Naphthyridine deratives or salts thereof

Details Naphthyridine deratives or salts thereof Naphthyridine deratives or salts thereof

1999-12-21

2001-09-25

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S081000

Reexamination Certificate

active

06294547

ABSTRACT:

This application is a 371 of PCT/JP98/02921 filed Jun. 30, 1998.
1. TECHNICAL FIELD
The present invention relates to novel naphthyridine compounds capable of showing antagonism for tachykinin receptors, in particular, antagonism for neurokinin A receptors (NK-2 receptors); salts thereof, hydrates thereof or solvates thereof; and pharmaceutical compositions containing said compounds. The compounds of the present invention are useful as prophylactic or therapeutic agents for diseases for which tachykinin receptors are considered to be responsible, such as asthma, bronchitis, pollakiuria, urinary incontinence and colitis.
2. BACKGROUND ART
The term “tachykinins” is a general term for a group of peptides having similar structures, which are neuropeptides widely present in nervous system. Tachykinins participate in olfaction, vision, audition, movement control, gastric movement, and salivation control. In addition, it has recently become apparent that tachykinins also have other various physiological actions such as contraction of respiratory tract smooth muscle, contraction of bladder smooth muscle, contraction of intestinal tract smooth muscle, induction of airway hyperresponsiveness, increase in vascular permeability, cough induction, pain infliction, mucus hyper-secretion, edema induction, vasodilation, vomitting induction, diuresis acceleration, anxiety symptom induction, macrophage activation, mast cell activation, etc. Therefore, there has been suggested possibility that antagonists against tachykinins may become effective therapeutic agents for diseases whose pathosis deeply involve the above-mentioned actions, such as asthma, bronchitis, pneumonia, chronic obstructive pulmonary disease, pollakiuria, urinary incontinence, colitis, diabetes, central diseases, various pains, allergic disease, rheumatoid arthritis, osteoarthritis, various inflammations, etc. As typical tachykinins derived from mammals, there are substance P, neurokinin A and neurokinin B. There are also N-terminal extension subtypes of neurokinin A.
For these three main tachykinins, at least three receptors are known. According to the relative selecting properties of these receptors having affinity for substance P, neurokinin A or neurokinin B, respectively, the receptors are classified into neurokinin-1 (NK-1) receptor, neurokinin-2 (NK-2) receptor and neurokinin-3 (NK-3) receptor. Through these receptors, tachykinins exhibit widely various physiological actions. It is known that NK-2 receptors participate in airflow limitation in asthma [Bertrand, C. et al., Am. J. Physiol. 265, L507-L511 (1993); Perretti, F. et al., Eur. J. Pharmacol. 273, 129-135 (1995)]. In addition, it is known that NK-2 receptors participate also in airway hyperresponsiveness in asthma and that antagonists at NK-2 receptors inhibit the hyper-responsiveness substantially completely [Biochot, E. et al., Br. J. Pharmacol. 114, 259-261 (1995)]. It is also known that the antagonists at NK-2 receptors inhibit the release of a chemical mediator from lungs by antigen challenge [Ciabattoni, G. et al., Pharmacodyn. Ther. 328, 357-358 (1994)] and also suppress airway edema in asthma [Tousignant C., et al., Br. J. Pharmacol. 108, 383-386 (1993)]. Further, it has been revealed by clinical experiments that antagonists at NK-1 and NK-2 receptors protected the bronchoconstriction induced by bradykinin in asthmatic patients [Ichinose, M. et al., Lancet 340, 1248-1251 (1992)].
