Naphthyridine derivatives

Details Naphthyridine derivatives Naphthyridine derivatives

2002-04-19

2004-05-25

Dentz, Bernard (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S122000, C546S123000

Reexamination Certificate

active

06740662

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a naphthyridine derivative useful as a medicament, particularly as a type IV phosphodiesterase inhibitor.
BACKGROUND ART
Asthma is a respiratory disease which repeats wheeze and attack by the contraction of airway. The number of the patients has been increasing steadily and is predicted to further increase hereafter.
Xanthine derivatives such as aminophylline and theophylline and &bgr;-stimulators such as procaterol are now mainly used as bronchodilator for the treatment of asthma.
The functional mechanism of these compounds is to alleviate contraction of airway smooth muscle by increasing intracellular cyclic adenosine 3′,5′-monophosphate (cAMP) concentration through the activation of an intracellular cAMP producing enzyme, adenylate cyclase, or the inhibition of a cAMP hydrolyzing enzyme, phosphodiesterase (PDE) in airway smooth muscle (
Internal Medicine
, 69, 207-214 (1992)).
It is known that increased intracellular cAMP concentration induces inhibition of the contraction of airway smooth muscle (
Clin. Exp. Allergy
, 22, 337-344 (1992),
Drugs of the Future
, 17, 799-807 (1992)), which is useful in improving conditions of asthma.
However, it is known that the xanthine derivatives express systemic side effects such as hypotension and cardiotonic action (
J. Cyclic Nucleotide and Protein Phosphoxylation Res
., 10, 551-564 (1985),
J. Pharmacol. Exp. Ther
., 257, 741-747 (1991)), and the &bgr;-stimulators are apt to cause desensitization and, when the dosage is increased, generate side effects such as finger tremor and palpitation.
On the other hand, it has been revealed that PDE is divided into at least five different types of from I to V, and each of them has different distribution or function (
Pharmacol. Ther
., 51, 13-33 (1991)). Particularly, type IV PDE does not act upon cyclic guanosine 3′,5′-monophosphate (cGMP) but specifically hydrolyze cAMP among nucleotides, and its presence is recognized in both of airway smooth muscle and infiltrating cells.
Also, it has been reported that type IV PDE inhibitors show inhibitory action upon eosinophiles infiltration by antigens and platelet-activating factors in guinea pig (
Eur. J. Pharmacol
., 255, 253-256 (1994)) and inhibit liberation of detrimental proteins (MBP, ECP) from eosinophiles (
Br. J. Pharmacol
., 115, 39-47 (1995)). It has been also reported that they show inhibitory action upon the contraction of airway smooth muscle by contractile substances (histamine, methacholine, LTD
4
) (
Br. J. Pharmacol
., 113, 1423-1431 (1994)), inhibit production of IL-4, a cytokine which is said to deeply participate in asthma (
J. Invest. Dermatol
., 100, 681-684 (1993)), express inhibitory action upon the acceleration of vascular permeability in the airway (
Fundam. Clin. Pharmacol
., 6, 247-249 (1992)) and show inhibitory action upon airway hypersensitivity (
Eur. J. Pharmacol
., 275, 75-82 (1995)). Thus, it is expected that a type IV PDE inhibitor will become an asthma-treating agent having less side effects.
As compounds having type IV PDE inhibitory activity, a large number of compounds are known including naphthyridine derivatives. The present applicant has previously reported a naphthyridine derivative represented by the following formula in which the 4-position (R
6
) is a cyclic substituent such as an aryl, a heteroaryl or a cycloalkyl and the 3-position (R
5
) is unsubstituted or a substituted lower alkyl group (WO 96/06843).
(wherein R
5
represents a hydrogen atom or a lower alkyl group and R
6
represents an aryl group having a substituent, a heteroaryl group having a substituent, a cycloalkyl group or an adamantyl group. See the reference for other details.)
DISCLOSURE OF THE INVENTION
