U.S. patent application number 10/226815 was filed with the patent office on 2003-07-31 for method of using 5-(arysulfonyl)-, 5-(arylsulfanyl)-and 5-(arylsulfanyl)thiazolidine-2,4-diones for inhibition of farnesyl-protein transferase.
This patent application is currently assigned to American Cyanamid Company. Invention is credited to Ayral-Kaloustian, Semiramis, Birnberg, Gary H., Cheung, Katherine, Epstein, Joseph William, Macewan, Gloria, Salaski, Edward James.
Application Number | 20030144301 10/226815 |
Document ID | / |
Family ID | 27616371 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030144301 |
Kind Code |
A1 |
Ayral-Kaloustian, Semiramis ;
et al. |
July 31, 2003 |
Method of using 5-(arysulfonyl)-, 5-(arylsulfanyl)-and
5-(arylsulfanyl)thiazolidine-2,4-diones for inhibition of
farnesyl-protein transferase
Abstract
This invention relates to a method of using novel
5-(arylsulfonyl)-, 5-(arylsulfinyl)- and
5-(arylsulfanyl)thiazolidine-2,4-diones of Formula (1), wherein Ar,
Ar', R.sub.6, m and n are as defined in the specification as
inhibitors of Ras FPTase, and may be used as an alternative to, or
in conjunction with, traditional cancer therapy for treating ras-
oncogene-dependent tumors, such as cancers of the pancreas, colon,
bladder, and thyroid. 1
Inventors: |
Ayral-Kaloustian, Semiramis;
(Tarrytown, NY) ; Epstein, Joseph William;
(Monroe, NY) ; Birnberg, Gary H.; (Tuxedo Park,
NY) ; Salaski, Edward James; (Tenafly, NJ) ;
Macewan, Gloria; (Monroe, NY) ; Cheung,
Katherine; (Paramus, NJ) |
Correspondence
Address: |
Daniel B. Moran
Five Giralda Farms
Madison
NJ
07940
US
|
Assignee: |
American Cyanamid Company
Madison
NJ
|
Family ID: |
27616371 |
Appl. No.: |
10/226815 |
Filed: |
August 23, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60314621 |
Aug 24, 2001 |
|
|
|
Current U.S.
Class: |
514/256 ;
514/151; 514/314; 514/342; 514/369 |
Current CPC
Class: |
A61K 31/426 20130101;
A61K 31/4439 20130101; A61K 31/427 20130101; A61K 31/4709
20130101 |
Class at
Publication: |
514/256 ;
514/314; 514/342; 514/369; 514/151 |
International
Class: |
A61K 031/506; A61K
031/4709; A61K 031/4439; A61K 031/427; A61K 031/655 |
Claims
What we claim is:
1. A method of treating, inhibiting or controlling a ras-associated
disease by inhibiting farnesyl-protein transferase(FPTase) enzyme
in a mammal in need thereof which comprises administering to said
mammal an effective amount of a compound of Formula (I): 46wherein:
Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,
5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl,
substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl,
2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl,
2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of
the formula: 47R.sub.1 is hydrogen, fluoro, bromo, chloro, iodo,
alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon
atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy,
phenoxy, or benzyloxy; R.sub.2 is hydrogen, fluoro, bromo, chloro,
iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,
trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or 2; R.sub.6 is
hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl,
imidazolylpropyl, or --CO.sub.2Y; Y is 2-methoxyethyl, alkyl is 1
to 6 carbon atoms, benzyl, or substituted benzyl; W is 48E- and Z-
--CH.dbd.CH--, --CONH--, --CONHCH.sub.2--, --CONHCH.sub.2CH.sub.2--
or --CH.sub.2--CH.sub.2--; n is an integer of 1 to 9; Ar' is
thienyl, pyridinyl or a moiety of the formula 49R.sub.3, R.sub.4,
R.sub.5, are independently selected from hydrogen, alkoxy of 1 to 6
carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro,
iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy,
trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl,
--CO.sub.2R.sub.7, --CONHR.sub.8, --CH.sub.2CONHR.sub.9,
--NHCO.sub.2R.sub.10, --NHCOR.sub.11, and --NHCONHR.sub.12; R.sub.7
is selected from H, and alkyl of 1 to 6 carbon atoms, R.sub.8 is
selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.9 is
selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.10 is
selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl,
and chlorophenyl; R.sub.11 is selected from alkyl of 1 to 6 carbon
atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon
atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;
R.sub.12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6
carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon
atoms)phenyl; provided that when W is 50n is other than 2 or
pharmaceutically acceptable salts thereof.
2. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 1, m is 2, W is 51or a pharmaceutically acceptable salt
thereof.
3. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3, m is 2, W is 52or a pharmaceutically acceptable salt
thereof.
4. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3-6, m is 2, W is 53or a pharmaceutically acceptable salt
thereof.
5. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 1, m is 2, W is 54Ar is a moiety of the formula 55or a
pharmaceutically acceptable salt thereof.
6. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3, m is 2, W is 56Ar is a moiety of the formula 57or a
pharmaceutically acceptable salt thereof.
7. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3-6, m is 2, W is 58Ar is a moiety of the formula 59or a
pharmaceutically acceptable salt thereof.
8. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 1, m is 2, W is 60Ar is a moiety of the formula 61Ar' is a
moiety of the formula 62or a pharmaceutically acceptable salt
thereof.
9. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3 , m is 2, W is 63Ar is a moiety of the formula 64Ar' is a
moiety of the formula 65or a pharmaceutically acceptable salt
thereof.
10. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3-6, m is 2, W is 66Ar is a moiety of the formula 67Ar' is a
moiety of the formula 68or a pharmaceutically acceptable salt
thereof.
11. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 1, m is 2, W is 69Ar is a moiety of the formula 70Ar' is thienyl
or pyridinyl; or a pharmaceutically acceptable salt thereof.
12. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3, m is 2, W is 71Ar is a moiety of the formula 72Ar' is thienyl
or pyridinyl; or a pharmaceutically acceptable salt thereof.
13. The method according to claim 1 wherein R.sub.6 is hydrogen, n
is 3-6, m is 2, W is 73Ar is a moiety of the formula 74Ar' is
thienyl or pyridinyl; or a pharmaceutically acceptable salt
thereof.
14. The method according to claim 1 wherein m is 2, Ar is phenyl
substituted in the 4-position by iodo, methoxy, trifluoromethoxy,
4-pyridyloxy; Ar' is phenyl substituted in the 2-position by chloro
or methyl, and in the 5-position by amino, chloro, a carbamic acid
ester, a substituted carboxamide group, or in the 4-position by
nitro or a carbamic acid ester; W is an acetylenic group, and n is
the integer 3 or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 wherein the compound is selected from the
group consisting of
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfany-
l)thiazolidine-2,4-dione,
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphe-
nylsulfanyl)thiazolidine-2,4-dione,
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-
-(4-methoxy-phenylsulfanyl)thiazolidine-2,4-dione,
5-(4-Methoxyphenylsulfa-
nyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)
thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphe-
nylsulfonyl)thiazolidine-2,4-dione,
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-- methoxyphenylsulfonyl)
thiazolidine-2,4-dione, 5-[11-(4-Chlorophenyl)undec-
-10-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-
-2,4-dione,
5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-
thiazolidine-2,4-dione,
5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenz-
enesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-
-tolylsulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-
-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent--
4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidin-
e-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)t-
hiazolidine-2,4-dione,
N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxoth-
iazolidine-5-sulfonyl}phenyl)acetamide,
5-[5-(4-Chlorophenyl)pent-4-ynyl]--
5-(quinoline-8-sulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent--
4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazolidine-2,4-dione,
5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thiazolid-
ine-2,4-dione,
5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-yn-
yl]thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalen-
e-1-sulfonyl)thiazolidine-2,4-dione,
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl-
]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolid-
ine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy-
)benzenesulfonyl]thiazolidine-2,4-dione,
5-[5-(2,4-Dichlorophenyl)pent-4-y-
nyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazolidine-
-2,4-dione,
5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)t-
hiazolidine-2,4-dione,
5-(4-lodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent--
4-ynyl]thiazolidine-2,4-dione, 5-(4-Methoxybenzene
sulfonyl)-5-[5-(4-nitro- phenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-(4-Methoxybenzene
sulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione-
,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]--
thiazolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phe-
noxybenzenesulfonyl)thiazolidine-2,4-dione,
5-(4-lodobenzenesulfonyl)-5-[5-
-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thia-
zolidine-2,4-dione,
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthale-
ne-2-sulfonyl)thiazolidine-2,4-dione,
5-[5-(2-Methyl-4-nitrophenyl)pent-4--
ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]thiazolidine-2,4-dione,
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thi-
azolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitroph-
enyl)-pent-4-ynyl]thiazolidine-2,4-dione,
5-(4-lodobenzenesulfonyl)-5-[5-(-
2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]th-
iazolidine-2,4-dione, p1
5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-me-
thoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(2,5-Dimethylphenyl)pent-
-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazol-
idine-2,4-dione,
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-
sulfonyl)thiazolidine-2,4-dione,
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(-
4-iodobenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(5-Chloro-2-methylpheny-
l)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesu-
lfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]--
5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiaz-
olidine-2,4-dione,
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxy-
benzene-sulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Bromo-2-methy-phenyl)pent-
-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazo-
lidine-2,4-dione,
(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin--
5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
(3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pe-
nt-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
N-tert-Butyl-3-{5-[5-(4-i-
odo-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benza-
mide,
(3-{5-[5-(4-lodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-yn-
yl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,
(4-{5-[5-(4-Methoxybenz-
enesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbam-
ic Acid tert-Butyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothi-
azolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl
Ester,
(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl-
}-3-trifluoromethylphenyl)-carbamic Acid tert-Butyl Ester,
N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazol-idin-5--
yl]pent-1-ynyl}-4-methyl-benzamide,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-t-
rifluoromethylphenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]t-
hiazolidine-2,4-dione,
3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazo-
lidin-5-yl]pent-1-ynyl}-4-methylbenzoic Acid Methyl Ester,
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazol-
idine-2,4-dione,
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfon-
yl)thiazolidine-2,4-dione,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-th-
iazolidin-5-yl]pent-1-ynyl}benzonitrile,
5-[5-(4-Methanesulfonylphenyl)-pe-
nt-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-
-3-methylbenzoic Acid Methyl Ester,
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-p-
yrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,
5-(4-lodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazol-
idine-2,4-dione,
5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluorometh-
oxybenzenesulfonyl)thiazolidine-2,4-dione,
5-(3-Methoxybenzenesulfonyl)-5--
(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,
5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,-
4-dione,
5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiaz-
olidine-2,4-dione,
5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-yn-
yl)thiazolidine-2,4-dione,
5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-su-
lfonyl)thiazolidine-2,4-dione,
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene--
4-sulfonyl)thiazolidine-2,4-dione,
5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(t-
oluene-4-sulfonyl)thiazolidine-2,4-dione,
5-(3-Biphenyl-4-yl-prop-2-ynyl)--
5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dio-
ne,
5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-
thiazolidine-2,4-dione,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiaz-
olidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl-
}-4-methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl-
}-4-methylphenyl)carbamic Acid 4-Chloro-phenyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl-
}-4-methylphenyl)carbamic Acid Methyl Ester,
(3-{5-[5-(4-Methoxybenzenesul-
fonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic
Acid Isopropyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-
-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Neopentyl Ester,
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl-
}-4-methylphenyl)carbamic Acid Butyl Ester,
(3-{5-[5-(4-Methoxybenzenesulf-
onyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic
Acid Isobutyl,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidi-
n-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1--
pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,
N-[3-(5-{5-[(4-Methoxyph-
enyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-
-2,2-dimethylpropanamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-
-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,
N-Benzyl-N'-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolid-
in-5-yl}-1-pentynyl)-4-methylphenyl]urea,
N-(4-Methoxyphenyl)-N'-[3-(5-{5-- [(4-methoxy
phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
-methylphenyl]urea,
N-(4-Chlorophenyl)-N'-[3-(5-{5-[(4-methoxy-phenyl)sulf-
onyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1--
pentynyl)-methylphenyl]-N'-(4-methylphenyl)urea,
4-Chloro-N-[3-(5-{5-[(4-m-
ethoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-meth-
ylphenyl]benzamide,
4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4--
dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1--
pentynyl)-4-methylphenyl][1,1'-biphenyl]-4-carboxamide,
4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thia-
zolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-th-
iazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfon-
yl)-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4--
dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}--
1,3-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyr-
idinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,
5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,-
3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thien-
ylsulfonyl)-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentyn-
yl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfon-
yl}-1,3-thiazolidine-2,4-dione,
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[-
5-(2-pyridinyl)-2-thienyl]sulfonyl-1,3-thiazolidine-2,4-dione,
tert-Butyl
3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-
-pentynyl)-4-methylphenylcarbamate, tert-Butyl
3-{5-[2,4-dioxo-5-(2-thieny-
l-sulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,
tert-Butyl
3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazol-
idin-5-yl}-1-pentynyl)-4-methylphenylcarbamate, tert-Butyl
3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5--
yl)-1-pentynyl]-4-methylphenyl-carbamate, tert-Butyl
3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2-thienyl]sulfonyl}-1,3-thiazolidin--
5yl)-1-pentynyl]-4-methylphenyl-carbamate,
N-(tert-Butyl)-3-(5-{5-[(5-chlo-
ro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methy-
lbenzamide,
N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiaz-
olidin-5-yl]-1-pentynyl}-4-methylbenzamide,
N-(tert-Butyl)-3-(5-{5-[(3,4-d-
imethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-met-
hylbenzamide,
N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl-
]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-
-3-methylbenzoic Acid,
N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)--
2,4-dioxo-thiazolidin-4-yl]propionamide,
N-[2-(4-Chlorophenyl)ethyl]-3-[5--
(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,
5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiazolidin-
e-2,4-dione,
5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesul-
fonyl)thiazolidine-2,4-dione,
5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxyben- zenesulfonyl)
thiazolidine-2,4-dione, 5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(-
4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,
5-(3-Phenylallyl)-5-(tolu- ene-4-sulfonyl)thiazolidine-2,4-dione,
Enantiomer of(3-{5-[5-(4-Methoxyben- zene
sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carba-
mic Acid tert-Butyl Ester (less polar), Enantiomer
of(3-{5-[5-(4-Methoxybe- nzene
sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carb-
amic Acid tert-Butyl Ester (more polar),
5-[5-(4-Chlorophenyl)pent-4-ynyl]-
-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione, Benzyl
5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-m-
ethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
4-Nitrobenzyl 5-[(4-methoxyphenyl)
sulfonyl]-5-{5-[2-methyl-5-({[(4-nitro-
carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylat-
e, Methyl
5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[-
(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Isopropyl
5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl-
)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Neopentyl
5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)-
carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxyla-
te, Butyl
5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(-
4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
Isobutyl
5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)--
5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxy-
benzenesulfonyl)thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]--
5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sul-
fonyl)-thiazolidine-2,4-dione,
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodo-
benzenesulfonyl)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione, and
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-di-
oxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester.
16. The method of claim 1 wherein the compound is selected from the
group consisting of
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfony-
l)thiazolidine-2,4-dione,
5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2--
ynyl]thiazolidine-2,4-dione,
5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]thi- azolidine-2,4-dione,
5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-
thiazolidine-2,4-dione,
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-be-
nzenesulfonyl)thiazolidine-2,4-dione,
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-
-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,
5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidi-
ne-2,4-dione,
5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)th-
iazolidine-2,4-dione,
5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]th-
iazolidine-2,4-dione,
5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-
thiazolidine-2,4-dione,
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-b-
enzenesulfonyl)thiazolidine-2,4-dione,
5-(Naphthalene-2-sulfonyl)-5-(3-phe-
nyl-prop-2-ynyl)thiazolidine-2,4-dione,
5-(Toluene-4-sulfonyl)-5-[3-(4-tri-
fluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,
5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2-
,4-dione,
5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazol-
idine-2,4-dione,
5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2--
ynyl]thiazolidine-2,4-dione,
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-p-
henyl)-prop-2-ynyl]thiazolidine-2,4-dione,
5-[3-(4-Chloro-phenyl)-prop-2-y-
nyl]-5-(toluene-3-sulfonyl)thiazolidine-2,4-dione,
5-[3-(3-Chloro-phenyl)--
prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,
5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dio-
ne,
5-Benzenesulfonyl-5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]th-
iazolidine-2,4-dione,
5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5-
-(toluene-4-sulfonyl)thiazolidine-2,4-dione,
5-Benzenesulfonyl-5-[3-(3-chl-
oro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,
5-[3-(4-Chlorophenyl)-2-pr-
opynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione,
5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)thiazolidi-
ne-2,4-dione,
5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-
-prop-2-ynyl]thiazolidine-2,4-dione,
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-
-(quinoline-2-sulfonyl)thiazolidine-2,4-dione,
5-[3-(3,5-Bis-trifluorometh-
yl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione, and
5-[3-(4-Chloro-phenyl)--
prop-2-ynyl]-5-(p-tolylsulfanyl)thiazolidine-2,4-dione or a
pharmaceutically acceptable salt thereof.
