Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-09
2004-07-20
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S389000, C514S390000, C514S425000, C548S300100, C548S316400, C548S317100
Reexamination Certificate
active
06765003
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to some O-sulfonyl hydroxamic and carboxylic acids displaying potent and selective inhibitory activity against some Matrix MetalloProteinases (MMPs), to their use for the treatment of diseases in which the proteolytic activity of these MMPs is involved, to methods for their preparation, and to pharmaceutical compositions containing them.
BACKGROUND OF THE INVENTION
Under physiological conditions MMPs play an important role in normal tissue turnover and development. However, increased MMP activity and/or impairment of the physiological MMP inhibitors has been associated with a variety of pathological conditions such as cancer, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis, stroke, arteriosclerosis, restenosis and age-related macular degeneration. In cancer, the contribution of MMPs is manifold and not limited to destruction of the extracellular matrix required for local and distal invasion. The proteolytic action of MMPs generates active matrix protein fragments, and influence the release, activation and bioavailability of growth factors. In addition, MMPs are involved in cell migration and in the processing or shedding of cell surface proteins. It is now believed that the proteolytic action of MMPs plays a very important role in tumor growth, apoptosis and angiogenesis (see Noel, A. et al., ‘Emerging Roles for Proteinases in Cancer’, Invasion Metastasis 17:221-239, 1997). Among the several MMPs known to date, gelatinase-A (MMP-2) is currently reputed as the main target in cancer.
Potent MMP inhibitors (MMPIs) were disclosed three decades ago (e.g., see Dickens, J. P. et al., U.S. Pat. No. 4,599,361), but only recently some of them entered clinical trials, and none has arrived at the market yet. Questions remain concerning their specificity, bioavailability, and potential long-tens toxicity (see Hodgson, J., ‘Remodeling MMPIs’, Biotechnology 13:554-557, 1995), especially because they are primarily intended (in arthritis and cancer, at least) for prolonged therapy. Marimastat, the most advanced MMPI in the clinic, and other compounds currently investigated in patients such as Novartis CGS27023A and Agouron AG3340, have been reported to cause a musculoskeletal syndrome characterized by joint pain and stiffness, which may be severe and dose-limiting. Although the cause of this toxicity is not well understood at this moment, it is thought to arise from an impairment in the normal tissue remodeling that is governed by one or more of the MMPs, primarily fibroblast collagenase (MMP-1). We have extended these observations by developing an animal model of joint toxicity, involving treatment of rats for 10 days with MMPIs at exposures close to that required for antitumor efficacy in mice (human prostate DU-145 model). In this rat model, MMPIs characterized by poor selectivity (i.e., comparable potency against MMP-2 and MMP-1), such as marimastat and Roche Ro31-9790, elicited histological alteration of stifle joints (hypertrophic fibrosis of ligaments, interstitial hypertrophic fibrosis of skeletal muscles, hypertrophic fibroplasia of the periostium and synovium, chondrodysplasia, and decreased endochondrial ossification of the ephyseal plate); in some cases, clinical symptoms (abnormal posture, reluctance to move, abnormal gait) were also observed. Thus, there is a strong need for better MMPIs, especially as far as the properties referred to above (specificity, bioavailability, long-term toxicity) are concerned. The compounds of the present invention are intended to provide these advantages.
INFORMATION DISCLOSURE
A previous disclosure by the Pharmacia & Upjohn Company, PCT Patent Application WO 98/13340 (U.S. Pat. No. 5,847,153), provides a broad range of &bgr;-sulfonyl hydroxamic acid derivatives, their preparation, and their activity against various enzymes of the MMP family, predominantly stromelysin and gelatinase. These compounds are generically described by the formula (Ia):
wherein R
1
is C
4-12
alkyl, C
4-12
alkenyl, C
4-12
alkynyl, —(CH
2
)
h
—C
3-8
cycloalkyl, —(CH
2
)
h
-aryl, or —(CH
2
)
h
-het; R
2
is C
1-12
alkyl, C
2-12
alkenyl, C
2-12
alkynyl, —(CH
2
)
h
—C
3-8
cycloalkyl, —(CH
2
)
h
—C
3-8
cycloalkenyl, —(CH
2
)
h
-aryl, —(CH
2
)
h
-het, —(CH
2
)
h
—Q, —(CH
2
)
l
—X—R
4
, or —(CH
2
)
l
—CHR
5
R
6
.
