Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-15
2002-08-13
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S088000, C546S122000
Reexamination Certificate
active
06433174
ABSTRACT:
This application is a 371 of PCT/JP99/07049, filed Dec. 15, 1999.
TECHNICAL FIELD
The present invention relates to a process for producing novel naphthyridine derivatives having an antagonistic action against tachykinin receptors, especially neurokinin A receptor (NK-2 receptor), intermediates used in this process, and a process for producing such intermediates.
BACKGROUND ART
The compounds acting antagonistically to various types of tachykinin receptors have been reported. For instance, JP-A-4-261155 discloses a compound having an antagonistic action against neurokinin receptors (especially NK-2 receptor). Further, JP-A-5-140103 describes a compound which antagonizes against substance P, neurokinin A or neurokinin B receptor. These compounds have a single ring containing a nitrogen atom, such as a piperidine ring, in the molecule, but no compound having a naphthyridine ring has ever been disclosed.
Regarding the compounds having a naphthyridine ring, JP-A-58-57379 discloses a compound having an anti-vertiginous action. However, it has never been reported that these compounds having a naphthyridine ring have an antagonistic action against tachykinin receptors.
DISCLOSURE OF THE INVENTION
The present invention is designed to provide a process for producing the novel naphthyridine derivatives showing a high activity as a tachykinin receptor antagonist, intermediates used in this process, and a process for producing such intermediates.
As a result of extensive studies on the subject matter, the present inventors found that the novel naphthyridine derivatives having a naphthyridine ring as the basic skeleton have a prominent antagonistic action against tachykinin receptors and are well applicable as pharmaceuticals. The present inventors have also pursued studies on the way of production of these derivatives and worked out a production process which can well withstand its industrial application. These findings underlie the present invention.
The novel naphthyridine derivatives of the present invention have the asymmetric carbon atoms, so that they exist as a single optically active compound or a racemate thereof, and each of them has an outstanding activity as a tachykinin receptor antagonist. Also, part of the novel naphthyridine derivatives of the present invention can be used as an intermediate for the synthesis of the other part of the naphthyridine derivatives of the present invention.
The optically active compounds comprising the novel naphthyridine derivatives of the present invention can be easily obtained as required by, for instance, optically resolving their intermediates. A diastereomer salt produced by acting an optically active amine to a racemate of the synthesis intermediate can be optically resolved by, for instance, a method making use of the difference in their physicochemical properties. Further, by using an isomeric crystallization method, it is possible to obtain an objective optically active product of the intermediate in a higher yield than obtainable with ordinary optical resolution. Using such optically active substances, it is possible to obtain the optically active compounds comprising the novel naphthyridine derivatives of the present invention at high efficiency.
The present invention has been achieved on the basis of the above findings.
Thus, the present invention provides:
(i) A process for producing a novel naphthyridine derivative, which comprises carrying out a condensation reaction between a compound represented by the following formula (1):
wherein R
1
, R
2
and R
3
represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group, an amino group or a halogen atom, or R
1
and R
2
or R
2
and R
3
are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group; and X
1
and X
2
represent respectively a halogen atom, and a compound represented by the following formula (2):
wherein Y represents an aryl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group; and Z represents a halogen atom, a hydroxyl group, a lower alkylcarbonyloxy group or an arylcarbonyloxy group, to produce a compound represented by the following formula (3):
wherein R
1
, R
2
, R
3
, X
1
, X
2
and Y have the same meaning as defined above.
(ii) The process described in (i) above, wherein in the formula (1), R
1
and R
2
are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom, aryl group, heteroaryl group and trifluoromethyl group; and R
3
represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, an amino group or a halogen atom.
(iii) The process described in (i) above, wherein in the formula (1), R
1
and R
2
are combined to form a cyclic group with the interposition of a C2-C5 alkylene group or a C2-C5 alkenylene group, which cyclic group may have a substituent selected from lower alkyl group, lower alkoxyl group, halogen atom and trifluoromethyl group; R
3
represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, an amino group or a halogen atom; and in the formula (2), Y represents a phenyl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group.
(iv) The process described in (i) above, wherein in the formula (1), R
1
and R
2
are combined to form a cyclic group with the interposition of a butylene group or a butenylene group; R
3
represents a hydrogen atom, an aryl group, an amino group or a halogen atom; and in the formula (2), Y represents a phenyl group.
(v) A process for producing a novel naphthyridine derivative, which comprises acylating the amino group of a compound represented by the following formula (3)′:
wherein R
1
′, R
2
′ and R
3
′ represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group, an amino group or a halogen atom, or R
1
′ and R
2
′ or R
2
′ and R
3
′ are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group, and at least one of R
1
′, R
2
′ and R
3
′ is an amino group; X
1
and X
2
represent respectively a halogen atom; and Y represents an aryl group which may have 1 to 3 substituents selected from halogen atom and lower alkoxyl group, to produce a compound represented by the formula (3)″:
wherein R
1
″, R
2
″ and R
3
″ represent independently a hydrogen atom, a lower alkyl group, a lower alkoxyl group, an aryl group, a heteroaryl group or a halogen atom, or R
1
″ and R
2
″ or R
2
″ and R
3
″ are combined to form a cyclic group with the interposition of a saturated or unsaturated carbon-carbon bond, which cyclic group may contain 1 to 3 hetero-atoms selected from nitrogen atom, oxygen atom and sulfur atom and may also have a substituent selected from lower alkyl group, aryl group, heteroaryl group, lower alkoxyl group, halogen atom and trifluoromethyl group, and at least one of R
1
″, R
2
″ and R
3
″ is a lower alkylcarbonylamino group or an arylcarbonylamino group; and X
1
, X
2
and Y have the same meaning as defined above.
(vi) The process described in (v) above, wherein in the formula (3)&pri
Nagai Masashi
Satoh Yoshitaka
Tsuda Makoto
Yamazaki Hiroko
Dentz Bernard
Nields & Lemack
Nippon Kayaku Kabushiki Kaisha
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