Thus, it is known that the antagonists at NK-2 receptors are useful as a prophylactic or therapeutic agent for asthma. It is also known that the antagonists at NK-2 receptors and antagonists at NK-1 receptors are useful also as an antitussive in the case of bronchitis, etc [Advenier, C. et al., Eur. J. Pharmacol. 250, 169-171 (1993); Yasumitsu, R. et al. Eur. J. Pharmacol. 300, 215-219 (1996)]. The antagonists at NK-2 receptors are considered to be useful as a prophylactic and therapeutic agent for pollakiuria and urinary incontinence [Croci, T. et al., J. Pharm. Pharmacol. 46, 383-385 (1994); Palea S., et al., J. Pharm. Exp. Ther. 277, 700-705 (1996)]. In addition, they are considered to be hopeful as a prophylactic and therapeutic agent for colitis [Maggi, C. A. et al., Drugs of the Future 18, 155-158 (1993)]. It is known that NK-2 receptor participates in various pains [Santucci, V. et al., Eur. J. Pharmacol. 237, 143-146 (1993); Wiesenfeld-Hallin, Z. et al., Eur. J. Pharmacol. 251, 99-102 (1994)] and inflammations [Lam F.Y. et al., Br. J. Pharmacol. 118, 2107, 2114 (1996)] and that the antagonists at NK-2 receptors suppress the pains and inflammations. It is known that NK-2 receptors participate also in central diseases such as anxiety [S. C. Stratton et al., Br. J. Pharmacol. 112 (supplement) 49p (1993)]. Further, it has been reported that the antagonists at NK-1 receptors markedly suppress experimental vomiting caused by chemotherapeutic drugs such as cisplatin, analgesics such as morphine, and X-ray irradiation, etc. [Bountra, C. et al., Eur. J. Pharmacol. 249, R3-R4 (1993), Tatterall, F. D. et al., Eur. J. Pharmacol. 250, R5-R6 (1993)].
Compounds antagonistic to tachykinins at the tachykinin receptors of the above-mentioned types have been reported. For example, Japanese Patent Unexamined Publication No. 4-261155 discloses compounds capable of showing antagonism for neurokinin receptors (in particular, NK-2 receptor). In addition, Japanese Patent Unexamined Publication No. 5-140103 discloses compounds capable of showing antagonism for substance P receptor, neutokinin A receptor or neurokinin B receptor. These compounds have a single ring containing at least one nitrogen atom. From these compounds, the compounds of the present invention are structually and strikingly different in that they have a naphthyridine ring as shown in the chemical formula (1) described hereinafter. On the other hand, various compounds having a naphthyridine ring are also known. For example, Japanese Patent Unexamined Publication No. 58-57379 discloses naphthyridine compounds having antidinic effect. However, it has not been reported at all that these compounds show antagonism for a tachykinin receptor.
DISCLOSURE OF THE INVENTION
An object of the present invention is to provide novel naphthyridine compounds, a process for producing them, and pharmaceutical compositions containing them as an active ingredient.
In particular, the present invention is intended to provide naphthyridine compounds used for preventing or treating pathological phenomena caused by tachykinins and diseases caused by tachykinins.
The present inventors found that novel naphthyridine derivatives represented by the general formula (1) and pharmaceutically acceptable salts thereof are antagonistic to tachykinins, whereby the present invention has been accomplished.
That is, the present invention relates to the following items (1) to (15).
(1) A novel naphthyridine derivative represented by the following general formula (1):
wherein R
1
, R
2
and R
3
are independently selected from the group consisting of hydrogen atom; lower alkyl groups; halogeno-lower-alkyl groups; aryl groups; heteroaryl groups; lower alkoxy groups; hydroxyl group; amino group; halogen atoms; trifluoromethyl group; amino protecting groups represented by NR
a
COR
b
wherein R
a
and R
b
are independently a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group; lower acyloxy groups; nitro group; cyano group; amino protecting groups represented by NR
a
R
b
wherein R
a
and R
b
are independently a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group; lower alkylsulfonylamino groups; lower alkoxycarbonyl groups; carboxyl group; lower acyl groups; carbamoyl group; aminocarbonyl groups represented by CONR
a
R
b
wherein R
a
and R
b
are independently a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group; aminocarbonyl groups re

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