Triazolo-1,4-diazepine compounds and medicinal composition...

Details Triazolo-1,4-diazepine compounds and medicinal composition... Triazolo-1,4-diazepine compounds and medicinal composition...

1999-12-23

2002-08-13

Coleman, Brenda (Department: 1624)

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

Organic compounds

Unsubstituted hydrocarbyl chain between the ring and the -c-...

C514S219000

Reexamination Certificate

active

06433167

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
This application is a national stage entry under 35 U.S.C. §371 of PCT/JP98/02783, filed Jun. 23, 1998.
TECHNICAL FIELD
The present invention relates to a novel triazolo-1,4-diazepine compound having a platelet activating factor (PAF) antagonistic action and a thromboxane A
2
(TxA
2
) synthesis inhibiting action and a pharmaceutical composition, etc. having said compound or its hydrate or its pharmaceutically acceptable salt as an active ingredient.
BACKGROUND ART
PAF and TxA
2
interact with each other and are involved in various allergic, inflammatory, and hypersecretory diseases such as asthma, arthritis, rhinitis, bronchitis and urticaria obliterative, or circulatory ischemic diseases obstructive thrombotic diseases, arteriosclerosis, pulmonary hypertension, and further gastric ulcer, psoriasis, etc. and other conditions. Accordingly, in the treatment of these diseases, a higher therapeutic effect can be expected from simultaneously suppressing rather than individually suppressing the actions of PAF or TxA
2
.
In the past, as a compound simultaneously suppressing the actions of PAF and TxA
2
, there has been known the 1,4-dihydropyridine compound disclosed in Japanese Unexamined Patent Publication (Kokai) No. 8-40904.
On the other hand, the fact that a 1,4-diazepine compound has an anti-PAF action is described in, for example, Japanese Unexamined Patent Publication (Kokai) Nos. 2-49787, 2-191281, 2-256682, etc. However, these compounds do not have the action of simultaneously suppressing the actions of PAF and TxA
2
.
DISCLOSURE OF THE INVENTION
In view of the above circumstances, an object of the present invention is to provide a 1,4-diazepine compound which simultaneously suppresses the actions of PAF and TxA
2
.
The present inventors synthesized triazolo-1,4-diazepine compounds having various substituent groups and engaged in repeated studies on the actions of the compounds and, as a result, found that a triazolo-1,4-diazepine compound having the following formula (I) possesses a superior PAF antagonistic action and thromboxane A
2
synthesis inhibiting action, whereby the present invention has been completed.
That is, in accordance with the present invention, there is provided a triazolo-1,4-diazepine compound having the formula (I):
wherein A represents CO, CO—B, or B, B represents a C
1
to C
6
alkylene group or a C
2
to C
6
alkylene group having an oxygen atom interposed in the middle thereof, X represents N—O or CH, n represents an integer of 2 to 6, R represents a hydroxyl group, a C
1
to C
6
lower alkyloxy group or a C
1
to C
6
lower alkylamino group, provided that these groups may be substituted with an N,N-dimethylamino group, an N,N-diethylamino group, a phenyl group, or a heterocyclic group such as a pyridyl group, a morpholino group, a piperazino group, an imidazolyl group, and R
1
represents a hydrogen atom or a C
1
to C
3
lower alkyl group.
In accordance with the present invention, there are further provided a pharmaceutical composition containing the compound having the formula (I) or its hydrate or its pharmaceutically acceptable salt as an active ingredient, in particular an antiallergic or antiinflammatory pharmaceutical composition.
BEST MODE FOR WORKING THE INVENTION
The present invention will be explained in further detail below.
In the triazolo-1,4-diazepine compound having the formula (I), as mentioned above, A represents CO, CO—B, or B, and B represents a C
1
to C
6
alkylene group or a C
2
to C
6
alkylene group having an oxygen atom interposed in the middle thereof. Preferably, A represents CO—CH
2
, CO—CH
2
OCH
2
, or a C
1
to C
4
alkylene group, in particular CH
2
(methylene group). Specifically, B is preferably a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a hexamethylene group, a group (CH