17. The method of claim 1 wherein the ras-associated disease in
mammals is selected from the group consisting of cancers of the
pancreas, breast, lung, colon, epidermis, prostate, bladder,
thyroid,myelodysplastic tumors and myeloid leukemia.
18. The method of claim 1 wherein the ras-associated disease in
mammals is selected from metastasis, suppressing angiogenesis, and
inducing apoptosis.
19. The method of claim 1 wherein the ras-associated proliferative
disease in mammals is restenosis, neurofibromatosis, endometriosis,
and psoriasis.
20. The method of claim 1 wherein the ras-associated disease in
mammals is prenyl modifications or proteins.
Description
[0001] "This application claims priority from copending provisional
application Serial No. 60/314,621 filed Aug. 24, 2001 the entire
disclosures of which is hereby incorporated by reference."
FIELD OF THE INVENTION
[0002] This invention relates to a method of using novel
5-(arylsulfonyl)-, 5-(arylsulfinyl)- and
5-(arylsulfanyl)thiazolidine-2,4- -diones of formula (I) as
inhibitors of Ras FPTase, and may be used as an alternative to, or
in conjunction with, traditional cancer therapy for treating ras-
oncogene-dependent tumors, such as cancers of the pancreas, colon,
bladder, and thyroid. Compounds in the invention may also be useful
for controlling metastasis, suppressing angiogenesis, inducing
apoptosis, and in treating Ras-associated proliferative diseases
other than cancer, such as restenosis, neuro-fibromatosis,
endometriosis, and psoriasis. These compounds may also inhibit
prenylation of proteins other than Ras, and thus be effective in
the treatment of diseases associated with other prenyl
modifications of proteins.
BACKGROUND OF THE INVENTION
[0003] Mammalian H-, K-, and N-Ras proteins, encoded by H-, K-, and
N-ras proto-oncogenes, respectively, are 21 kD GTP-binding proteins
which possess intrinsic GTPase activity and play a fundamental role
in cell proliferation and differentiation (G. L. Bolton, J. S.
Sebolt-Leopold, and J. C. Hodges, Annu. Rep. Med. Chem., 1994, 29,
165; R. J. A. Grand in "New Molecular Targets in Cancer
Chemotherapy" J. D. Kerr, and P. Workman, Eds., CRC Press, Boca
Raton, Fla., 1994, p. 97). Specific mutations in the ras gene
impair GTPase activity of Ras, leading to uninterrupted growth
signals and to the transformation of normal cells into malignant
phenotypes. Mutant ras oncogenes are found in approximately 25% of
all human cancers, including 90% of pancreatic, 50% of colon, and
50% of thyroid tumors (J. L. Bos, Cancer Res., 1989, 49, 4682). It
has been shown that normal cells transfected with mutant ras gene
become cancerous and that unfarnesylated, cytosolic mutant Ras
protein does not anchor in cell membranes and cannot induce this
transformation (J. F. Hancock, H. Paterson, and C. J. Marshall,
Cell, 1990, 63, 133). Posttranslational modification and plasma
membrane association of mutant Ras is essential for this
transforming activity. The first and required step in the
processing of Ras is farnesylation at the cysteine residue of its
carboxyl terminal motif, CAAX (C=Cys-186, A=aliphatic amino acid,
X=usually methionine, serine or glutamine). Since its
identification, the enzyme farnesyl-protein transferase (FPTase)
that catalyzes this first processing step has emerged as a
promising target for therapeutic intervention (H. -W. Park, S. R.
Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese, Science,
1997, 275,1800; P. J. Casey, P. A. Solski, C. J. Der, and J. E.
Buss, Proc. Natl. Acad. Sci. U.S.A., 1989, 86, 8323; S.
Ayral-Kaloustian and J. S. Skotnicki, Annu. Rep. Med. Chem., 1996,
31, 165, and references therein). Major milestones have been
achieved with small molecules, such as mimics of the tetrapeptide
CAAX and analogs of farnesyl pyrophosphate, that show efficacy
without toxicity in vitro as well as in mouse models bearing
ras-dependent tumors or human xenografts with H-, N-, or K-ras
mutations (S. Ayral-Kaloustian and J. S. Skotnicki, Annu. Rep. Med.
Chem., 1996, 31, 165, and references therein; T. M. Williams, Exp.
Opin. Ther. Patents, 1998, 8, 553, and references therein). Several
low-molecular weight compounds that inhibit FPTase have entered
Phase I trials in humans (SCH-66336, Pharmaprojects, 1998, No.
5128; R-115777, Pharmaprojects, 1998, No. 5532).
[0004]
5-[3-aryl-prop-2-ynyl]-5-(arylsulfonyl)thiazolidine-2,4-diones and
5-[3-aryl-prop-2-ynyl]-5-(arylsulfanyl)thiazolidine-2,4-diones
which possess antihyperglycemic activity, are reported in U.S. Pat.
Nos. 5,574,051 and 5,605,918.
[0005] Accordingly, there is still a need for drugs for treating
and preventing cancer. In particular, there is a need for drugs
which inhibit or treat the growth of tumors expressing an activated
Ras oncogene and which include cancers of the pancreas, colon,
bladder and thyroid.
BRIEF SUMMARY OF THE INVENTION
[0006] This invention is concerned with a method of treating,
inhibiting or controlling a ras-associated disease by inhibiting
farnesyl-protein transferase(FPTase) enzyme in a mammal in need
thereof, which comprises administering to said mammal an effective
amount of a compound of Formula (I): 2
[0007] wherein:
[0008] Ar is 1 -naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,
5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl,
substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl,
2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl,
2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of
the formula: 3
[0009] R.sub.1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1
to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy,
azido, nitro, acetamido, trifluoromethoxy, phenoxy, or
benzyloxy;
[0010] R.sub.2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1
to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy,
phenoxy, or benzyloxy;
[0011] m is 0, 1 or 2;
[0012] R.sub.6 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl,
substituted benzyl, imidazolylpropyl, or --CO.sub.2Y;
[0013] Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl,
or substituted benzyl; W is 4
[0014] E- and Z- --CH.dbd.CH--, --CONH--, --CONHCH.sub.2--,
--CONHCH.sub.2CH.sub.2-- or --CH.sub.2--CH.sub.2--;
[0015] n is an integer of 1 to 9;
[0016] Ar' is thienyl, pyridinyl or a moiety of the formula 5
[0017] R.sub.3, R.sub.4, R.sub.5, are independently selected from
hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon
atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido,
cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy,
methanesulphonyl, 1-pyrrolyl, --CO.sub.2R.sub.7, --CONHR.sub.8,
--CH.sub.2CONHR.sub.9, --NHCO.sub.2R.sub.10, --NHCOR.sub.11, and
--NHCONHR.sub.12;
[0018] R.sub.7 is selected from H, and alkyl of 1 to 6 carbon
atoms,
[0019] R.sub.8 is selected from H, and alkyl of 1 to 6 carbon
atoms;
[0020] R.sub.9 is selected from H, and alkyl of 1 to 6 carbon
atoms;
[0021] R.sub.10 is selected from alkyl of 1 to 6 carbon atoms,
benzyl, nitrobenzyl, and chlorophenyl;
[0022] R.sub.11 is selected from alkyl of 1 to 6 carbon atoms,
benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl,
alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;
[0023] R.sub.12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1
to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon
atoms)phenyl;
[0024] provided that when W is 6
[0025] n is other than 2 or pharmaceutically acceptable salts
thereof.
[0026] Among the preferred groups of compounds of Formula (I) of
this invention including pharmaceutically acceptable salts thereof
are those in the subgroups below, wherein the other variables of
Formula (I) in the subgroups are as defined above wherein:
[0027] a.) R.sub.6 is hydrogen, n is 1, m is 2, W is 7
[0028] b.) R.sub.6 is hydrogen, n is 3, m is 2, W is 8
[0029] c.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is 9
[0030] d.) R.sub.6 is hydrogen, n is 1, m is 2, W is 10
[0031] Ar is a moiety of the formula 11
[0032] e.) R.sub.6 is hydrogen, n is 3, m is 2, W is 12
[0033] Ar is a moiety of the formula 13
[0034] f.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is 14
[0035] Ar is a moiety of the formula 15
[0036] g.) R.sub.6 is hydrogen, n is 1, m is 2, W is 16
[0037] Ar is a moiety of the formula 17
[0038] Ar' is a moiety of the formula
[0039] h.) R6 is hydrogen, n is 3, m is 2, W is 18
[0040] Ar is a moiety of the formula 19
[0041] Ar' is a moiety of the formula 20
[0042] i.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is 21
[0043] Ar is a moiety of the formula 22
[0044] Ar' is a moiety of the formula
[0045] j.) R.sub.6 is hydrogen, n is 1, m is 2, W is 23
[0046] Ar is a moiety of the formula 24
[0047] Ar' is thienyl or pyridinyl;
[0048] k.) R.sub.6 is hydrogen, n is 3, m is 2, W is 25
[0049] Ar is a moiety of the formula 26
[0050] Ar' is thienyl or pyridinyl;
[0051] l.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is 27
[0052] Ar is a moiety of the formula 28
[0053] Ar' is thienyl or pyridinyl;
[0054] Additionally preferred compounds of this invention include
compounds of Formula (I) in which m is 2, Ar is phenyl substituted
in the 4-position by iodo, methoxy, trifluoromethoxy, 4-pyridyloxy;
Ar' is phenyl substituted in the 2-position by chloro or methyl,
and in the 5-position by amino, chloro, a carbamic acid ester, a
substituted carboxamide group, or in the 4-position by nitro or a
carbamic acid ester; W is an acetylenic group, and n is the integer
3.
[0055] Specifically preferred compounds of this invention according
to Formula (I) for treating or controlling ras oncogene-dependent
tumors and associated proliferative diseases in warm-blooded
animals preferably mammals, most preferably humans in need thereof
are the following compounds or a pharmaceutically acceptable salt
thereof:
[0056]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)thiazo-
lidine-2,4-dione,
[0057]
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)thiazol-
idine-2,4-dione,
[0058]
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)th-
iazolidine-2,4-dione,
[0059]
5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazoli-
dine-2,4-dione,
[0060]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)thiazol-
idine-2,4-dione,
[0061]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazo-
lidine-2,4-dione,
[0062]
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)thiazol-
idine-2,4-dione,
[0063] 5-[11
-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenyl-sulfonyl)t-
hiazolidine-2,4-dione,
[0064]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazo-
lidine-2,4-dione,
[0065]
5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiaz-
olidine-2,4-dione,
[0066]
5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiaz-
olidine-2,4-dione,
[0067]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2-
,4-dione,
[0068]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazoli-
dine-2,4-dione,
[0069]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazo-
lidine-2,4-dione,
[0070]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiaz-
olidine-2,4-dione,
[0071]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazol-
idine-2,4-dione,
[0072]
N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sul-
fonyl}phenyl)acetamide,
[0073]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)thiazolid-
ine-2,4-dione,
[0074]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazol-
idine-2,4-dione,
[0075]
5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thi-
azolidine-2,4-dione,
[0076]
5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]thiaz-
olidine-2,4-dione,
[0077] 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1
-sulfonyl)thiazolidine-2,4-dione,
[0078]
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl-
)thiazolidine-2,4-dione,
[0079]
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thi-
azolidine-2,4-dione,
[0080]
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzene-
sulfonyl]thiazolidine-2,4-dione,
[0081]
5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)t-
hiazolidine-2,4-dione,
[0082]
5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazo-
lidine-2,4-dione,
[0083]
5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazo-
lidine-2,4-dione,
[0084]
5-(4-lodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolid-
ine-2,4-dione,
[0085] 5-(4-Methoxybenzene
sulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiaz-
olidine-2,4-dione,
[0086] 5-(4-Methoxybenzene
sulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-y-
nyl]thiazolidine-2,4-dione,
[0087]
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-y-
nyl]thiazolidine-2,4-dione,
[0088] 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]
-5-(4-phenoxybenzenesulfo- nyl)thiazolidine-2,4-dione,
[0089]
5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-
thiazolidine-2,4-dione,
[0090]
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl-
)thiazolidine-2,4-dione
[0091]
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl-
)thiazolidine-2,4-dione,
[0092]
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-be-
nzenesulfonyl]-thiazolidine-2,4-dione,
[0093]
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfo-
nyl)thiazolidine-2,4-dione,
[0094]
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-yn-
yl]thiazolidine-2,4-dione,
[0095]
5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]-
thiazolidine-2,4-dione,
[0096]
5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-y-
nyl]-thiazolidine-2,4-dione,
[0097]
5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfo-
nyl)thiazolidine-2,4-dione,
[0098]
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thia-
zolidine-2,4-dione,
[0099]
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)t-
hiazolidine-2,4-dione,
[0100]
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)t-
hiazolidine-2,4-dione,
[0101]
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thia-
zolidine-2,4-dione,
[0102]
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfo-
nyl)thiazolidine-2,4-dione,
[0103]
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxyben-
zenesulfonyl)thiazolidine-2,4-dione,
[0104]
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxyben-
zenesulfonyl)thiazolidine-2,4-dione,
[0105]
5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfony-
l)thiazolidine-2,4-dione,
[0106]
5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfo-
nyl)thiazolidine-2,4-dione,
[0107]
5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-ethoxybenzenesulfony-
l)thiazolidine-2,4-dione,
[0108]
5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-
thiazolidine-2,4-dione,
[0109]
(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
[0110]
(3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-
-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,
[0111]
N-tert-Butyl-3-{5-[5-(4-iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-
-yl]pent-1-ynyl}-4-methylbenzamide,
[0112]
(3-{5-[5-(4-lodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-y-
nyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,
[0113]
(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-
-1-ynyl}-3-methylphenyl)carbamic Acid tert-Butyl Ester,
[0114]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,
[0115]
(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-3-trifluoromethylphenyl)-carbamic Acid tert-Butyl
Ester,
[0116]
N-tert-Butyl-3-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidi-
n-5-yl]pent-1-ynyl}-4-methyl-benzamide,
[0117]
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-y-
nyl]thiazolidine-2,4-dione,
[0118]
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4--
ynyl]-thiazolidine-2,4-dione,
[0119]
3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent--
1-ynyl}-4-methylbenzoic Acid Methyl Ester,
[0120]
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)t-
hiazolidine-2,4-dione,
[0121]
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazol-
idine-2,4-dione,
[0122]
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent--
1-ynyl}benzonitrile,
[0123]
5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)t-
hiazolidine-2,4-dione,
[0124]
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
-ynyl}-3-methylbenzoic Acid Methyl Ester,
[0125]
5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl-
]thiazolidine-2,4-dione,
[0126]
5-(4-lodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]t-
hiazolidine-2,4-dione,
[0127]
5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzene-
sulfonyl)thiazolidine-2,4-dione,
[0128]
5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazol-
idine-2,4-dione,
[0129]
5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolid-
ine-2,4-dione,
[0130]
5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazol-
idine-2,4-dione,
[0131]
5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)thiazolid-
ine-2,4-dione,
[0132]
5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine--
2,4-dione,
[0133]
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine--
2,4-dione,
[0134]
5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidi-
ne-2,4-dione,
[0135]
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)thiazol-
idine-2,4-dione,
[0136]
5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2-
,4-dione,
[0137]
5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfon-
yl)thiazolidine-2,4-dione, (
[0138]
3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,
[0139]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester,
[0140]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid 4-Chloro-phenyl Ester,
[0141]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid Methyl Ester,
[0142]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid Isopropyl Ester,
[0143]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid Neopentyl Ester,
[0144]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid Butyl Ester,
[0145]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent--
1-ynyl}-4-methylphenyl)carbamic Acid Isobutyl,
[0146]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,
[0147]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,
[0148]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,
[0149]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,
[0150]
N-Benzyl-N'-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thi-
azolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
[0151]
N-(4-Methoxyphenyl)-N'-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dio-
xo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
[0152]
N-(4-Chlorophenyl)-N'-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-diox-
o-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,
[0153]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-methylphenyl]-N'-(4-methylphenyl)urea,
[0154]
4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thia-
zolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
[0155]
4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thi-
azolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
[0156]
N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5--
yl}-1-pentynyl)-4-methylphenyl][1,1'-biphenyl]-4-carboxamide,
[0157]
4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-
-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,
[0158]
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]--
1,3-thiazolidine-2,4-dione,
[0159]
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazol-
idine-2,4-dione,
[0160]
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-
-1,3-thiazolidine-2,4-dione,
[0161]
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulf-
onyl}-1,3-thiazolidine-2,4-dione,
[0162]
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sul-
fonyl}-1,3-thiazolidine-2,4-dione,
[0163]
5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentyn-
yl]-1,3-thiazolidine-2,4-dione,
[0164]
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thi-
azolidine-2,4-dione,
[0165]
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfo-
nyl]-1,3-thiazolidine-2,4-dione,
[0166]
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]-
sulfonyl),1,3-thiazolidine-2,4-dione,
[0167]
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl-
]sulfonyl}-1,3-thiazolidine-2,4-dione,
[0168] tert-Butyl
3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-th-
iazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,
[0169] tert-Butyl
3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5--
yl]-1-pentyn-yl}-4-methylphenylcarbamate,
[0170] tert-Butyl
3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-th-
iazolidin-5-yl}-1-pentynyl)-4-methylphenyl-carbamate,
[0171] tert-Butyl
3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1-
,3-thiazolidin-5yl)-1-pentynyl]-4-methylphenyl-carbamate,
[0172] tert-Butyl
3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}--
1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,
[0173]
N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-
-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,
[0174]
N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidi-
n-5-yl]-1-pentynyl}-4-methylbenzamide,
[0175]
N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,-
3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,
[0176]
N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfon-
yl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,
[0177]
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
-ynyl}-3-methylbenzoic Acid,
[0178]
N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazo-
lidin-4-yl]propionamide,
[0179]
N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dio-
xo-thiazolidin-5-yl]propionamide,
[0180]
5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiaz-
olidine-2,4-dione,
[0181]
5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)-
thiazolidine-2,4-dione,
[0182]
5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)thiazolidi-
ne-2,4-dione,
[0183]
5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazo-
lidine-2,4-dione,
[0184]
5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,
[0185] Enantiomer of(3-(5-[5-(4-Methoxybenzene
sulfonyl)-2,4-dioxothiazoli-
din-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester
(less polar),
[0186] Enantiomer of(3-{5-[5-(4-Methoxybenzene
sulfonyl)-2,4-dioxothiazoli-
din-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester
(more polar),
[0187]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)thiazo-
lidine-2,4-dione,
[0188] Benzyl
5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4--
ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxyla-
te,
[0189] 4-Nitrobenzyl
5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4--
nitrobenzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolid-
ine-3-carboxylate,
[0190] Methyl
5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-
-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
[0191] Isopropyl
5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent--
4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxy-
late,
[0192] Neopentyl
5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopent-
yloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-car-
boxylate,
[0193] Butyl
5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-
-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,
[0194] Isobutyl
5-(5-{5-[(isobutoxycarbonyl)amino]-2-methylphenyl}pent-4-y-
nyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylat-
e,
[0195]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-m-
ethoxybenzenesulfonyl)thiazolidine-2,4-dione,
[0196]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-me-
thyl-thiazolidine-2,4-dione,
[0197]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-
-4-sulfonyl)thiazolidine-2,4-dione,
[0198]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-ni-
trobenzyl)thiazolidine-2,4-dione, and
[0199]
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)--
2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester.
