Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-22
2002-12-03
Rao, Deepak R. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S253010, C514S254060
Reexamination Certificate
active
06489324
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new compounds and pharmaceutically acceptable salts thereof.
More particularly, it relates to new compounds and pharmaceutically acceptable salts thereof which are useful as inhibitors of matrix metalloproteinases (hereinafter to be referred to as MMP) or the production of tumor necrosis factor a (hereinafter to be referred to as TNF&agr;), to pharmaceutical compositions comprising the same, to use of the same as medicaments, and to methods for using the same therapeutically in the treatment and/or the prevention of MMP- or TNF&agr;-mediated diseases.
BACKGROUND ART
Some piperazine compounds to be useful as metalloproteinase inhibitors, or the like are known (WO 97/20824, etc.).
DISCLOSURE OF THE INVENTION
One object of the present invention is to provide new and useful compounds and pharmaceutically acceptable salts thereof, and to provide a process for preparing said new compound and salts thereof, which have pharmacological activities such as MMP- or TNF&agr;-inhibitory activity and the like.
Another object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said compound or a pharmaceutically acceptable salt thereof.
A further object of the present invention is to provide use of said compounds and pharmaceutically acceptable salts thereof as medicaments for prophylactic and therapeutic treatment of MMP- or TNF&agr;-mediated diseases.
A still further object of the present invention is to provide a method for using the same for the treatment and/or the prevention of MMP- or TNF&agr;-mediated diseases in mammals, especially humans.
The compounds of the present invention have inhibitory activity on MMP or the production of TNF&agr;, and are useful for the treatment and/or prevention of diseases such as stroke, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and other diseases characterized by matrix metalloproteinase activity, as well as AIDS, sepsis, septic shock and other diseases caused by the production of TNF&agr;.
There are a number of structurally related metalloproteases which effect the breakdown of structural proteins. Matrix-degrading metalloproteases, such as gelatinase (MMP-2, MMP-9), stromelysin (MMP-3) and collagenase (MMP-1, HMP-8, MMP-13), are involved in tissue matrix degradation and have been implicated in many pathological conditions involving abnormal connective tissue and basement membrane matrix metabolism, such as arthritis (e.g., osteoarthritis and rheumatoid arthritis), cerebral diaease (e.g., stroke, etc.), tissue ulceration (e.g., corneal, epidermal and gastric ulcerations), abnormal wound healing, periodontal disease, bone disease (e.g., Paget's disease and osteoporosis), tumor metastasis or invasion and HIV-infection.
A tumor necrosis factor is recognized to be involved in many infections and autoimmime diseases. Furthermore, it has been shown that TNF is the prime mediator of the inflammatory response seen in sepsis and septic shock.
The object compounds of the present invention are novel and can be represented by the following formula (I):
wherein
A is a sulfonyl or a carbonyl;
R
1
is an optionally substituted aryl, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl;
R
2
is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;
R
3
is an optionally substituted lower alkyl, an optionally substituted lower alkoxy, an optionally substituted aryloxy, an optionally substituted lower alkenyl, an optionally substituted aryl, an optionally substituted heterocyclic group or an optionally substituted amino:
R
4
is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group;
R
5
is a hydrogen, an optionally substituted lower alkyl, an optionally substituted aryl or an optionally substituted heterocyclic group; and
R
10
is a hydroxy or a protected hydroxy,
provided that when A—R
3
is methylsulfonyl, then R
1
is an aryl substituted by a substituent selected from the group consisting of halogen, cyano, nitro, amino, acylamino, lower alkylamino, carbamoyl, hydroxy, lower alkoxy, phenoxy, lower alkyl, aryl and heterocyclic group, an optionally substituted heterocyclic group, an optionally substituted lower alkyl or an optionally substituted lower alkenyl, and the above-mentioned heterocyclic group is each selected from the group consisting of
unsaturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 to 5 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms,
unsaturated 3- to 8-membered heteromonocyclic group containing sulfur atom,
unsaturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
saturated 3- to 8-membered heteromonocyclic group containing oxygen atom,
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms and
unsaturated condensed 7- to 13-membered heterocyclic group containing 1 or 2 oxygen atoms,
and a pharmaceutically acceptable salt thereof.
The object compounds of the present invention can be prepared by the following processes.
In the above formulas (II), (III), (IV), (V), (VI), (VII), (VIII), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVIII), (XIX), (XX), (XXI) and (XXII), A, R
1
, R
2
, R
3
, R
4
and R
5
are as defined above, R
10a
is a protected hydroxy, X is a leaving group, R
1a
is a heterocyclic group having a substituent which is aryl substituted by acyloxy, R
1b
is a heterocyclic group having a substituent which is aryl substituted by hydroxy, R
1c
is a heterocyclic group having a substituent which is aryl substituted by cyanoalkyloxy, R
1d
is a heterocyclic group having a substituent which is aryl substituted by alkoxycarbonylalkyloxy, R
3a
is an alkyl substituted by halogen, R
3b
is a di(lower)alkylamino(lower)alkyl, an N-containing heterocyclic-(lower)-alkyl or an optionally substituted heterocyclic-thio(lower)alkyl, R
3c
is a protected carboxy(lower)alkyl or a protected carboxy(lower)alkyl-amino, R
3d
is a carboxy(lower)alkyl or a carboxy(lower)alkylamino, R
3e
is an N-containing heterocyclic-carbonyl(lower)alkyl, an optionally substituted amino-carbonyl(lower)alkyl or an optionally substituted amino-carbonyl(lower)alkylamino, R
3f
is a hydroxy(lower)alkyl, and R
11
is a di(lower)alkylamino, an N-containing heterocyclic group or an optionally substituted heterocyclic-thiol. Heterocyclic group, aryl, acyl, alkyl, alkoxy, protected oxy and halogen in the R
1a
, R
1b
, R
1c
, R
1d
, R
3a
, R
3b
, R
3c
, R
3d
, R
3e
, R
3f
and R
11
are as defined below.
The starting compounds (II), (VI), (XIV) and (XVI) can be prepared according to the following Preparations or by a conventional method.
Suitable pharmaceutically acceptable salts of the object compounds may be conventional non-toxic salts and include an acid addition salt such as an organic acid salt (e.g., acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with a base such as an amino acid (e.
Kayakiri Natsuko
Neya Masahiro
Oku Teruo
Sato Kentaro
Yamazaki Hitoshi
Fujisawa Pharmaceutical Co. Ltd.
Liu Hong
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Rao Deepak R.
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