U.S. patent application number 10/348206 was filed with the patent office on 2004-01-01 for imidazolyl derivatives.
This patent application is currently assigned to Societe de Conseils de Recherches et D'Application Scientefiques, S.A.S., a France corporation. Invention is credited to Dong, Zheng Xin, Shen, Yeelana.
Application Number | 20040002531 10/348206 |
Document ID | / |
Family ID | 26780621 |
Filed Date | 2004-01-01 |
United States Patent
Application |
20040002531 |
Kind Code |
A1 |
Dong, Zheng Xin ; et
al. |
January 1, 2004 |
Imidazolyl derivatives
Abstract
The present invention is directed to imidazolyl derivatives of
formula (II), wherein the variables are defined in the
specification, which are useful as prenyl transeferase
inhibitors.
Inventors: |
Dong, Zheng Xin;
(Framingham, MA) ; Shen, Yeelana; (Franklin,
MA) |
Correspondence
Address: |
FISH & RICHARDSON PC
225 FRANKLIN ST
BOSTON
MA
02110
US
|
Assignee: |
Societe de Conseils de Recherches
et D'Application Scientefiques, S.A.S., a France
corporation
|
Family ID: |
26780621 |
Appl. No.: |
10/348206 |
Filed: |
January 21, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10348206 |
Jan 21, 2003 |
|
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10151265 |
May 20, 2002 |
|
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6509336 |
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Current U.S.
Class: |
514/397 ;
548/312.1 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 403/06 20130101; C07D 403/14 20130101 |
Class at
Publication: |
514/397 ;
548/312.1 |
International
Class: |
C07D 403/02; A61K
031/4178 |
Claims
What is claimed is:
1. A compound of formula (I), 80or a pharmaceutically acceptable
salt thereof, wherein ------- represents an optional bond; m, n, p,
and q are each independently 0 or 1; T for each occurrence is
independently selected from the group consisting of
CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and NR.sup.28; X is N--Y,
O or S where Y is selected from the group consisting of H,
CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17, S(O).sub.2R.sup.18,
C(O)R.sup.19, C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23,
C(O)OR.sup.24, C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32; Z is selected from the group
consisting of H, cyano, halo, CR.sup.14R.sup.15R.sup.16,
S(O)R.sup.17, S(O).sub.2R.sub.18 and C(O)R.sup.19; R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.26 and R.sup.27 are
each independently selected from the group consisting of H, halo,
hydroxy, thio and cyano, or an optionally substituted moiety
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy,
alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl
amino; or R.sup.1 and R.sup.2 when on adjacent positions, or
R.sup.4 and R.sup.5, or R.sup.11 and R.sup.12, are taken together
to form a bivalent radical selected from the group consisting of
--O--CH.sub.2--O--, --O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--, --O--CH.sub.2--CH.sub.2--CH.- sub.2--
and --CR.sup.33.dbd.CR.sup.34--CR.sup.35.dbd.CR.sup.36--; R.sup.7,
R.sup.8 and R.sup.9 are each independently selected from the group
consisting of H, halo, aryl, alkyl, substituted alkyl, alkyloxy,
alkylthio, aryloxy, arylthio amino, mono- or di-alkylamino,
hydroxycarbonyl, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl, arylalkyl and substituted
arylalkyl; R.sup.10 is selected from the group consisting of H,
amino, azido, hydroxy, halo, alkyl, substituted alkyl, cyano,
hydroxyalkyl, hydroxycarbonyl, aminoalkyl, mono- or
di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy,
alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl,
carboxyalkyl, cycloalkyl, cycloalkylamino, cycloalkylhydroxy,
imidazoyl, substituted imidazoyl, aminocarbonylalkyl, aryloxy,
thio, alkylthio, OS(O.sub.2)R.sup.18, OC(O)R.sup.19,
OC(O)NR.sup.20R.sup.21, OC(S)NR.sup.22R.sup.23,
OS(O)NR.sup.29R.sup.30, OS(O).sub.2NR.sup.31R.sup.32 and arylthio;
and R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21, R.sup.22,
R.sup.23, R.sup.24, R.sup.25, R.sup.28, R.sup.29, R.sup.30,
R.sup.31, R.sup.32 and R.sup.37 for each occurrence are each
independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl and arylalkyl; or
R.sup.20 and R.sup.21, or R.sup.22 and R.sup.23, or R.sup.29 and
R.sup.30, or R.sup.31 and R.sup.32 are taken together to form a
bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.- 37--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s-- and
--(CR.sup.38R.sup.39).sub.t--, where r and s are each independently
1 to 3 and t is 2 to 6; R.sup.33, R.sup.34, R.sup.35, R.sup.36,
R.sup.38 and R.sup.39 are each independently selected from the
group consisting of H, halo, cyano, alkyl, substituted alkyl, aryl,
substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio,
alkylamino, arylamino, hydroxy and thio.
2. A compound according to claim 1, wherein m, n, p and q are each
0.
3. A compound according to claim 2, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12 and R.sup.13
are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.
4. A compound according to claim 3, wherein R.sup.10 is OH, H,
halo, azido, amino, mono- or di-alkylamino, OS(O.sub.2)R.sup.18,
OC(O)NR.sup.20R.sup.21 or OS(O).sub.2NR.sup.31R.sup.32.
5. A compound according to claim 4, wherein R.sup.7, R.sup.8 and
R.sup.9 are each H, alkyl, substituted alkyl, amino or
cyanoarylalkyl.
6. A compound according to claim 5, wherein X is N--Y and Y is H,
CR.sup.14R.sup.15R.sup.16, S(O).sub.2R.sup.18,
C(O)NR.sup.20R.sup.21 or S(O).sub.2NR.sup.29R.sup.30.
7. A compound according to claim 6, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.11, R.sup.12 and R.sup.13 are each halo or
hydrogen.
8. A compound according to claim 7, wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.11, R.sup.12 and R.sup.13 are each chloro or
hydrogen.
9. A compound according to claim 8, wherein R.sup.7, R.sup.8, and
R.sup.9 are each (C.sub.1-C.sub.4)alkyl or hydrogen.
10. A compound according to claim 9 wherein, R.sup.7, R.sup.8, and
R.sup.9 are each methyl or hydrogen.
11. A compound according to claim 10, wherein R.sup.10 is OH,
amino, OS(O.sub.2)R.sup.18, or OC(O)NR.sup.20R.sup.21.
12. A compound according to claim 11, wherein R.sup.4, R.sup.5 and
R.sup.6 are each H.
13. A compound according to claim 12, wherein Z is hydrogen.
14. A compound according to claim 13, wherein Y is H, methyl,
S(O).sub.2R.sup.18, C(O)NR.sup.20R.sup.21 or
S(O).sub.2R.sup.29R.sup.30.
15. A compound according to claim 14, wherein said compound is of
the formula 81wherein R.sup.10 is OH and Y is H; R.sup.10 is
NH.sub.2 and Y is --S(O).sub.2--CH.sub.3; R.sup.10 is OH and Y is
--S(O).sub.2--CH.sub.3; R.sup.10 is OH and Y is
--C(O)--N(CH.sub.3).sub.2- ; R.sup.10 is NH.sub.2 and Y is
--C(O)--N(CH.sub.3).sub.2; R.sup.10 is NH.sub.2 and Y is H;
R.sup.10 is OH and Y is 82R.sup.10 is NH.sub.2 and Y is 83R.sup.10
is OH and Y is --S(O).sub.2-Phenyl; R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2-Phenyl; R.sup.10 is OH and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2; R.sup.10 is NH.sub.2 and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2; R.sup.10 is OH and Y is
--CH.sub.3; or R.sup.10 is NH.sub.2 and Y is --CH.sub.3.
16. A compound according to claim 15, wherein said compound is of
the formula 84wherein R.sup.10 is OH and Y is H; R.sup.10 is
NH.sub.2 and Y is --S(O).sub.2--CH.sub.3; R.sup.10 is OH and Y is
--S(O).sub.2--CH.sub.3; or R.sup.10 is OH and Y is
--C(O)--N(CH.sub.3).sub.2.
17. A compound according to claim 16, wherein said compound is of
the formula 85wherein R.sup.10 is OH and Y is H; or R.sup.10 is OH
and --S(O).sub.2--CH.sub.3.
18. A compound of formula (II), 86or a pharmaceutically acceptable
salt thereof, wherein ------- represents an optional bond, provided
that only one of the optional bonds is present in a compound of
formula (I); m, n, p, and q are each independently 0, 1 or 2;
T.sup.1, T.sup.2, T.sup.3 and T.sup.4 for each occurrence are each
independently selected from the group consisting of
CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and NR.sup.28; X is N--Y,
O or S where Y is selected from the group consisting of H,
CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17, S(O).sub.2R.sup.18,
C(O)R.sup.19, C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23,
C(O)OR.sup.24, C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32; Z is selected from the group
consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo,
CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17, S(O).sub.2R.sup.18,
C(O)R.sup.19, C(O)NR.sup.20R.sup.21, C(O)OR.sup.24,
C(S)NR.sup.22R.sup.23, C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32, provided that when the optional bond
connected to Z is present then Z is oxygen or sulfur; R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.26 and R.sup.27 for
each occurrence are each independently selected from the group
consisting of H, halo, hydroxy, thio and cyano, or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl,
alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and
alkyl carbonyl amino; or each pair of R.sup.1 and R.sup.2, R.sup.4
and R.sup.5, and R.sup.11 and R.sup.12 when on adjacent positions,
is independently taken together to form a bivalent radical selected
from the group consisting of --O--CH.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--- , --O--CH.sub.2--CH.sub.2--CH.sub.2--
and --CR.sup.33.dbd.CR.sup.34--CR.su- p.35.dbd.CR.sup.36--;
R.sup.7, R.sup.8 and R.sup.9 are each independently H, halo, amino,
cyano, hydroxycarbonyl, or an optionally substituted moiety
selected from the group consisting of aryl, alkyl, alkyloxy,
alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl, provided that
when R.sup.7, R.sup.8 or R.sup.9 is bound to one of the nitrogen
atoms of the imidazolyl ring, R.sup.7, R.sup.8 or R.sup.9 is H or
an optionally substituted moiety selected from the group consisting
of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl; R.sup.10 is
selected from the group consisting of H, amino, azido, hydroxy,
halo, alkyl, substituted alkyl, cyano, hydroxycarbonyl, mono- or
di-alkylamino, alkyloxy, cycloalkyl, cycloalkylamino,
cycloalkyloxy, imidazolyl, substituted imidazolyl, aryloxy, thio,
alkylthio, arylthio, OS(O).sub.2R.sup.18, OC(O)R.sup.19,
OC(O)NR.sup.20R.sup.21, OC(S)NR.sup.22R.sup.23,
OS(O)NR.sup.29R.sup.30 and OS(O).sub.2NR.sup.31R.sup.32; R.sup.17
and R.sup.18, for each occurrence are each independently H, OH or
an optionally substituted moiety selected from the group consisting
of alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.28, R.sup.29, R.sup.30, R.sup.31and R.sup.32 for
each occurrence are each independently H or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl; or each pair
of R.sup.20 and R.sup.21, R.sup.22 and R.sup.23, R.sup.29 and
R.sup.30, and R.sup.31 and R.sup.32 is independently taken together
to form a bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.40--(CH.- sub.2).sub.s--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CR.sup.38R.sup.39).sub.t-- and
--(CH.sub.2).sub.r--NR.sup.40--(C(O)).s- ub.u--, where r and s are
each independently 1 to 3, t is 2 to 6 and u is 1 or 2; R.sup.33,
R.sup.34, R.sup.35, R.sup.36, R.sup.38 and R.sup.39 for each
occurrence are each independently selected from the group
consisting of H, amino, halo, cyano, alkyl, substituted alkyl,
aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio,
mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
and R.sup.40 is H, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O).sub.2NR.sup.31R.sup.32 or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
19. A compound according to claim 18 wherein m, n, p and q are each
0.
20. A compound according to claim 19 wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12 and R.sup.13
are each H, halo, alkyl, substituted alkyl, cyano or alkyloxy.
21. A compound according to claim 20 wherein R.sup.10 is OH, H,
halo, azido, amino, mono- or di-alkylamino, OS(O).sub.2R.sup.18,
OC(O)NR.sup.20R.sup.21 or OS(O).sub.2NR.sup.31R.sup.32.
22. A compound according to claim 21 wherein R.sup.7, R.sup.8 and
R.sup.9 are each H, alkyl, substituted alkyl or cyanoarylalkyl.
23. A compound according to claim 22 wherein X is N--Y and Y is H,
CR.sup.14R.sup.15R.sup.16, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(O)OR.sup.24 or
S(O).sub.2NR.sup.31R.sup.32.
24. A compound according to claim 23 wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.11, R.sup.12 and R.sup.13 are each halo or H.
25. A compound according to claim 24 wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.11, R.sup.12 and R.sup.13 are each chloro or H.
26. A compound according to claim 25 wherein R.sup.7, R.sup.8, and
R.sup.9 are each (C.sub.1-C.sub.4)alkyl or H.
27. A compound according to claim 26 wherein R.sup.7, R.sup.8, and
R.sup.9 are each methyl or H.