[0200] Additionally specifically preferred compounds of this
invention according to Formula (I) for treating or controlling ras
oncogene-dependent tumors and associated proliferative diseases in
warm-blooded animals preferably mammals, most preferably humans in
need thereof are the following compounds or a pharmaceutically
acceptable salt thereof:
[0201]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)thiazo-
lidine-2,4-dione,
[0202]
5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2-
,4-dione,
[0203]
5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]thiazolidine-2,4-dione,
[0204]
5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2-
,4-dione,
[0205]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)thi-
azolidine-2,4-dione,
[0206]
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thi-
azolidine-2,4-dione,
[0207]
5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thia-
zolidine-2,4-dione,
[0208]
5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolid-
ine-2,4-dione,
[0209]
5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]thiazolidine-2,4--
dione,
[0210]
5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,-
4-dione,
[0211]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)th-
iazolidine-2,4-dione,
[0212]
5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-
-dione,
[0213]
5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-
thiazolidine-2,4-dione,
[0214]
5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazoli-
dine-2,4-dione,
[0215]
5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidi-
ne-2,4-dione,
[0216]
5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiaz-
olidine-2,4-dione,
[0217]
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]thi-
azolidine-2,4-dione,
[0218]
5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5(toluene-3-sulfonyl)thiazolidin-
e-2,4-dione,
[0219]
5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]thiazolidine-2-
,4-dione,
[0220]
5-Benzenesulfonyl-5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-
thiazolidine-2,4-dione,
[0221]
5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5(toluene-4-sulfo-
nyl)thiazolidine-2,4-dione,
[0222]
5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]thiazolidine-2-
,4-dione,
[0223]
5-[3(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-t-
hiazolidinedione,
[0224]
5-[3(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)thiaz-
olidine-2,4-dione,
[0225]
5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-2-ynyl-
]thiazolidine-2,4-dione,
[0226]
5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)thiazoli-
dine-2,4-dione,
[0227]
5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4--
dione, and
[0228]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)thiazolidine-
-2,4-dione.
[0229] It is understood that the definition of compounds of Formula
(I) when R.sub.1to R.sub.12, contain asymmetric carbons, encompass
all possible stereoisomers and mixtures thereof which possess the
activity discussed below. In particular, the definition encompasses
racemic modifications and any optical isomers which possess the
indicated activity. Optical isomers may be obtained in pure form by
standard separation techniques or enantiomer specific synthesis. It
is understood that this invention encompasses all crystalline forms
of compounds of Formula (I). The pharmaceutically acceptable salts
of the basic compounds of this invention are those derived from
such organic and inorganic acids as: lactic, citric, acetic,
tartaric, fumaric, succinic, maleic, malonic, hydrochloric,
hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and
similarly known acceptable acids. Where R.sub.1 to R.sub.12, or Y
contains a carboxyl group, salts of the compounds in this invention
may be formed with bases such as alkali metals (Na, K, Li) or
alkaline earth metals (Ca or Mg).
[0230] For the compounds of Formula (I) defined above and referred
to herein, unless otherwise noted, the following terms are
defined:
[0231] Halogen, as used herein means chloro, fluoro, bromo and
iodo.
[0232] Alkyl as used herein means a branched or straight chain
having from 1 to 6 carbon atoms. Exemplary alkyl groups include
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl
and hexyl.
[0233] Aryl as used herein means an aromatic radical wherein Ar is
1 -naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl,
5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl,
substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl,
2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl,
2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-furanyl,
2-benzo-[b]-thienyl or a moiety of the formula: 29
[0234] and further defined an aromatic radical Ar' is thienyl,
pyridinyl or a moiety of the formula 30
[0235] Alkoxy as used herein means an --O-alkyl group in which the
alkyl group is as previously described. Exemplary alkoxy groups
include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and
t-butoxy.
[0236] Alkyne as used herein means an alkynyl group 31
[0237] is present.
[0238] Phenyl as used herein refers to a 6-membered aromatic
ring.
[0239] Carbamic acid ester is --NHCO.sub.2R.sub.10 where preferred
R.sub.10 is alkyl of 1 to 6 carbon atoms.
[0240] Substituted carboxamide is --CONHR.sub.8 wherein R.sub.8 is
alkyl of 1 to 6 carbon atoms.
[0241] Substituted 2-pyridinyl and substituted benzyl, unless
otherwise provided for herein, preferably has from 1 to 3
substituents independently selected from fluoro, chloro, bromo,
iodo, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6
carbon atoms, trifluoromethyl and trifluoromethoxy.
[0242] This invention provides a method of treatment, by
administration of an effective amount of compounds of Formula (I),
of ras oncogene-dependent tumors, which include cancers of the
pancreas, colon, bladder, and thyroid; a method of controlling
metastasis, suppressing angiogenesis, and inducing apoptosis; a
method of treating Ras-associated proliferative diseases other than
cancer, which include restenosis, neuro-fibromatosis,
endometriosis, and psoriasis The compounds of Formula (I) may also
inhibit prenylation of proteins other than Ras, and thus provide a
method of treatment of diseases associated with other prenyl
modifications of proteins.
[0243] The compounds of Formula (I) inhibit farnesyl-protein
transferase and the farnesylation of the oncogene protein Ras.
Thus, this invention further provides a method of inhibiting
farnesyl protein transferase, (e.g., Ras farnesyl protein
transferase) in mammals, especially humans, by the administration
of an effective amount of the compounds of Formula (I). The
administration of the compounds of this invention to patients, to
inhibit farnesyl protein transferase, is useful in the treatment of
the cancers and other diseases described below.
[0244] This invention provides a method for inhibiting or treating
the abnormal growth of cells, including transformed cells by
administering an effective amount of a compound of Formula (I).
Abnormal growth of cells refers to cell growth independent of
normal regulatory mechanisms (e.g., loss of contact inhibition).
This includes abnormal growth of tumor cells (tumors) expressing an
activated Ras oncogene; tumor cells in which the Ras protein is
activated as a result of oncogenic mutation in another gene; and
benign and malignant cells of other proliferative diseases in which
aberrant Ras activation occurs.
[0245] This invention also provides a method for inhibiting or
treating tumor growth by administering an effective amount of a
compound of Formula (I), described herein, to a mammal (e.g., a
human) in need of such treatment. In particular, this invention
provides a method for inhibiting or treating the growth of tumors
expressing an activated Ras oncogene by administration of an
effective amount of a compound of Formula (I). Examples of tumors
which may be inhibited or treated include, but are not limited to,
lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g.,
pancreatic carcinoma such as, for example, exocrine pancreatic
carcinoma), colon cancers (e.g., colorectal carcinomas, such as,
for example, colon adenocarcinoma and colon adenoma), myeloid
leukemias (for example, acute myelogenous leukemia (AML)), thyroid
follicular cancer, myelodysplastic syndrome (MDS), bladder
carcinoma, epidermal carcinoma, breast cancer and prostate
cancer.
[0246] This invention also provides a method for inhibiting or
treating proliferative diseases, both benign and malignant, wherein
Ras proteins are aberrantly activated as a result of oncogenic
mutation in other genes-i.e., the Ras gene itself is not activated
by mutation to an oncogenic form-with said inhibition or treatment
being accomplished by the administration of an effective amount of
a compound of Formula (I), to a mammal (e.g., a human) in need of
such treatment. For example, the benign proliferative disorder
neurofibromatosis, or tumors in which Ras is activated due to
mutation or overexpression of tyrosine kinase oncogenes (e.g., neu,
src, abl, lck, and fyn), may be inhibited or treated by the
compounds of Formula (I).
[0247] Additionally, this invention provides a method of inhibition
or treating the abnormal growth of cells, by administration of an
effective amount of compounds of Formula (I), of
ras-oncogene-dependent tumors, which tumors include cancers of the
pancreas, colon, bladder, and thyroid. Without wishing to be bound
by theory, these compounds may function through the inhibition of
G-protein function, such as ras p21, by blocking G-protein
isoprenylation, thus making them useful in the treatment of
proliferative diseases such as tumor growth and cancer. Without
wishing to be bound by theory, the compounds of Formula (I) inhibit
Ras farnesyl-protein transferase, and thus antiproliferative
activity of ras-transformed cells and other prenyl modifications of
proteins.
DETAILED DESCRIPTION OF THE INVENTION
[0248] Compounds of this invention may be prepared according to the
methods and procedures described in U.S. Pat. Nos. 5,605,918 and
5,574,051, which are hereby incorporated herein by reference; in
Wrobel, J., et al., J. Med. Chem. 1998, 41 (7), 1084-91 and as
outlined in Schemes I through XI described herein. 32
[0249] As shown in Scheme I, arylthiol VI where Ar is hereinbefore
defined is reacted with 2 or more equivalents of a strong base such
as lithium diisopropylamide, lithium bis(trimethylsilylamide), and
the like followed by reaction with one or more equivalents of
5-bromothiazolidine-2,4-dione IV(Zask et al, J. Med. Chem. 1990,
33, 1418-1423) to produce a 5-arylsulfanylthiazolidine-2,4-dione
VII in an aprotic solvent such as tetrahydrofuran (THF) or hexane
at temperatures (e.g. 0.degree. to -78.degree. C.) followed by
warming to about ambient temperature for 1 to 10 h.
[0250] The 5-arylsulfanylthiazolidine-2,4-dione VII may then be
oxidized to afford 5-arylsulfonylthiazolidine-2,4-dione V.
Following the procedure of Zask et al (J. Med. Chem. 1990, 33,
1418-1423), the oxidation is conveniently performed using excess (2
to 20 equivalents) aqueous hydrogen peroxide in acetic acid at
ambient or higher (30.degree. to 80.degree. C.) reaction
temperatures for 1 to 10 h.
[0251] The 5-arylsulfanylthiazolidine-2,4dione VII may also be
oxidized to afford 5-arylsulfinylthiazolidine-2,4-dione Va by
bubbling oxygen in the presence of isobutyraldehyde in a solvent
which includes acetonitrile for 18 hours.
[0252] The 5-arylsulfonylthiazolidine-2,4-dione V may also be
prepared by reacting one or more equivalents of an alkali metal
arylsulfinate VIII, where M is an alkali metal with
5-bromothiazolidine-2,4-dione IV in suitable solvents which include
polar aprotic solvents such as N,N-dimethylformamide (DMF),
tetrahydrofuran (THF) or protic solvents such as low molecular
weight alcohols (methyl alcohol, ethyl alcohol and isopropanol and
the like), or water.
[0253] Alternatively, the alkali metal arylsulfinate VIII can also
be prepared by reduction of an arylsulfonyl chloride with sodium
iodide in acetone (Harwood, Julia, and Thuillier, Tetrahedron,
1980, 36, 2483-2487). 33
[0254] As shown in Scheme II arylalkynes XI, wherein Ar' is as
previously defined, and LG is a suitable leaving group which
include iodo, bromo and p-toluenesulfonyloxy, can be prepared via a
two step process from commercially available aryl iodides or aryl
bromides where Ar' is hereinbefoe defined or those aryl iodides or
aryl bromides described in the the art. In the first step, alcohol
X is prepared by the reaction of the appropriate aryl iodide or
bromide with one or more equivalents of a terminal alkyne-ol IX, in
the presence of a catalytic amount of a palladium(II) reagent such
as dichlorobis(triphenylphosphine)palladium(II- ) and a catalytic
amount of a copper(I) reagent such as copper(I) iodide. This
reaction is also performed in the presence of one or more
equivalents of a secondary or tertiary amine such as diethylamine
or triethylamine. The secondary or tertiary amine may be used as
solvent, or alternatively a halocarbon solvent such as chloroform
may be s employed. Temperatures up to 80.degree. C. are commonly
used, with reaction times varying from 1 h to 2 days. Alkyne XI
wherein Ar' is hereinbefore defined and LG is p-toluenesulfonyloxy
is most conveniently prepared from alcohol X by reaction with
p-toluenesulfonyl chloride in a solvent such as dichloromethane and
in the presence of N,N-dimethylaminopyridine and triethylamine at
0.degree. C. to 30.degree. C., from one hour to 6 hours; or when LG
is iodo, alcohol X is reacted with iodine, in the presence of
triphenylphosphine and imidazole in a solvent such as ether, or
acetonitrile, at a temperature of 0.degree. C. to room temperature
for 8 hours to 24 hours; alternatively alkyne XI wherein LG is
p-toluenesulfonyloxy is reacted with sodium iodide in acetone at
room temperature from 8 hours to 36 hours to give alkyne XI wherein
LG is iodo; or when LG is bromo, X is reacted with carbon
tetrabromide in the presence of triphenylphosphine in a solvent
such as THF at 0.degree. C. to 35.degree. C. for 8 hours to 72
hours to give alkyne XI wherein LG is bromo. 34
[0255] Referring to Scheme III:
5-substituted-5-(arylsulfanyl)thiazolidine- -2,4-diones of Formula
(I) may be prepared by reaction of the appropriate
5-(arylsulfanyl)thiazolidine-2,4-dione VII with 2 or more
equivalents of a base. Two equivalents of base effect deprotonation
of both the thiazolidinedione nitrogen atom and at the C-5 position
to form a dianion. Common bases to accomplish this deprotonation
include alkali metal hydrides such as sodium hydride, alkali metal
alkyls such as butyl lithium or alkali metal amide bases such as
lithium diisopropylamide or lithium bis(trimethylsilyl)amide.
Convenient solvents include THF and DMF. Reaction temperatures may
be varied from -78.degree. C. to room temperature. Two minutes to 1
h after the base is introduced, one or more equivalents of the
appropriate alkylating agent, alkyne XI is added to the reaction
mixture and this is allowed to stir at 0.degree. C. or room
temperature for a period of from 1 h to 3 days. Alkylation occurs
primarily on the thiazolidindione C-5 carbon atom to afford the
5-substituted-5-(arylsulfanyl)thiazolidine-2,4-dione of Formula
(I), m=0 which may then be oxidized to afford
5-arylsulfonylthiazolidine-2,4-dione of Formula (I) wherein m=2 by
the procedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423).
