Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-07
2003-07-22
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S367000, C514S397000, C514S400000, C546S014000, C546S274700, C548S159000, C548S171000, C548S305400, C548S311700, C548S312100, C548S333500
Reexamination Certificate
active
06596738
ABSTRACT:
This application is a 371 of PCT/JP00/01316 filed Mar. 3, 2000.
TECHNICAL FIELD
This invention relates to new heterocyclic compounds having pharmacological activity, to processes for their production and to a pharmaceutical composition containing the same.
BACKGROUND ART
Some imidazole derivatives, which have inhibiting activity to adenosine deaminase (hereinafter described as ADA) are known, for example, by Drug Development Research 28, p253-258 (1993).
DISCLOSURE OF INVENTION
This invention relates to novel heterocyclic compounds which have pharmacological activity such as ADA inhibiting activity, to processes for their production, to a pharmaceutical composition containing the same and to a use thereof.
Accordingly, one object of this invention is to provide the novel heterocyclic compounds which have an ADA inhibiting activity.
Another object of this invention is to provide processes for their production of the new heterocyclic compounds.
A further object of this invention is to provide a pharmaceutical composition containing, as active ingredient, the new heterocyclic compounds.
Still further object of this invention is to provide a use of the new heterocyclic compounds for manufacturing a medicament for treating or preventing various diseases.
The new heterocyclic compounds of this invention can be represented by the following general formula (I):
wherein
B is
[wherein R
1
is hydrogen or lower alkyl;
R
2
is hydrogen or lower alkyl; and
X is hydrogen or hydroxy protective groups], lower alkanoyl or hydroxyimino(lower)alkyl;
A is lower alkylene;
W is heterocyclic or carbocyclic group, each of which may have one or more substituent(s);
Z is heterocyclic group selected from the group consisting of imidazolyl, triazolyl, imidazopyridyl and adenyl, each of which may have one or more substituent(s);
or a salt thereof,
provided that when W is aryl which may have one or more substituent(s), then (i) Z is triazolyl, imidazopyridyl or adenyl, each of which may have one or more substituent(s); (ii) Z is imidazolyl which may have one or more substituent(s) and B is lower alkanoyl or hydroxyimino(lower)alkyl; or (iii) Z is imidazolyl which may have one or more substituent(s) and R
1
and R
2
are both lower alkyl.
The compounds of formula (I) may contain one or more asymmetric centers and thus they can exist as syn- or anti-isomers. In each instance, the invention includes both mixtures and separate individual isomers.
The compounds of the formula (I) may exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers.
The compounds of the formula (I) and a salt thereof can be in a form of solvate, which is included within the scope of the present invention. The solvate preferably includes a hydrate and an ethanolate.
Also included in the scope of this invention are radiolabelled derivatives of the compounds of formula (I) which are suitable for biological studies.
According to the present invention, the object compound (I) or a salt thereof can be prepared by the processes which are illustrated in the following scheme.
wherein A, R
1
, R
2
, W, X and Z are each as defined above,
R
3
is lower alkyl, optionally substituted ar(lower)alkyl, ar(lower)alkylamino, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl, each of which may have one or more substituent(s),
W
1
is heterocyclic group or carbocyclic group, each of which has nitro,
W
2
is heterocyclic group or carbocyclic group, each of which has amino,
W
3
is heterocyclic group or carbocyclic group, each of which has a group of the following formula:
—NH—C(O)—R
3
(R
3
is as defined above),
X
1
is hydroxy protective group,
Z, is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has carboxy,
Z
2
is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has guanidinocarbonyl,
Z
3
is imidazolyl, triazolyl, imidazopyridyl or adenyl, each of which has carbamoyl.
R
4
is lower alkyl, carbocyclic(lower)alkyl or heterocyclic(lower)alkyl,
W
4
is carbocyclic or heterocyclic group, each of which has lower alkylamino, carbocyclic(lower)alkylamino or heterocyclic(lower)alkylamino,
W
5
is carbocyclic or heterocyclic group, each of which has a hydroxy protective group,
R
5
and R
6
are lower alkyl, heterocyclic(lower)alkyl or carbocyclic(lower)alkyl,
R
7
is hydrogen or methanesulfonyl,
W
6
is heterocyclic or carbocyclic group, each of which has OR
5
or OR
6
[wherein R
5
and R
6
are as defined above].
R
8
is hydrogen,
R
9
is lower alkyl,
R
10
is lower alkyl, and
Y is halogen.
The starting compound (II), wherein B is
can be prepared by the following processes.
wherein A, R
1
, R
2
, W and X
1
are each as defined above.
In the above and subsequent description of the present specification, suitable examples of the various definitions to be included within the scope of the present invention are explained in detail as follows.
The term “lower” is intended to mean a group having one to six carbon atom(s), unless otherwise indicated.
Suitable “lower alkyl” and “lower alkyl moiety” in the terms “hydroxyimino(lower)alkyl”, “optionally substituted ar(lower)alkyl”, “ar(lower)alkylamino”, “N-containing heterocyclic(lower)alkyl”, “heterocyclicthio(lower)alkyl”, “phenyl(lower)alkylamino”, “phenyl(lower)alkyl”, “lower alkylphenyl(lower)alkyl”, “lower alkoxyphenyl(lower)alkyl”, “benzimidazolyl(lower)alkyl”, “pyridyl(lower)alkyl”, “benzothiazolylthio(lower)alkyl”, “indolyl(lower)alkyl” and “lower alkylcarbamoyl” may include straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, or the like.
Suitable “lower alkylene” may include straight or branched one having one to eight carbon atom(s), such as methylene, ethylene, propylene, butylene, amylene, hexylene, or the like.
Suitable “heterocyclic group” for W and “heterocyclic moiety” in the terms “heterocyclic(lower)alkyl” heterocyclicthio(lower)alkyl for R
3
or R
4
, etc., may include the one containing at least one heteroatom selected from nitrogen, sulfur and oxygen atom, and may include saturated or unsaturated, monocyclic or bicyclic heterocyclic group. Preferable heterocyclic group may be N-containing heterocyclic group containing one to four nitrogen atom(s).
Suitable “N-containing heteromonocyclic group” may include the following groups.
(1) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to four nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.;
(2) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to three nitrogen atom(s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc.;
(3) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, etc.;
(4) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two oxygen atom(s) and one to three nitrogen atom(s), for example, morpholinyl, etc.;
(5) unsaturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s), for example, thiazolyl, thiadiazolyl, etc.;
(6) saturated three to eight membered (more preferably five to six membered) heteromonocyclic group containing one to two sulfur atom(s) and one to three nitrogen atom(s), for example, thiomorpholinyl, etc.
Suitable “N-containing heterobicyclic group may include benzimidazolyl, benzothiazolyl, imidazopyridyl, indolyl, isoindolyl, indazolyl, purinyl, adenyl, quinolyl, isoquinolyl, etc.
Suitable non N-containing heterocyclic group may include the following groups.
(1) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl, dihydrodithionyl,
Kinoshita Takayoshi
Nakamura Katsuya
Nakanishi Isao
Seki Nobuo
Terasaka Tadashi
Fujisawa Pharmaceutical Co. Ltd.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Powers Fiona T.
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