28. A compound according to claim 27 wherein R.sup.10 is OH, amino,
OS(O).sub.2R.sup.18, OC(O)NR.sup.20R.sup.21 or
OS(O).sub.2NR.sup.31R.sup.- 32.
29. A compound according to claim 28 wherein R.sup.4, R.sup.5 and
R.sup.6 are each H.
30. A compound according to claim 29 wherein Z is hydrogen, halo or
C(O)NR.sup.20R.sup.21.
31. A compound according to claim 30 wherein Y is H, methyl,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(O)OR.sup.24 or S(O).sub.2NR.sup.31R.sup.32.
32. A compound according to claim 31 wherein said compound is of
the formula: 87wherein Z is H, R.sup.10 is OH and Y is H; Z is H,
R.sup.10 is NH.sub.2 and Y is --S(O).sub.2--CH.sub.3; Z is H,
R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3; Z is H, R.sup.10 is
OH and Y is --C(O)--N(CH.sub.3).sub.2; Z is H, R.sup.10 is NH.sub.2
and Y is --C(O)--N(CH.sub.3).sub.2; Z is H, R.sup.10 is NH.sub.2
and Y is H; Z is H, R.sup.10 is OH and Y is 88Z is H, R.sup.10 is
NH.sub.2 and Y is 89Z is H, R.sup.10 is OH and Y is
--S(O).sub.2-Phenyl; Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2-Phenyl; Z is H, R.sup.10 is OH and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2; Z is H, R.sup.10 is NH.sub.2 and
Y is --C(O)--N(CH.sub.2CH.sub.3).sub.2; Z is H, R.sup.10 is OH and
Y is --CH.sub.3; Z is H, R.sup.10 is NH.sub.2 and Y is --CH.sub.3;
Z is H, R.sup.10 is OH and Y is 90Z is H, R.sup.10 is NH.sub.2 and
Y is 91Z is H, R.sup.10 is OH and Y is 92Z is H, R.sup.10 is
NH.sub.2 and Y is 93Z is H, R.sup.10 is OH and Y is 94Z is H,
R.sup.10 is NH.sub.2 and Y is 95Z is H, R.sup.10 is OH and Y is
--C(O)--CH.sub.3; Z is H, R.sup.10 is NH.sub.2 and Y is
--C(O)--CH.sub.3; Z is H, R.sup.10 is OH and Y is
--S(O).sub.2--CF.sub.3; Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CF.sub.3; Z is H, R.sup.10 is OH and Y is
--S(O).sub.2--CH.sub.2--CF.sub.3; Z is H, R.sup.10 is NH.sub.2 and
Y is --S(O).sub.2--CH.sub.2--CF.sub.3; Z is H, R.sup.10 is OH and Y
is 96Z is H, R is NH.sub.2 and Y is 97Z is H, R.sup.10 is OH and Y
is 98Z is H, R.sup.10 is NH.sub.2 and Y is 99Z is H, R.sup.10 is OH
and Y is 100Z is H, R.sup.10 is NH.sub.2 and Y is 101Z is H,
R.sup.10 is OH and Y is 102Z is H, R.sup.10 is NH.sub.2 and Y is
103Z is H, R.sup.10 is OH and Y is --C(O)--NH.sub.2; Z is H,
R.sup.10 is NH.sub.2 and Y is --C(O)--NH.sub.2; Z is H, R.sup.10 is
OH and Y is 104Z is H, R.sup.10 is NH.sub.2 and Y is 105Z is Cl,
R.sup.10 is NH.sub.2 and Y is 106Z is Cl, R.sup.10 is NH.sub.2 and
Y is --S(O).sub.2--CH.sub.3; Z is H, R.sup.10 is OH and Y is 107Z
is H, R.sup.10 is NH.sub.2 and Y is 108Z is H, R.sup.10 is OH and Y
is 109Z is H, R.sup.10 is NH.sub.2 and Y is 110
33. A compound according to claim 32 wherein said compound is of
the formula: 111wherein Z is H, R.sup.10 is OH and Y is H; Z is H,
R.sup.10 is NH.sub.2 and Y is --S(O).sub.2--CH.sub.3; Z is H,
R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3; Z is H, R.sup.10 is
OH and Y is --C(O)--N(CH.sub.3).sub.2; Z is H, R.sup.10 is OH and Y
is --C(O)--CH.sub.3; or Z is H, R.sup.10 is NH.sub.2 and Y is
--C(O)--CH.sub.3.
34. A pharmaceutical composition comprising an effective amount of
a compound according to claim 1 or a pharmaceutically acceptable
salt thereof and a pharmaceutically acceptable carrier.
35. A method of treating a tumor, fibrosis, restenosis, neoplasm,
fungal infection, arteriosclerosis, carcinoma, benign tumor, retina
disease, hepatitis, renal disease, myeloid leukemia, viral
infection, nervous system tumor, viral infection, breast tumor,
pancreas tumor, or brain tumor in a subject in need thereof, which
comprises administering to said subject an effective amount of a
compound according to claim 1.
36. A method of inhibiting prenyl transferase in a subject in need
thereof, which comprises administering to said subject an effective
amount of a compound according to claim 1 or a pharmaceutically
acceptable salt thereof.
37. A pharmaceutical composition comprising an effective amount of
a compound according to claim 18 or a pharmaceutically acceptable
salt thereof and a pharmaceutically acceptable carrier.
38. A method of treating a tumor, fibrosis, restenosis, neoplasm,
fungal infection, arteriosclerosis, carcinoma, benign tumor, retina
disease, hepatitis, renal disease, myeloid leukemia, viral
infection, nervous system tumor, viral infection, breast tumor,
pancreas tumor, or brain tumor in a subject in need thereof, which
comprises administering to said subject an effective amount of a
compound according to claim 18.
39. A method of inhibiting prenyl transferase in a subject in need
thereof, which comprises administering to said subject an effective
amount of a compound according to claim 18 or a pharmaceutically
acceptable salt thereof.
40. A process for synthesizing a compound of formula 3, according
to the scheme below, which comprises reacting a compound of formula
1, according to the scheme below, with an arylalkylmagnesium
chloride of formula 2, according to the scheme below, in which case
X.sup.3 is Cl--Mg and p=1-2, or an aryllithium of formula 2, in
which case X.sup.3 is Li and p=0, in an inert organic solvent,
until the reaction is substantially complete, 112wherein P is a
protecting group; m, n, p, and q are each independently 0, 1 or 2;
T.sup.1, T.sup.2, T.sup.3 and T.sup.4 for each occurrence are each
independently selected from the group consisting of
CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and NR.sup.28; Y is
selected from the group consisting of H, CR.sup.14R.sup.15R.sup.16,
S(O)R.sup.17, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32; Z is selected from the group
consisting of H, hydroxy, alkoxy, aryloxy, cyano, halo,
CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17, S(O).sub.2R.sup.18,
C(O)R.sup.19, C(O)NR.sup.20R.sup.21, C(O)OR.sup.24,
C(S)NR.sup.22R.sup.23, C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32, provided that when the optional bond
connected to Z is present then Z is oxygen or sulfur; R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.11, R.sup.12,
R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.26 and R.sup.27 for
each occurence are each independently selected from the group
consisting of H, halo, hydroxy, thio and cyano, or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl,
alkyloxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino and
alkyl carbonyl amino; or each pair of R.sup.1 and R.sup.2, R.sup.4
and R.sup.5, and R.sup.11 and R.sup.12 when on adjacent positions,
is independently taken together to form a bivalent radical selected
from the group consisting of --O--CH.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--- , --O--CH.sub.2--CH.sub.2--CH.sub.2--
and --CR.sup.33.dbd.CR.sup.34--CR.su- p.35.dbd.CR.sup.36--;
R.sup.7, R.sup.8 and R.sup.9 are each independently H, halo, amino,
cyano, hydroxycarbonyl, or an optionally substituted moiety
selected from the group consisting of aryl, alkyl, alkyloxy,
alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl, provided that
when R.sup.7, R.sup.8 or R.sup.9 is bound to one of the nitrogen
atoms of the imidazolyl ring, R.sup.7, R.sup.8 or R.sup.9 is H or
an optionally substituted moiety selected from the group consisting
of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl; R.sup.17 and
R.sup.18, for each occurrence are each independently H, OH or an
optionally substituted moiety selected from the group consisting of
alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.28, R.sup.29, R.sup.30, R.sup.31and R.sup.32 for
each occurrence are each independently H or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl; or each pair
of R.sup.20 and R.sup.21, R.sup.22 and R.sup.23, R.sup.29 and
R.sup.30, and R.sup.31 and R.sup.32 is independently taken together
to form a bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.40--(CH.sub.2).sub.s--- ,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CR.sup.38R.sup.39).sub.t-- and
--(CH.sub.2).sub.r--NR.sup.40--(C(O)).sub.u--, where r and s are
each independently 1 to 3, t is 2 to 6 and u is 1 or 2; R.sup.33,
R.sup.34, R.sup.35, R.sup.36, R.sup.38 and R.sup.39 for each
occurrence are each independently selected from the group
consisting of H, amino, halo, cyano, alkyl, substituted alkyl,
aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio,
mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
and R.sup.40 is H, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O).sub.2NR.sup.31R.sup.32 or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
41. A process for synthesizing a compound of formula 2, according
to the scheme below, which comprises reacting a compound of formula
1, according to the scheme below, with a chlorinating reagent until
the reaction is substantially complete, 113wherein m, n, p, and q
are each independently 0, 1 or 2; T.sup.1, T.sup.2, T.sup.3 and
T.sup.4 for each occurrence are each independently selected from
the group consisting of CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2
and NR.sup.28; X is N--Y, O or S where Y is selected from the group
consisting of H, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(S)NR.sup.22R.sup.23, C(O)OR.sup.24, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32; Z is
selected from the group consisting of H, hydroxy, alkoxy, aryloxy,
cyano, halo, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(O)OR.sup.24, C(S)NR.sup.22R.sup.23, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32, provided
that when the optional bond connected to Z is present then Z is
oxygen or sulfur; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.26 and R.sup.27 for each occurrence are each
independently selected from the group consisting of H, halo,
hydroxy, thio and cyano, or an optionally substituted moiety
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy,
alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl
amino; or each pair of R.sup.1 and R.sup.2, R.sup.4 and R.sup.5,
and R.sup.11 and R.sup.12 when on adjacent positions, is
independently taken together to form a bivalent radical selected
from the group consisting of --O--CH.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--O--CH.sub.2--, --CH.sub.2--CH.sub.2--CH.sub.2-- and
--CR.sup.33.dbd.CR.sup.34--CR.sup.35.dbd.CR.sup.36--; R.sup.7,
R.sup.8 and R.sup.9 are each independently H, halo, amino, cyano,
hydroxycarbonyl, or an optionally substituted moiety selected from
the group consisting of aryl, alkyl, alkyloxy, alkylthio, aryloxy,
arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O).sub.2-alkyl,
cyanoarylalkyl and arylalkyl, provided that when R.sup.7, R.sup.8
or R.sup.9 is bound to one of the nitrogen atoms of the imidazolyl
ring, R.sup.7, R.sup.8 or R.sup.9 is H or an optionally substituted
moiety selected from the group consisting of aryl, alkyl,
alkoxycarbonyl, alkyl-S(O)-alkyl, alkyl-S(O).sub.2-alkyl,
cyanoarylalkyl and arylalkyl; R.sup.17 and R.sup.18, for each
occurrence are each independently H, OH or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl; R.sup.19,
R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24, R.sup.25,
R.sup.28, R.sup.29, R.sup.30, R.sup.31and R.sup.32 for each
occurrence are each independently H or an optionally substituted
moiety selected from the group consisting of alkyl, alkenyl,
cycloalkyl, aryl, arylalkyl and heterocyclyl; or each pair of
R.sup.20 and R.sup.21, R.sup.22 and R.sup.23, R.sup.29 and
R.sup.30, and R.sup.31 and R.sup.32 is independently taken together
to form a bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.40--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CR.sup.38R.sup.39).sub.t-- and
--(CH.sub.2).sub.r--NR.sup.40--(C(O)).sub.u--, where r and s are
each independently 1 to 3, t is 2 to 6 and u is 1 or 2; R.sup.33,
R.sup.34, R.sup.35, R.sup.36, R.sup.38 and R.sup.39 for each
occurrence are each independently selected from the group
consisting of H, amino, halo, cyano, alkyl, substituted alkyl,
aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio,
mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
and R.sup.40 is H, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O).sub.2NR.sup.31R.sup.32 or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
42. A process for synthesizing a compound of formula 3, according
to the scheme below which comprises reacting a compound of formula
2 with anhydrous liquid ammonia or an inert organic solvent
saturated with anhydrous ammonia when n, p and q are each 0, or
ammonium hydroxide when n, p and q are each not 0, until the
reaction is substantially complete 114wherein m, n, p, and q are
each independently 0, 1 or 2; T.sup.1, T.sup.2, T.sup.3 and T.sup.4
for each occurrence are each independently selected from the group
consisting of CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and
NR.sup.28; X is N--Y, O or S where Y is selected from the group
consisting of H, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(S)NR.sup.22R.sup.23, C(O)OR.sup.24, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32; Z is
selected from the group consisting of H, hydroxy, alkoxy, aryloxy,
cyano, halo, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(O)OR.sup.24, C(S)NR.sup.22R.sup.23, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32, provided
that when the optional bond connected to Z is present then Z is
oxygen or sulfur; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15,
R.sup.16, R.sup.26 and R.sup.27 for each occurrence are each
independently selected from the group consisting of H, halo,
hydroxy, thio and cyano, or an optionally substituted moiety
selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy,
alkylthio, arylthio, alkylamino, arylamino and alkyl carbonyl
amino; or each pair of R.sup.1 and R.sup.2, R.sup.4 and R.sup.5,
and R.sup.11 and R.sup.12 when on adjacent positions, is
independently taken together to form a bivalent radical selected
from the group consisting of --O--CH.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--- , --O--CH.sub.2--CH.sub.2--CH.sub.2--
and --CR.sup.33.dbd.CR.sup.34--CR.su- p.35.dbd.CR.sup.36--;
R.sup.7, R.sup.8 and R.sup.9 are each independently H, halo, amino,
cyano, hydroxycarbonyl, or an optionally substituted moiety
selected from the group consisting of aryl, alkyl, alkyloxy,
alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl, provided that
when R.sup.7, R.sup.8 or R.sup.9 is bound to one of the nitrogen
atoms of the imidazolyl ring, R.sup.7, R.sup.8 or R.sup.9 is H or
an optionally substituted moiety selected from the group consisting
of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl; R.sup.17 and
R.sup.18, for each occurrence are each independently H, OH or an
optionally substituted moiety selected from the group consisting of
alkyl, alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.28, R.sup.29, R.sup.30, R.sup.31and R.sup.32 for
each occurrence are each independently H or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl; or each pair
of R.sup.20 and R.sup.21, R.sup.22 and R.sup.23, R.sup.29 and
R.sup.30, and R.sup.31 and R.sup.32 is independently taken together
to form a bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.40--(CH.sub.2).sub.s--- ,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CR.sup.38R.sup.39).sub.t-- and
--(CH.sub.2).sub.r--NR.sup.40--(C(O)).sub.u--, where r and s are
each independently 1 to 3, t is 2 to 6 and u is 1 or 2; R.sup.33,
R.sup.34, R.sup.35, R.sup.36, R.sup.38 and R.sup.39 for each
occurrence are each independently selected from the group
consisting of H, amino, halo, cyano, alkyl, substituted alkyl,
aryl, substituted aryl, alkyloxy, aryloxy, alkylthio, arylthio,
mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl and thio;
and R.sup.40 is H, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O).sub.2NR.sup.31R.sup.32 or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority benefit of and is a
continuation of U.S. application Ser. No. 10/151,265, filed May 20,
2002, now U.S. Pat. No. 6,509,336, which is a divisional of U.S.
