Purine derivatives and medicaments comprising the same as...

Details Purine derivatives and medicaments comprising the same as... Purine derivatives and medicaments comprising the same as...

2002-07-23

2004-05-11

Berch, Mark L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S234200, C514S252020, C514S263200, C514S263300, C514S263330, C514S263340, C514S263350, C514S263370, C514S263370, C514S263400, C544S118000, C544S122000, C544S264000, C544S267000, C544S269000, C544S238000, C544S270000, C544S271000, C544S276000, C544S277000, C544S319000, C544S326000, C544S329000

Reexamination Certificate

active

06734187

ABSTRACT:

TECHNICAL FIELD
The present invention relates to novel purine derivatives. More precisely, it relates to purine derivatives having inhibitory activity against phosphodiesterase IV. The present invention also relates to synthetic intermediates for the preparation of said novel purine derivatives.
BACKGROUND ART
Cyclic AMP (cAMP) is an important second messenger which is involved in relaxation of respiratory tract smooth muscles and control of inflammatory cells, and the messenger is decomposed by phosphodiesterase (hereinafter abbreviated as “PDE” in the specification) to be converted into inactive 5′-AMP. Therefore, it is believed that suppression of the decomposition of cAMP by PDE may increase the concentration of cAMP, thereby bronchodilatation and anti-inflammatory action can be achieved. For this reason, PDE inhibitors having inhibitory action against the decomposition of cAMP have been focused as medicaments for the treatment of asthma. In addition, five PDE isozymes (PDE I, II, III, IV and V) have recently been isolated, and their specific tissue distributions have been revealed (Adv. Second Messenger Phosphoprotein Res., 22, 1 (1988); Trends Pharm., Sci., 11, 150 (1990)).
Among inhibitors for these isozymes, in particular, inhibitors specific for PDE IV have been suggested to be possibly useful for the treatment of asthma (Thorax 46, 512 (1991)). As a compound having specific inhibitory activity against PDE IV, for example, the compound disclosed in Japanese Patent Unexamined Publication (Kokai) No. 50-157360/1975 (Rolipram) has been known.
Although various compounds have been known as PDE IV inhibitors (for example, compounds disclosed in Japanese Patent Unexamined Publication (Kokai) No. 4-253945/1992, International Patent Publication in Japanese (Kohyo) Nos. 6-504782/1994, 7-504442/1995, 8-501318/1996 and 9-500376/1997 and so forth), they have not been used clinically so far, and development of novel compounds having PDE IV inhibitory activity has been desired.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide a novel compound having specific inhibitory activity against PDE IV, of which possible usefulness for treatment of asthma has been suggested. Another object of the present invention is to provide a medicament comprising a compound that has the aforementioned characteristic as an active ingredient. A further object of the present invention is to provide a synthetic intermediate useful for efficient preparation of the aforementioned compound.
The inventors of the present invention earnestly conducted researches to achieve the foregoing objects. As a result, they found that particular class of purine derivatives represented by the following formula had excellent inhibitory activity against PDE IV. They also found that these compounds were useful as active ingredients of medicaments, and they were extremely useful as, for example, as active ingredients of antiasthmatic agents. The present invention was achieved on the basis of these findings.
The present invention thus provides purine derivatives represented by the following formula (I), salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof:
wherein R
1
represents a C
1
-C
4
alkyl group or difluoromethyl group; R
2
represents tetrahydrofuranyl group, a C
1
-C
7
alkyl group, a C
1
-C
1
haloalkyl group, a C
2
-C
7
alkenyl group, bicyclo[2,2,1]hept-2-yl group, or a C
3
-C
8
cycloalkyl group; X represents hydrogen atom, a halogen atom, or nitro group; and A represents a group represented by the following formula:
