. a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O. N and S and any aryl ring in R is optionally substituted as defined for the Ph group in R1 = -C 1.3 alky lene-Ph in this claim 1 ; -CH2-NR18- where R18 represents any value defined for R1 ; -CH2S-; -CH2O-: -CH2-CHR - where R represents any value defined for R16: -CH=CR20- where R20 represents any value defined for R16: -CH2NR -T- where R ' represents any value defined for R . T represents -(CH2)n- where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R16 other than H: -CH2NR23-SO2- where R23 represents any value defined for R16 ;-CH2-NR -CO-T- where R24 represents any value defined for R . T represents -(CH2)n- where n is 0-4 and T is optionally monosubstituted with R where R' represents any value for R other than H: -CO-NR '-T- where R 3 represents any value defined for R16. T represents -(CH2)n- where n is 1-4 and T is optionally monosubstituted with R'6 where R 6 represents any value for R16 other than H; -CH2S-T- where T represents -(CH2)n- where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R16 other than H: -CH2O-T- where T represents -(CH2)n- where n is 1-4 and T is optionally monosubstituted with R where R represents any value for R other than H:A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms where the heteroatoms are independently selected from O. N & S; or a -S-S- dimer thereof when R2=H: or a N-oxide thereof; or an enantiomer. diastereoisomer. pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier.
파르네실 트랜스퍼라제 억제제로서의 4-머캅토피롤리딘 유도체본 발명은 하기 화학식 I의 화합물의 라스 파르네실화의 억제제; 또는 하기 R2가 H인 경우의 -S-S- 이량체; 또는 이의 거울상 이성질체, 광학 이성질체, 약학적으로 허용가능한 염, 약물 전구체 또는 용매화물과 약학적으로 허용가능한 희석제 또는 담체를 포함하는 암 치료용 약학 조성물에 관한 것이다:화학식 I상기 식에서, R1은 예를 들어 H 및 추가로 명세서에서 정의한 의미이며; R2는 예를 들어 H 및 추가로 명세서에서 정의한 의미이며; R3은 H 또는 명세서에서 정의한 의미를 갖는 치환체이며; p는 R3이 동일하거나 상이할 수 있는 0 내지 3이며; L은 연결부, 예를 들어 -CO-NH2- 및 추가로 명세서에서 정의한 의미이며; A는 페닐; 나프틸; O, N 및 S로부터 개별적으로 선택되는 5 이하의 헤테로원자를 함유하는 5-10원 모노시클릭 또는 비시클릭 헤테로아릴 고리로부터 선택된다.하기 화합물중 임의의 화합물 또는 이의 약학적으로 허용가능한 염: (2S)-2-{2-벤질-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-벤조일아미노}-4-메틸설파닐부티르산 메틸 에스테르; (2S)-2-{2-벤질-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-벤조일아미노}-4-메틸설파닐부티르산; (2S)-2-({2-페닐-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-4-메틸설파닐부티르산 메틸 에스테르; (2S)-2-({2-페닐-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-4-메틸설파닐부티르산; (2S)-2-({3-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-나프탈렌-1-카르보닐}-아미노)-4-메틸설파닐부티르산 메틸 에스테르; (2S)-2-({3-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-나프탈렌-1-카르보닐}-아미노)-4-메틸설파닐부티르산; (2S)-2-({-3-페닐-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-4-메틸설파닐부티르산 메틸 에스테르; (2S)-2-({-3-페닐-5-[([2S,4S]-4-설파닐피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-4-메틸설파닐부티르산; (2S,4S)-2-[{N-(4-메톡시벤질)-N-(나프탈렌-1-일메틸)-아미노}-메틸]-피롤리딘-4-티올; N-(나프탈렌-1-일메틸)-N-([2S,4S]-4-설파닐피롤리딘-2-일메틸)-펜탄아미드; N-(나프탈렌-1-일메틸)-N-([2S,4S]-4-설파닐피롤리딘-2-일메틸)-2-(피리딘-3-일)-아세타미드; N-((2S,4S)-4-설파닐-피롤리딘-2-일메틸)-3-메틸-N-(2-나프탈렌-1-일-에틸)부티르아미드; N-([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-N-(2-나프탈렌-1-일-에틸)-2-피리딘-3-일-아세타미드; (2S,4S)-2-{[(3-메톡시프로필)-(2-나프탈렌-1-일에틸)아미노]메틸}-피롤리딘-4-티올; N-([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-2-(4-메톡시-페닐)-N-(2-나프탈렌-2-일-에틸)-아세타미드; (2S,4S)-2-{[(2-(4-메톡시페닐)에틸)-(2-나프탈렌-1-일에틸)아미노]메틸}-피롤리딘-4-티올; N-(2,2-디페닐-에틸)-N-([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-3-메틸-부티르아미드; N-([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-3,3-디메틸-N-(2-나프탈렌-2-일-에틸)-부티르아미드; N-(2,2-디페닐-에틸)-N-([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-3,3-디메틸-부티르아미드; (2S)-2-{3-[([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-(3-메톡시-프로필)-아미노]-벤조일아미노}-4-메틸설파닐-부티르산; N-([2S,4S]-4-설파닐피롤리딘-2-일메틸)-3,3-디메틸-N-(2-나프탈렌-1-일-에틸)-부티르아미드; (2S)-4-카르바모일-2-({2-페닐-5-[([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-부티르산; 및 (2S)-4-카르바모일-2-({2-페닐-5-[([2S,4S]-4-설파닐-피롤리딘-2-일메틸)-아미노]-페닐카르보닐}-아미노)-부티르산 메틸 에스테르.