We have now found that the combination of few particular groups R
1
and R
2
in a molecule of formula (Ia) provides distinct advantages over the other compounds of this class of MMPIs. Said combination, which is an object of the present invention, is associated with outstanding potency (Ki in the picomolar range) against the gelatinases, in particular MMP-2, and relatively weak activity against fibroblast collagenase (MMP-1). Further, we have found that the same combination confers good potency (low nanoM range) and even higher selectivity for MMP-2 to the corresponding carboxylates, which were previously described as intermediates but not claimed as such. Finally, we have found that the same combination provides advantages in the pharmacokinetic parameters, in particular lower clearance and higher oral bioavailability, and that antitumor efficacy in rodents can be achieved in the absence of joint toxicity.
DESCRIPTION OF THE INVENTION
The present invention provides 3-arylsulfonyl-2-methyl propanoic acid derivatives of formula (I):
or pharmaceutically acceptable salts thereof wherein:
X is either HO—NH— (hydroxamic acids) or HO— (carboxylic acids);
R
1
is selected from phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, benzamido (i.e., —NH—CO-Ph) or benzamido substituted on the terminal Ph ring by C
1-4
alkyl, fluoro, chloro, cyano, C
1-4
alkoxy;
R
2
is selected from:
(a) —S—Ar or —S—CH
2
—Ar, wherein Ar is a monocarbocyclic or bicarbocyclic aromatic moiety, preferably phenyl, naphthyl and biphenyl, which is either unsubstituted or substituted with one or two substituents selected from the group consisting of C
1-4
alkyl, phenyl, benzyl, C
1-4
alkoxy, fluoro, chloro, bromo, nitro, cyano, hydroxy, amino, dimethylamino, acetamido, methylthio and acetyl;
(b) O—Ar, wherein Ar is as defined above;
(c) —S-Het or —S—CH
2
-Het, wherein Het is a heterocyclic ring selected from the group consisting of pyridine, pyrimidine, pyridazine, pyrazine, 1,2,5-triazine, imidazole, thiophene, furan, pyrrole, pyrazole, 1,3-thiazole, 1,3-oxazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 1,3,4-oxadiazole, 1,2,3,4-tetrazole, quinoline, isoquinoline, indole, 1,3-benzoxazole, 1,3-benzothiazole, benzimidazole, [1,3]oxazolo[4,5-b]pyridine, [1,3]thiazolo[4,5-b]pyridine, [1,2,3,4]tetrazolo[1,5-b]pyridazine and purine, and wherein said Het group can be substituted with one to three substituents selected from the group consisting of C
1-4
alkyl, phenyl, pyridyl, benzyl, C
1-4
alkoxy, methylthio, fluoro, chloro, nitro, cyano, hydroxy, oxo, amino, methylamino, dimethylamino, 2-dimethylaminoethyl, acetamido and acetyl;
(d) 2,5-dioxo-1-imidazolidinyl or 2,4-dioxo-1-imidazolidinyl, which can be substituted at the carbon atom with one or two methyl groups, or with C
2-4
linear or branched alkyl, phenyl, benzyl or hydroxymethyl, and at the nitrogen atom with C
1-4
linear or branched alkyl.
The compounds of the present invention can be converted to pharmaceutically acceptable salts, where appropriate, according to conventional methods. The term ‘pharmaceutically acceptable salts’ refers to acid addition salts useful for administering the compounds of this invention and includes hydrochloride, sulfate, phosphate, acetate, propionate, lactate, mesylate, maleate, malate, succinate, tartrate, citrate, 2-hydroxyethyl sulfonate, fumarate and the like. Alternatively, the compounds of this invention, especially when X in formula (I) is hydroxy, may form metal salts, such as sodium, potassium, calcium or magnesium, or ammonium salts, or salts with an appropriate organic amine or amino acid such as arginine, procaine and the like. Any salt may be eithe
Abrate Francesca
Bissolino Pierluigi
Cremonesi Paolo
Jabes Daniela
Mantegani Sergio
Akin Gump Strauss Hauer & Feld & LLP
Mason Dwayne L.
Patel Sudhaker B.
Pharmacia Italia SpA
Raymond Richard L.
LandOfFree
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