2
OCH
2
) having an oxygen atom interposed between one methylene group and another methylene group, etc. X, as mentioned before, is N—O or CH. Further, as mentioned above, n is an integer of 2 to 6, preferably 4. Further, R is a hydroxyl group, a C
1
to C
6
lower alkyloxy group, or a C
1
to C
6
lower alkylamino group. The above groups may be substituted with an N,N-dimethylamino group, an N,N-diethylamino group, a phenyl group, or a heterocyclic group such as a pyridyl group, a morpholino group, piperazino group, imidazolyl group etc. Preferably a C
1
to C
3
lower alkyloxy group (which may be substituted with an N,N-dimethylamino group, N,N-diethylamino group, pyridyl group, morpholino group, piperazino group, or imidazolyl group), particularly preferably a C
1
to C
3
lower alkyloxy group. R
1
is a hydrogen atom or a C
1
to C
3
lower alkyl group, preferably a methyl group.
Among the triazolo-1,4-diazepine compounds of the present invention, specific examples of particularly preferable compounds are Compound 4, Compound 6, Compound 7, Compound 9, Compound 10, and Compound 11 described in the Examples below.
Note that the compound of the present invention may optionally, form a hydrate or salt thereof. These, of course, are included in the present invention.
The compound of the present invention is produced by ordinary methods, but the representative methods among these are as follows.
(Production Method 1)
wherein, A, X, n, R, and R
1
are as defined above, A′ represents a hydroxyl group, a halogen atom, a mesyloxy group, a tosyloxy group, etc.
That is, the desired compound having the formula (I) can be obtained by the condensation reaction between the compound of the formula (II) and the compound of the formula (III) in an ordinary method.
As the compound represented by the formula (III), an acid halide such as an acid chloride or acid bromide; an active ester such as N-hydroxybenzotriazole or N-hydroxysuccinimide; etc. a symmetric acid anhydride; a mixed acid anhydride such as an alkyl carbonic acid, methane sulfonic acid, or p-toluene sulfonic acid, etc. may be mentioned. The reaction in the case of using these compounds is carried out in the absence of a solvent or in the presence of a solvent which is not involved in the reaction such as toluene, xylene, chloroform, dichloromethane, tetrahydrofuran, or dimethylformamide, etc. under heating, for example, by a condensation reaction such as a dehalogenation reaction etc. In this case, a more preferable result is obtained if the reaction is carried out in the presence of an inorganic salt such as sodium hydrogencarbonate, sodium carbonate, or sodium hydroxide or an organic salt such as triethylamine, pyridine, or piperazine.
When a free carboxylic acid is used as the compound of formula (III), a more preferable result is obtained, if the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodimide or 1,1′-carbonyldiimidazole etc.
When a compound containing an alkyl group to which a halide etc. or a leaving group is bonded is used, as the compound of formula (III), the reaction is carried out using an inorganic salt such as potassium carbonate, sodium carbonate, calcium carbonate, sodium hydroxide, a hydrogenated alkali metal such as sodium hydride or potassium hydride, or an organic salt such as triethylamine, pyridine, or piperazine, optionally, in the presence of a catalyst such as a crown ether etc. In particular, the reaction is suitably carried out with sodium hydride in dimethylformamide in the presence of a crown ether catalyst.
(Production Method 2)
The starting material (III) usable in the above production method 1 may be produced by, for example, the following method A or method B:
wherein, A, A
1
, n, and R are the same as defined above, A
2
represents a group stable under alkaline conditions such as a t-butyldiphenylsilyloxy group or t-butyldimethylsilyloxy group or a group the same as A
1
, and m is an integer of 3 to 7.
The above steps will be explained in brief below.
(Method A)
The compound of formula (IV) is allowed to react with hydroxylamine in an ordinary method to form an oxime, then is allowed to react, in an inert solvent, in the p

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