wherein R
3
represents hydrogen atom, a halogen atom, hydroxyl group, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxyl group, amino group, a C
1
-C
4
alkylamino group, or a C
2
-C
8
dialkylamino group; R
4
and R
5
each independently represent hydrogen atom, a halogen atom, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxyl group, amino group, a C
1
-C
4
alkylamino group, pyrrolidinyl group, morpholino group, a C
2
-C
8
dialkylamino group, or a group represented by —Y—(CH
2
)
n
—B {Y represents —O—, —S—, —NHCO—, or —N(R
6
)— (R
6
represents hydrogen atom or a C
1
-C
4
alkyl group), n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted},
provided that either R
4
or R
5
represents —Y—(CH
2
)
n
—B {Y represents —O—, —S—, —NHCO—, or —N(R
6
)— (R
6
represents hydrogen atom or a C
1
-C
4
alkyl group)} when X represents hydrogen atom, and
(i) n represents an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted when Y represents —O—, —S—, or —NHCO—, or
(ii) n represents an integer of from 1 to 4, and B represents a heterocyclic residue when Y represents —N(R
6
)—.
According to preferred embodiments of the present invention, there are provided the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein A is a group represented by the following formula:
wherein R
3
is hydrogen atom, a halogen atom, hydroxyl group, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxyl group, amino group, a C
1
-C
4
alkylamino group or a C
2
-C
8
dialkylamino group; one of R
4
and R
5
is hydrogen atom, a halogen atom, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxyl group, amino group, a C
1
-C
4
alkylamino group, pyrrolidinyl group, morpholino group, or a C
2
-C
8
dialkylamino group, and the other is —Y—(CH
2
)
n
—B (Y is —O—, —S—, —NHCO—, or —N(R
6
)— (R
6
represents hydrogen atom or a C
1
-C
4
alkyl group), n is an integer of from 0 to 4, and B represents a phenyl group, a naphthyl group, or a heterocyclic residue, each of which may be substituted);
the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R
1
is a C
1
-C
4
alkyl group; R
2
is tetrahydrofuranyl group, a C
1
-C
6
alkyl group, a C
1
-C
3
haloalkyl group or a C
3
-C
8
cycloalkyl group, and A is a group represented by the following formula:
wherein R
3
is hydrogen atom, a halogen atom, hydroxyl group, a C
1
-C
4
alkyl group, or a C
1
-C
4
alkoxyl group; R
4
is hydrogen atom, a halogen atom, a C
1
-C
4
alkyl group, a C
1
-C
4
alkoxyl group, a C
1
-C
4
alkylamino group, or a C
2
-C
8
dialkylamino group, R
5
is —Y—(CH
2
)
n
—B (Y is —O—, —S—, or —NHCO—, n is an integer of from 1 to 4, and B represents a heterocyclic residue which may be substituted); and
the aforementioned purine derivatives, salts thereof, or N-oxides thereof, or hydrates thereof or solvates thereof, wherein R
1
is a C
1
-C
3
alkyl group; R
2
is a C
3
-C
8
cycloalkyl group, and A is a group represented by the following formula:
wherein R
3
is hydrogen atom, a C
1
-C
3
alkyl group, or a C
1
-C
3
alkoxyl group; R
4
is a C
1
-C
3
alkyl group, a C
1
-C
3
alkoxyl group or a C
1
-C
3
alkylamino group; R
5
is —Y—(CH
2
)
n
—B (Y is —O—, n is an integer of from 1 to 4, and B is a heterocyclic residue which may be substituted).
According to another aspect of the present invention, medicaments are provided which contain a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof as an active ingredient. These medicaments are preferably provided as pharmaceutical compositions which contain the aforementioned active ingredient and an additive for pharmaceutical preparation, and they can be used as, for example, antiasthmatic agents for preventive and/or therapeutic treatment of asthma.
According to further aspects of the present invention, there are provided use of a substance selected from the group consisting of the aforementioned purine derivatives, salts thereof, and N-oxide compounds thereof, and hydrates thereof and solvates thereof for the manufacture of the aforementioned medicaments; methods for preventive and/or therapeutic treatment of asthma which comprise the step of

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