Processes for preparing 3-arylsulfur hydroxamic acids

Details Processes for preparing 3-arylsulfur hydroxamic acids Processes for preparing 3-arylsulfur hydroxamic acids

2002-05-08

2003-02-11

Sololn, T. A. (Department: 1626)

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

Organic compounds

Sulfur containing

C568S056000, C568S058000

Reexamination Certificate

active

06518460

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods of preparing matrix metalloprotease inhibitors, particularly 3-arylsulfur hydroxamic acids.
2. Background Information
I. MMP Inhibitors
Matrix metalloproteases (“MMPs”) are a family of proteases (enzymes) involved in the degradation and remodeling of connective tissues. MMP expression is stimulated by growth factors and cytokines in the local tissue environment, where these enzymes act to specifically degrade protein components of the extracellular matrix, such as collagen, proteoglycans (protein core), fibronectin and laminin. Excessive degradation of extracellular matrix by MMPs is implicated in the pathogenesis of many diseases, including rheumatoid arthritis, osteoarthritis, multiple sclerosis, bone resorptive diseases (such as osteoporosis), chronic obstructive pulmonary disease, cerebral hemorrhaging associated with stroke, periodontal disease, aberrant angiogenesis, tumor invasion and metastasis, corneal and gastric ulceration, ulceration of skin, aneurysmal disease, and in complications of diabetes.
Furthermore, inhibitors of MMP also are known to substantially inhibit the release of tumor necrosis factor (TNF) from cells and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, restenosis, graft versus host reactions and autoimmune disease.
MMP inhibition is, therefore, recognized as a good target for therapeutic intervention. Consequently, inhibitors of MMPs provide useful treatments for diseases associated with the excessive degradation of extracellular matrix and diseases mediated via TNF and several MMP inhibitors are currently being developed for such uses.
One particular class of MMP inhibitors are the 3-arylsulfur hydroxamic acids described in EP 0 780 386 A1, published Jun. 25, 1997. This publication discloses MMP inhibitors of Formula I,
Y—C(═O)—C(R
1
)(R
2
)—CH
2
—S(O)
n
R
3
where n, Y, R
1
, R
2
and R
3
are as described below in the Summary of the Invention.
WO 97/24117, published Jul. 10, 1997, discloses 3-aryl sulfur hydroxamic acids of formula, HON(H)—C(═O)—C
p
(R
1
)(R
2
)—C(R
3
)(R
4
)—S(O)
n
—C
m
(R
5
)(R
6
)—Ar, where p, m, n and R
1
, R
2
, R
3
, R
4
, R
5
, R
6
and Ar are as described in WO 97/24117.
WO 98/05635, published Feb. 12, 1998, discloses 3-arylsulfur hydroxamic acids of formula B—S(O)
0-2
—CHR
1
—CH
2
—CO—NHOH, where B and R
1
are as described in in WO 98/05635.
WO 98/13340, published Apr. 2, 1998, discloses &bgr;-sulfonyl hydroxamic acids of HONHC(═O)—CHR
2
—CH
2
—S(O)
2
R
1
where R
1
and R
2
are as described therein.
However, the processes disclosed in these publications for preparing 3-arylsulfur hydroxamic acids proceed via the nucleophilic attack of a thiol on the &bgr;-carbon of a carboxylate derivative, either displacing a leaving group at the &bgr;-carbon or performing a Michael reaction on an &agr;,&bgr; unsaturated ester or acid. Thus, the disclosed processes are limited by the availability of the corresponding thiols and the &bgr;-substituted carboxylate derivatives and &agr;,&bgr; unsaturated esters. This invention provides novel processes and novel intermediates that are not dependent on the availability of the reagents used in the above publications.
The use of 3-arylsulfonyl hydroxamic acids as MMP inhibitors is also described in WO 97/49679 A1, published Dec. 31, 1997.
II. Preparation of Aryl Alkyl Sulfides