The oxidation is conveniently performed using excess (2 to 20
equivalents) aqueous hydrogen peroxide in acetic acid at ambient or
higher (30.degree. C. to 80.degree. C.) reaction temperatures for 1
to 10 h. 35
[0256] Referring to Scheme IIIa:
5-substituted-5-(arylsulfinyl)thiazolidin- e-2,4-diones of Formula
(I) may be prepared by reaction of the appropriate
5-(arylsulfinyl)thiazolidine-2,4-dione Va in the presence of a
base. Common bases include alkali metal hydrides such as sodium
hydride, alkali metal alkyls such as butyl lithium or alkali metal
amide bases such as lithium diisopropylamide or lithium
bis(trimethylsilyl)amide. Convenient solvents include THF and DMF.
Reaction temperatures may be varied from -78.degree. C. to room
temperature. Two minutes to 1 h after the base is introduced, one
or more equivalents of the appropriate alkylating agent, alkyne XI
is added to the reaction mixture and this is allowed to stir at
0.degree. C. or room temperature for a period of from 1 h to 3
days. Alkylation occurs primarily on the thiazolidindione C-5
carbon atom to afford the
5-substituted-5-(arylsulfinyl)thiazolidine-2,4-dione of Formula
(I), m=1. 36
[0257] As shown in Scheme IV:
5-substituted-5-(arylsulfonyl)thiazolidine-2- ,4-diones of Formula
(I) may be prepared by reaction of the appropriate
5-(arylsulfonyl)thiazolidine-2,4-dione V with 2 or more equivalents
of a base. Two equivalents of base effect deprotonation of both the
thiazolidinedione nitrogen atom and at the C-5 position to form a
dianion. Common bases to accomplish this deprotonation include
alkali metal hydrides such as sodium hydride, alkali metal alkyls
such as butyl lithium or alkali metal amide bases such as lithium
diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient
solvents include THF and DMF. Reaction temperatures vary from
-78.degree. C. to room temperature. Two minutes to 1 h after the
base is introduced, one or more equivalents of the appropriate
alkylating agent, alkyne XI is added to the reaction mixture and
the reaction is allowed to stir at 0.degree. C. or room temperature
for a period of from 1 h to 3 days. Alkylation occurs exclusively
on the thiazolidindione C-5 carbon atom to afford the
5-substituted-5-(arylsulfonyl)thiazolidine-2,4-dione of formula
(I).
[0258] As shown in Scheme V, a compound of Formula (I), wherein at
least one of R.sub.3, R.sub.4, or R.sub.5 of the moiety 37
[0259] is a nitro group, and as shown in formula I' where R.sub.3
is a nitro group, is reacted with a reducing agent, such as iron in
acetic acid or tin in hydrochloric acid, or other agents known to
effect this reduction to give an amine XIII. 38
[0260] As further shown in Scheme V, compounds of Formula (I),
wherein at least one of R.sub.3, R.sub.4, or R.sub.5is amino, as
shown in amine XIII can be prepared by hydrolysis of carbamate XII,
wherein at least one of R.sub.3, R.sub.4, or R.sub.5 of Formula (I)
is a t-butoxycarbonylamino group, by the use of an acid, such as
trifluoroacetic acid, or aqueous hydrochloric acid at 0.degree. C.
to 60.degree. C., from 0.5 h to 4 h.
[0261] Substituted amine XIV, wherein at least one of R.sub.3,
R.sub.4, or R.sub.5 is --NHCO.sub.2R.sub.10 wherein R.sub.10 is
selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl,
chlorophenyl; substituted amine XV, wherein at least one of
R.sub.3, R.sub.4, or R.sub.5 is --NHCOR.sub.11, wherein R.sub.11 is
selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, alkyl(1
to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl,
biphenyl; substituted amine XVI wherein at least one of R.sub.3,
R.sub.4, or R.sub.5 is --NHCONHR.sub.12 wherein R.sub.12 is benzyl,
alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, alkyl(1 to 6 carbon
atoms)phenyl can each be prepared by reaction of the amine XIII,
respectively with an appropriate alkoxycarbonyl or
aryloxycarbonylchloride; acid chloride, or similarly activated acyl
compound; or an isocyanate, in an inert solvent, in the presence of
an acid scavenger such as triethylamine, at 0.degree. C. to
40.degree. C., for 0.5 h to 24 h. 39
[0262] Referring to Scheme VI: compounds of formula (I), wherein at
least one of R.sub.3, R.sub.4, or R.sub.5is the azido group, as in
azide XVII may be prepared from amine XIII, by reaction with sodium
nitrite in acetic acid at 0.degree. C. to 20.degree. C., for 10 min
to 30 min, followed by a metal azide, such as lithium azide for 1 h
to 3 h at 10.degree. C. to 25.degree. C. 40
[0263] Referring to Scheme VII: compounds of formula (I), wherein
at least one of R.sub.3, R.sub.4, or R.sub.5 is a carboxyl group as
in carboxylic acid XIX can be prepared from the corresponding
ester, such as the methyl ester as in ester XVIII by hydrolysis
with a base such as potassium carbonate in a solvent such as
methanol, or water, followed by acidification with an acid, such as
hydrochloric acid. 41
[0264] Referring to Scheme VIII: Compounds of Formula (I), wherein
Ar' is hereinbefore define and at least one of R.sub.3, R.sub.4, or
R.sub.5 are as described above, and W is Z- --CH.dbd.CH-- in alkene
XXI may be prepared from the corresponding compounds of formula (I)
wherein W is 42
[0265] in alkyne XX by reduction with hydrogen and a catalyst, such
as platinum or palladium in a solvent such as an alcohol, or THF at
0.degree. to 30.degree. C. for 1/2 h to 8 h; 43
[0266] As shown in Scheme IX: compounds of Formula (I) as in alkene
XXVI, wherein either R.sub.3, R.sub.4, and R.sub.5 are as
previously defined as substituents on Ar'+0, and W is E-
--CH.dbd.CH--, may be prepared by alkylation of
5-arylsulfonylthiazolidine-2,4-dione V with an alkene XXV under
conditions as described in Scheme III for the corresponding alkyne.
Alkenes XXIV wherein W is E- --CH.dbd.CH--, can be prepared by
coupling an iodophenyl compound where Ar' is hereinbefore defined
with an E-stannane XXII in the presence of
tetrakistriphenyl-phosphine palladium(0) and copper(I) iodide in a
solvent such as DMF at room temperature for 1 h to 3 days and
subsequent conversion to alcohol XXIII to alkene XXIV, wherein LG
is iodo, may be accomplished in a manner analogous to that shown in
Scheme II. A compound such as XXV, above, wherein LG is a leaving
group, such as, bromo or iodo is used to alkylate
5-arylsulfonylthiazolidine-2,4-dione V as described herein before
in Scheme III. 44
[0267] Referring to Scheme X: compounds of formula (I), wherein Ar'
is herein before described and W is --CH.sub.2--CH.sub.2-- as in
dione XXVII, can be prepared from a compound of formula (I) wherein
W is either 45
[0268] or E- or Z- --CH.dbd.CH--, by hydrogenation in the presence
of palladium or platinum in a solvent such as methanol plus 5%
water; alternatively, 5-arylsulfonylthiazolidine-2,4-dione V can be
alkylated with XXVIII to give dione XXVII.
STANDARD PHARMACOLOGICAL TEST PROCEDURES
[0269] The ability of the compounds of this invention to inhibit
FPTase was evaluated in the standard pharmacological in vitro test
procedures described below. Data for representative examples is
summarized in Table I.
[0270] Enzyme test procedure: FPTase inhibition in vitro assay was
performed according to James, G. L., Brown, M. S., and Goldstein,
J. L., Methods in Enzymology, 1995, 255, 38-46; and Garcia, M. A.,
et al., J. Biol. Chem., 1993, 268, 18415-18420.
[0271] Materials--Purified FPTase (Moomaw, J. F. and Casey, P. J.,
J. Biol. Chem., 1992, 267, 17438-17443), purified His.sub.6-Ras,
inhibitor compounds at 10 mg/ml or 10 mM in 100% DMSO, .sup.3H--FPP
(50,000 dpm/pmol) Amersham, TCA/SDS (6%/2%), TCA (6%), Glass fiber
filters (0.22-0.45 m), vacuum manifold or 96 well filtration
plates.
[0272] Methods--1. Dilute FPTase inhibitors from stock solutions to
2.5.times. in 2.5% DMSO, 10 mM DTT, 0.5% octyl-B-glucoside. 2.
Solution #1 is added to FPTase reaction in a volume of 20 ml. 3.
Standard reaction mix, 50 ml, contains 50 mM Tris (7.5), 10 mM
ZnCl.sub.2, 3 mM MgCl.sub.2, 20 mM KCl, 5 mM DTT, 0.2%
octyl-B-glucoside, 1% DMSO, 40 mM His.sub.6-Ras, 10 ng FPTase, and
various concentrations of FPTase inhibitors. 4. Incubate for 30-90
min at 25.degree. C. 5. Stop reactions with TCA/SDS (6%/2%), hold
at 40.degree. C. for 45-60 min. 6. Filter by manifold or 96 well
plate, wash filter 3-5.times. with TCA (6%). 7. Add scintillant to
filters, measure .sup.3H--FPP incorporation into Ras protein.
[0273] Analysis of Results--Percent inhibition by test compounds is
determined by the following:
[0274] (cpm from precipitated Ras with test compounds)-(background
cpm).times.100=% inhibition.
[0275] (cpm from precipitated Ras without test
compounds)-(background cpm)
[0276] Cell-based test procedure: Tumor inhibition in vitro assay
was performed according to P. Skehan, R. Storeng, D. Scudiero, A.
Monks, J. McMohan, D. Vistica, J. Warren, H. Bokesh, S. Kenney, and
M. R. Boyd, J. Natl. Cancer Instit., 1990, 82 (13), 1107-1112; L.
V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S.
Tosini, P. Skehan, D. A. Scudiero, A. Monks, and M. R. Boyd, J.
Natl. Cancer Instit., 1990, 82 (13), 1113-1118; A. Monks, et al.,
J. Natl. Cancer Instit., 1991, 83, 757-766; M. R. Boyd and K. D.
Paull, Drug Development Res., 1995, 34, 91-109; and S. P. Fricker
and R. G. Buckley, Anticancer Research, 1996, 16, 3755-3760.
[0277] Materials--Cell Lines: Human tumor cell lines LS174T, HTB39,
LoVo and CaCo2. Cell Media: RPMI 1640 (or DMEM medium and McCoy's
medium) with 10% Fetal Bovine Serum supplemented with L-glutamine
and Pennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM
stock in 100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid
(TCA): 50% (w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1%
Acetic Acid. Tris Base: 10 mM in water.
[0278] Methods--Cells are plated at 2000 cells per well, per 200
.mu.l media, and allowed to adhere overnight at 37.degree. C. At 24
h post plating, compounds are added directly at a volume of 0.5
.mu.l. Compound is first diluted in DMSO to generate concentrations
of compound or reference standard of: 1, 5, 10 and 25 .mu.M.
Dilutions can be made in an identical 96 well plate so that
compounds can be added using a multichannel micropipettor set at
0.5 .mu.l. The cells are then incubated for four days after which
the media is removed using a 12 well manifold by first tipping the
plate forward at a 45 degree angle and then inserting the manifold
in an upright orientation to prevent the tips of the manifold from
disturbing cells at the bottom of the plate. 200 .mu.l of normal
saline is then added to each well using an 8 well multichannel
pipettor, followed by the careful addition of 50 .mu.l of 50% TCA.
The plates are then incubated for 2 h at 4.degree. C, after which
the supernatant is removed using the same technique as above and
the plates washed twice with 200 .mu.l water. The plates are then
air dried and 50 .mu.l of SRB stock solution is carefully added so
that the entire bottom of each well is covered. This again can be
used using an 8 well multichannel pipettor. The SRB is incubated
with fixed cells for 15 min at room temperature, after which the
SRB is removed with the manifold as described above and the plates
washed twice with 350 .mu.l of 1% acetic acid per well each time.
The plates are then air dried after which the bound SRB is released
from protein by the addition of 200 .mu.l of Tris base.
Resolubilizing the SRB is aided by placing the plates on a rotator
for 15-30 min. The absorbance of each well is determined at 550 or
562 nm using a microtiter plate reader.
[0279] Analysis of Results--Each compound or dilution thereof is
performed in triplicate. Outliers are identified by visual
inspection of the data. Each plate should have a control (vehicle
only). A standard curve is constructed by plotting the
concentration of compound against the average absorbance calculated
at that concentration. A curve is plotted and the concentration at
which the curve passes through the 50% absorbance mark seen in the
control well is the IC.sub.50 calculated for that compound.
1TABLE I in vitro FTase Inhibition Assay IC.sub.50 H-Ras* IC.sub.50
K-Ras* Ex. No. .mu.M .mu.M 96 0.7 97 0.075-0.15 3.5-5.5 101
0.01-0.03 0.11-1.0 102 0.03-0.032 1.4 103 0.03-0.05 0.9-10 104
0.03-0.054 0.23-0.9 105 0.05-0.15 1.5-1.7 106 0.23-0.25 1.3-1.7 107
0.18-0.2 0.62-0.7 108 0.13-0.18 .sup. 9->10 109 0.065-0.13
1.4-2.1 110 0.4 7 111 0.11-0.15 0.3-0.55 112 0.59-0.60 1.4-1.5 113
0.05-0.06 0.75-0.8 114 0.013-0.032 0.032-0.32 115 0.012-0.32
0.16-0.23 116 0.005-0.01 0.017-0.04 117 0.02-0.03 0.51-1.0 118 0.07
1.9 119 0.13-0.14 1.3-1.7 120 0.018-0.032 0.53-1.0 121 0.12 1.6 122
0.03-0.05 0.23-1.0 123 0.08-0.082 1.0-2.8 124 0.052-0.08 0.91-1.3
125 0.03 0.4 126 0.09 1.7 127 0.12-0.14 1.3-1.5 128 0.001-0.032
0.02-0.22 129 0.1 0.6-0.79 130 0.023-0.056 0.32-1.0 131 0.006-0.032
0.08-0.31 132 0.041-0.073 0.21-1.0 133 0.04-0.2 0.054-1.0 134
0.014-0.85 0.43-0.68 135 0.02-0.032 1.9-2.1 136 0.043-0.05 1.0-1.9
137 0.021-0.4 0.037-0.8 138 0.023-0.032 0.3-0.42 139 0.17-0.14
0.6-5.0 140 0.15-0.3 1.0-3.6 141 0.021-0.032 0.30-0.34 142
0.017-0.03 0.04-1.0 143 0.03 0.85 144 0.04-0.041 0.32-0.55 145
1.2-1.7 5.6-10 147 0.0068-0.21 0.08-0.1 148 0.0045-0.12 0.023-0.031
149 0.45-0.5 1.0-4.9 150 0.0074-0.032 0.016-0.068 151 0.53-0.7
0.21-1.0 152 0.011-0.016 0.1-0.23 153 0.17-0.2 1.0-6.1 154
0.07-0.15 1.0-2.5 155 0.01-0.32 0.42-0.44 157 0.27 5.0 158 0.15 3.8
159 0.65 >10 161 0.9 10 162 1.21 4.0 163 1.3 10 164 0.15 >10
166 0.15 5.3 167 1.5 10 168 0.28 10 169 0.1 1.8 170 0.38 4.7 171
0.2 3.3 175 0.01-0.032 0.053-0.52 176 0.0032-0.032 0.03-0.32 177
0.011-0.032 0.086-0.1 178 0.017-0.032 0.01 179 0.002-0.032
0.005-0.07 180 0.002-0.032 0.007-0.09 181 0.01-0.032 0.10-0.13 182
0.005-0.01 0.032-0.056 189 0.10 1.2 217 0.10 8.5 220 0.09 3.0 222
0.0033 0.033 223 0.063 >1 226 0.03-0.05 0.1-3.2 227 0.007-0.01
0.21-0.4 228 0.004-0.07 0.23-1 229 0.006-0.02 0.1-0.7 230
0.003-0.0035 0.02-0.5 231 0.01-0.021 0.1-1 232 0.005-0.01 0.04-0.64
233 2.9 10 *H-Ras or K-Ras used as substrates for farnesylation
[0280] Compounds of this invention were tested in cell-based assays
against human tumor cell lines DLD-1 and LoVo and ras-transformed
rat fibroblast cell lines, RAT-H-ras and RAT-K-ras, and the parent
cell line RAT-2, as described under Assays. The range observed for
inhibition of cell growth was IC.sub.50=7 to 18 .mu.M. The results
are displayed in Table I.
