US2004157872A1PendingUtilityA1
Compounds useful for inhibition of farnesyl protein transferase
Priority: Jun 17, 1997Filed: Feb 9, 2004Published: Aug 12, 2004
Est. expiryJun 17, 2017(expired)· nominal 20-yr term from priority
C07D 401/14
50
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Claims
Abstract
Novel compounds of the formula: or a pharmaceutically acceptable salt or solvate thereof, wherein: a represents N or NO − ; R 1 and R 3 are the same or different and each represents halo; R 2 and R 4 are the same or different and each is selected from H and halo, provided that at least one of R 2 and R 4 is H; T is a substituent selected from SO 2 R or Z is O or S; n is zero or an integer from 1 to 6; R is alkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or N(R 5 ) 2 ; R 5 is H, alkyl, aryl, heteroaryl or cycloalkyl. Also disclosed are methods of inhibiting farnesyl protein transferase and methods for treating tumor cells.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
a represents N or NO − ;
R 1 and R 3 are the same or different and each represents halo;
R 2 and R 4 are the same or different and each is selected from H and halo, provided that at least one of R 2 and R 4 is H;
T is a substituent selected from SO 2 R or
Z is O or S;
n is zero or an integer from 1 to 6;
R is alkyl aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, or N(R 5 ) 2 ;
R 5 is H, alkyl, aryl, heteroaryl or cycloalkyl.
2 . The compound of claim 1 having the formula:
wherein a, T, R 1 and R 3 are as defined in claim 1 .
3 . The compound of claim 1 having the formula:
wherein a, T, R 1 , R 3 and R 4 are as defined in claim 1 .
4 . The compound of claim 1 having the formula:
wherein a, T, R 1 , R 2 and R 4 are as defined in claim 1 .
5 . The compound of claim 1 having the formula:
wherein a, T, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .
6 . The compound of claim 1 having the formula:
wherein a, T, R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .
7 . The compound of claim 2 , wherein R 1 is bromo and R 3 is chloro.
8 . The compound of claim 3 , wherein R 1 is bromo, R 3 is chloro and R 4 is bromo.
9 . The compound of claim 4 , wherein R 1 is bromo, R 2 is bromo and R 3 is chloro.
10 . The compound of claim 7 , wherein T is —SO 2 methyl or a group
wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide, 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen with a group R 9 ; R 9 is selected from —C(O)N(R 10 ) 2 , —CH 2 C(O)N(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(O)R 11 , —C(O)OR 11 , alkyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R 10 independently represents H, alkyl, aryl, or aralkyl; and R 11 is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
11 . The compound of claim 8 , wherein T is —SO 2 methyl or a group
wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide. 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen with a group R 9 ; R 9 is selected from —C(O)N(R 10 ) 2 , —CH 2 C(O)N(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(O)R 11 , —C(O)OR 11 , alky, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R 10 independently represents H, alkyl, aryl, or aralkyl; and R 11 is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
12 . The compound of claim 9 , wherein T is —SO 2 methyl or a group
wherein R is a 3-pyridinyl N-oxide, 4-pyridinyl N-oxide, 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl group, wherein: the 4-piperdinyl, 3-piperdinyl or 3-pyrrolidinyl groups may be substituted on the piperindinyl or pyrrolidinyl nitrogen With a group R 9 ; R 9 is selected from —C(O)N(R 10 ) 2 , —CH 2 C(O)N(R 10 ) 2 , —SO 2 R 10 , —SO 2 N(R 10 ) 2 , —C(O)R 11 , —C(O)OR 11 , alkyl, aryl, aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; each R 10 independently represents H, alkyl, aryl, or aralkyl; and R 11 is alkyl, aryl, aralkyl, heteroaryl or heterocycloalkyl.
13 . The compound of claim 10 , wherein the carbon in the C-11 position is in the R-configuration.
14 . The compound of claim 11 , wherein the carbon in the C-11 position is in the R-configuration.
15 . The compound of claim 12 , wherein the carbon in the C-11 position is in the R-configuration.
16 . The compound of claim 10 , wherein the carbon in the C-11 position is in the S-configuration.
17 . The compound of claim 11 , wherein the carbon in the C-11 position is in the S-configuration.
18 . The compound of claim 12 , wherein the carbon in the C-11 position is in the S-configuration.
19 . A compound of claim 1 having the formula:
20 . A method of treating tumor cells expressing an activated ras oncogene comprising administering an effective amount of a compound of claim 1 .
21 . The method of claim 20 Wherein tumor cells treated are pancreatic tumor cells, lung cancer cells, myeloid leukemia tumor cells, thyroid follicular tumor cells, myelodysplastic tumor cells, epidermal carcinoma tumor cells, bladder carcinoma tumor cells, colon tumors cells, breast tumor cells and prostate tumor cells.
22 . A method of treating tumor cells wherein the Ras protein is activated as a result of oncogenic mutation in genes other than the Ras gene, comprising administering an effective amount of a compound of claim 1 .
23 . A method of inhibiting farnesyl protein transferase comprising the administration of an effective amount of the compound of claim 1 .
24 . A pharmaceutical composition for inhibiting farnesyl protein transferase comprising an effective amount of compound of claim 1 in combination with a pharmaceutically acceptable carrier.Cited by (0)
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