Aryl haloalkyl sulfides are valuable intermediates in synthetic organic processes and they are commonly made by free radical halogenation of a precursor aryl alkyl sulfide. The aryl alkyl sulfide is in turn typically available via sulfonation of a precursor aryl hydrocarbon, reduction to an aryl thiol and alkylation of the thiol. It would be useful to have methods of directly converting arylsulfonyl derivatives to aryl methyl sulfides.
There have been various reports of the reactions between trialkyl phosphites and aryl sulfonyl derivatives. See, for example, R. W. Hoffman, T. R. Moore and B. J. Kagan, (“The Reaction between Triethyl Phosphite and and Alkyl and Aryl Sulfonyl Chlorides”)
J. Am. Chem. Soc.,
78:6413-6414 (1956); J. M. Klunder and K. Barry Sharpless, (“A Convenient Synthesis of Sulfinate Esters from Sulfonyl Chlorides”)
J. Org. Chem.,
52:2598-2602 (1987); and J. Cadogan (“Oxidation of Tervalent Organic Compounds of Phosphorous”)
Quarterly Reviews,
16:208-239 (1962). The reaction of benzensulfenyl chloride with triethylphosphite to yield ethyl phenyl sulfide has also been reported, T. Mukaiyama and H. Ueki, (“The Reactions of Sulfur-containing Phosphonium Salts”)
Tetr. Lett.,
35:5429-5431 (1967). Aryl sulfonyl chlorides have also been converted to aryl methyl sulfides in three steps by treatment of an aryl sulfonyl chloride with lithium diphenylphosphide, Ph
2
PLi, to afford a P-diphenyl-aryl sulfophosphamide followed by cathodic reduction and methylation of the resulting aryl thiolate, J. Pilard and J. Simonet. (“The Cathodic Cleavage of the S-P Bond. Synthesis and Electrochemical Behaviour of Sulfonamide Phosphorous Analogues”),
Tetr. Lett.,
38(21):3735-3738 (1997).
SUMMARY OF THE INVENTION
In one aspect, this invention provides processes for the preparation of a compound of Formula I:
Y—C(═O)—C(R
1
)(R
2
)—CH
2
—S(O)
n
R
3
Formula I
wherein:
Y is hydroxy or XONX—, where each X is independently hydrogen, lower alkyl or lower acyl;
R
1
is hydrogen or lower alkyl;
R
2
is hydrogen, lower alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, or R
1
and R
2
together with the carbon atom to which they are attached form a cycloalkyl or heterocyclo group;
R
3
is aryl; and
n is 0, 1 or 2;
comprising the steps of:
(1) alkylating a compound of Formula II,
RO—C(═O)—CH(R
1
)(R
2
)
Formula II
where R is alkyl or hydrogen, with an arylmethylthio derivative of Formula III, ArSCH
2
—Z, wherein Ar is an aryl group and Z is a leaving group, to provide a compound of Formula IV,
RO—C(═O)—C(R
1
)(R
2
)—CH
2
SAr, and
Formula IV
(2) converting the compound of Formula IV to a compound of Formula I by replacing the group RO— with XONH— and optionally oxidizing the ArS group as necessary in either order.
The invention also provides novel aryl haloalkyl sulfide and aryl alkyl sulfide intermediates useful for the preparation of compounds of Formula I and novel methods of preparing aryl alkyl sulfides.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term “(Cr
p-q
) alkyl” means a linear or branched fully-saturated hydrocarbon radical having p to q carbon atoms; for example, a “C
1-4
alkyl” means a linear or branched fully saturated hydrocarbon radical having one to four carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl.
Unless otherwise specified, the term “lower alkyl” means a C
1-4
alkyl radical.
As used herein, the term “(C
3-6
) cycloalkyl” means a fully saturated cyclic hydrocarbon radical of three to six ring carbon atoms, e.g., cyclopropyl, cyclopentyl and the like.
As used herein, the term “lower acyl” refers to a group —C(═O)R, where R is a (C
1-4
)alkyl radical.
As used herein, the term “loweralkoxy” refers to a group —OR, where R is a (C
1-4
)alkyl radical.
As used herein, the term “(C
7-10
)alkoxy” refers to a group OR, where R is a (C
7-10
)alkyl radical.
As used herein, the term “aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, halo, nitro, cyano, optionally substituted phenyl, —OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl), acyl, —COOR (where R is hydrogen or alkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
As used

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