[0281] The following examples (239-267) of the invention were
tested using the procedure described above with changes in the
materials used as described below. The results are displayed in
Table II.
[0282] Materials--Cell Lines: Human tumor cell lines DLD-1 and
LoVo; ras-transformed rat fibroblast cell lines, RAT-H-ras and
RAT-K-ras (growth inhibited by standard FPTase inhibitors), and the
parent cell line RAT-2 (resistant to standard FPTase inhibitors).
Cell Media: RPMI 1640 (or DMEM medium and McCoy's medium) with 10%
Fetal Bovine Serum supplemented with L-glutamine and
Pennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM
stock in 100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid
(TCA): 50% (w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1%
Acetic Acid. Tris Base: 10 mM in water.
2 TABLE II in vitro FTase Inhibition Assay IC.sub.50 (wi. H-
IC.sub.50 (wi. K- Ras) Ras) Ex. No. .mu.M .mu.M 239 0.7 10 240 0.5
>10 241 1.5 >10 242 1 >10 243 0.3 10 244 0.1 7 245 0.05 3
246 0.3 10 247 0.3 10 248 0.45 5.5 249 0.4 6 250 1.5 10 251 0.15
8.5 252 0.08 8 253 0.09 4.5 254 0.5 >10 255 0.15 10 256 0.8 10
257 0.035 >10 258 2 10 259 0.15 6.5 260 0.1 3 261 0.3 3 262 0.07
2 263 0.15 6.5 264 0.3 >10 265 1.5 >10 266 0.5 >10 267 5
>10 *H-Ras or K-Ras used as substrates for farnesylation
[0283] Examples 239-267of this invention were tested in cell-based
assays against human tumor cell lines DLD-1 and LoVo and
ras-transformed rat fibroblast cell lines, RAT-H-ras and RAT-K-ras,
and the parent cell line RAT-2, as described under Assays. The
range observed for inhibition of cell growth was IC.sub.50=7 to
>40 .mu.M. Results are displayed in Table II.
[0284] Compounds of this invention were tested for in vivo effects
in rats against various tumors. For the compound of example 114,
when tested against a K-ras dependent human colon carcinoma (LoVo),
the following results were obtained (Table III):
3TABLE III In Vivo Data for the Compound of Example 114 A Drug
Treatment mg/kg b c d b c d b c d per dose Day 8 % T/C (p) Day 15 %
T/C (p) Day 22 % T/C (p) 0.5% 88 308 598 Methocel 0.4% Tween 80
Cpd. 61 70 0.10 238 77 0.14 454 76 0.08 (100 PO) Cpd. 45 51 0.02
110 36 <.01 255 43 <.01 (75 IP) Cpd. 65 74 0.15 146 47 0.02
258 43 <0.01 (50 IP) Cpd. 31 35 <0.01 125 41 <.01 251 42
<.01 (100 IP) Vincristine 14 16 <0.01 24 8 <.01 84 14
<.01 (1 IP) 2% Tween 39 121 198 in D5W Cpd. 86 221 0.95 182 150
0.84 324 163 0.92 (75* IP) 20% BCD 62 146 339 in 0.1 N HCl Cpd. 50
81 0.22 138 95 0.44 299 88 0.31 (100 PO) A Drug Treatment mg/kg b c
d b c d e per dose Day 29 % T/C (p) Day 36 % T/C (p) S/T 0.5% 748
1264 10/10 Methocel 0.4% Tween 80 Cpd. 608 81 0.20 934 74 0.09
10/10 (100 PO) Cpd. 504 67 0.09 764 60 0.03 8/10 (75 IP) Cpd. 445
59 0.07 964 76 0.16 5/10 (50 IP) Cpd. 341 46 0.01 559 44 0.01 9/10
(100 IP) Vincristine 139 19 <0.01 194 15 <.01 9/10 (1 IP) 2%
Tween 287 424 10/10 in D5W Cpd. 478 167 0.92 666 157 0.91 10/10
(75* IP) 20% BCD 499 813 10/10 in 0.1 N HCl Cpd. 641 128 0.77 872
107 0.60 9/10 (100 PO) a) Compound of Example 114(100 IP)
administered once a day on days 1 through 20. All other doses of
cpd. Were administered on days 1 through 20 BID. Vincristine
administered on days 5, 9 and 13. prepared in 2% Tween 80 in D5W.
b) Mean Tumor Weight in mg. c) % T/C = Mean Tumor Weight of Treated
Group .times. 100Mean Tumor Weight of Placebo Group d) Statistical
analysis (Student's t-test) of Tumor Weight. A p-value (p .ltoreq.
0.05) indicates a statistical significant reduction in Tumor.
Weight of Treated Group, compared to Placebo Control. e) S/T = No.
Survivors/No.Treated on Day +35 post tumor cell implantation
[0285] Examples 100, and 103,when tested in rats against Rat-2
fibroblasts transformed by oncogenic H-ras for 11 days, i.p., the
following results were obtained for day 11 (Table IV):
4TABLE IV Ex. No. Dose, mg/kg % T/C 100 100 44 100 30 60 100 10 100
103 100 No efficacy at this dose % T/C = Mean Tumor Weight of
Treated Group .times. 100 Mean Tumor Weight of Placebo Group
[0286] In a similar model when tested in rats against Rat-2
fibroblasts transformed by oncogenic K-ras for 25 days, i.p, the
compound of example 100 showed no efficacy at 100 mg/kg.
[0287] Based on the results of these standard pharmacological test
procedures, the compounds of this invention are useful as agents
for treating, inhibiting or controlling ras-associated diseases by
inhibiting farnesyl-protein transferase enzyme, when administered
in amounts ranging from about 10 to about 200 mg/kg of body weight
per day. A preferred regimen for optimum results would be from
about 10 mg to about 100 mg/kg of body weight per day and such
dosage units are employed that a total of from about 100 mg to
about 1000 mg of the active compound for a subject of about 70 kg
of body weight are administered in a 24 hour period.
[0288] The dosage regimen for treating mammals may be adjusted to
provide the optimum therapeutic response. For example, several
divided doses may be administered daily or the dose may be
proportionally reduced as indicated by the exigencies of the
therapeutic situation. A decidedly practical advantage is that
these active compounds may be administered in any convenient manner
such as by the oral, intravenous, intramuscular or subcutaneous
routes.
[0289] The active compounds may be orally administered, for
example, with an inert diluent or with an assimilable edible
carrier, or they may be enclosed in hard or soft shell gelatin
capsules, or they may be compressed into tablets or they may be
incorporated directly with the food of the diet. For oral
therapeutic administration, these active compounds may be
incorporated with excipients and used in the form of ingestible
tablets, buccal tablets, troches, capsules, elixirs, suspensions,
syrups, wafers and the like. Such compositions and preparations
should contain at least 0.1% of active compound. The percentage of
the compositions and preparations may, of course, be varied and may
conveniently be between about 2% to about 60% of the weight of the
unit. The amount of active compound in such therapeutically useful
compositions is such that a suitable dosage will be obtained.
Preferred compositions or preparations according to the present
invention are prepared so that an oral dosage unit form contains
between 10 and 1000 mg of active compound. The tablets, troches,
pills, capsules and the like may also contain the following: a
binder such as gum tragacanth, acacia, corn starch or gelatin;
excipients such as dicalcium phosphate; a disintegrating agent such
as corn starch, potato starch, alginic acid and the like; a
lubricant such as magnesium stearate; and a sweetening agent such
as sucrose, lactose, or saccharin may be added or a flavoring agnet
such as peppermint, oil of wintergreen or cherry flavoring. When
the dosage unit form is a capsule, it may contain, in addition to
materials of the above type, a liquid carrier. Various other
materials may be present as coatings or to otherwise modify the
physical form of the dosage unit. For instance, tablets, pills or
capsules may be coated with shellac, sugar or both. A syrup or
elixir may contain the active compound, sucrose, as a sweetening
agent, methyl and propylparabens as preservatives, a dye and
flavoring such as cherry or orange flavor. Of course, any material
used in preparing any dosage unit form should be pharmaceutically
pure and substantially non-toxic in the amounts used. In addition,
these active compounds may be incorporated into sustained-release
preparations and formulations.
[0290] These active compounds may also be administered parenterally
or intraperitoneally. Solutions or suspensions of these active
compounds as a free base or pharmacologically acceptable salt can
be prepared in water suitably mixed with a surfactant such as
hydroxypropylcellulose. Dispersions can also be prepared in
glycerol, liquid polyethylene glycols, and mixtures therof in oils.
Under ordinary conditions of storage and use, these preparations
contain a preservative to prevent the growth or microorganisms.
[0291] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and starage and must be
prepared against the contaminating action of microorganisms such as
bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid poly-ethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0292] The present invention accordingly provides a pharmaceutical
composition which comprises a compound of Formula (I) of this
invention in combination or association with a pharmaceutically
acceptable carrier. In particular, the present invention provides a
pharmaceutical composition which comprises an effective amount of a
compound of this invention and a pharmaceutically acceptable
carrier.
[0293] As used in accordance with this invention, the term
providing an effective amount of a compound means either directly
administering such compound, or administering a prodrug,
derivative, or analog which will form an effective amount of the
compound within the body.
[0294] The present invention provides a method of treatment of ras
oncogene-dependent tumors, such as cancers of the pancreas, colon,
bladder, and thyroid; a method of controlling metastasis,
suppressing angiogenesis, and inducing apoptosis; a method of
treating Ras-associated proliferative diseases other than cancer,
such as restenosis, neuro-fibromatosis, endometriosis, and
psoriasis. The compounds of the present invention may also inhibit
prenylation of proteins other than Ras, and thus provide a method
of treatment of diseases associated with other prenyl modifications
of proteins.
[0295] The invention will be more fully described in conjunction
with the following specific examples which are not to be construed
as limiting the scope of the invention.
EXAMPLE 1
5-(3-Methoxyphenyl-4-sulfonyl)-thiazolidine-2,4-dione
[0296] To a solution of 5-bromothiazolidine-2,4-dione (6.66 g, 34.0
mmol, Zask et al, J. Med. Chem. 1990, 33, 1418-1423) and
3-methoxybenzenethiol (5.00 g, 35.7 mmol) in dry THF (150 mL) at
-78.degree. C. was added sodium bis(trimethylsilyl)amide (1.0M in
THF, 56 mL, 56 mmol) dropwise. After 30 min. the reaction mixture
was warmed to room temperature. After an additional hour, 2N HCl
was added to pH=1. The layers were separated and the aqueous phase
was extracted with ethyl acetate. The combined organic phase was
dried (MgSO4), concentrated and flash chromatographed (3:1
hexanes:ethyl acetate) to provide
5-(3-methoxyphenyl-4-sulfanyl)thia- zolidine-2,4-dione, as a white
solid (4.86 g, 56%); a sample of
5-(3-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione (4.70 g, 18.4
mmol) was oxidized with 9.4 ml of 30% hydrogen peroxide in 50 ml of
acetic acid at 45.degree. C. for 3 hours to give 3.4 g (64%) of the
title compound as a glass; NMR(CDCl.sub.3) .delta.3.9 (s,3H), 5.53
(s,1H), 7.3 (m,1H), 7.42 (s,1H), 7.53 (m,2H); MS m/Z 285.9 (M-H)
(calcd. For C.sub.10H.sub.9NO.sub.5S.sub.2)
EXAMPLE 2
5-(4-Fluorophenyl-4-sulfonyl)-thiazolidine-2,4-dione
[0297] In the manner of Example 1 above 4-fluorobenzenethiol and
bromothiazolidinedione gave
5-(4-fluorophenyl-4-sulfanyl)-thiazolidine-2,- 4-dione, which on
oxidation gave the title compound [U.S. Pat. No. 5,605,918;
February 1997;Wrobel, et al.].
EXAMPLE 3
5-(4-lodophenyl-4-sulfonyl)-thiazolidine-2,4-dione
[0298] To a solution of 5-bromothiazolidinedione (5.94 g, 30.3
mmol) in 100 ml of absolute ethanol was added sodium
4-iodophenylsulfinate (9.67 g, 33.3 mmol)and this slurry was
stirred for about 18 hours at room temperature. Solvent was removed
and the residue was combined with water and was acidified with 2N
hydrochloric acid. The organic portion was chromatographed on
silica gel with hexanes-ethyl acetate (3:1) to give 5.8 g (50%) of
the title compound, mp 190-193.degree. C.
[0299] In a like manner to the procedure of Example 3 above, the
following aryl sulfinate salts which are either commercially
available, or are prepared by the reduction of the corresponding
sulfonyl chloride with sodium iodide in acetone (Harwood, Julia,
and Thuillier, Tetrahedron, 1980, 36, 2483-2487), were reacted with
5-bromothiazolidinedione to give the indicated product,
5-arylsulfonylthiazolidinediones of Examples 4-17:
5 EX. No. SULFINATE SALT PRODUCT MELTING POINT .degree. C. 4 Sodium
4-Trifluoro- 5-(4-Trifluoromethoxy- 108-110 methoxybenzenesulfinate
benzenesulfonyl)-thiazol- idine-2,4-dione 5 Sodium 3-Nitrobenzene
5-(3-Nitrobenzenesulfonyl)- 139-140 sulfinate
thiazolidine-2,4-dione 6 Sodium 4-Nitrobenzene
5-(4-Nitrobenzenesulfonyl)- 182-183 sulfinate
thiazolidine-2,4-dione 7 Sodium 4-(Pyridin-4-
5-[4-(Pyridin-4-yloxy)- 160 with yloxy)benzenesulfinate
benzenesulfonyl]-thiazolidine-2,4- decomp. dione 8 Sodium
4-Phenoxy- 5-(4-Phenoxybenzene sulfonyl)- 160-162 benzene-sulfinate
thiazolidine-2,4-dione 9 Sodium 4-Benzyloxy- 5-(4-Benzyloxybenzene-
190-200 benzenesulfinate sulfonyl)-thiazolidine-2,4-dione decomp.
10 Sodium 3,4-Dimethoxy- 5-(3,4-Dimethoxybenzene- 220-222 benzene
sulfinate sulfonyl)-thiazolidine-2,4-dione 11 Sodium
N-Acetyl-3-amino- N-[5-(2,4-Dioxothiazolidine-5- 217-219
4-methoxyphenyl-sulfinate sulfonyl)-2-methoxy-phenyl]- acetamide 12
Sodium 5-Chloro- 5-(5-Chloro-thiophene-2- 133-135
thiophene-2-sulfinate sulfonyl)-thiazolidine-2,4-dione 13 Sodium
Thiophene-2- 5-(Thiophene-2-sulfonyl)- 176-177 sulfinate
thiazolidine-2,4-dione 14 Sodium 5-Pyridin-2-yl-
5-(5-Pyridin-2-yl-thiophene-2- 168-170 thiophene-2-sulfinate
sulfonyl)-thiazolidine-2,4-dione 15 Sodium 4-Butoxybenzene
5-(4-Butoxybenzenesulfonyl)- 120-121 sulfinate
thiazolidine-2,4-dione 16 Sodium 1-Naphthalenyl)
5-[(1-Naphthalenyl)sulfonyl]-2,4- 187-188 sulfinate
thiazolidinedione 17 Sodium (8-Quinolinyl) 5-[(8-Quinolinyl)sulfon-
yl]-2,4- amorphous sulfinate thiazolidinedione solid
EXAMPLE 18
5-(2,5-Dichlorophenyl)pent-4-yn-1-ol
[0300] A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3
mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd
II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g,
0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen
for three days. This was diluted with dichloromethane and the oily
layer was adsorbed onto silica gel and eluted with hexanes-ethyl
acetate (5:1) to give 5-(2,5-dichloro-phenyl)pent-4-yn-1-ol, 13.7 g
(82%); NMR (CDCl3) .delta.1.9 (m,2H), 2.6 (t,2H), 3.85 (t,2H), 7.2
(dd,1H), 7.28 (m,1H), 7.4 (d,2H).
EXAMPLE 19
5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol
[0301] Preparation of the title compound with 4-bromophenyl methyl
sulphone (5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol)
according to the procedure in Example 18 yielded 5.12 g (87%) of
yellow oil which was characterized as
5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl.sub.3)
.delta.1.88-1.93 (m,2H), 2.56-2.60 (t, J=6.99, 2H), 3.04 (s,3H),
3.80-3.84 (t, J=6.15,2H), 7.56 (d, J=5.1, 2H), 7.85 (d,J=4.8, 2H).
