| 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors -> Monitor Keywords |
|
|
  3-mercaptopyrrolidines as farnesyl protein transferase inhibitorsUSPTO Application #: 20050209217Title: 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors Abstract: The present invention relats to inhibitors 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 —CH2—NH— 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 a N-oxide or a pharmaceutically-acceptable salt, prodrug or solvate thereof. Processes for their preparation, their use as therapeutic agents and pharmaceutical compositions containing them. A particular use is in cancer therapy. (end of abstract)
Agent: Morgan Lewis & Bockius LLP - Washington, DC, US Inventors: Francis Thomas Boyle, James Michael Wardleworth USPTO Applicaton #: 20050209217 - Class: 514218000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Seven-membered Consisting Of Two Nitrogens And Five Carbon Atoms The Patent Description & Claims data below is from USPTO Patent Application 20050209217. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This invention relates to compounds that inhibit farnesylation of mutant ras gene products through inhibition of the enzyme farnesyl-protein transferase (FPTase). The invention also relates to methods of manufacturing the compounds, pharmaceutical compositions and methods of treating diseases, especially cancer, which are mediated through farnesylation of ras. [0002] Cancer is believed to involve alteration in expression or function of genes controlling cell growth and differentiation. Whilst not wishing to be bound by theoretical considerations the following text sets out the scientific background to ras in cancer. Ras genes are frequently mutated in tumours. Ras genes encode guanosine triphosphate (GTP) binding proteins which are believed to be involved in signal transduction, proliferation and malignant transformation. H-, K- and N-ras genes have been identified as mutant forms of ras (Barbacid M, Ann. Rev. Biochem. 1987, 56: 779-827). Post translational modification of ras protein is required for biological activity. Farnesylation of ras catalysed by FPTase is believed to be an essential step in ras processing. It occurs by transfer of the farnesyl group of farnesyl pyrophosphate (FPP) to a cysteine at the C-terminal tetrapeptide of ras in a structural motif called the CAAX box. After further post-translational modifications, including proteolytic cleavage at the cysteine residue of the CAAX box and methylation of the cysteine carboxyl, ras is able to attach to the cell membrane for relay of growth signals to the cell interior. In normal cells activated ras is believed to act in conjunction with growth factors to stimulate cell growth. In tumour cells it is believed that mutations in ras cause it to stimulate cell division even in the absence of growth factors (Travis J, Science 1993, 260: 1877-1878), possibly through being permanently in GTP activated form rather than cycled back to GDP inactivated form. Inhibition of farnesylation of mutant ras gene products will stop or reduce activation. [0003] One class of known inhibitors of farnesyl transferase is based on farnesyl pyrophosphate analogues; see for example European patent application EP 534546 from Merck. Inhibitors of farnesyl transferase based on mimicry of the CAAX box have been reported. Reiss (1990) in Cell 62, 81-8 disclosed tetrapeptides such as CVIM (Cys-Val-Ile-Met). James (1993) in Science 260, 1937-1942 disclosed benzodiazepine based peptidomimetic compounds. Lerner (1995) in J. Biol. Chem. 270, 26802 and Eisai in International Patent Application WO 95/25086 disclosed further peptidomimetic compounds based on Cys as the first residue. Bristol-Myers Squibb in European Patent Application EP 696593 disclosed for the first time farnesyl transferase inhibitors having a 4-sulfanylpyrrolidine residue in the first position. It is believed that there has been no disclosure of such compounds having a 3-sulfanyl pyrrolidine moiety in the first position. [0004] According to one aspect of the present invention there is provided an inhibitor of ras farnesylation of Formula I 2 [0005] wherein: [0006] R.sup.1 is selected from H; --C.sub.1-4alkyl; --CO--C.sub.1-4alkyl, --CO--O--C.sub.1-4alkyl; --CO--O--C.sub.2-4alkenyl; --C.sub.1-4alkylene-CONR.sup.4R.sup.5 (wherein R.sup.4 and R.sup.5 are independently selected from H and C.sub.1-4alkyl); --C.sub.1-4alkylene-COOR.sup.6 (wherein R.sup.6 is selected from H and C.sub.1-4alkyl); --C.sub.1-3alkylene-Ph and --CO--O(CH.sub.2).sub.nPh wherein the phenyl groups in --C.sub.1-3alkylene-Ph and --CO--O(CH.sub.2).sub.nPh are optionally substituted by R.sup.a and/or R.sup.b and R.sup.a and R.sup.b are independently selected from C.sub.1-4alkyl, halogen, hydroxy, C.sub.1-4alkoxy, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino- , C.sub.1-4alkanoylamino, nitro, cyano, carboxy, carbamoyl, C.sub.1-4alkoxycarbonyl, thiol, C.sub.1-4alkylsulfanyl, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonyl and sulfonamido, and n=0-4; [0007] R.sup.2 is selected from H; --C.sub.1-4alkyl; --COC.sub.1-4alkyl; and --COOC.sub.1-4alkyl; and --C.sub.1-3alkylene-Ph optionally substituted on the phenyl ring by R.sup.a and or R.sup.b; [0008] R.sup.3 is selected from H; OH; CN; CF.sub.3; NO.sub.2; --C.sub.1-4alkyl; --C.sub.1-4alkylene-R.sup.7; --C.sub.2-4alkenylene-R.su- p.7; --C.sub.2-4alkynylene-R.sup.7; R.sup.7; OR.sup.7 (where R.sup.7 is selected from 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.sup.7 is optionally substituted by R.sup.a and/or R.sup.b); C.sub.2-4alkenyl; halogen; --(CH.sub.2).sub.nCOOR.sup.8 (where n.sup.1=0-3 and R.sup.8 represents H, C.sub.1-4alkyl, or C.sub.2-4alkenyl); --CONR.sup.9R.sup.10 (where R.sup.9 and R.sup.10 independently represent H, C.sub.1-4alkyl, C.sub.2-4alkenyl, --O--C.sub.1-4alkyl, --O--C.sub.2-4alkenyl or --C.sub.1-3alkylenePh (wherein Ph is optionally substituted by R.sup.a and R.sup.b as hereinabove defined); --CON(R.sup.11)OR.sup.12 (where R.sup.11 and R.sup.12 independently represent H, C.sub.1-4alkyl or C.sub.2-4alkenyl); [0009] a group of Formula II: --CONR.sup.13--CR.sup.13aR.sup.14--COOR.sup.- 17, (where R.sup.13 and R.sup.13a are independently H or C.sub.1-4alkyl, R.sup.17is H or C.sub.1-6alkyl, R.sup.14 is selected from the side chain of a lipophilic amino acid, carbamoylC.sub.1-4alkyl, N-(monoC.sub.1-4alkyl)carbamoylC.sub.1-4alkyl and N-(diC.sub.1-4alkyl)car- bamoylC.sub.1-4alkyl) the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; a lactone of formula: 3 [0010] C.sub.1-4alkyl monosubstituted on carbon with .dbd.N--OH; [0011] a group of Formula -X-R.sup.15 (where X is selected from O, CO, CH.sub.2, S, SO, SO.sub.2 and R.sup.15 is selected from C.sub.1-6alkyl, 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.sup.15 is optionally substituted by R.sup.a and/or R.sup.b; [0012] p is 0-3 in which R.sup.3 values can be the same or different; [0013] L is a linking moiety selected from the following groups written from left to right in 4 [0014] (wherein the piperazine and perhydro-1,4-diazepine rings are optionally substituted); --CO--NR.sup.16--; --CH.sub.2--NR.sup.16-; --CH.sub.2S--; --CH.sub.2O--: --CH.sub.2--CHR.sup.16; --CH.dbd.CR.sup.16-; --CH.sub.2NR.sup.16-T-; --CH.sub.2NR.sup.16--SO.sub.- 2--; --CH.sub.2--NR.sup.16--CO-T.sup.1-; --CO--NR.sup.16-T-; --CH.sub.2S-T-; --CH.sub.2O-T- (where R.sup.16 is selected from H, C.sub.1-4alkyl, C.sub.1-4alkylene-Z, --CO--C.sub.1-4alkylene-Z, --CO--C.sub.1-6alkyl, --COZ, Z and Z is selected from --O--C.sub.1-4alkyl, 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.sup.16 is optionally substituted by R.sup.a and/or R.sup.b as hereinabove defined; [0015] where, T represents --(CH.sub.2)m- where m is 1-4 and T is optionally monosubstituted with any value of R.sup.16 other than H; and [0016] where T.sup.1 represents --(CH.sub.2)m.sup.1- wherein m.sup.1 is 0-4 and T is optionally monosubstituted with any value of R.sup.16 other than H); [0017] 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; [0018] or a --S--S-- dimer thereof when R.sup.2=H; or a N-oxide thereof; [0019] or a pharmaceutically acceptable salt, prodrug or solvate thereof. [0020] In another aspect of the invention there is provided an inhibitor of ras farnesylation of Formula I [0021] wherein: [0022] R.sup.1 is selected from H; --C.sub.1-4alkyl; --C.sub.1-3alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from C.sub.1-4alkyl, halogen, OH, C.sub.1-4alkoxy, C.sub.1-4alkanoyl, C.sub.1-4alkanoyloxy, amino, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, C.sub.1-4alkanoylamino, nitro, cyano, carboxy, carbamoyl, C.sub.1-4alkoxycarbonyl, thiol, C.sub.1-4alkylsulfanyl. C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonyl and sulfonamido; --CO--C.sub.1-4alkyl; --CO--O--C.sub.1-4alkyl; --CO--O--C.sub.2-4alkenyl; --CO--O--(CH.sub.2).sub.nPh optionally substituted on Ph as defined for substitution on Ph in R.sup.1=--C.sub.1-3alkylene-Ph above and n=0-4; [0023] --C.sub.1-4alkylene-CONR.sup.4R.sup.5 where R.sup.4 & R.sup.5 are independently selected from H and C.sub.1-4alkyl; and --C.sub.1-4alkylene-COOR.sup.6 where R.sup.6 is selected from H, C.sub.1-4alkyl; [0024] R.sup.2 is selected from H; --C.sub.1-4alkyl; --C.sub.1-3alkylene-Ph optionally substituted on Ph as defined for substitution on Ph in R.sup.1=--C.sub.1-3alkylene-Ph above; --COC.sub.1-4alkyl; and --COOC.sub.1-4alkyl; Continue reading... Full patent description for 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors or other areas of interest. ### Previous Patent Application: Method for preparing 6-aminomethyl-6,11-dihydro-5h-dibenz[b,e]azepine Next Patent Application: Phenyl-and pyridyl-diazaheterocycles having a tnf-modulating activity Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the 3-mercaptopyrrolidines as farnesyl protein transferase inhibitors patent info. IP-related news and info Results in 0.3566 seconds Other interesting Feshpatents.com categories: Medical: Surgery , Surgery(2) , Surgery(3) , Drug , Drug(2) , Prosthesis , Dentistry |
||