application Ser. No. 09/719,720, filed May 22, 2001, now U.S. Pat.
No. 6,420,555, which is an application under 35 U.S.C. .sctn.371 of
PCT International Application No. PCT/US99/13303, filed Jun. 11,
1999, which claims benefit as a continuation of U.S. application
Ser. No. 09/098,141 and U.S. application Serial No. 60/089,483,
both filed Jun. 16, 1998, all of which are incorporated by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] The present invention is directed to imidazolyl derivatives
which are useful as prenyl transferase inhibitors.
[0003] The Ras family of proteins are important in the signal
transduction pathway modulating cell growth. The protein is
produced in the ribosome, released into the cytosol, and
post-translationally modified. The first step in the series of
post-translational modifications is the alkylation of Cys.sup.168
with farnesyl or geranylgeranyl pyrophosphate in a reaction
catalyzed by prenyl transferase enzymes such as farnesyl
transferase and geranylgeranyl transferase (Hancock, J F, et al.,
Cell 57:1167-1177 (1989)). Subsequently, the three C-terminal amino
acids are cleaved (Gutierrez, L., et al., EMBO J. 8:1093-1098
(1989)), and the terminal Cys is converted to a methyl ester
(Clark, S., et al., Proc. Nat'l Acad. Sci. (USA) 85:4643-4647
(1988)). Some forms of Ras are also reversibly palmitoylated on
cysteine residues immediately N-terminal to Cys.sup.168 (Buss, J E
et al., Mol. Cell. Biol. 6:116-122 (1986)). It is believed that
these modifications increase the hydrophobicity of the C-terminal
region of Ras, causing it to localize at the surface of the cell
membrane. Localization of Ras to the cell membrane is necessary for
signal transduction (Willumsen, B M, et al., Science 310:583-586
(1984)).
[0004] Oncogenic forms of Ras are observed in a relatively large
number of cancers including over 50 percent of colon cancers and
over 90 percent of pancreatic cancers (Bos, J L, Cancer Research
49:4682-4689 (1989)). These observations suggest that intervention
in the function of Ras mediated signal transduction may be useful
in the treatment of cancer.
[0005] Previously, it has been shown that the C-terminal
tetrapeptide of Ras is a "CAAX" motif (wherein C is cysteine, A is
an aliphatic amino acid, and X is any amino acid). Tetrapeptides
having this structure have been shown to be inhibitors of prenyl
transferases (Reiss, et al., Cell 62:81-88 (1990)). Poor potency of
these early farnesyl transferase inhibitors has prompted the search
for new inhibitors with more favorable pharmacokinetic behavior
(James, G L, et al., Science 260:1937-1942 (1993); Kohl, N E, et
al., Proc. Nat'l Acad. Sci. USA 91:9141-9145 (1994); deSolms, S J,
et al., J. Med. Chem. 38:3967-3971 (1995); Nagasu, T, et al.,
Cancer Research 55:5310-5314 (1995); Lerner, E C, et al., J. Biol.
Chem. 270:26802-26806 (1995); Lerner, E C, et al., J. Biol. Chem.
270:26770 (1995); and James, et al., Proc. Natl. Acad. Sci. USA
93:4454 (1996)).
[0006] Recently, it has been shown that a prenyl transferase
inhibitor can block growth of Ras-dependent tumors in nude mice
(Kohl, N. E., et al., Proc. Nat'l Acad. Sci. USA 91:9141-9145
(1994)). In addition, it has been shown that over 70 percent of a
large sampling of tumor cell lines are inhibited by prenyl
transferase inhibitors with selectivity over non-transformed
epithelial cells (Sepp-Lorenzino, I., et al., Cancer Research,
55:5302-5309 (1995)).
SUMMARY OF THE INVENTION
[0007] In one aspect, this invention provides a compound of formula
(I), 1
[0008] or a pharmaceutically acceptable salt thereof,
[0009] wherein
[0010] ------- represents an optional bond;
[0011] m, n, p, and q are each independently 0 or 1;
[0012] T for each occurrence is independently selected from the
group consisting of CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and
NR.sup.28;
[0013] X is N--Y, O or S where Y is selected from the group
consisting of H, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(S)NR.sup.22R.sup.23, C(O)OR.sup.24, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32;
[0014] Z is selected from the group consisting of H, cyano, halo,
CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17, S(O).sub.2R.sup.18 and
C(O)R.sup.19;
[0015] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.26 and R.sup.27 are each independently selected from the
group consisting of H, halo, hydroxy, thio and cyano, or an
optionally substituted moiety selected from the group consisting of
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, aryl,
arylalkyl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino,
arylamino and alkyl carbonyl amino;
[0016] or R.sup.1 and R.sup.2 when on adjacent positions, or
R.sup.4 and R.sup.5, or R.sup.11 and R.sup.12, are taken together
to form a bivalent radical selected from the group consisting of
--O--CH.sub.2--O--, --O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--- , --O--CH.sub.2--CH.sub.2--CH.sub.2--
and --CR.sup.33.dbd.CR.sup.34--CR.su- p.35.dbd.CR.sup.36--;
[0017] --R.sup.7, R.sup.8 and R.sup.9 are each independently
selected from the group consisting of H, halo, aryl, alkyl,
substituted alkyl, alkyloxy, alkylthio, aryloxy, arylthio amino,
mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl,
alkyl-S(O)-alkyl, alkyl-S(O).sub.2-alkyl, cyanoarylalkyl, arylalkyl
and substituted arylakyl;
[0018] R.sup.10 is selected from the group consisting of H, amino,
azido, hydroxy, halo, alkyl, substituted alkyl, cyano,
hydroxyalkyl, hydroxycarbonyl, aminoalkyl, mono- or
di-alkylaminoalkyl, mono- or di-alkylamino, alkoxy,
alkylcarbonylalkyl, cyanoalkyl, alkyloxycarbonylalkyl,
carboxyalkyl, cycloalkyl, cycloalkylamino, cycloalkylhydroxy,
imidazoyl, substituted imidazoyl, aminocarbonylalkyl, aryloxy,
thio, alkylthio, OS(O.sub.2)R.sup.18, OC(O)R.sup.19,
OC(O)NR.sup.20R.sup.21, OC(S)NR.sup.22R.sup.23,
OS(O)NR.sup.29R.sup.30, OS(O).sub.2NR.sup.31R.sup.32 and
arylthio;
[0019] 13 and R.sup.17, R.sup.18, R.sup.19, R.sup.20, R.sup.21,
R.sup.22, R.sup.23, R.sup.24, R.sup.25, R.sup.28, R.sup.29,
R.sup.30, R.sup.31, R.sup.32 and R.sup.37 for each occurrence are
each independently selected from the group consisting of H, alkyl,
substituted alkyl, alkenyl, cycloalkyl, aryl and arylalkyl;
[0020] or R.sup.20 and R.sup.21, or R.sup.22 and R.sup.23, or
R.sup.29 and R.sup.30, or R.sup.31 and R.sup.32 are taken together
to form a bivalent radical selected from the group consisting of
--(CH.sub.2).sub.r--NR.sup.- 37--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s-- and
--(CR.sub.38R.sup.39).sub.t--, where r and s are each independently
1 to 3 and t is 2 to 6;
[0021] R.sup.33, R.sup.34, R.sup.35, R.sup.36, R.sup.38 and
R.sup.39 are each independently selected from the group consisting
of H, halo, cyano, alkyl, substituted alkyl, aryl, substituted
aryl, alkyloxy, aryloxy, alkylthio, arylthio, alkylamino,
arylamino, hydroxy and thio.
[0022] A preferred group of compounds of the immediately foregoing
compounds is where m, n, p and q are each 0.
[0023] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.11, R.sup.12 and R.sup.13 are each H, halo, alkyl,
substituted alkyl, cyano or alkyloxy.
[0024] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.10 is OH, H, halo, azido, amino, mono- or
di-alkylamino, OS(O.sub.2)R.sup.18, OC(O)NR.sup.20R.sup.21 or
OS(O).sub.2NR.sup.31R.sup.32.
[0025] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8 and R.sup.9 are each H, alkyl,
substituted alkyl, amino or cyanoarylalkyl.
[0026] A preferred group of compounds of the immediately foregoing
compounds is where X is N--Y and Y is H, CR.sup.14R.sup.15R.sup.16,
S(O).sub.2R.sup.18, C(O)NR.sup.20R.sup.21 or
S(O).sub.2NR.sup.29R.sup.30.
[0027] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12
and R.sup.13 are each halo or hydrogen.
[0028] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12
and R.sup.13 are each chloro or hydrogen.
[0029] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8, and R.sup.9 are each
(C.sub.1-C.sub.4)alkyl or hydrogen.
[0030] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8, and R.sup.9 are each methyl or
hydrogen.
[0031] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.10 is OH, amino, OS(O.sub.2)R.sup.18, or
OC(O)NR.sup.20R.sup.21.
[0032] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.4, R.sup.5 and R.sup.6 are each H.
[0033] A preferred group of compounds of the immediately foregoing
compounds is where Z is hydrogen.
[0034] A preferred group of compounds of the immediately foregoing
compounds is where Y is H, methyl, S(O).sub.2R.sup.18,
C(O)NR.sup.20R.sup.21 or S(O).sub.2R.sup.29R.sup.30.
[0035] A preferred group of compounds of the immediately foregoing
compounds is where said compounds are of the formula: 2
[0036] wherein R.sup.10 is OH and Y is H;
[0037] R.sup.10 is NH.sub.2 and Y is --S(O).sub.2--CH.sub.3;
[0038] R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3;
[0039] R.sup.10 is OH and Y is --C(O)--N(CH.sub.3).sub.2;
[0040] R.sup.10 is NH.sub.2 and Y is --C(O)--N(CH.sub.3).sub.2;
[0041] R.sup.10 is NH.sub.2 and Y is H;
[0042] R.sup.10 is OH and Y is 3
[0043] R.sup.10 is NH.sub.2 and Y is 4
[0044] R.sup.10 is OH and Y is --S(O).sub.2-Phenyl;
[0045] R.sup.10 is NH.sub.2 and Y is --S(O).sub.2-Phenyl;
[0046] R.sup.10 is OH and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2;
[0047] R.sup.10 is NH.sub.2 and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2;
[0048] R.sup.10 is OH and Y is --CH.sub.3; and
[0049] R.sup.10 is NH.sub.2 and Y is --CH.sub.3.