MS m/Z 239 (M+H cald. for C.sub.12H.sub.14O.sub.3S 238.3)
[0302] In a manner described in Example 19 immediately above the
following acetylenic alcohols of Examples 20-48 were prepared from
the corresponding iodobenzene or bromobenzene and 4-pentyn-1-ol
(structures were confirmed as above by NMR):
6 EX. No. PRODUCT Mass Spectrum M+ 20
5-(2-Methyl-5-nitrophenyl)pent-4-yn-1-ol 220 (M + H) 21
5-(2-Methoxy-5-nitrophenyl)pent-4-yn-1-ol 235.0 22
5-(2-Methoxy-4-nitrophenyl)pent-4-yn-1-ol 235.0 23
5-(4-Nitro-2-trifluoromethylphenyl)pent-4-yn-1-ol 273.0 24
5-(3-Fluoro-5-nitrophenyl)pent-4-yn-1-ol 223.0 25
5-(3-Fluoro-4-methoxy-5-nitrophenyl)pent-4-yn-1-ol 254.2 (M + H) 26
5-(4-Methoxy-2-nitrophenyl)pent-4-yn-1-ol 234.2 (M + H) 27
[3-Chloro-4-(5-hydroxypent-1-ynyl)phenyl]-carbamic Acid tert-Butyl
Ester 28 5-(4-Pyrrol-1-ylphenyl)pent-4-yn-1-ol 226.2 (M + H) 29
5-(2,5-Dimethylphenyl)pent-4-yn-1-ol 189.1 (M + H) 30
5-(5-Chloro-2-methylphenyl)pent-4-yn-1-ol 208.8 (M + H) 31
5-(4-Chloro-2-methylphenyl)pent-4-yn-1-ol 208.0 32
5-(2,4-Dimethylphenyl)pent-4-yn-1-ol 188.1 33
5-(2-Methyl-4-nitrophenyl)pent-4-yn-1-ol 219.0 34
5-(4-Bromo-2-methylphenyl)pent-4-yn-1-ol 253.0 35
3-(5-Hydroxypent-1-ynyl)-4-methylbenzoic Acid Methyl 232.1 Ester 36
4-(5-Hydroxypent-1-ynyl)-3-methylbenzoic Acid Methyl 232.1 Ester 37
5-(4-tert-Butylphenyl)pent-4-yn-1-ol 38
[4-Methyl-3-(5-hydroxypent-1-ynyl)phenyl] carbamic Acid tert-Butyl
Ester 39 5-(2-Chlorophenyl)pent-4-yn-1-ol 40
5-(2,4-Dichlorophenyl)pent-4-yn-1-ol 41 4-(5-Hydroxypent-1-ynyl)tr-
ifluoromethyl benzene 42
4-(5-Hydroxypent-1-ynyl)trifluoromethoxy-b- enzene 43
[3-Methyl-4-(5-hydroxypent-1-ynyl)phenyl] carbamic Acid tert-Butyl
Ester 44 N-tert-Butyl-3-(5-hydroxypent-1-ynyl)-4- methylbenzamide
45 4-(5-Hydroxypent-1-ynyl)phenylcarbamic Acid tert-Butyl Ester 46
3-(5-Hydroxypent-1-ynyl)-4-methyl- benzoic Acid Methyl Ester 47
5-(4-Chlorophenyl)pent-4-yn-1-- ol 48
5-(3-Chlorophenyl)pent-4-yn-1-ol
EXAMPLE 49
6-(4-Chlorophenyl)hex-5-yn-1-ol
[0303] In a manner described in Example 18 above, 5-hexyn-1-ol was
reacted with 1-chloro-4-iodobenzene to give the title compound, MS
m/Z exact mass 209.724 (M+H) (calcd. For C.sub.12H.sub.13OCl
209.70).
EXAMPLE 50
11-(4-Chlorophenyl)undec-10-yn-1-ol
[0304] In a manner described in Example 18 above, 10-undecyn-1-ol
was reacted with 1-chloro-4-iodobenzene to give the title compound;
NMR (CDCl.sub.3) .delta.1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H),
2.36-2.41 (m,2H), 3.61-3.66(m,2H), 7.16-7.31 (m, 4H).
EXAMPLE 51
3-(4-Phenoxyphenyl)prop-2-yn-1-ol
[0305] Preparation of the title compound with commercial available
4-bromo-diphenyl ether (5.93 g, 23.8 mmol) according to the
procedure in Example 18 yielded 440 mg (8.2%) of brown oil which
was characterized as 3-(4-phenoxyphenyl)prop-2-yn-1-ol:
[0306] NMR (CDCl.sub.3) .delta.4.50 (d, J=6), 6.91 (d, J=2.01, 1H),
6.93 (d, J=2.01, 1H), 7.01 (d, J=0.63, 1H), 7.04 (d, J=1.17, 1H),
7.11-7.16 (m, 1H), 7.36 (d, J=0.6, 1H),7.38 (d, J=2.52, 2H), 7.41
(d, J=1.92, 1H). MS m/z 224.08 (M+ calcd. for
C.sub.15H.sub.12O.sub.2=224.08)
EXAMPLE 52
3-Biphenyl-4-yl-prop-2-yn-1-ol
[0307] In a manner described in Example 18 above, propargyl alcohol
was reacted with 4-bromobiphenyl to give the title compound as
white crystals: NMR (CDCl.sub.3) .delta.4.53 (d, J=4.74, 2H), 7.38
(d, J=7.17, 1H), 7.42-7.60 (m, 8H). MS m/z 208 (M+ calcd. for
C.sub.15H.sub.12O=208.3- ).
EXAMPLE 53
3-Thiophene-2-yl-prop-2-yn-1-ol
[0308] In a manner described in Example 18 above, propargyl alcohol
was reacted with 2-bromothiophene to give the title compound as a
brown oil which was used in the next step without further
purification.
EXAMPLE 54
1-Chloro-4-(5-iodopent-1-ynyl)benzene
[0309] 5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol),
4-dimethylaminopyridine (8.9 g, 73 mmol), p-toluenesulfonyl
chloride (34.7 g, 182 mmol), and 62 ml of triethylamine were
combined in 330 ml of dichloromethane at 0.degree. C. The mixture
was stirred for 30 min. at 0.degree. then 18 hours at room
temperature. Dilution with 200 ml of dichloromethane followed by
washing with brine, drying over magnesium sulfate, filtration
through silica gel with hexane-ethyl acetate, 8:1, gave a yellow
solid on evaporation. Crystallization from ether gave
5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorless
crystals (31.7 g, 49% yield). This was converted to the title
compound by reaction with sodium iodide in acetone, and was used in
subsequent reactions with no further purification; MS m/z 303.9 (M+
calcd. for C.sub.11H.sub.10ClI=304.6).
EXAMPLE 55
1-(5-lodo-pent-1 -ynyl)-4-methanesulfonylbenzene
[0310] Preparation of the title compound with tosylated alcohol of
Example 19, 5-(4-methanesulfonylphenyl)pent-4-yn-1-ol (3.14 g, 8.35
mmol), NaI (6.26 g, 41.76 mmol) following the procedure of Example
54 yielded 2.8 g (96%) of the title compound as a red oil: NMR
(CDCl.sub.3) .delta.2.06-2.15 (m, 2H), 2.58-2.63 (t, J=6.78, 2H),
3.04 (s, 3H), 3.33-3.37 (t, J=6.69, 2H), 7.57 (d, J=1.77, 2H), 7.85
(d, J=4.95, 2H). MS m/z 348.9 (M+H cald. for
C.sub.12H.sub.13O.sub.2S 348=349.2).
EXAMPLE 56
1,4-Dichloro-2-(5-iodopent-1-ynyl)benzene
[0311] 5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol),
triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8
mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was
stirred under nitrogen at 0.degree. C., and to this was slowly
added iodine (21.3 g, 83.8 mmol). The solution was allowed to warm
to room temperature and stirring was continued for 18 hours. This
was chromatographed on silica gel with hexane to give the title
compound (14.7 g,72%), MS m/z 337.9 (M-H calcd. for
C.sub.11H.sub.9Cl.sub.2I=338.0).
[0312] In the manner described in Example 55, above, the following
alcohols were converted to the corresponding iodides of Examples
56-88, and structures were confirmed as above by NMR:
7 EX. No. ALCOHOL PRODUCT MASS SPECTRUM 56
5-(2,4-Dichlorophenyl)-pent- 1,5-Dichloro-2-(5-iodo- 337.9
4-yn-1-ol pent-1-ynyl)benzene 57 5-(2-Methyl-5-nitro-
2-(5-Iodopent-1-ynyl)-1- 330 phenyl)pent-4-yn-1-ol
methyl-4-nitro-benzene 58 5-(2-Methoxy-5-nitro-
2-(5-Iodopent-1-ynyl)-1- 345.1 phenyl)pent-4-yn-1-ol
methoxy-4-nitro-benzene 59 5-(2-Methoxy-4-nitro-
1-(5-Iodopent-1-ynyl)-2- 345.0 phenyl)pent-4-yn-1-ol
methoxy-4-nitro-benzene 60 5-(4-Nitro-2-trifluoro-methyl-
1-(5-Iodopent-1-ynyl)-4- 383.0 phenyl)pent-4-yn-1-ol
nitro-2-trifluoro- methylbenzene 61 5-(3-Fluoro-5-nitro-
1-Fluoro-3-(5-iodopent-1- 334 phenyl)pent-4-yn-1-ol
ynyl)-5-nitrobenzene 62 5-(3-Fluoro-4-methoxy-5-
1-Fluoro-5-(5-iodopent-1- nitrophenyl)pent-4-yn-1-ol
ynyl)-2-methoxy-3- nitrobenzene 63 5-(4-Methoxy-2-nitro-
1-(5-Iodopent-1-ynyl)-4- phenyl)pent-4-yn-1-ol
methoxy-2-nitro-benzene 64 [3-Chloro-4-(5-hydroxy-pent-
[3-Chloro-4-(5-iodo-pent-1- [mp 104- 1-ynyl)-phenyl]-carbamic
ynyl)phenyl]-carbamic acid 106.degree. C.] acid tert-butyl ester
tert-butyl ester 65 5-(4-Pyrrol-1-yl-phenyl)-pent-
1-[4-(5-Iodopent-1-ynyl)- 335.7 4-yn-1-ol phenyl]-1H-pyrrole 66
5-(2,5-Dimethylphenyl)- 1-(5-Iodopent-1-ynyl)-2,5- 298.0
pent-4-yn-1-ol dimethyl-benzene 67 5-(5-Chloro-2-methyl-
4-Chloro-2-(5-iodopent-1- 317.9 phenyl)-pent-4-yn-1-ol
ynyl)-1-methyl-benzene 68 5-(4-Chloro-2-methyl-
4-Chloro-1-(5-iodopent-1- 317.9 phenyl)pent-4-yn-1-ol
ynyl)-2-methyl-benzene 69 5-(2,4-Dimethyl-phenyl)pent-
1-(5-Iodopent-1-ynyl)-2,4- 298.0 4-yn-1-ol dimethyl-benzene 70
5-(2-Methyl-4-nitro-phenyl)- 1-(Iodopent-1-ynyl)-2- 328.9
pent-4-yn-1-ol methyl-4-nitrobenzene 71 5-(4-Bromo-2-methyl-phenyl)
4-Bromo-1-(5-iodopent-1- 361.9 pent-4-yn-1-ol
ynyl)-2-methyl-benzene 72 3-(5-Hydroxypent-1-ynyl)-4-
3-(5-Iodopent-1-ynyl)-4- 341.9 methylbenzoic acid methyl
methylbenzoic acid methyl ester ester 73
4-(5-Hydroxy-pent-1-ynyl)-3- 3-(5-Iodopent-1-ynyl)-4- 341.9
methylbenzoic acid methyl methylbenzoic Acid Methyl ester Ester 74
[4-Methyl-3-(5-hydroxypent- [3-(5-Iodopent-1-ynyl)-4- 399.9
1-ynyl)phenyl]carbamic acid methylphenyl]carbamic tert-butyl ester
acid tert-butyl ester 75 5-(2-Chlorophenyl)-pent-4-
1-Chloro-2-(5-iodopent-1- 304.0 yn-1-ol ynyl)benzene 76
5-(2,4-Dichlorophenyl)pent- 2,4-Dichloro-1-(5-iodo- 337.9 4-yn-1-ol
pent-1-ynyl)benzene 77 4-(5-Hydroxypent-1- 1-(5-Iodopent-1-ynyl)-4-
337.9 ynyl)trifluoromethyl-benzene trifluoromethylbenzene 78
4-(5-Hydroxypent-1- 1-(5-Iodopent-1-ynyl)-4- ynyl)trifluoromethoxy-
trifluoromethoxy-benzene benzene 79 [3-Methyl-4-(5-hydroxypent-
[4-(5-Iodopent-1-ynyl)-3- 399.9 1-ynyl)-phenyl]carbamic
methylphenyl]carbamic Acid tert-Butyl Ester Acid tert-Butyl Ester
80 N-tert-Butyl-3-(5- N-tert-Butyl-3-(5-iodo-pent- 383.8
hydroxypent-1-ynyl)-4- 1-ynyl)-4-methyl- methylbenzamide benzamide
81 4-(5-hydroxypent-1- [4-(5-Iodopent-1-ynyl)- 385.9
ynyl)phenylcarbamic Acid phenyl]carbamic Acid tert- tert-Butyl
Ester Butyl Ester 82 3-(5-Hydroxypent-1-ynyl)-4-
3-(5-Iodopent-1-ynyl)-4- methylbenzoic Acid Methyl methylbenzoic
Acid Methyl Ester Ester 83 5-(3-Nitrophenyl)pent-4-yn-
1-(5-Iodopent-1-ynyl)-3- 315.8 1-ol nitrobenzene 84
5-(4-Nitrophenyl)pent-4-yn- 1-(5-Iodopent-1-ynyl)-4- 315.9 1-ol
nitrobenzene 85 5-(4-tert-Butylphenyl)pent-4-
1-tert-Butyl-4-(5-iodo-pent- 326.0 yn-1-ol 1-ynyl)benzene 86
5-(3-Chlorophenyl)pent-4- 1-Chloro-3-(5-iodopent-1- 304.0 yn-1-ol
ynyl)benzene 87 6-(4-Chlorophenyl)hex-5-yn-
1-(4-Chlorophenyl)-6-iodo- 1-ol 1-hexyne 88
11-(4-Chlorophenyl)-undec- 1-(4-Chlorophenyl)-11- 10-yn-1-ol
iodo-1-undecyne
EXAMPLE 89
1-(3-Bromo-1-propynyl)-4-phenoxybenzene
[0313] A solution of 3-(4-phenoxyphenyl)prop-2-yn-1-ol of Example
51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol),
carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred
at room temperature for 3 days. Evaporation of the solution, and
chromatography of the residue gave the title compound as a brown
oil: NMR (CDCl.sub.3) .delta.4.16 (s, 2H), 6.91 (d, J=2.1, 1H),
6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d, J=1.14, 1H),
7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98, 2H), 7.42
(d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C.sub.15H.sub.11BrO
287.155).
[0314] In the manner described in Example 89, above, the following
alcohols were converted to the corresponding bromides of Examples
90-91:
8 mass EX. No. ALCOHOL PRODUCT spectrum 90 3-Thiophene-2-ylprop-2-
2-(3-Bromoprop-1-ynyl)-thiophene 201.9 (M + H) yn-1-ol 91
3-Biphenyl-4-ylprop-2-yn- 4-(3-Bromoprop-1-ynyl)- 270 (M - H) 1-ol
biphenyl
EXAMPLE 92
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-
-2,4-dione
[0315] To a solution of
5-(4-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-di- one [U.S. Pat
No. 5,605,918; February 1997; Wrobel, et al.](1.00 g, 3.92 mmol)in
THF (40 ml) was added NaH (0.34 g, 8.62 mmol) at 0.degree. C. and
stirring was continued for 30 minutes. To this was added a solution
of 1-(4-chlorophenyl)-5-iodo-1-pentyne (1.25 g, 4.12 mmol)in 3 ml
of THF. This was then stirred at room temperature for 18 hours, and
then quenched in water. The resultant oil was chromatographed on
silica gel using hexane:ethyl acetate (4:1) to give the title
compound as a pale yellow solid, m.p. 106-109.degree. C.
[0316] In the manner described in Example 92 immediately above, the
appropriate substituted alkyl iodide was reacted with a
substituted-phenyl thiazolidinedione to give the following
compounds of Examples 93-96:
EXAMPLE 93
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine--
2,4-dione
[0317] MS m/z 444.2 (calcd for C.sub.22H.sub.20ClNO.sub.3S.sub.2
445.99).
EXAMPLE 94
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)-thiazoli-
dine-2,4-dione
[0318] mp 54-56.degree. C., MS m/z 514.0 (calcd. for
C.sub.27H.sub.30ClNO.sub.3 516.1).