The present inventors have conducted studies with the aim of providing a novel compound which efficiently and selectively inhibits type IV PDE and is useful for preventing and treating respiratory diseases such as bronchial asthma with less side effects and also of providing a medicament containing the same.
The inventors have further conducted extensive studies on compounds having inhibitory activity upon type IV PDE and, as a result, found that a compound in which a specific substituent (—X—R
6
) is introduced into the 3-position of the compound previously reported (WO96/06843) is a novel compound and has a strong type IV PDE inhibitory action, as well as excellent oral absorbability and metabolic stability. Therefore, they have found that the compound is markedly useful as a type IV PDE inhibitor, thus resulting in the accomplishment of the invention.
Accordingly, the invention relates to a novel naphthyridine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof and a medicament containing the same as the active ingredient.
(wherein each symbol has the following meaning;
R
1
: —R
0
, -a lower alkylene-cycloalkyl or -a cycloalkyl
R
0
: -a lower alkyl,
R
2
, R
3
, and R
4
: —H, —R
0
, -a halogen, -a lower alkylene-OH, -a lower alkylene-SH, -a lower alkylene-O—R
0
, -a lower alkylene-S—R
0
, -a lower alkylene-O—CO—R
0
, -a lower alkylene-S—CO—R
0
, —OH, —O—R
0
, —S—R
0
, —SO—R
0
, —SO
2
—R
0
, —NH
2
, —NHR
0
, —NR
0
2
, -a cycloalkyl, —CO—R
0
, or —CH═N—OR
9
, which may be the same or different from one another,
R
9
: —H, —R
0
or -a lower alkylene-aryl,
R
5
: a cycloalkyl which may be substituted with a group selected from R
10
, a cycloalkenyl which may be substituted with a group selected from R
10
, a heterocyclic group which may be substituted with a group selected from R
10
, or phenyl which may be substituted with a group selected from R
10
,
R
6
: —OH, —OR
7
, —COOH, —COOR
7
, —CONH
2
, —CONHR
7
, —CON(R
7
)
2
, —O—COR
7
, —O—COOR
7
, —CHO, —COR
7
, —NH
2
, —NHR
7
, —N(R
7
)
2
, —NHCOR
7
, —N(R
7
)COR
7
, —NHSO
2
R
7
, —N(R
7
)SO
2
R
7
, —CN, —NHCOOR
7
, —N(R
7
)COOR
7
, —C(NH)NH
2
, —NHC(NH)NH
2
or —N(R
7
)C(NH)NH
2
, or a group represented by the formula —Y—R
8
,
R
7
: a lower alkyl which may be substituted with a group selected from the group consisting of —OH, -phenyl, -a halogen, —OR
0
, —CO
2
H, —CO
2
R
0
, —NH
2
, —NHR
0
, —NR
2
, —NO
2
, —CN, and —COR
0
,
R
8
: a cycloalkyl which may be substituted with a group selected from R
10
, an aryl which may be substituted with a group selected from R
10
, or a heterocyclic group which may be substituted with a group selected from R
10
,
R
10
: —OH, -phenyl, -a halogen, —OR
0
, —CO
2
H, —CO
2
R
0
, —NH
2
, —NHR
0
, —NR
0
2
, —NO
2
, —CN or —COR
0
, or a group described in R
7
.
Y: a bond, —O—, —COO—, —CONH—, —CON(R
7
)—, —O—CO—, —O—COO—, —CO—, —NH—, —N(R
7
)—, —NHCO—, —N(R
7
)CO—, —NHCOO—, —N(R
7
)COO—, —NHSO
2
—, or —N(R
7
)SO
2
—, and
X: a bond or a lower alkylene, or a lower alkenylene. The same shall apply hereinafter.).
Also, according to the invention, there is provided a medicament, particularly a type IV PDE inhibitor, which comprises the naphthyridine derivative or a salt thereof.
The following describes the invention in detail.
The term “lower” as used herein means a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms and examples of the “lower alkyl” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, and the like. Preferred is an alkyl having from 1 to 4 carbon atoms, and particularly preferred is methyl or ethyl. The “lower alkylene” means a divalent group formed by removing any one hydrogen atom from the above “lower alkyl” and is preferably an alkylene having from 1 to 4 carbon atoms, particularly preferably methylene, ethylene or propylene. The “lower alkenylene” means a group having one or more double bonds at any position in the “lower alkylene” having two or more carbon atoms, and is preferably an alkenylene having 2 to 4 carbon atoms.
The “cycloalkyl” is preferably a cycloalkyl having from 3 to 8 carbon atoms, particularly preferably cyclopropyl or cyclohexyl. The “cycloalkenyl” is preferably a cycloalkenyl having from 5 to 8 carbon atoms, particularly pr

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