[0050] A preferred group of compounds of the immediately foregoing
compounds is where said compounds are of the formula 5
[0051] wherein R.sup.10 is OH and Y is H;
[0052] R.sup.10 is NH.sub.2 and Y is --S(O).sub.2--CH.sub.3;
[0053] R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3;
[0054] R.sup.10 is NH.sub.2 and Y is --S(O).sub.2--CH.sub.3;
and
[0055] R.sup.10 is OH and Y is --C(O)--N(CH.sub.3).sub.2.
[0056] A preferred group of compounds of the immediately foregoing
compounds is where said compounds are of the formula 6
[0057] wherein R.sup.10 is OH and Y is H; and
[0058] R.sup.10 is OH and --S(O).sub.2--CH.sub.3.
[0059] In another aspect, this invention provides a compound of
formula (II), 7
[0060] or a pharmaceutically acceptable salt thereof,
[0061] wherein
[0062] ------- represents an optional bond, provided that only one
of the optional bonds is present in a compound of formula (I);
[0063] m, n, p, and q are each independently 0, 1 or 2;
[0064] T.sup.1, T.sup.2, T.sup.3 and T.sup.4 for each occurrence
are each independently selected from the group consisting of
CR.sup.26R.sup.27, S, O, C(O), S(O).sub.2 and NR.sup.28;
[0065] X is N--Y, O or S where Y is selected from the group
consisting of H, CR.sup.14R.sup.15R.sup.16, S(O)R.sup.17,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(S)NR.sup.22R.sup.23, C(O)OR.sup.24, C(S)OR.sup.25,
S(O)NR.sup.29R.sup.30 and S(O).sub.2NR.sup.31R.sup.32;
[0066] Z is selected from the group consisting of H, hydroxy,
alkoxy, aryloxy, cyano, halo, CR.sup.14R.sup.15R.sup.16,
S(O)R.sup.17, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(O)OR.sup.24, C(S)NR.sup.22R.sup.23,
C(S)OR.sup.25, S(O)NR.sup.29R.sup.30 and
S(O).sub.2NR.sup.31R.sup.32, provided that when the optional bond
connected to Z is present then Z is oxygen or sulfur;
[0067] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6,
R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16,
R.sup.26 and R.sup.27 for each occurrence are each independently
selected from the group consisting of H, halo, hydroxy, thio and
cyano, or an optionally substituted moiety selected from the group
consisting of alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkyl-alkyl, aryl, arylalkyl, alkyloxy, aryloxy, alkylthio,
arylthio, alkylamino, arylamino and alkyl carbonyl amino;
[0068] or each pair of R.sup.1 and R.sup.2, R.sup.4 and R.sup.5,
and R.sup.11 and R.sup.12 when on adjacent positions, is
independently taken together to form a bivalent radical selected
from the group consisting of --O--CH.sub.2--O--,
--O--CH.sub.2--CH.sub.2--O--, --O--CH.dbd.CH--,
--O--CH.sub.2--CH.sub.2--, --O--CH.sub.2--CH.sub.2--CH.sub.2-- and
--CR.sup.33.dbd.CR.sup.34--CR.sup.35.dbd.CR.sup.36--;
[0069] R.sup.7, R.sup.8 and R.sup.9 are each independently H, halo,
amino, cyano, hydroxycarbonyl, or an optionally substituted moiety
selected from the group consisting of aryl, alkyl, alkyloxy,
alkylthio, aryloxy, arylthio, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl, provided that
when R.sup.7, R.sup.8 or R.sup.9 is bound to one of the nitrogen
atoms of the imidazolyl ring, R.sup.7, R.sup.8 or R.sup.9 is H or
an optionally substituted moiety selected from the group consisting
of aryl, alkyl, alkoxycarbonyl, alkyl-S(O)-alkyl,
alkyl-S(O).sub.2-alkyl, cyanoarylalkyl and arylalkyl;
[0070] R.sup.10 is selected from the group consisting of H, amino,
azido, hydroxy, halo, alkyl, substituted alkyl, cyano,
hydroxycarbonyl, mono- or di-alkylamino, alkyloxy, cycloalkyl,
cycloalkylamino, cycloalkyloxy, imidazolyl, substituted imidazolyl,
aryloxy, thio, alkylthio, arylthio, OS(O).sub.2R.sup.8,
OC(O)R.sup.19, OC(O)NR.sup.20R.sup.21, OC(S)NR.sup.22R.sup.23,
OS(O)NR.sup.29R.sup.30 and OS(O).sub.2NR.sup.31R.sup.32;
[0071] R.sup.17 and R.sup.18, for each occurrence are each
independently H, OH or an optionally substituted moiety selected
from the group consisting of alkyl, alkenyl, cycloalkyl, aryl,
arylalkyl and heterocyclyl;
[0072] R.sup.19, R.sup.20, R.sup.21, R.sup.22, R.sup.23, R.sup.24,
R.sup.25, R.sup.28, R.sup.29, R.sup.30, R.sup.31 and R.sup.32 for
each occurrence are each independently H or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl;
[0073] or each pair of R.sup.20 and R.sup.21, R.sup.22 and
R.sup.23, R.sup.29 and R.sup.30, and R.sup.31 and R.sup.32 is
independently taken together to form a bivalent radical selected
from the group consisting of
--(CH.sub.2).sub.r--NR.sup.40--(CH.sub.2).sub.s--,
--(CH.sub.2).sub.r--O--(CH.sub.2).sub.s--,
--(CR.sup.38R.sup.39).sub.t-- and
--(CH.sub.2).sub.u--NR.sup.40--(C(O)).sub.u--, where r and s are
each independently 1 to 3, t is 2 to 6 and u is 1 or 2;
[0074] R.sup.33, R.sup.34, R.sup.35, R.sup.36, R.sup.38 and
R.sup.39 for each occurrence are each independently selected from
the group consisting of H, amino, halo, cyano, alkyl, substituted
alkyl, aryl, substituted aryl, alkyloxy, aryloxy, alkylthio,
arylthio, mono- or di-alkylamino, arylamino, hydroxy, heterocyclyl
and thio;
[0075] and R.sup.40 is H, S(O).sub.2R.sup.18, C(O)R.sup.19,
C(O)NR.sup.20R.sup.21, C(S)NR.sup.22R.sup.23, C(O)OR.sup.24,
C(S)OR.sup.25, S(O).sub.2NR.sup.31R.sup.32 or an optionally
substituted moiety selected from the group consisting of alkyl,
alkenyl, cycloalkyl, aryl, arylalkyl and heterocyclyl.
[0076] A preferred group of compounds of the immediately foregoing
compounds is where m, n, p and q are each 0.
[0077] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.11, R.sup.12 and R.sup.13 are each H, halo, alkyl,
substituted alkyl, cyano or alkyloxy.
[0078] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.10 is OH, H, halo, azido, amino, mono- or
di-alkylamino, OS(O).sub.2R.sup.18, OC(O)NR.sup.20R.sup.21 or
OS(O).sub.2NR.sup.31R.sup.32.
[0079] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8 and R.sup.9 are each H, alkyl,
substituted alkyl or cyanoarylalkyl.
[0080] A preferred group of compounds of the immediately foregoing
compounds is where X is N--Y and Y is H, CR.sup.14R.sup.15R.sup.16,
S(O).sub.2R.sup.18, C(O)R.sup.19, C(O)NR.sup.20R.sup.21,
C(O)OR.sup.24 or S(O).sub.2NR.sup.31R.sup.32.
[0081] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12
and R.sup.13 are each halo or H.
[0082] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.1, R.sup.2, R.sup.3, R.sup.11, R.sup.12
and R.sup.13 are each chloro or H.
[0083] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8, and R.sup.9 are each
(C.sub.1-C.sub.4)alkyl or H.
[0084] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.7, R.sup.8, and R.sup.9 are each methyl or
H.
[0085] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.10 is OH, amino, OS(O).sub.2R.sup.18,
OC(O)NR.sup.20R.sup.21 or OS(O).sub.2NR.sup.31R.sup.32.
[0086] A preferred group of compounds of the immediately foregoing
compounds is where R.sup.4, R.sup.5 and R.sup.6 are each H.
[0087] A preferred group of compounds of the immediately foregoing
compounds is where Z is hydrogen, halo or
C(O)NR.sup.20R.sup.21.
[0088] A preferred group of compounds of the immediately foregoing
compounds is where Y is H, methyl, S(O).sub.2R.sup.18,
C(O)R.sup.19, C(O)NR.sup.20R.sup.21, C(O)OR.sup.24 or
S(O).sub.2NR.sup.31R.sup.32.
[0089] A preferred group of compounds of the immediately foregoing
compounds is where said compounds are of the formula: 8
[0090] wherein Z is H, R.sup.10 is OH and Y is H;
[0091] Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CH.sub.3;
[0092] Z is H, R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3;
[0093] Z is H, R.sup.10 is OH and Y is
--C(O)--N(CH.sub.3).sub.2;
[0094] Z is H, R.sup.10 is NH.sub.2 and Y is
--C(O)--N(CH.sub.3).sub.2;
[0095] Z is H, R.sup.10 is NH.sub.2 and Y is H;
[0096] Z is H, R.sup.10 is OH and Y is 9
[0097] Z is H, R.sup.10 is NH.sub.2 and Y is 10
[0098] Z is H, R.sup.10 is OH and Y is --S(O).sub.2-Phenyl;
[0099] Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2-Phenyl;
[0100] Z is H, R.sup.10 is OH and Y is
--C(O)--N(CH.sub.2CH.sub.3).sub.2;
[0101] Z is H, R.sup.10 is NH.sub.2 and Y is
--C(O)--N(CH.sub.2CH.sub.3).s- ub.2;
[0102] Z is H, R.sup.10 is OH and Y is --CH.sub.3;
[0103] Z is H, R.sup.10 is NH.sub.2 and Y is --CH.sub.3;
[0104] Z is H, R.sup.10 is OH and Y is 11
[0105] Z is H, R.sup.10 is NH.sub.2 and Y is 12
[0106] Z is H, R.sup.10 is OH and Y is 13
[0107] Z is H, R.sup.10 is NH.sub.2 and Y is 14
[0108] Z is H, R.sup.10 is OH and Y is 15
[0109] Z is H, R.sup.10 is NH.sub.2 and Y is 16
[0110] Z is H, R.sup.10 is OH and Y is --C(O)--CH.sub.3;
[0111] Z is H, R.sup.10 is NH.sub.2 and Y is --C(O)--CH.sub.3;
[0112] Z is H, R.sup.10 is OH and Y is --S(O).sub.2--CF.sub.3;
[0113] Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CF.sub.3;
[0114] Z is H, R.sup.10 is OH and Y is
--S(O).sub.2--CH.sub.2--CF.sub.3;
[0115] Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CH.sub.2--CF.su- b.3;
[0116] Z is H, R.sup.10 is OH and Y is 17
[0117] Z is H, R.sup.10 is NH.sub.2 and Y is 18
[0118] Z is H, R.sup.10 is OH and Y is 19
[0119] Z is H, R.sup.10 is NH.sub.2 and Y is 20
[0120] Z is H, R.sup.10 is OH and Y is 21
[0121] Z is H, R.sup.10 is NH.sub.2 and Y is 22
[0122] Z is H, R.sup.10 is OH and Y is 23
[0123] Z is H, R.sup.10 is NH.sub.2 and Y is 24
[0124] Z is H, R.sup.10 is OH and Y is --C(O)--NH.sub.2;
[0125] Z is H, R.sup.10 is NH.sub.2 and Y is --C(O)--NH.sub.2;
[0126] Z is H, R.sup.10 is OH and Y is 25
[0127] Z is H, R.sup.10 is NH.sub.2 and Y is 26
[0128] Z is Cl, R.sup.10 is NH.sub.2and Y is 27
[0129] Z is Cl, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CH.sub.3;
[0130] Z is H, R.sup.10 is OH and Y is 28
[0131] Z is H, R.sup.10 is NH.sub.2 and Y is 29
[0132] Z is H, R.sup.10 is OH and Y is 30
[0133] Z is H, R.sup.10 is NH.sub.2 and Y is 31
[0134] A preferred group of compounds of the immediately foregoing
compounds is where said compounds are of the formula: 32
[0135] wherein Z is H, R.sup.10 is OH and Y is H;
[0136] Z is H, R.sup.10 is NH.sub.2 and Y is
--S(O).sub.2--CH.sub.3;
[0137] Z is H, R.sup.10 is OH and Y is --S(O).sub.2--CH.sub.3;
[0138] Z is H, R.sup.10 is OH and Y is
--C(O)--N(CH.sub.3).sub.2;
[0139] Z is H, R.sup.10 is OH and Y is --C(O)--CH.sub.3; and
[0140] Z is H, R.sup.10 is NH.sub.2 and Y is --C(O)--CH.sub.3.
[0141] In another aspect, this invention provides a pharmaceutical
composition comprising an effective amount of a compound of formula
(I) or (II), as defined hereinabove, or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable
carrier.
[0142] In yet another aspect, this invention provides a method of
treating a tumor, fibrosis or restenosis in a subject in need
thereof, which comprises administering to said subject an effective
amount of a compound of formula (I) or (II), as defined
hereinabove, or a pharmaceutically acceptable salt thereof.