EXAMPLE 95
5-(4-Methoxyphenyisulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2-
,4-dione
[0319] This was used in the next step without further
purification
EXAMPLE 96
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine--
2,4-dione
[0320] This was used in the next step without further
purification
EXAMPLE 97
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-
-2,4-dione
[0321] To a solution of
5-[5-(4-Chlorphenyl)pent-4-ynyl]-5-(4-methoxypheny- l
sulfanyl)-thiazolidine-2,4-dione of Example 92 above, (0.87 g, 2.0
mMol) in glacial acetic acid (30 ml) at 60.degree. C. was added 30%
hydrogen peroxide (0.82 ml, 8.0 mmol). After 30 minutes the
reaction mixture was evaporated and the residue was subjected to
chromatography to give the title compound, MS (M-H) m/z 462.0
(calcd. For C.sub.21H.sub.18CINO.sub.5- S.sub.2 463.96).
EXAMPLE 98
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine--
2,4-dione
[0322]
5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazo-
lidine-2,4-dione (0.30 g, 0.81 mmol) and isobutyraldehyde (0.37 ml,
4.04 mmol) were dissolved in acetonitrile (40 ml). Oxygen was
bubbled through this solution for 18 hours, and then the solution
was evaporated and the residue was subjected to chromatography on
silica gel (hexane-ethyl acetate, 1:1) to give 0.108 g, 28% yield
of the title compound, mp 145-148.degree. C., MS m/z 476.0.
EXAMPLE 99
5-[1-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidi-
ne-2,4-dione
[0323]
5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-th-
iazolidine-2,4-dione was converted to the title compound using the
procedure of Example 98 immediately above, mp 114-121.degree.
C.
EXAMPLE 100
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-
-2,4-dione
[0324] To a solution of
5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No.
5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF
(50 ml) was added sodium hexamethyldisilazide (1.0 M solution in
THF--19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and
this was stirred for 15 minutes. To this was added
1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5
minutes, and this solution was stirred overnight at room
temperature. The reaction mixture was quenched in water, and the
solid that was obtained was recrystallized from methanol to give
1.59 g of the title compound as colorless crystals, m.p.
172-174.degree.; NMR (CDCl.sub.3) .delta.1.59 (m, 1H); 2.0(m, 1H);
2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H);
3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H)
[0325] In a manner essentially that of Example 100, the following
products of Examples 101-171 were obtained by alkylation of an
arylthiazolidine-2,4-dione with the appropriate iodo or bromo
compound. All structures were verified by NMR and gave spectra
consistent with that shown in Example 100:
9 Ex. melting mass No. Product point .degree. C. spectrum m/z (M -
H) 101 5-[5-(2-Chlorophenyl)pent- -4-ynyl]-5-(4- 133-135 463.0
methoxybenzenesulfonyl)thiazolidine-2- ,4- dione 102
5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4- 134-136 463.0
methoxybenzenesulfonyl)thiazolidine-2,4- dione 103
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p- 176-177 447.0
tolylsulfonyl)thiazolidine-2,4-dione 104
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 157-159 558.8
iodobenzenesulfonyl)thiazolidine-2,4-dione 105
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 450.9
fluorobenzenesulfonyl)thiazolidine-2,4- dione 106
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- 193-194 525.0
phenoxybenzenesulfonyl)-thiazolidine-2,4- dione 107
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5- 150-153 483.0
(naphthalene-2-sulfonyl)thiazolidine-2,4- dione 108
N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4- 232 490.0
dioxothiazolidine-5- decomp. sulfonyl}phenyl)acetamide 109
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5- pale 484.0
(quinoline-8-sulfonyl)thiazolidine-2,4-dione yellow solid 110
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4- tan solid 477.9
nitrobenzenesulfonyl)thiazolidine-2,4-dione 111
5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4- 181-184 539.0
chlorophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 112
5-(4-Butoxybenzenesulfonyl)-5-[5-(4- 116-118 505.0
chlorophenyl)-pent-4-ynyl]-thiazolidine-2,4- dione 113
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5- 172-174 483.0
(naphthalene-1-sulfonyl)-thiazolidine-2,4- dione 114
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4- 124-126 497.4
methoxy-benzenesulfonyl)-thiazolidine-2,4- dione 115
5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4- yellow 593.3
iodobenzenesulfonyl)-thiazolidine-2,4-dione amorphous solid 116
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4- 179-180 560.5
(pyridin-4-yloxy)benz- decomp. enesulfonyl]thiazolidine-2,4-dione
117 5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4- 129-133 497.4
methoxybenzenesulfonyl)-thiazolidine-2,4- dione 118
5-(4-Methoxybenzenesulfonyl)-5-[5-(3- 126-130 473.5
nitrophenyl)pent-4-ynyl]thiazolidine-2,4- dione 119
5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4- 190-191 535.6
phenoxybenzenesulfonyl)thiazolidine-2,4- dione 120
5-(4-Iodobenzenesulfonyl)-5-[5-(4- 205-207 569.4
nitrophenyl)pent-4-ynyl]thiazolidine-2,4- dione 121
5-(4-Methoxybenzene sulfonyl)-5-[5-(4- 156-158 473.5
nitrophenyl)pent-4-ynyl]thiazolidine-2,4- dione 122
5-(4-Methoxybenzene sulfonyl)-5-[5-(2- yellow oil 487.5
methyl-5-nitrophenyl)pent-4- ynyl]thiazolidine-2,4-dione 123
5-(4-Methoxybenzenesulfonyl)-5-[5-(2- orange 503.5
methoxy-5-nitrophenyl)pent-4- solid ynyl]thiazolidine-2,4-dione 124
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5- 203-204 549.6
(4-phenoxybenzenesulfonyl-thiazolidine- 2,4-dione 125
5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5- 188-190 583.4
nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 126
5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]- 168-172 507.6
5-(naphthalene-1-sulfonyl)-thiazolidine-2,4- dione 127
5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5- 197-200 507.6
(naphthalene-2-sulfonyl)-thiazolidine-2,4- dione 128
5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5- 199 572.6
[4-(pyridin-4-yloxy)- decomp. benzenesulfonyl]thiazolidine-
2,4-dione 129 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5- 210-212
549.6 (4-phenoxybenzenesulfonyl)-thiazolidine- 2,4-dione 130
5-(4-Methoxybenzenesulfonyl)-5-[5-(2- yellow 487.5
methyl-4-nitrophenyl)-pent-4-ynyl]- glass thiazolidine-2,4-dione
131 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methy- l-4- 150-152 657.5
nitrophenyl)pent-4-ynyl]-thiazolidine-2,4- dione 132
5-(4-Methoxybenzenesulfonyl)-5-[5-(2- yellow 503.5
methoxy-4-nitrophenyl)pent-4- gum ynyl]thiazolidine-2,4-dion- e 133
5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5- white 491.5
(4-methoxybenzenesulfonyl)-thiazolidine- solid 2,4-dione 134
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4- 129-130 552.4
iodobenzenesulfonyl)-thiazolidine-2,4-dione 135
5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4- 149-150 456.6
methoxybenzenesulfonyl)-thiazolidine-2,4- dione 136
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4- 155-156 456.6
methoxybenzenesulfonyl)-thiazolidine-2,4- dione 137
5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4- 153-154 552.4
iodobenzenesulfonyl)-thiazolidine-2,4-dione 138
5-[5-(5-Chloro-2-methylphenyl)pent-4- 121-122 477.0
ynyl]-5-(4-methoxybenzene-sulfonyl)- thiazolidine-2,4-dione 139
5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]- 196 549.0
5-(4-trifluoromethoxybenzene-sulfonyl)- decomp.
thiazolidine-2,4-dione 140 5-[5-(4-Chloro-2-methylphenyl)pent-4-
197 559.9 ynyl]-5-(4-trifluoromethoxy- decomp.
benzenesulfonyl)-thiazolidine-2,4-dione 141
5-[5-(4-Chloro-2-methylphenyl)-pent-4- 93-99 591.4
ynyl]-5-(4-iodobenzene-sulfonyl)- thiazolidine-2,4-dione 142
5-[5-(4-Chloro-2-methylphenyl)pent-4- yellow 477.0
ynyl]-5-(4-methoxybenzene-sulfonyl)- foam thiazolidine-2,4-dione
143 5-[5-(4-Bromo-2-methy-phenyl)pent-4- white 540.0
ynyl]-5-(4-methoxybenzene-sulfonyl)- foam thiazolidine-2,4-dione
144 5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]- 146-147 617.3
5-(4-iodobenzenesulfonyl)-thiazolidine-2,4- dione 145
(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4- yellow 543.7
dioxothiazolidin-5-yl]pent-1- solid ynyl}phenyl)carbamic Acid
tert-Butyl Ester 146 (3-Chloro-4-{5-[5-(4-methoxybenzene yellow oil
578.1 sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
ynyl}phenyl)carbamic Acid tert-Butyl Ester 147
N-tert-Butyl-3-{5-[5-(4-iodo- white 637.5 benzenesulfonyl)-2,4-di-
oxothiazol-idin-5- powder yl]-pent-1-ynyl}-4-methyl-benzamide 148
(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4- 172-175 653.5
dioxothiazolidin-5-yl]-pent-1-ynyl}-4- methylphenyl)carbamic Acid
tert-Butyl Ester 149 (4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-
yellow 557.7 dioxo-thiazolidin-5-yl]pent-1-ynyl}-3- solid
methylphenyl)carbamic Acid tert-Butyl Ester 150
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 116-118 557.7
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
tert-Butyl Ester 151 (4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- tan
solid 611.6 dioxothiazolidin-5-yl]pent-1-ynyl}-3-
trifluoromethylphenyl)-carbamic Acid tert- Butyl Ester 152
N-tert-Butyl-3-{5-[5-(4-methoxy- 205-208 541.7
benzenesulfonyl)-2,4-dioxothiazol-idin-5- yl]pent-1-ynyl}-4-methy-
l-benzamide 153 5-(4-Methoxybenzenesulfonyl)-5-[5-(4- 160-163 496.5
trifluoromethylphenyl)pent-4- ynyl]thiazolidine-2,4-dione 154
5-(4-Methoxybenzenesulfonyl)-5-[5-(4- 120-123 512.5
trifluoromethoxyphenyl)pent-4- ynyl]thiazolidine-2,4-dione 155
3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 119-121 500.6
dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4- methylbenzoic Acid Methyl
Ester 156 5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4- yellow oil
484.6 methoxybenzenesulfonyl)-thiazolidine-2,4- dione 157
5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5- 134-138 468.6
(toluene-4-sulfonyl)thiazolidine-2,4-dione 158
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 174-178 453.5
dioxo-thiazolidin-5-yl]pent-1- ynyl}benzonitrile 159
5-[5-(4-Methanesulfonylphenyl)-pent-4- 190-193 490.6
ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4- dione 160
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 128-130 500.6
dioxothiazolidin-5-yl]pent-1-ynyl}-3- methylbenzoic Acid Methyl
Ester 161 5-(4-Methoxybenzenesulfonyl)-5-[5-(4- 206-207 493.6
pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine- 2,4-dione 162
5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1- 194-195 589.5
yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione 163
5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4- 204-206 547.6
trifluoromethoxybenzenesulfonyl)- thiazolidine-2,4-dione 164
5-(3-Methoxybenzenesulfonyl)-5-(5- 133-135 434.5
thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4- dione 165
5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2- brown 390.5
yl-pent-4-ynyl)-thiazolidine-2,4-dione gum 166
5-(4-Methoxybenzenesulfonyl)-5-(5- 60-66 434.5
thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4- dione 167
5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin- tan solid 403.0
3-ylprop-2-ynyl)-thiazolidine-2,4-dione 168
5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene- brown 392.1
4-sulfonyl)-thiazolidine-2,4-dione solid 169
5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene- 179-180 462
4-sulfonyl)-thiazolidine-2,4-dione 170 5-[3-(4-Phenoxyphenyl)prop--
2-ynyl]-5- 64-66 478.1 (toluene-4-sulfonyl)-thiazolidine-2,4-dione
171 5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4- orange
methoxybenzenesulfonyl)-thiazolidine-2,4- oil dione
EXAMPLE 172
5-Pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione
[0326] In the manner of Example 100 above, 5-iodo-1-pentyne is
reacted with 5-(toluene-4-sulfonyl)thiazolidine-2,4-dione to give
the title compound, mp 226.degree. C., THEORY: C,53.4, H,4.48,
N,4.15 FOUND: C,53.3, H,4.58, N,4.13.
EXAMPLE 173
5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dio-
ne
[0327] A solution of
5-pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4- -dione(1.0
mmol), 4-pentyn-1-ol (1.0 mmol), bistriphenylphosphine(Pd II)
chloride (0.20 mmol), and copper(I) iodide (0.10 mmol) in 50 ml of
diethylamine was stirred under nitrogen for three days. This was
diluted with dichloromethane and the product was purified by
chromatography to give the title compound as a light beige solid,
mp 173-176.degree. C., THEORY: C,57.95, H,4.38 N,6.76. FOUND:
C,57.68, H,4.35, N,6.70.
EXAMPLE 174
5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-th-
iazolidine-2,4-dione
[0328]
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-
-1-ynyl}-4-methylphenyl)carbamic acid, tert-butyl ester was
subjected to acid hydrolysis which gave the title compound as a
brown solid, MS m/Z 458.9 (calcd. For
C.sub.22H.sub.22N.sub.2O.sub.5S.sub.2 458.56).
EXAMPLES 175 TO 194
[0329] The following general procedure was used to prepare the
compounds of Examples 175 to 194. A solution of 1.15 g (2.5 mmol)
of compound of Example 174, above, in a total of 50 mL of
dichloromethane was divided equally in ten-20 mL scintillation
vials. To each vessel was added 0.13 mL (3 eq), of
diisopropylethylamine, the appropriate acylating agent (1.2 eq, 0.3
mmol) and the mixture was allowed to react in an orbital shaker
overnight. Crude reaction mixtures were checked by Mass Spec for
product. Once product formation was confirmed, the solutions were
evaporated to dryness under reduced pressure, taken up in 1 mL of
dichloromethane and purified via preparative HPLC. Each product
fraction was then evaporated to dryness in the vacuum apparatus,
characterized via mas spectrometry.
10 Ex. Mass Spectrum No. Product (M - H) 175
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 591.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Benzyl Ester 176 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 636.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
4-Nitro-Benzyl Ester 177 (3-{5-[5-(4-Methoxybenzenesulfonyl)-- 2,4-
611.0 dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic
Acid 4-Chloro-phenyl Ester 178
(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 515.0
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Methyl Ester 179 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 543.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Isopropyl Ester 180 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 571.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Neopentyl Ester 181 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 557.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Butyl Ester 182 (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4- 557.1
dioxothiazolidin-5-yl]pent-1-ynyl}-4- methylphenyl)carbamic Acid
Isobutyl 183 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-
-1,3- 526.9 thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-
methylpropanamide 184 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-
-dioxo-1,3- 555.0 thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,-
3- dimethylbutanamide 185 N-[3-(5-{5-[(4-Methoxyphenyl)sulf-
onyl]-2,4-dioxo-1,3- 541.0 thiazolidin-5-yl}-1-pentynyl)-4-methylp-
henyl]-2,2- dimethylpropanamide 186 N-[3-(5-{5-[(4-Methoxyp-
henyl)sulfonyl]-2,4-dioxo-1,3- 574.9 thiazolidin-5-yl}-1-pentynyl)-
-4-methylphenyl]-2- phenylacetamide 187
N-Benzyl-N'-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4- 589.9
dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea 188
N-(4-Methoxyphenyl)-N'-[3-(5-{5-t(4-methoxy 606.0
phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
methylphenyl]urea 189 N-(4-Chlorophenyl)-N'-[3-(5-{5-[(4-methoxy-
609.9 phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl-
)-4- methylphenyl]urea 190 N-[3-(5-{5-[(4-Methoxyphenyl)sul-
fonyl]-2,4-dioxo-1,3- 590.0 thiazolidin-5-yl}-1-pentynyl)-
-methylphenyl]-N'-(4- methylphenyl)urea 191
4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo- 596.0
1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide 192
4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4- 590.9
dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylphenyl]benzamide
193 N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3- 636.9
thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1'-biphenyl]-
4-carboxamide 194 4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-su-
lfonyl]-2,4- 617.0 dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
methylphenyl]benzamide
EXAMPLES 195 TO 213
[0330] The following general procedure was used to prepare the
compounds of Examples 195 to 213. A solution of 800 mg of each
sulfone in 20 mL anhydrous DMF was distributed evenly among 4 vials
(0.57-0.75 mmol each). To each was added 2.1 eq 1.0M NaHMDS under a
stream of N2 and reacted in an orbital shaker for 45 min. 1.05
equivalents of the appropriate alkylating agent was dissolved in 2
mL DMF and added under N2 to the above vials. The reactions were
allowed to shake overnight at room temp.
[0331] Each vial was diluted with 5 ml H.sub.2O, acidified with
2NHCl, then extracted with ethyl acetate. Crude extracts were
evaporated to dryness under reduced pressure in a vacuum apparatus,
dissolved in 1 mL of dichloromethane, then purified via preparative
HPLC. The product fractions were collected, and evaporated to
dryness under reduced pressure and analyzed via MS and NMR.
