3-mercaptopyrrolidines as farnesyl protein transferase inhibitors
View Patent ↗The present invention relates to inhibitors of ras farnesylation of the Formula I wherein: R 1 is for example H and further values as defined in the specification; R 2 is for example H and further values as defined in the specification; R 3 is for example H or a substituent having values as defined in the specification; p is 0-3 in which R 3 values can be the same or different; L is a linking moiety for example —CH 2— 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 upto 5 heteroatoms where the heteroatoms are independently selected from O, N & S; or a —S—S— dimer thereof when R 2 ═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.
1. A compound of the formula B:
wherein:
X is O or H 2 ;
e is 0;
t is 1 to 4;
R 2′ , R 3′ , R 4′ , and R 5′ are independently selected from: H; C 1-8 alkyl, alkenyl, alkynyl, aryl, heterocycle, —CO—NR 6′ R 7′ or —CO—OR 6′ , unsubstituted or substituted with one or more of:
1) aryl or heterocycle, unsubstituted or substituted with:
a) C 1-4 alkyl,
b) (CH 2 ) t OR 6′ ,
c) (CH 2 ) t NR 6′ R 7′ ,
d) halogen,
2) C 3-6 cycloalkyl,
3) OR 6′ ,
4) SR 6′ , S(O)R 6′ , SO 2 R 6′ ,
5) —NR 6 ′ R 7′ ,
6) —NR 6′ —CO—R 7′ ,
7) —NR 6′ —CO—NR 7′ R 8′ ,
8) —O—CO—NR 6′ R 7′ ,
9) —O—CO—OR 6′ ,
10) —O—NR 6′ R 7′ ,
11) —SO 2 NR 6′ R 7′ ,
12) —NR 6′ —SO 2 —R 7′ ,
13) —CO—R 6′ , or
14) —CO—OR 6′ ;
and any two of R 2′ , R 3′ , R 4′ , and R 5′ are optionally attached to the same carbon atom;
Y is aryl, heterocycle, unsubstituted or substituted with one or more of:
1) C 1-4 alkyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) NR 6′ R 7′ ,
c) C 3-6 cycloalkyl,
d) aryl or heterocycle,
e) HO,
2) aryl or heterocycle,
3) halogen,
4) OR 6′ ,
5) NR 6′ R 7′ ,
6) CN,
7) NO 2 , or
8) CF 3 ;
R 6′ , R 7′ and R 8′ are independently selected from: H; C 1-4 alkyl, C 3-6 cycloalkyl, heterocycle, aryl, aroyl, heteroaroyl, arylsulfonyl, heteroarylsulfonyl, unsubstituted or substituted with:
a) C 1-4 alkoxy,
b) aryl or heterocycle,
c) halogen,
d) HO,
e) —CO—R 9′ ,
f) —SO 2 R 9′ , wherein
R 6′ and R 7′ may be joined in a ring, and
R 7′ and R 8′ may be joined in a ring;
R 9′ is C 1-4 alkyl or aralkyl;
a pharmaceutically acceptable salt thereof.
2. The compound (2 S )-2-(2-methoxy-ethyl)-1-((cis)-3-sulfanyl-pyrrolidin-2-ylmethyl)-4-naphthoyl-piperazine or a pharmaceutically acceptable salt thereof.
3. A pharmaceutical composition which comprises a compound according to claim 1 or 2 and a pharmaceutically-acceptable carrier.
4. A process for preparing compounds of the Formula B as defined in claim 1 which comprises deprotecting a compound of Formula VI:
wherein X 8 represents the right hand side of the Formula B as defined in claim 1 , Pr 1 is H or an amino protecting group, Pr 2 is H or a thio protecting group and any functional groups in X 8 are optionally protected with the proviso that there is at least one protecting group and optionally, if desired, converting the product thus obtained into a pharmaceutically-acceptable salt thereof.
5. A method of treating a disease or medical condition mediated through farnesylation of CAAX-containing proteins which comprises administering to a warm-blooded animal an effective amount of a compound according to claim 1 or 2 , wherein said disease or medical condition is carcinoma of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid or skin.
6. A method of treating a disease or medical condition mediated through farnesylation of CAAX-containing proteins which comprises administering to a warm-blooded animal an effective amount of a compound according to claim 1 or 2 , wherein said disease or medical condition is a hematopoietic tumor of lymphoid lineage selected from acute lymphocytic leukemia, B-cell lymphoma and Burketts lymphoma.
7. A method of treating a disease or medical condition mediated through farnesylation of CAAX-containing proteins which comprises administering to a warm-blooded animal an effective amount of a compound according to claim 1 or 2 , wherein said disease or medical condition is a hematopoietic tumor of myeloid lineage selected from acute or chronic myelogenous leukemias and promyelocytic leukemia.
8. A method of treating a disease or medical condition mediated through farnesylation of CAAX-containing proteins which comprises administering to a warm-blooded animal an effective amount of a compound according to claim 1 or 2 , wherein said disease or medical condition is a tumor of mesenchymal origin selected from fibrosarcoma and rhabdomyosarcoma.
9. A method of treating a disease or medical condition mediated through farnesylation of CAAX-containing proteins which comprises administering to a warm-blooded animal an effective amount of a compound according to claim 1 or 2 , wherein said disease or medical condition is a tumor selected from melanoma, seminoma, teratocarcinoma, neuroblastoma and glioma.