[0143] In still another aspect, this invention provides a method of
inhibiting prenyl transferase in a subject in need thereof, which
comprises administering to said subject an effective amount of a
compound of formula (I) or (II), as defined hereinabove, or a
pharmaceutically acceptable salt thereof.
[0144] In yet another aspect, the present invention is directed to
a process for synthesizing a compound of formula 3, according to
the scheme below, which comprises reacting a compound of formula 1,
according to the scheme below, with an arylalkylmagnesium chloride
of formula 2, according to the scheme below, in which case X.sup.3
is Cl--Mg and p=1-2, or an aryllithium of formula 2, in which case
X.sup.3 is Li and p=0, in an inert organic solvent, until the
reaction is substantially complete, 33
[0145] wherein P is a protecting group and the other substituents
are as defined for the compound of formula (II) hereinabove.
[0146] In still another aspect, the present invention is directed
to a process for synthesizing a compound of formula 2, according to
the scheme below, which comprises reacting a compound of formula 1,
according to the scheme below, with a chlorinating reagent until
the reaction is substantially complete, 34
[0147] wherein the substituents are as defined for the compound of
formula II hereinabove.
[0148] In an even further aspect, the present invention is directed
to a process for synthesizing a compound of formula 3, according to
the scheme below, which comprises reacting a compound of formula 2
with anhydrous liquid ammonia or an inert organic solvent saturated
with anhydrous ammonia when n, p and q are each 0, or ammonium
hydroxide when n, p and q are each not 0, until the reaction is
substantially complete 35
[0149] wherein the substituents are as defined for the compound of
formula (II) hereinabove.
DETAILED DESCRIPTION
[0150] Listed below are definitions of various terms used to
describe this invention. These definitions apply to the terms as
they are used throughout this specification and claims, unless
otherwise limited in specific instances, either individually or as
part of a larger group.
[0151] In the portion of the compound of formula (I) or (II), where
the two optional bonds are shown, only one of the optional bonds
may be present in a compound. When the optional bond directly
attached to the variable Z is present then Z is an oxygen or
sulfur.
[0152] The term "alkyl" refers to straight or branched chain
unsubstituted hydrocarbon groups of 1 to 20 carbon atoms,
preferably 1 to 7 carbon atoms.
[0153] The term "substituted alkyl" refers to an alkyl group
substituted by, for example, one to four substituents, such as,
halo, hydroxy, alkoxy, oxo, alkanoyl, aryloxy, alkanoyloxy, amino,
alkylamino, arylamino, aralkylamino, disubstituted amines in which
the 2 amino substituents are selected from alkyl, aryl or aralkyl;
alkanoylamino, aroylamino, aralkanoylamino, substituted
alkanoylamino, substituted arylamino, substitituted
aralkanoylamino, thiol, alkylthio, arylthio, aralkylthio,
alkylthiono, arylthiono, aralkylthiono, alkylsulfonyl,
arylsulfonyl, aralkylsulfonyl, sulfonamido, e.g. SO.sub.2NH.sub.2,
substituted sulfonamido, nitro, cyano, carboxy, carbamyl, e.g.
CONH.sub.2, substituted carbamyl e.g. CONH alkyl, CONH aryl, CONH
aralkyl or cases where there are two substituents on the nitrogen
selected form alkyl, aryl or aralkyl; alkoxycarbonyl, aryl,
substituted aryl, guanidino and heterocycles, such as indolyl,
imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,
pyrimidyl and the like. Where noted above where the substituent is
further substituted it will be with alkyl, alkoxy, aryl or
aralkyl.
[0154] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine.
[0155] The term "aryl" refers to monocyclic or bicyclic aromatic
group having 6 to 12 carbon atoms in the ring portion such as
phenyl, naphthyl, biphenyl and diphenyl, each of which may be
substituted.
[0156] The term "arylalkyl" refers to an aryl group bonded directly
through an alkyl group, such as benzyl.
[0157] The term "substituted aryl" refers to an aryl group
substituted by, for example, one to five substituents such as
alkyl; substituted alkyl, halo, trifluoromethoxy, trifluoromethyl,
hydroxy, alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino,
arylalkylamino, arylalkylamino, dialkylamino, alkanoylamino, thiol,
alkylthio, ureido, nitro, cyano, carboxy, carboxyalkyl, carbamyl,
alkoxycarbonyl, alkylthiono, arylthiono, alkylsulfonyl,
sulfonamido, aryloxy and the like. The substituent may be further
substituted by hydroxy, alkyl, alkoxy, aryl, substituted aryl,
substituted alkyl, or arylalkyl.
[0158] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four double bonds.
[0159] The term "substituted alkenyl" refers to an alkenyl group
substituted by, for example, one to three substituents, such as,
aryl, substituted aryl, halo, hydroxy, alkoxy, alkanoyl,
alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol,
alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano,
carboxy, carbamyl, substituted carbamyl, guanidino, indolyl,
imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl pyridyl,
pyrimidyl and the like.
[0160] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 20 carbon atoms, preferably 2 to 15
carbon atoms, and most preferably 2 to 8 carbon atoms, having one
to four triple bonds.
[0161] The term "substituted alkynyl" refers to an alkynyl group
substituted by, for example, a substituent, such as, halo, hydroxy,
alkoxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino,
alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl,
sulfonamido, nitro, cyano, carboxy, carbamyl, substituted carbamyl,
guanidino and heterocyclo, e.g. imidazolyl, furyl, thienyl,
thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
[0162] The term "cycloalkyl" refers to an optionally substituted,
saturated cyclic hydrocarbon ring systems, preferably containing 1
to 3 rings and 3 to 7 carbons per ring which may be further fused
with an unsaturated C3-C7 carbocyclic ring. Exemplary groups
include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl.
Exemplary substituents include one or more alkyl groups as
described above, or one or more groups described above as alkyl
substituents.
[0163] The terms "heterocycle", heterocyclic and "heterocyclyl"
refer to an optionally substituted, fully saturated or unsaturated,
aromatic or non-aromatic cyclic group, for example, which is a 4 to
7 membered monocyclic, 7 to 11 membered bicyclic, or 10 to 15
membered tricyclic ring system, which has at least one heteroatom.
Each ring of the heterocyclic group containing a heteroatom may
have 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, oxygen and
sulfur, where the nitrogen and sulfur heteroatoms may also
optionally be oxidized and the nitrogen heteroatoms may also
optionally be quaternized. The heterocyclic group may be attached
at any heteroatom or carbon atom.
[0164] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, indolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxazepinyl, azepinyl,
4-piperidonyl, pyridyl, N-oxo-pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl,
thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane
and tetrahydro-1,1-dioxothienyl, dioxanyl, isothiazolidinyl,
thietanyl, thiiranyl, triazinyl, tetrazolyl and triazolyl, and the
like.
[0165] Exemplary bicyclic heterocyclic groups include
benzothiazolyl, benzoxazolyl, benzothienyl, quinuclidinyl,
quinolinyl, quinolinyl-N-oxide, tetrahydroisoquinolinyl,
isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl,
benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl,
indazolyl, pyrrolopyridyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl) or
furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazoliny (such
as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxaxolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0166] Exemplary substituents include one or more alkyl groups as
described above or one or more groups described above as alkyl
substituents. Also included are smaller heterocycles, such as,
epoxides and aziridines.
[0167] The term "heteroatoms" shall include oxygen, sulfur and
nitrogen.
[0168] A compound of formula (I) or (II) may form pharmaceutically
acceptable salts which are also within the scope of this invention.
Pharmaceutically acceptable (i.e. non-toxic, physiologically
acceptable) salts are preferred, although other salts are also
useful, e.g., in isolating or purifying the compounds of this
invention.
[0169] A compound of formula (I) or (II) may form salts with alkali
metals such as sodium, potassium and lithium, with alkaline earth
metals such as calcium and magnesium, with organic bases such as
dicyclohexylamine, tributylamine, pyridine and amino acids such as
arginine, lysine and the like. Such salts may be obtained, for
example, by exchanging the carboxylic acid protons, if they contain
a carboxylic acid, with the desired ion in a medium in which the
salt precipitates or in an aqueous medium followed by evaporation.
Other salts can be formed as known to those skilled in the art.
[0170] A compound of formula (I) or (II) may form salts with a
variety of organic and inorganic acids. Such salts include those
formed with hydrogen chloride, hydrogen bromide, methanesulfonic
acid, sulfuric acid, acetic acid, trifluoroacetic acid, maleic
acid, benzenesulfonic acid, toluenesulfonic acid and various others
(e.g., nitrates, phosphates, tartrates, citrates, succinates,
benzoates, ascorbates, salicylates and the like). Such salts may be
formed by reacting a compound of formula (I) or (II) in an
equivalent amount of the acid in a medium in which the salt
precipitates or in an aqueous medium followed by evaporation.
[0171] As is well known to those skilled in the art, the known and
potential uses of prenyl transferase inhibitors are varied and
multitudinous, such as for treating restenosis or a tissue
proliferative disease. Examples of tissue proliferative disease
include both those associated with benign cell proliferation such
as fibrosis, benign prostatic hyperplasia, atherosclerosis and
restenosis; and those associated with malignant cell proliferation
such as cancer (e.g., ras mutant tumors). Examples of such tumors
include breast, colon, pancreas, prostate, lung, ovarian, epidermal
and hematopoietic cancers (Sepp-Lorenzino, I, et al., Cancer
Research, 55:5302, 1995). Other diseases and conditions that prenyl
transferase inhibitors can be used for is in the treatment of
neoplasm, fungal infection, arteriosclerosis, retina disease,
hepatitis, renal disease, myeloid leukemia, viral infection,
nervous system tumor and viral infection.
[0172] Accordingly, the present invention includes within its scope
pharmaceutical compositions comprising, as an active ingredient, at
least one of the compounds of Formula I in association with a
pharmaceutically acceptable carrier.
[0173] The compounds of this invention can be administered by oral,
parenteral (e.g., intramuscular, intraperitoneal, intravenous or
subcutaneous injection, or implant), nasal, vaginal, rectal,
sublingual or topical routes of administration and can be
formulated with pharmaceutically acceptable carriers to provide
dosage forms appropriate for each route of administration.
[0174] Solid dosage forms for oral administration include capsules,
tablets, pills, powders and granules. In such solid dosage forms,
the active compound is admixed with at least one inert
pharmaceutically acceptable carrier such as sucrose, lactose, or
starch. Such dosage forms can also comprise, as is normal practice,
additional substances other than such inert diluents, e.g.,
lubricating agents such as magnesium stearate. In the case of
capsules, tablets and pills, the dosage forms may also comprise
buffering agents. Tablets and pills can additionally be prepared
with enteric coatings.
[0175] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, the elixirs containing inert diluents commonly used in the
art, such as water. Besides such inert diluents, compositions can
also include adjuvants, such as wetting agents, emulsifying and
suspending agents, and sweetening, flavoring and perfuming
agents.
[0176] Preparations according to this invention for parenteral
administration include sterile aqueous or non-aqueous solutions,
suspensions, or emulsions. Examples of non-aqueous solvents or
vehicles are propylene glycol, polyethylene glycol, vegetable oils,
such as olive oil and corn oil, gelatin, and injectable organic
esters such as ethyl oleate. Such dosage forms may also contain
adjuvants such as preserving, wetting, emulsifying, and dispersing
agents. They may be sterilized by, for example, filtration through
a bacteria-retaining filter, by incorporating sterilizing agents
into the compositions, by irradiating the compositions, or by
heating the compositions. They can also be manufactured in the form
of sterile solid compositions which can be dissolved in sterile
water, or some other sterile injectable medium immediately before
use.
[0177] Compositions for rectal or vaginal administration are
preferably suppositories which may contain, in addition to the
active substance, excipients such as coca butter or a suppository
wax.
[0178] Compositions for nasal or sublingual administration are also
prepared with standard excipients well known in the art.
[0179] Further, a compound of this invention can be administered in
a sustained release composition such as those described in the
following patents. U.S. Pat. No. 5,672,659 teaches sustained
release compositions comprising a bioactive agent and a polyester.
U.S. Pat. No. 5,595,760 teaches sustained release compositions
comprising a bioactive agent in a gelable form. U.S. application
Ser. No. 08/929,363 filed Sep. 9, 1997, teaches polymeric sustained
release compositions comprising a bioactive agent and chitosan.
U.S. application Ser. No. 08/740,778 filed Nov. 1, 1996, teaches
sustained release compositions comprising a bioactive agent and
cyclodextrin. U.S. application Ser. No. 09/015,394 filed Jan. 29,
1998, teaches absorbable sustained release compositions of a
bioactive agent. The teachings of the foregoing patents and
applications are incorporated herein by reference.
[0180] The dosage of active ingredient in the compositions of this
invention may be varied; however, it is necessary that the amount
of the active ingredient be such that a suitable dosage form is
obtained. The selected dosage depends upon the desired therapeutic
effect, on the route of administration, and on the duration of the
treatment. Generally, dosage levels of between 0.0001 to 100 mg/kg
of body weight daily are administered to humans and other animals,
e.g., mammals, to obtain effective release of growth hormone.
