Process for preparing hydroxamic acids

Details Process for preparing hydroxamic acids Process for preparing hydroxamic acids

1999-04-07

2001-09-11

Solola, T. A (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C564S301000

Reexamination Certificate

active

06288246

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to a process for preparing hydroxamic acids from carboxylic acid intermediates, wherein the carboxylic acid intermediate does not possess reactive substituents such as hydroxy or amino groups.
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-&agr;) 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.
Matrix metalloproteinase inhibitors are well known in the literature. Specifically, PCT publication WO 96/33172 published Oct. 24, 1996, refers to cyclic arylsulfonylamiro hydroxamic acids that are useful as MMP inhibitors. U.S. Pat. No. 5,672,615, PCT Publication WO 97/20824, PCT Publication WO 98/08825, PCT Publication WO 98/27069, and PCT Publication WO 98/34918, published Aug. 13, 1998, entitled “Arylsulfonyl Hydroxamic Acid Derivatives” all refer to cyclic hydroxamic acids that are useful as MMP inhibitors. PCT Publications WO 96/27583 and WO 98/07697, published Mar. 7, 1996 and Feb. 26, 1998, respectively, refer to arylsulfonyl hydroxamic acids. PCT Publication W/O 98/03516, published Jan. 29, 1998 refers to phosphinates with MMP activity. PCT Publication WO 98/34915, published Aug. 13, 1998, entitled “N-Hydroxy-&bgr;-Sulfonyl Propionamide Derivatives,” refers to propionylhydroxamides as useful MMP inhibitors. PCT Publication WO 98/33768, published Aug. 6, 1998, entitled “Arylsulfonylamino Hydroxamic Acid Derivatives,” refers to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT Publication WO 98/30566, published Jul. 16, 1998, entitled “Cyclic Sulfone Derivatives,” refers to cyclic sulfone hydroxamic acids as MMP inhibitors. U.S. Provisional Patent Application No. 60/55208, filed Aug. 8, 1997, refers to biaryl hydroxamic acids as MMP inhibitors. U.S. Provisional Patent Application Serial No. 60/55207, filed Aug. 8, 1997, entitled “Aryloxyarylsulfonylamino Hydroxamic Acid Derivatives,” refers to aryloxyarylsulfonyl hydroxamic acids as MMP inhibitors. Each of the above referenced publications and applications is hereby incorporated by reference in its entirety.
SUMMARY OF THE INVENTION
The present invention relates to a process for preparing a molecule containing a hydroxamic acid group, comprising reacting hydroxylamine, or a salt thereof, with a ((C
1
-C
6
)alkyl)
3
silyl halide, preferably ((C
1
-C
6
)alkyl)
3
silyl chloride, in the presence of a base, followed by reaction with a carboxylic acid halide containing molecule followed by reaction with an acid, with the proviso that the carboxylic acid halide containing molecule does not contain a hydroxy, primary amine, secondary amine or thiol group.
The present invention relates to a process for preparing a compound of the formula
Z is >CH
2
or >NR
1
;
Q is (C
1-
C
6
)alkyl, (C
6
-C
10
)aryl, (C
2
-C
9
)heteroaryl, (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
1
-C
6
)alkyl, (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
1
-C
6
)alkyl, (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
)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
1
-C
6
)alkyl, (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
1
-C
6
)alkyl, (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
)aldoxy(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;
R
1
is hydrogen, (C
1
-C
6
)alkyl, (C
6
-C
10
)aryl(C
1
-C
6
)alkyl, (C
2
-C
9
)heternryl(C
1
-C
6
)alkyl or a group of the formula
wherein R
2
and R
3
are independently hydrogen, (C
1
-C
6
)alkyl or R
2
and R
3
are taken together to form a three to seven membered cycloalkyl ring, 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
;
and R
4
is (C
1
-C
6
)alkyl;
n is an integer from one to six; comprising:
a) reacting hydroxylamine, or a salt thereof, with a ((C
1
-C
6
)alkyl)
3
silyl halide, preferably trimethylsilyl chloride, in the presence of a first base (preferably pyndine, 2,6-lutidine or diisopropylethylamine), in a solvent (preferably pyridine) to form an in situ ((C
1
-C
6
)alkyl)
3
silylated hydroxylamine,
b) reaction of said in situ ((C
1
-C
6
)alkyl)
3
silylated hydroxylamine with a compound of the formula
 wherein R
2
, R
3
, Z and Q are as defined above, with a second base (preferably pyridine, 2,6-lutidine or diisopropylethylamine) to form a compound of the formula
 wherein R
7
is ((C
1
-C
6
)alkyl)
3
—Si—, and R
8
is hydrogen or ((C
1
-C
6
)alkyl)
3
—Si—, and
c) hydro

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