11 Mass Ex. Spectrum No. Product (M - H) 195
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2- 473.8
thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione 196
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2- 439.9
thienylsulfonyl)-1,3-thiazolidine-2,4-dione 197
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4- 494.0
dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione 198
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4- 527.0
pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4- dione 199
5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)- 516.9
2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione 200
5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5- 509.8
dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4- dione 201
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2- 473.8
thienylsulfonyl)-1,3-thiazolidine-2,4-dione 202
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4- 527.9
dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione 203
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4- 560.9
pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4- dione 204
5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2- 550.9
pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4- dione 205
tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4- 569.0
dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4- methylphenylcarbamate
206 tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3- 533.0
thiazolidin-5-yl]-1-pentyn-yl}-4- methylphenylcarbamate 207
tert-Butyl 3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]- 587.1
2,4-dioxo-1,3-thiazol-idin-5-yl}-1-pentynyl)-4-
methylphenylcarbamate 208 tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-
620.1 pyridinyloxy)phenyl]sulfonyl}-1,3-thiazol-idin-5-yl)-
1-pentynyl]-4-methylphenylcarbamate 209 tert-Butyl
3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2- 610.0
thienyl]sulfonyl}-1,3-thiazol-idin-5-yl)-1-pentynyl]-4-
methylphenylcarbamate 210 N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thie-
nyl)sulfonyl]- 553.0 2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
- methylbenzamide 211 N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-t-
hienylsulfonyl)- 517.1 1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylb-
enzamide 212 N-(tert-Butyl)-3-(5-{5-[(3,4- 571.1
dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-
5-yl}-1-pentynyl)-4-methylbenzamide 213 N-(tert-Butyl)-3-[5-(2,4-d-
ioxo-5-{[5-(2-pyridinyl)-2- 594.0 thienyl]sulfonyl}-1,3-
thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide
EXAMPLE 214
4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}--
3-methylbenzoic Acid
[0332] To a solution of
4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiaz-
olidin-5-yl]pent-1-ynyl}-3-methylbenzoic acid methyl ester (Example
160) (0.29 g, 0.536 mmol) in THF (30 ml plus sufficient methanol to
dissolve the substrate) was added lithium hydroxide (0.75 ml of
1.0M in water), and this solution was stirred at room temperature
for 3 days. Dilution with water and acidification gave a solid
which was crystallized from hexane-ethyl acetate to give the title
compound as a light yellow solid mp 182-184.degree. C. THEORY: C,
56.66, H,4.34, N,2.87. FOUND: C,56.39, H,4.60, N,2.80.
EXAMPLE 215
N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-
-yl]propionamide
[0333] To a solution of
5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dion- e [U.S. Pat.
No. 5,605,918; February 1997; Wrobel, et al.] ((5.0 g, 17.4 mmol)
in 150 ml of DMF was added sodium bistrimethylsilylamide (36.6 ml
of 1.0 M solution in THF) and this solution was stirred for 15
minutes. To this was added methyl 3-iodopropionate (17.4 mmol) and
this solution was stirred for three hours and then was subjected to
an aqueous workup. The product was chromatographed (silica gel,
hexane-ethyl acetate-dichloromethane, 1:1:1) to give methyl
3-[5-(4-methoxybenzenesulf-
onyl)-2,4-dioxothiazolidin-4-yl]propionate, 4.48 g. This was
hydrolyzed with lithium hydroxide, THF, methanol to give
3-[5-(4-methoxybenzenesulfo-
nyl)-2,4-dioxothiazolidin-4-yl]propionic acid which was used
without further purification in the following procedure:
[0334] To a solution of the above acid (0.4 g, 1.1 mmol) in 15 ml
of dichloromethane plus 2 ml of DMF was added 4-chlorobenzylamine
(0.2 ml, 1.67 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.255
g, 1.33 mmol), and this was stirred at room temperature for 18
hours. Aqueous workup, and chromatography (silica gel,
chloroform-methanol--5%) gave the title compound as a colorless
solid, mp 90.degree. C. and decomposes over wide range.
EXAMPLE 216
N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thia-
zolidin-5yl]propionamide
[0335] In a like procedure to Example 215, above,
4-chlorophenethylamine gave the title compound as a white powder,
mp 189.degree. C. with decomposition.
EXAMPLE 217
5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidin-
e-2,4-dione
[0336] A sample of
5-[5-(4-chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-t-
hiazolidine-2,4-dione (Example 103) was hydrogenated in the
presence of Lindlars catalyst in ethanol to give the title compound
as a white solid, NMR (CDCl.sub.3) .delta.2.47 (s, 3H), 5.57
(apparent d of triplets, J=7.3, 11.6 Hz, 1H), 6.42 (br d, J=11.6
Hz, 1H) MS m/Z 499.0495 (M+ calcd. for
C.sub.21H.sub.20ClNO.sub.4S.sub.2 499.0523).
EXAMPLE 218
5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)-thiazo-
lidine-2,4-dione
[0337] A mixture of 4-pentyn-1-ol, 1.05 eq tri-n-butyltinhydride
and a catalytic amount of 1,1'-azobis(cyclohexanecarbonitrile), was
heated to 55.degree. C. overnight. The mixture was cooled, then
purified on silica gel using 6:1 hex: EtOAc to 4:1 as eluent to
give 86% yield of tri-n-butyl(4-pentenol)-5-ylstannane as a clear
liquid which contained both cis and trans isomers. Then,
4-chloroiodobenzene (1.0 equiv.) was dissolved in anhydrous DMF
under a nitrogen atmosphere.
Tri-n-butyl(4-pentenol)-5-ylstannane(1.0 equiv.) was added,
followed by tetrakis-triphenylphosphinePd(0)(0.1 equiv.) and Cul
(0.75 equiv.). The reaction was stirred at room temperature
overnight. The reaction was diluted with ether, filtered through a
small pad of celite and an excess of saturated aqueous NH.sub.4Cl
was added, and this was stirred for 1 h. Combined organics were
washed with brine, and dried over MgSO.sub.4 to afford a tan
semi-solid. This was purified using silica and 4:1 Hex: MeOtBu to
1:1. Obtained three cuts: 20% pure `Z` isomer, 26% mix, 19.6% `E`
isomer (desired trans isomer) which was a light tan low melting
solid.
[0338] A solution of imidazole (1.3 equiv.) and triphenylphosphine
(1.3 equiv.) in acetonitrile-ether was cooled to 0.degree. C.
Iodine (1.4 equiv.) was added in three portions, and the solution
was then allowed to warm to room temp overnight.
[0339] The mixture was dissolved in methylene chloride, and
directly preadsorbed onto silica gel and purified using 25:1
Hexanes: EtOAc as eluent to give the iodo-compound as a clear
liquid. In an oven-dried round bottom flask under nitrogen was
dissolved the sulfone in anhydrous DMF. Sodium hexamethyldisilazide
(1.0 M solution in THF--2.1 equiv.) was added dropwise at room
temperature and allowed to react at room temp for one hour. The
iodide (1.1 equiv.) was dissolved in DMF, then added in one portion
to the above solution., and allowed to react overnight.
[0340] The reaction was diluted with water, acidified to approx. pH
2 using 2N HCl, extracted with ethyl acetate (3.times.), combined
organics, washed with brine, dried over MgSO.sub.4 and concentrated
to afford an oil which was purified on silica gel using 1:2:1
CH.sub.2Cl.sub.2: hex: EtOAc to afford the title compound, 36% as
an off-white solid, mp 182-184.degree. C., E-double bond--NMR
(CDCl.sub.3) .delta.6.18 (td, 1H, J=22.5 Hz), 6.31 (d, 1H, J=22.5
Hz).
EXAMPLE 219
5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-
-dione
[0341] A sample of
5-[3-(4-Chlorophenyl)prop-2-ynyl]-5-(4-methoxy-benzenes-
ulfonyl)-thiazolidine-2,4-dione (U.S. Pat. No. 5,605,918; February
1997; Wrobel, et al.) was hydrogenated in the presence of palladium
on charcoal (10%) in methanol plus 2% water to give the title
compound as a colorless glass, NMR (CDCl.sub.3) .delta.1.57 (m,
1H); 1.97 (m, 1H); 2.20 (triplet of doublet), 1H); 2.45 (m, 1H);
2.61 (q, 2H); 3.92 (s, 3H); 7.0 (dd, 4H); 7.26 (d, 2H) 7.98 (d,
2H).
EXAMPLE 220
5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-
-2,4-dione
[0342] A sample of
5-(4-methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-
-ynyl]-thiazolidine-2,4-dione of Example 118 was reduced with iron
in acetic acid to give the title compound as crystals, m.p.
135-138.degree. C.
EXAMPLE 221
5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione
[0343] Alkylation with cinnamyl bromide (222 mg, 1.13 mmol) of
5-(4-methylphenylsulfonyl)-thiazolidine-2,4-dione (271 mg, 1.00
mmol) following the procedure in Example 3 yield 32 mg (8%) of
light yellow oil which was identified as
5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazoli- dine-2,4-dione:
NMR (CDCl.sub.3) .delta.2.49 (s, 3H), 3.06-3.13 (m, 1H), 3.34-3.42
(m, 1H), 6.01-6.11 (m, 1H), 6.60 (d, J=15.69, 1H), 7.26-7.26-7.31
(m, 5H), 7.42 (d, J=8.13, 2H), 7.85 (d, J=8.34, 2H) MS m/z 388.1
(M+H cald. for C.sub.19H.sub.17NO.sub.4S.sub.2 387.48)
EXAMPLE 222
Enantiomer of(3-{5-[5-(4-Methoxybenzene
sulfonyl)-2,4-dioxothiazolidin-5-y-
l]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (less
polar)
[0344] The compound of Example 150 was chromatographed on a chiral
column with hexane-ethanol 4:1 to give a less polar enantiomer,
retention time 14.5-16 min.
EXAMPLE 223
Enantiomer of(3-{5-[5-(4-Methoxybenzene
sulfonyl)-2,4-dioxothiazolidin-5-y-
l]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (more
polar)
[0345] Continued chromatography of the compounds in Example 223
gave a more polar enantiomer, retention time 19-21 min.
EXAMPLE 224
5-(4-methoxyphenyl-4-sulfinyl)-thiazolidine-2,4-dione
[0346] 5-(4-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione [U.S.
Pat. No. 5,605,918; February 1997; Wrobel, et al.] was oxidized as
described for Example 98 to give the title compound: NMR
(CDCl.sub.3) .delta.3.80 (S, 3H), 5.77 (S, 1H), 7.04 (d, 2H), 7.62
(d, 2H).
EXAMPLE 225
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-
-2,4-dione
[0347] By the method of Example 92, the compound of Example 224,
above, is converted to the title compound.
EXAMPLES 226-233
[0348] In the isolation of products of Examples 175 to 194 the
N-3-acylated products of Examples 227 to 234 were isolated and the
structures were verified by mass spectrometry and NMR:
12 Ex. No. Compound 226 Benzyl
5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2- methylphenyl)pent-4-ynyl-
]-5-[(4- methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
3-carboxylate 227 4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5--
{5-[2- methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)
phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3- carboxylate 228
Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-
methylphenyl}pent-4-ynyl)-5-[(4- methoxyphenyl)sulfonyl]-2,4-diox-
o-1,3-thiazolidine- 3-carboxylate 229 Isopropyl
5-(5-{5-[(isopropoxycarbonyl)-amino]-2- methylphenyl}pent-4-ynyl)-
-5-[(4- methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
3-carboxylate 230 Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-
- methyl-5-{[(neopentyloxy)carbonyl]-
amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3- thiazolidine-3-carboxyla-
te 231 Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-
methylphenyl}pent-4-ynyl)-5-[(4-methoxy- phenyl)sulfonyl]-2,4-dio-
xo-1,3-thiazolidine-3- carboxylate 232 Isobutyl
5-(5-{5-[(isobutoxycarbonyl)-amino]-2- methylphenyl}pent-4-ynyl)--
5-[(4- methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
3-carboxylate
EXAMPLE 233
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxyb-
enzenesulfonyl)-thiazolidine-2,4-dione
[0349] The compound of Example 97 is reacted with
1,3-dibromopropane and potassium carbonate in DMF to give
5-[5-(4-chlorophenyl)pent-4-ynyl]-3-(3-
-bromopropyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione,
and this is reacted with imidazole, sodium salt in DMF, and in the
presence of a catalytic amount of potassium iodide to give the
title compound as a light tan solid, mp 111-113.degree. C.
EXAMPLE 234
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-th-
iazolidine-2,4-dione
[0350]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thia-
zolidine-2,4-dione (Example 100) is reated with sodium hydride in
DMF, followed by methyl iodide to give the title compound as
colorless crystals, mp 113-115.degree. C.
EXAMPLE 235
3-(2,4-Diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione
[0351] 5-(Toluene-4-sulfonyl)thiazolidine-2,4-dione [U.S. Pat. No.
5,605,918; February 1997; Wrobel, et al.] was reacted with
2,4-diethoxybenzyl alcohol in the presence of triphenylphosphine
and diethyl diazodicarboxylate to give the title compound as
colorless crystals, mp 121-123.degree. C.
EXAMPLE 236
5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulf-
onyl)-thiazolidine-2,4-dione
[0352] The product of Example 237 is reacted with sodium
hexamethyldisilazide in DMF, followed by the addition of
1-chloro-4-(5-iodopent-1-ynyl)-benzene to give the title compound
as colorless crystals, mp 151-153.degree. C.
EXAMPLE 237
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenz-
yl)-thiazolidine-2,4-dione
[0353]
5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazol-
idine-2,4-dione is reacted with 4-nitrobenzyl bromide and potassium
carbonate in DMF to give the title compound as a light tan solid,
mp 172-175.degree. C.
EXAMPLE 238
[0354]
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)--
2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester
[0355]
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)--
thiazolidine-2,4-dione is reacted with
(2-methoxyethoxy)chloroformate and diisopropylethylamine in
methylene chloride to give the title compound as a solid, MS m/z
599.8 (calcd. for C.sub.25H.sub.23Cl.sub.2NO.sub.8S.sub.2
600.5).
[0356] Examples 239-267 were synthesized using the methods
described in U.S. Pat. Nos. 5,605918 and 5,574051 and in Wrobel,
J., et al., J. Med. Chem. 1998, 41 (7), 1084-91.
EXAMPLE 239
[0357]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)-thiaz-
olidine-2,4-dione
EXAMPLE 240
[0358]
5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine--
2,4-dione
EXAMPLE 241
[0359]
5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]-thiazolidine-2,4-dione
EXAMPLE 242
[0360]
5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine--
2,4-dione
EXAMPLE 243
[0361]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)-th-
iazolidine-2,4-dione
EXAMPLE 244
[0362]
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-th-
iazolidine-2,4-dione
EXAMPLE 245
[0363]
5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thi-
azolidine-2,4-dione
EXAMPLE 246
[0364]
5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazoli-
dine-2,4-dione
EXAMPLE 247
[0365]
5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]-thiazolidine-2,4-
-dione
EXAMPLE 248
[0366]
5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2-
,4-dione
EXAMPLE 249
[0367]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)-t-
hiazolidine-2,4-dione
EXAMPLE 250
[0368]
5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,-
4-dione
EXAMPLE 251
[0369]
5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-
-thiazolidine-2,4-dione
EXAMPLE 252
[0370]
5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazol-
idine-2,4-dione
EXAMPLE 253
[0371]
5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolid-
ine-2,4-dione
EXAMPLE 254
[0372]
5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thia-
zolidine-2,4-dione
EXAMPLE 255
[0373]
5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]-th-
iazolidine-2,4-dione
EXAMPLE 256
[0374]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-3-sulfonyl)-thiazoli-
dine-2,4-dione
EXAMPLE 257
[0375]
5-[3-(3-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazoli-
dine-2,4-dione
EXAMPLE 258
[0376]
5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]-thiazolidine--
2,4-dione
EXAMPLE 259
[0377]
5-Benzenesulfonyl-5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl-
]-thiazolidine-2,4-dione
EXAMPLE 260
[0378]
5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5-(toluene-4-sul-
fonyl)-thiazolidine-2,4-dione
EXAMPLE 261
[0379]
5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]-thiazolidine--
2,4-dione
EXAMPLE 262
[0380]
5-[3-(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4--
thiazolidinedione
EXAMPLE 263
[0381]
5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)-thi-
azolidine-2,4-dione
EXAMPLE 264
[0382]
5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-
-ynyl]-thiazolidine-2,4-dione
EXAMPLE 265
[0383]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)-thiazo-
lidine-2,4-dione
EXAMPLE 266
[0384]
5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-
-dione
EXAMPLE 267
[0385]
5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)-thiazolidin-
e-2,4-dione
* * * * *