[0181] A preferred dosage range is 0.01 to 100.0 mg/kg of body
weight daily which can be administered as a single dose or divided
into multiple doses.
[0182] A compound of formula (I) or (II) can be tested for activity
as an inhibitor of prenyl transferase according to the following in
vitro assay.
[0183] Farnesyl transferase activity is assayed by [.sup.3H]
farnesylation of recombinant human H-Ras protein wild type, using
microplate and filtration method. Incubation mixture contains, in a
total volume of 25 .mu.l: 50 mM Tris HCl (pH 7.5), 5 mM
dithiothreitol, 20 .mu.M ZnCl.sub.2, 40 mM MgCl.sub.2, 0.6 .mu.M
[.sup.3H] farnesyl pyrophosphate (22.3 Ci/mmol), 4 .mu.M H-Ras and
10 .mu.g of farnesyl transferase from human brain cytosol. Test
compounds are added in adequate solvent and incubations start by
addition of farnesyl transferase. After approximately 60 minutes at
approximately 37.degree. C., the reaction is stopped by addition of
100 .mu.l of 10% HCl in ethanol and allowed to incubate
approximately 15 minutes at approximately 37.degree. C., then 150
.mu.l of absolute ethanol are added and incubation mixture is
filtered on Unifilter GF/B microplates and washed 6 times with
ethanol. After addition of 50 .mu.l of Microscint 0, plates were
counted on a Packard Top Count scintillation counter.
Geranylgeranyl transferase activity is assayed by the same method,
but using 4 .mu.M human recombinant H-Ras CVLL type, 0.6 .mu.M
[.sup.3H] geranylgeranyl-pyrophosp- hate (19.3 Ci/mmol) and 100
.mu.g of geranylgeranyltransferase from human brain.
[0184] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Also,
all publications, patent applications, patents, and other
references mentioned herein are incorporated by reference.
[0185] The compounds of the present invention can be made according
to the following schemes and associated descriptions and by methods
well-known to those of ordinary skill in the art. The starting
materials and reagents are either commercially available or can be
synthesized according to published procedures well-known to those
of ordinary skill in the art. The substituents have the same
definitions as for the compound of formula (II), shown hereinabove.
36
[0186] This reaction is accomplished by the reaction of an aldehyde
or ketone of formula 1 with a phenylhydrazine of formula 2 in a
mixed acid/organic solvent or an acid solvent, such as acetic acid
at an elevated temperature, preferably at reflux temperatures.
37
[0187] Step 1
[0188] In Scheme 2, starting material 1 has a protecting group,
P.sup.1, such as a phenylsulfonyl or methylsulfonyl group, at
position 1 of the indole ring. An indole of formula 1 is treated in
an organic solvent, such as tetrahydrofuran, with active zinc at
about room temperature to give 3-indolylzinc iodide 2.
[0189] Step 2
[0190] Thereafter product 2 is coupled with an iodo- or
bromo-aromatic system 3 (X.sup.1=I or Br), such as iodobenzene in
the presence of a catalyst, such as
tetrakis(triphenylphosphine)palladium in an organic solvent at
about room temperature.
[0191] Step 3
[0192] Thereafter product 3 is hydrolyzed by using an appropriate
base, such as KOH or NaOH in a suitable solvent, such as methanol
at from about 0.degree. C. to about 100.degree. C. This step may
also be accomplished by treating with tetraalkylammonium fluoride,
such as tetrabutylammonium fluoride in a suitable organic solvent,
such as tetrahydrofuran, at an elevated temperature, preferably
reflux temperatures. 38
[0193] Step 1
[0194] In Scheme 3, compound 1 is reduced by using an appropriate
reducing agent, such as borane in an organic solvent containing a
suitable acid, such as tetrahydrofuran containing trifluoroacetic
acid at from about 0.degree. C. to about room temperature.
[0195] Step 2
[0196] Thereafter product 2 is protected by reacting with an
appropriate agent, such as methanesulfonyl chloride,
p-toluenesulfonyl chloride or phenylsulfonyl chloride in the
presence of a base, such as triethylamine or
N,N-diisopropylethylamine in an inert organic solvent, such as
dichloromethane or N,N-dimethylformamide at from about -78.degree.
C. to about room temperature.
[0197] Step 3
[0198] Thereafter product 3 is coupled with the chloride acid 4 in
the presence of an acid or Lewis acid, such as aluminum chloride,
in a solvent, such as carbon disulfide or dichloromethane at from
about -78.degree. C. to an elevated temperature such as 100.degree.
C. 39
[0199] In Scheme 4, compound 1 is oxidized by reacting it with an
oxidizing agent, for example,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone or manganese (III)
acetate dihydrate in an organic solvent, such as dioxane or acetic
acid from about room temperature to about 150.degree. C. 40
[0200] In Scheme 5, compound 1 which has an iodo- or
bromo-substituent at position 2 (X.sup.2=I or Br) is reacted with,
an alkyne 2 in the presence of a suitable catalyst, such as
palladium(II) acetate, an appropriate base such as potassium
carbonate and other agents which are necessary for the reaction,
such as triphenylphosphine/lithium chloride in an organic solvent,
such as N,N-dimethylformamide at from about room temperature to
about 150.degree. C. 41
[0201] Step 1
[0202] In scheme 6, compound 1 is treated with nitrous acid in a
solvent, such as water or sulfuric acid at from about 0.degree. C.
to 50.degree. C.
[0203] Step 2
[0204] Thereafter product 2 is reacted with compound 3 in the
presence of a suitable base, such as potassium hydroxide in a
solvent such as water at about 0.degree. C. The mixture is treated
with an acid, such as ethanolic hydrogen chloride at from about
50.degree. C. to about 80.degree. C. 42
[0205] Step 1
[0206] In Scheme 7, compound 1 is hydrolyzed by reacting with a
base, such as potassium hydroxide or sodium hydroxide in a solvent
mixture, such as water/ethanol or a solvent, such as ethanol or
water at an elevated temperature, preferably at reflux
temperatures.
[0207] Step 2
[0208] Thereafter product 2 is reacted with a primary or secondary
amine in the presence of a coupling agent such as
2-(1H-benzotriazole-1-yl)-1,1- ,3,3-tetramethyluronium
hexafluorophosphate and a base, such as diisopropylethylamine in an
organic solvent, such as N,N-dimethylformamide at from about
0.degree. C. to about room temperature. 43
[0209] In Scheme 8, the reaction is accomplished by reacting 1 with
an appropriate decarboxylating agent, such as quinoline/copper at
an elevated temperature, preferably at reflux temperatures to
obtain a compound of formula 2. 44
[0210] Step 1
[0211] In Scheme 9, compound 1 is reduced by reacting with a
suitable reducing agent, such as sodium borohydride in a suitable
organic solvent, such as ether or tetrahydrofuran, yielding
intermediate 2.
[0212] Step 2
[0213] Thereafter product 2 is reacted with an appropriate reagent,
such as thionyl chloride or methanesulfonyl chloride to convert the
hydroxy group into an active leaving group, such as chloro- or
methylsulfonate group (L.sup.1=Cl or CH.sub.3S(O).sub.2O--).
[0214] Step 3
[0215] Thereafter product 3 is reacted with an imidazole of formula
4 in the presence of a suitable base, such as potassium carbonate
in an organic solvent, such as acetonitrile at an elevated
temperature, preferably at reflux temperatures. If the optional
protecting group P is not stable under the reaction condition and
hydrolyzed, another additional step may be needed to introduce the
Y group at the nitrogen in the indole ring. If this additional step
is required, the intermediate is treated with Y--L, in which L is
an active leaving group, for example Y--Cl, e.g., methanesulfonyl
chloride or dimethylcarbamoyl chloride, in an inert organic solvent
at from about -78.degree. C. to about room temperature. 45
[0216] In Scheme 10, compound 1 is reacted with an imidazole of
formula 2, in which R.sup.7 is an optional protective group, such
as a dimethylamino sulfonyl group, which can be removed after the
addition. The reaction takes place in the presence of a suitable
base, such as butyl lithium. If R.sup.8 is hydrogen at position 2
of the imidazole then it needs to be temporarily protected with a
protecting group, such as triethylsilane by reacting it with an
appropriate reagent, such as chlorotriethylsilane. If the optional
protective group P, such as a methylsulfonyl group is not stable
under the reaction condition and cleaved off, another reagent which
can introduce a Y group at the nitrogen of the indole ring, for
example Y--Cl, e.g., methanesulfonyl chloride or dimethylcarbamoyl
chloride, may be added into the reaction mixture to obtain the
desired compound 3. The chlorotriethylsilyl group is hydrolyzed
during the work-up procedure. 46
[0217] In Scheme 11, compound 1 is reacted with an
arylalkylmagnesium chloride (X.sup.3=Cl--Mg, p=1-2) or an
aryllithium (X.sup.3=Li, p=0) shown as compound 2, in an inert
organic solvent, such as tetrahydrofuran. If the optional
protective group P, is not stable under the reaction condition and
cleaved off, another reagent which can introduce a Y group at the
nitrogen of the indole ring, for example Y--Cl, e.g.,
methanesulfonyl chloride or dimethylcarbamoyl chloride, may be
added into the reaction mixture to obtain the desired compound 3.
4748
[0218] Step 1
[0219] In Scheme 12, the first reaction is accomplished by the
reaction of an aldehyde or ketone of formula 1 with a
phenylhydrazine of its derivative of formula 2 in a mixed
acid/organic solvent or an acid solvent, such as acetic acid at an
elevated temperature, preferably at reflux temperatures.
[0220] Step 2
[0221] Thereafter product 3 is reacted with Y--L, in which L is an
active leaving group, such as a chloride group, in the presence of
a suitable base, such as triethylamine or diisoproplethylamine in
an inert organic solvent, such as dichloromethane or
N,N-dimethylformamide at from about -78.degree. C. to about room
temperature.
[0222] Step 3
[0223] Thereafter product 4 is converted into alkyl- (n=1 or 2) or
arylmagnesium (n=0, M=MgX.sup.3, in which X.sup.3=halide, e.g., Cl
or Br) halide or alkyl-(n=1 or 2) or aryl-(n=0, M=Li) lithium by
reacting with metallic magnesium, lithium metal or alkyllithium,
such as butyllithium in an inert organic solvent, such as ether or
tetrahydrofuran at about -12.degree. C. to about room
temperature.
[0224] Step 4
[0225] Thereafter product 5 is reacted with ketone 6 in an inert
organic solvent, such as ether or tetrahydrofuran at from about
-12.degree. C. to about room temperature. 4950
[0226] Step 1
[0227] In Scheme 13, starting material 1 is reduced by reacting
with a reducing agent, such as borane in an organic solvent, such
as tetrahydrofuran containing an acid, such as trifluoroacetic acid
at from about 0.degree. C. to about room temperature.
[0228] Step 2
[0229] Thereafter product 2 is reacted with Y--L, in which L is an
active leaving group, such as a chloro group, in the presence of a
suitable base, such as triethylamine or diisopropylethylamine in an
organic solvent, such as dichloromethane or N,N,-dimethylformamide
at from about -78.degree. C. to about room temperature, yielding
compound 3.
[0230] Step 3
[0231] Thereafter product 3 is converted into alkyl- (n=1 or 2) or
arylmagnesium (n=0, M=MgX.sup.5, in which X.sup.5=halide, e.g., Cl
or Br) halide or alkyl- (n=1 or 2) or aryl-(n=0) lithium (M=Li) by
reacting with metallic magnesium, lithium metal or alkyllithium,
such as butyllithium in an inert organic solvent, such as ether or
tetrahydrofuran at about -12.degree. C. to about room
temperature.
[0232] Step 4
[0233] Thereafter product 4 is reacted with ketone 5 in an inert
organic solvent, such as ether or tetrahydrofuran at from about
-12.degree. C. to about room temperature. 51
[0234] In Scheme 14, compound 1 can be converted to compound 2 by
reacting with a suitable group of reagents, such as methyl
sulfoxide/concentrated HCl or potassium persulfate/sodium acetate
in a suitable solvent, such as water or an alcohol. 52
[0235] In Scheme 15, compound 1 can be converted to compound 3 by
reacting with compound 2 in the presence of suitable base. 53
[0236] In Scheme 16, compound 1 can be converted to compound 3 by
reacting it with compound 2 under suitable conditions. 54
[0237] Step 1
[0238] In Scheme 17, compound 1 is converted to compound 2, in
which P.sup.4--O-- is an active leaving group, such as
methylsulfonate, p-toluenesulfonate or trifluoromethanesulfonate by
reacting it with a suitable reagent, such as methanesulfonyl
chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonic
anhydride in an inert organic solvent, such as dichloromethane.
[0239] Step 2
[0240] Thereafter product 2 is reacted with sodium azide to yield
compound 3 in an organic solvent, such as N,N-dimethylformamide at
from about room temperature to an elevated temperature, such as
about 60.degree. C.
