Process for alkylating hindered sulfonamides

Details Process for alkylating hindered sulfonamides Process for alkylating hindered sulfonamides

1999-04-09

2001-05-08

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S424000, C560S125000, C560S150000

Reexamination Certificate

active

06229025

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for alkylating hindered sulfonamides by Michael addition to propiolates and to novel intermediates prepared in said process. The products of the aforesaid reaction can be converted into matrix metalloproteinase inhibitors.
Inhibitors of matrix metalloproteinase (MMP) are known to be useful for the treatment of a condition selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by inhibition of metalloproteinase or ADAM (including TNF-a) expression. In addition, the products which can be prepared from the compounds and processes of the present invention may be used in combination therapy with standard non-steroidal anti-inflammatory drugs (hereinafter NSAID'S), COX-2 inhibitors and analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.
The alkylsulfonamides that can be prepared by the methods of the present invention are described in the literature. PCT Publications WO 96/27583 and WO 98/07697, published Mar. 7, 1996 and Feb. 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids, and structures referred to herein as formula V. The above references refer to methods of preparing sulfonamides using methods other than those described in the present invention. Each of the above referenced publications is hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to a compound of the formula
wherein R
1
is (C
1
-C
6
)alkyl or optionally substituted benzyl;
R
2
and R
3
are independently (C
1
-C
6
)alkyl or R
2
and R
3
are taken together to form a three to seven membered cycloalkyl, a pyran-4-yl ring or a bicyclo ring of the formula
wherein the asterisk indicates the carbon atom common to R
2
and R
3
;
Q is (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryloxy(C
1
-C
6
)alkyl, (C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryloxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryloxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl;
wherein each (C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl moieties of said (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryloxy(C
1
-C
6
)alkyl, (C
6
-C
10
)aryloxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryloxy(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
6
-C
10
)aryl(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl(C
2
-C
9
)heteroaryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
6
-C
10
)aryl, (C
6
-C
10
)aryl(C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryloxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryloxy(C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryloxy(C
2
-C
9
)heteroaryl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl, (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
6
-C
10
)aryl or (C
2
-C
9
)heteroaryl(C
1
-C
6
)alkoxy(C
2
-C
9
)heteroaryl is optionally substituted on any of the ring carbon atoms capable of forming an additional bond by one or more substituents per ring independently selected from fluoro, chloro, bromo, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, perfluoro(C
1
-C
3
)alkyl, perfluoro(C
1
-C
3
)alkoxy and (C
6
-C
10
)aryloxy;
and Y is hydrogen, (C
1
-C
6
)alkyl or a suitable protecting group.
Preferred compounds of formula IV are those wherein R
2
and R
3
are taken together to form a cyclobutyl, cyclopentyl, pyran-4-yl ring or a bicyclo ring of the formula
wherein the asterisk indicates the carbon atom common to R
2
and R
3
;
and wherein Q is 4-(4-fluorophenoxy)phenyl.
The present invention also relates to a process for preparing a compound of the formula
wherein R
1
, R
2
, R
3
, Q and Y are as defined above;
comprising, reacting a compound of the formula
wherein R
1
is optionally substituted benzyl; and R
2
, R
3
, R
4
and Q are as defined above;
with a compound of the formula
wherein Y is (C
1
-C
6
)alkyl;
in the presence of a base, such as tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, preferably tetrabutylammonium fluoride, and a polar solvent, such as tetrahydrofuran, acetonitrile, tert-butanol, t-amyl alcohols and N,N-dimethylformamide, preferably tetrahydrofuran.
The present invention also relates to a process comprising reducing said compound of the formula
wherein R
1
, R
2
, R
3
Y and Q are as defined above;
with a reducing agent, such as palladium catalysts and a source of hydrogen, preferably hydrogen over palladium on carbon, in a solvent, such as alcohols or tetrahydrofuran, preferably ethanol, to form a compound of the formula
wherein R
5
is hydrogen; and
R
2
, R
3
, Y and Q are as defined above.
The present invention also relates to a process further comprising reacting said compound of formula III, wherein R
5
is hydrogen, with amines such as dicyclohexylamine to form the amine salts such as dicyclohexylammonium salt of the compound of formula III.
The term “protecting group” as a substituent for Y is as described in Greene and Wuts,
Protective Groups in Organic Synthesis,
(John Wiley & Sons, Inc., Wiley Interscience Second Edition, 1991).
The term “alkyl”, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term “alkoxy”, as used herein, includes O-alkyl groups wherein “alkyl” is defined above.
The term “aryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl.
The term “heteroaryl”, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocyclic compound by removal of one hydrogen, such as pyridyl, furyl, p

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