[0241] Step 3
[0242] Thereafter product 3 is reduced to compound 4 by reacting it
with an appropriate reducing agent, such as triphenylphosphine with
water in a suitable solvent such as pyridine. 55
[0243] Step 1
[0244] In Scheme 18, compound 1 can be converted to compound 2
which has an active leaving group, such as a chloro group, by
reacting with an appropriate reagent, such as thionyl chloride at
from about room temperature to an elevated temperature, preferably
at about 38.degree. C.
[0245] Step 2
[0246] Thereafter product 2 is reacted with an appropriate agent,
such as liquid ammonia at from low temperature, such as -78.degree.
C., to an elevated temperature.
EXAMPLE 1
(.+-.)-3-(3-Chlorophenyl)-5-[(4-chlorophenyl)hydroxyl(1-methyl-1H-imidazol-
-5-yl)methyl]indole
[0247] To a solution of 1-methylimidazole (53 mg) in anhydrous THF
(3 mL) was added dropwise a solution of butyllithium in hexane (1.6
M, 430 .mu.L) at about -78.degree. C. The mixture was stirred at
about -78.degree. C. for about 15 minutes. To the solution was
added dropwise a solution of chlorotriethylsilane in THF (1.0M, 660
.mu.L). The mixture was warmed to room temperature and stirred at
room temperature for 1 hour. The mixture was cooled to about
-78.degree. C. and to it was added dropwise a solution of
butyllithium in hexane (1.6M, 430 .mu.L). The solution was stirred
at about -78.degree. C. for about 1 hour and in the following 15
minutes, it was warmed to about -15.degree. C. The solution was
cooled to about -78.degree. C. To it was added dropwise a solution
of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole
(95 mg) (see preparation #7) in THF (2 mL). The mixture was warmed
to room temperature and stirred for about 2 hours. The solution was
cooled to about 0.degree. C. and to it was added methanol and
water. The mixture was stirred for about 2 hours. The solution was
concentrated in vacuo. The residue was dissolved in dichloromethane
(DCM) and washed with water once. The organic layer was dried over
anhydrous MgSO.sub.4, filtered, and concentrated in vacuo. The
crude product was purified by column chromatography, on silica,
eluting with DCM/MeOH 95:5. Affording the title compound Rf=0.20
(silica, DCM/MeOH 9:1), MS (ES) 447.2; Calc. MW=447.4. 60 mg,
yield: 63%.
[0248] Alternatively, the compound of Example 1,
(.+-.)-3-(3-chlorophenyl)-
-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole
can be synthesized according to the following procedure. To a
solution of 1-methylimidazole (53 mg) in anhydrous THF (3 mL) was
added dropwise a solution of butyllithium in hexane (1.6 M, 430
.mu.L) at about -78.degree. C. The mixture was stirred at about
-78.degree. C. for about 15 minutes. To the solution was added
dropwise a solution of chlorotriethylsilane in THF (1.0M, 660
.mu.L). The mixture was warmed to room temperature and stirred at
room temperature for about 1 hour. The mixture was cooled to about
-78.degree. C. and to it was added dropwise a solution of
butyllithium in hexane (1.6M, 430 .mu.L). The solution was stirred
at about -78.degree. C. for about 1 hour and in the following 15
minutes, it was warmed to about -15.degree. C. The solution was
cooled to about -78.degree. C. To it was added dropwise a solution
of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline
(95 mg) (see preparation #6) in THF (2 mL). The mixture was warmed
to room temperature and stirred for about 2 hours. The solution was
cooled to about 0.degree. C. and to it was added methanol and
water. The mixture was stirred for about 2 hours. The solution was
concentrated in vacuo. The residue was dissolved in dichloromethane
(DCM) and washed with water once. The organic layer was dried over
anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel eluting
with DCM/MeOH 95:5, affording the title compound.
[0249] The enantiomers of the title compound can be separated by
using techniques known in the art, such as prep HPLC over a chiral
column.
EXAMPLE 2
(.+-.)-1-Methylsulfonyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-me-
thyl-1H-imidazol-5-yl)methyl]indole
[0250] To a solution of 1-methylimidazole (88 mg) in anhydrous THF
(3 mL) was added dropwise a solution of butyllithium in hexane (1.6
M, 694 .mu.L) at about -78.degree. C. The mixture was stirred at
about -78.degree. C. for about 15 minutes. To the solution was
added dropwise a solution of chlorotriethylsilane in THF (1.0 M,
1.08 mL). The mixture was warmed to room temperature and stirred
for about 1 hour. The solution was cooled to about -78.degree. C.
To it was added dropwise a solution of butyllithium in hexane (1.6
M, 694 .mu.L). The mixture was stirred at about -78.degree. C. for
about 1 hour and then warmed to about -15.degree. C. It was stirred
at about -15.degree. C. for about 15 minutes. The solution was
cooled to about -78.degree. C. To the solution was added dropwise a
solution of 1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-
-chlorobenzoyl) indoline (150 mg) (see preparation #6) in THF (2
mL). The mixture was warmed to room temperature and stirred for
about 2 hours. The solution was cooled to about -78.degree. C. To
it was added dropwise methanesulfonyl chloride (116 mg). The
solution was slowly warmed to room temperature and stirred
overnight. The solution was cooled to about 0.degree. C. To it was
added water and stirred for about 2 hours. The solution was diluted
with DCM and the organic layer was separated and concentrated in
vacuo. The crude product was purified by column chromatography on
silica, eluting with CHCl.sub.3/MeOH 95:5 affording the title
compound as a solid. MS (ES): 525.1; Calc. MW=525.5. 30 mg, yield:
17%.
[0251] Alternatively, the compound of Example 2,
(.+-.)-1-Methylsulfonyl-3-
-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)met-
hyl]indole can be synthesized according to the following
procedure.
[0252] To a solution of 1-methylimidozole (88 mg) in anhydrous THF
(1.5 mL) was added dropwise a solution of butyllithium in hexane
(1.6M, 694 .mu.L) at about -78.degree. C. The mixture was stirred
at about -78.degree. C. for about 30 min. To the solution was added
dropwise a solution of chlorotriethylsilane in THF (1.0M, 1.11 mL).
The mixture was warmed to room temperature and stirred at room
temperature for about 1 hour. The solution was cooled to about
-78.degree. C. To it was added dropwise a solution of butyllithium
in hexane (1.6M, 694 .mu.L). The mixture was stirred at about
-78.degree. C. for about 1 hour and was warmed to about -15.degree.
C. during the following 30 min. The solution was cooled to about
-78.degree. C. To it was added dropwise of a solution of
1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole (150
mg) (see preparation #7) in THF (1 mL). The solution was warmed to
room temperature and stirred at room temperature for 19 hours. The
solution was cooled to -78.degree. C. To it were added dropwise
methanesulfonyl chloride (163 mg), then, diisopropylethylamine (87
mg). The solution was warmed to room temperature in 1 hour and
stirred at room temperature for 3 hours. To the solution was added
4 mL of 1N HCl aqueous solution and 4 mL of THF. The solution was
stirred at 0.degree. C. for 1.5 hours. The organic solvent was
removed in vacuo. The aqueous solution was neutralized to pH=8 by
adding 6N KOH aqueous solution at 0.degree. C. The aqueous solution
was extracted with DCM twice. The organic layers were combined and
washed with brine once, dried over MgSO.sub.4, filtered and
condensed in vacuo. The residue was purified by column
chromatography on silica, eluting with CH.sub.3Cl/MeOH/Et.sub.3N,
98:2:0.1 The title compound was obtained as a solid, 44 mg, yield:
25%. MS(ES) 525.2, Calc. MW=525.3.
[0253] Alternatively, the compound of Example 2,
(.+-.)-1-methylsulfonyl-(- 3-chlorophenyl)-5-[(4-chlorophenyl)
hydroxyl (1-methyl-1H-imidazol-5-yl) methyl]indole was also made
analogously to the method described for making Example Y, using
methanesulfonyl chloride in place of 4-morpholinecarbonyl chloride.
Yield: 77%. MS (Calc.): 526.46, MS(ES): 526.
[0254] The enantiomers of the title compound can be separated by
using a technique known in the art, such as preparative HPLC on a
chiral column.
EXAMPLE 3
(.+-.)-1-(N,N-Dimethylcarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)
hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole
[0255] The title compound was synthesized analogously to the second
method described for making Example 2, using dimethylcarbamyl
chloride in place of methanesulfonyl chloride. MS
(electrospray):518.2; calc. MW: 518.5.
EXAMPLE 4
(.+-.)-1-Methlsulfonyl-3-(3-chlorophenyl)-5-[amino(4-chloro-phenyl)(1-meth-
yl-1H-imidazol-5-yl)methyl]indole
[0256] Freshly distilled SOCl.sub.2 (18 ml) was injected into
(.+-.)-1-methylsulfonyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)
hydroxy (1-methyl-1H-imidazol-yl) methyl]indole (1) (1.74 g, 3.31
mmol, see Example 2) under N.sub.2 atmosphere and stirred at about
38.degree. C. for about 21 hrs. The mixture was evaporated to
dryness in vacuo. 1.9 g of the intermediate,
(.+-.)-1-methylsulfonyl-3-(3-cholorophenyl)-5-[chlor-
o(4-chlorophenyl)(1-methyl-1H-imidazol-yl) methyl]indole, was
obtained and it was used in the following reaction without further
purification. The crude intermediate was taken into 15 ml THF and
injected into 45 mL of liquid NH.sub.3 solution under N.sub.2 at
-78.degree. C. The mixture was stirred for about 2 h and gradually
warmed up to room temperature. The reaction solution was diluted by
methylene chloride and filtered. The filtrate was evaporated to
dryness in vacuo. The crude product was purified by flash
chromatograph over silica gel, eluting with a mixture of methylene
chloride and MeOH (5/0.2). The pure fractions were pooled and
stripped down. The amine was converted into HCl salt and
recrystallized from CH.sub.2Cl.sub.2/hexane. The precipitate was
filtered and dried under vacuum overnight, yielding 1.02 g (56%) of
the title compound. MS (Calc.) 525.46, MS (ES):525.2.
EXAMPLE 7
(.+-.)-1-(1-Pyrrolidinecarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)
hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole
[0257] The title compound was synthesized analogously to the second
method described for making Example 2, using 1-pyrrolidinecarbonyl
chloride in place of methanesulfonyl chloride. MS
(electrospray):544.3; calc. MW: 544.51.
EXAMPLE 11
(.+-.)-1-(N,N-Diethylcarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)
hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole
[0258] The title compound was synthesized analogously to the second
method described for making Example 2, using diethylcarbamyl
chloride in place of methanesulfonyl chloride. MS
(electrospray):546.2; calc. MW: 546.5.
EXAMPLE 21
(.+-.)-1-Acetyl-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H--
imidazol-5-yl)methyl]indole
[0259] The title compound was synthesized analogously to the first
method described for making example 2, using acetic anhydride in
place of methanesulfonyl chloride. MS(electrospray): 489.2; Calc.
MW: 489.4.
EXAMPLE V
(.+-.)-1-Methylsulfonyl-2-chloro-3-(3-cholorophenyl)-5-[amino(4-chlorophen-
yl)(1-methyl-1H-imidazol-yl) methyl]indole
[0260] The title compound was made analogously to the method
described in Example 4, except that
(.+-.)-1-methylsulfonyl-3-(3-cholorophenyl)-5-[(4--
chlorophenyl)hydroxy(1-methyl-1H-imidazol-yl) methyl]indole was
reacted with thionyl chloride for about 3 days instead of 21 hrs.
Yield: 55%. MS (Calc.):559.91, MS (ES): 559.00.
EXAMPLE Y
(.+-.)-1-(4-Morpholinecarbamoyl)-3-(3-chlorophenyl)-5-[(4-chlorophenyl)hyd-
roxy(1-methyl-1H-imidazol-5-yl)methyl]indole
[0261] A THF solution (75 ml) of 1-methylimidazole (5.28 ml, 66.12
mmol) was cooled down to about -78.degree. C., to which 2.5 M
n-butyllithium in hexane (28.25 ml, 70.628 mmol) was added under
N.sub.2 atmosphere. The mixture was stirred for about 30 min at
about -78.degree. C., then 1M chlorotriethylsilane (69.13 ml, 69.13
mmol) in THF was added dropwise. The cooling bath was removed and
the reaction solution was stirred for about another 2 hrs. Then it
was cooled down to about -78.degree. C. again, to which the same
volume of n-butyllithium solution was injected, and it was stirred
for about 1 hr and gradually warmed up to room temperature in about
40 min. Then it was cooled down to about -78.degree. C. for about
20 min, to which a THF solution of 3-(3-chlorophenyl)-5-(4-c-
hlorobenzoyl)indole (5.5 g, 15.027 mmol, see Preparation 8, below)
was added and stirred for about 15 min at about -78.degree. C.
After the cooling bath was removed, the mixture was stirred for
about 0.5 hr and 130 ml of ether was added. The mixture was stirred
at about 57.degree. C. under N.sub.2 atmosphere overnight. TLC
(CH.sub.2Cl.sub.2:MeOH 5/0.6, AcOEt:Hexane 1:1) showed the reaction
was complete. It was cooled down to about 0.degree. C. and 9 ml
(75.14 mmol) of 4-morpholinecarbonyl chloride was injected and
stirred for about 5 hrs. It was quenched by saturated NH.sub.4Cl
(100 ml.times.3). The organic layer was stripped down, and the
residue was taken into 250 ml CH.sub.2Cl.sub.2, which was washed
with 2M HCl, (100 ml.times.2), saturated NaHCO.sub.3 (100
ml.times.2) and brine (100 ml.times.3). The organic solution was
dried over Na.sub.2SO.sub.4 and stripped down. The crude product
was purified by silica gel flash chromatograph, eluting with a
mixture solution of CH.sub.2Cl.sub.2 and methanol (5:0.25). The
pure fractions were pooled and evaporated in vacuo to dryness. 7 g
of the title compound was obtained (yield 83%). MS (Calc.): 561.2,
MS (ES): 561.2.
EXAMPLE Z
(.+-.)-1-(4-Morpholinecarbamoyl)-3-(3-cholorophenyl)-5-[amino(4-chlorophen-
yl)(1-methyl-1H-imidazol-5-yl)methyl]indole
[0262] The title compound was made analogously to the method
described for making Example 4, using
(.+-.)-1-(4-morpholinecarbamoyl)-3-(3-chloropheny-
l)-5-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]indole
(see Example Y) in place of
(.+-.)-1-methylsulfonyl-(3-chlorophenyl)-5-[(4-chl-
orophenyl)hydroxyl(1-methyl-1H-imidazol-5-yl) methyl]indole. Yield:
72%. MS (Calc.): 560.49, MS (ES): 560.30.
[0263] The following compounds can be synthesized analogously to
the procedures detailed for Examples 1 to 4 but using the
appropriate starting materials and modifications, which are well
known to those of ordinary skill in the art. Examples 5, 6, 8, 10,
12, 16, 18, 20, 22, B, D, F, J, L, N, P, R and X can be synthesized
analogously to Example 4. Examples 9, 15, 17, 19, A, C, E, I, K, M,
O, Q and W can be synthesized to Example 2. Example U can be
synthesized analogously to Example V.
[0264] Examples 13 and 14 were obtained by reacting the compound of
Preparation 8, below, with iodomethane in the presence of
K.sub.2CO.sub.3 in DMF at about 80.degree. C. for about 5 hrs. The
resulting intermediate (where Y is methyl, see table of Examples
below) was divided into two lots. One lot was subjected to an
synthetic scheme analogous to the first procedure described for
Example 2 except the step of reacting it with methanesulfonyl
chloride was not conducted, to obtain the compound of Example 13.
The other lot of the intermediate was subjected to a synthetic
scheme analogous to Example 4 to obtain the compound of Example
14.
EXAMPLES
[0265]
1 56 Example No. Z Y R.sup.10 1 H H OH 2 H --S(O).sub.2--CH.sub.3
OH 3 H --C(O)--N(CH.sub.3).sub.2 OH 4 H --S(O).sub.2--CH.sub.3
NH.sub.2 5 H H NH.sub.2 6 H --C(O)--N(CH.sub.3).sub.2 NH.sub.2 7 H
57 OH 8 H 58 NH.sub.2 9 H --S(O).sub.2-Phenyl OH 10 H
--S(O).sub.2-Phenyl NH.sub.2 11 H --C(O)--N(CH.sub.2CH.sub.3).sub.2
OH 12 H --C(O)--N(CH.sub.2CH.sub.3).sub.2 NH.sub.2 13 H --CH.sub.3
OH 14 H --CH.sub.3 NH.sub.2 15 H 59 OH 16 H 60 NH.sub.2 17 H 61 OH
18 H 62 NH.sub.2 19 H 63 OH 20 H 64 NH.sub.2 21 H --C(O)--CH.sub.3
OH 22 H --C(O)--CH.sub.3 NH.sub.2 A H --S(O).sub.2--CF.sub.3 OH B H
--S(O).sub.2--CF.sub.3 NH.sub.2 C H
--S(O).sub.2--CH.sub.2--CF.sub.3 OH D H
--S(O).sub.2--CH.sub.2--CF.sub.3 NH.sub.2 E H 65 OH F H 66 NH.sub.2
I H 67 OH J H 68 NH.sub.2 K H 69 OH L H 70 NH.sub.2 M H 71 OH N H
72 NH.sub.2 O H --C(O)--NH.sub.2 OH P H --C(O)--NH.sub.2 NH.sub.2 Q
H 73 OH R H 74 NH.sub.2 U Cl 75 NH.sub.2 V Cl
--S(O).sub.2--CH.sub.3 NH.sub.2 W H 76 OH X H 77 NH.sub.2 Y H 78 OH
Z H 79 NH.sub.2
[0266] Preparation 1:
[0267] 2-(3-Chlorophenyl)-N-methoxy-N-methyl-acetamide
[0268] A solution of 3-chlorophenylacetic acid (5.00 g, 29.3 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (6.18 9, 32.2
mmol), and 1-hydroxybenzotriazole (HOBt; 4.00 g, 29.3 mmol) in
dichloromethane (DCM; 40 mL) was stirred at room temperature for
about 10 minutes. The solution was cooled to about 0.degree. C. To
it were added N,O-dimethylhydroxylamine HCl (2.86 g, 29.0 mmol) and
diisopropylethylamine (DIEA; 3.80 g, 29.3 mmol). The reaction
mixture was warmed to room temperature and stirred for about 5
hours. The solution was diluted with 100 mL of DCM and washed with
saturated NaHCO.sub.3 aqueous solution (2 times), 1N HCl aqueous
solution (2 times) and brine (2 times), dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The liquid obtained
was purified by column chromatography on silica eluting with
EtOAc/hexane 1:1. The title compound was obtained as colorless
liquid. Yield: 5.60 g, 89%. Rf=0.44 (silica, EtOAc/hexane 1:1).
.sup.1H NMR (300 MHz, CDCl.sub.3) 7.18-7.34 (m, 4H), 3.76 (S, 2H),
3.66 (S, 3H), 3.22 (S, 3H).
[0269] Preparation 2:
[0270] 2-(3-Chlorophenyl)-acetaldehyde
[0271] A suspension of LiAlH.sub.4 (1.90 g, 51 mmol) in anhydrous
ether (250 mL) was stirred at room temperature under nitrogen for
about 1 hour. The suspension was cooled to about -45.degree. C. To
it was added drops of a solution of
2-(3-chlorophenyl)-N-methoxy-N-methyl-acetamide (8.19 g, 38.3 mmol,
see Preparation 1) in 10 mL of anhydrous tetrahydrofuran (THF). The
mixture was warmed to about 0.degree. C. and stirred for about 3
hours. The solution was then cooled to about -45.degree. C. To this
solution was slowly added a solution of KHSO.sub.4 (13 g) in water
(about 30 mL) the resulting mixture was filtered through
CELITE.RTM.. The filtrate was concentrated in vacuo, the resulting
solution was diluted with DCM and washed with 1N HCl aqueous
solution (2 times), and brine (2 times) dried over anhydrous
MgSO.sub.4, filtered and concentrated in vacuo. The title compound
was obtained as a liquid (5.80 g), which was used immediately in
the next step without further purification. Rf=0.71 (silica,
EtOAc/hexane 1:3).
[0272] Preparation 3:
[0273] 3-(3-Chlorophenyl)indole
[0274] A solution of 2-(3-chlorophenyl)-acetaldehyde (5.80 g, 37.5
mmol) and phenylhydrazine (6.22 g, 57.5 mmol) in glacial acetic
acid (150 mL) was saturated with nitrogen by bubbling N.sub.2
through the solution. The solution was then refluxed for about 2.5
hours. Solvent was removed in vacuo and the residue obtained was
dissolved in DCM and washed with 1N HCl aqueous solution (2 times),
saturated NaHCO.sub.3 aqueous solution (2 times) and brine (2
times), dried over anhydrous MgSO.sub.4, filtered and concentrated
in vacuo. The crude product was purified by column chromatography
on silica, eluting with EtOAc/hexane 1:6. The title compound was
obtained as a reddish oil. Yield: 5.30 g, 62%. Rf=0.26 (silica,
EtOAc/hexane 1:4)
[0275] Preparation 4:
[0276] 3-(3-Chlorophenyl)-indoline
[0277] 3-(3-Chlorophenyl)indole (5.30 g, 23.3 mmol) was dissolved
in 50 mL of 1 M BH.sub.3 in THF. The mixture was cooled to about
0.degree. C. To the solution was added slowly TFA (50 mL). After
addition, the solution was stirred for about 10 minutes. To the
solution was added slowly 1M BH.sub.3 in THF (40 mL). The mixture
was stirred for about 5 minutes and then concentrated in vacuo. The
residue was purified by column chromatography on silica, eluting
with EtOAc/hexane 1:6. The title compound was obtained as an oil
(Yield; 3.93 g, 74%). Rf=0.20 (Silica, EtOAc/hexane 1:4) MS (ES):
229.1; Calc. MW=229.7.)
[0278] Preparation 5:
[0279] 1-Methylsulfonyl-3-(3-chlorophenyl)indoline
[0280] To a solution of 3-(3-chlorophenyl)indoline (3.88 g, 16.9
mmol) and DIEA (2.40 g, 18.6 mmol) in DCM (40 mL) was added
dropwise methanesulfonyl chloride (2.13 g, 18.6 mmol) at about
0.degree. C. The mixture was stirred for about 1.5 hours. The
solution was diluted with DCM and washed with saturated NaHCO.sub.3
solution (2 times), 1N HCl aqueous solution (2 times) and brine (2
times) and dried over anhydrous MgSO.sub.4, filtered and
concentrated in vacuo. The crude product was purified by column
chromatography on silica, eluting with EtOAc/hexane 1:4. The title
compound was obtained as an oil Yield: 4.40 g, 85%. Rf=0.41,
silica, EtOAc/hexane 1:2. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta.: 7.52 (d, 1H), 7.24-7.34 (m, 3H), 7.20 (s, 1H), 7.02-7.14
(m, 3H), 4.59 (t, 1H), 4.38 (t, 1H), 3.87 (dd, 1H), 2.92 (s,
3H).
[0281] Preparation 6:
[0282]
1-Methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indoline
[0283] To a solution of 1-methylsulfonyl-3-(3-chlorophenyl)indoline
(4.40 g, 14.3 mmol, see Preparation 5) and 4-chlorobenzoyl chloride
(3.25 g, 18.6 mmol) in CS.sub.2 (25 mL) was added portionwise
AlCl.sub.3 (7.62 g, 57.2 mmol) at about 0.degree. C. A brown
precipitate formed immediately. The mixture was stirred for about 2
hours. To the mixture was added slowly 100 mL of cold water
containing 3 mL of concentrated HCl. The solution was diluted with
DCM and the organic layer was separated and washed with 1 N HCl
aqueous solution (2 times), saturated NaHCO.sub.3 aqueous solution
(2 times) and brine (2 times), dried over anhydrous MgSO.sub.4,
filtered and concentrated in vacuo. The crude product was purified
by column chromatography on silica, eluting with EtOAc/hexane 1:2.
The title compound was obtained as a solid. Yield=3.90 g, 61%.
Rf=0.24 (silica, EtOAc/hexane 1:2). MS (ES): 445.2; Calc. MW=445.4,
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.: 7.67-7.76 (m, 3H),
7.53-7.59 (m, 2H), 7.48 (s, 1H), 7.44 (s, 1H), 7.30-7.32 (m, 2H),
7.20 (m, 1H), 7.09-7.14 (m, 1H), 4.65 (t, 1H), 4.50 (t, 1H), 3.98
(dd, 1H), 3.02 (s, 3H).
[0284] Preparation 7:
[0285]
1-Methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoyl)indole
[0286] A solution of
1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chlorobenzoy- l)indoline
(350 mg) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (356 mg) in
dioxane (6 mL) was refluxed under N.sub.2 for about 6 hours and
then heated at about 95.degree. C. overnight. The solvent was
removed. The residue was purified by column chromatography on
silica, eluting with EtOAc/hexane, 1:4. The title compound was
obtained as a solid. MS(ES): 443.2, calc. Mw=443.4. Rf=0.38,
silica, EtOAc/hexane, 1:2. 195 mg, yield: 56%.
[0287] Preparation 8:
[0288] 3-(3-Chlorophenyl)-5-(4-chlorobenzoyl)indole
[0289] To a solution of
1-methylsulfonyl-3-(3-chlorophenyl)-5-(4-chloroben- zoyl)indole
(11.44 g, 25.76 mmol, see Preparation 7) in anhydrous THF (150 ml)
was added tetrabutylammonium fluoride (33.5 ml, 1.0 M solution in
THF). The resulting solution was refluxed under nitrogen for about
3 hrs. The solvent was removed under reduced pressure. The residue
was dissolved in EtOAc and washed with 1N HCl (2 times), saturated
NaHCO.sub.3 aqueous solution (2 times) and brine (2 times), dried
over anhydrous MgSO.sub.4, filtered and concentrated in vacuo. The
residue was purified by column chromatography on silica, eluting
with EtOAc/hexane 1:4. The title compound was obtained as a yellow
solid. Yield=8.1 g, 86%.
* * * * *