Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-05-01
2004-09-28
Balasubramanian, Venkataraman (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252100, C514S252110, C514S256000, C514S248000, C514S252010, C544S336000, C544S357000, C544S407000, C544S295000, C544S111000, C544S250000, C544S238000
Reexamination Certificate
active
06797709
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel aromatic nitrogen containing 6-membered cyclic compound exhibiting a cGMP specific phosphodiesterase (PDE) inhibitory activity (PDE V inhibitory activity) and being useful as a medicament, and a process for preparing the same.
BACKGROUND ART
In general, it is known that cGMP, which is an intracellular second messenger, is decomposed and inactivated by phosphodiesterase which widely distributes in many cell types and tissues of the living body, and when said PDE activity is inactivated, the level of cGMP in cells is increased, and as a result, various pharmacological activities, for example, relaxation of vascular smooth muscle, relaxation of bronchial smooth muscle, and inhibition of platelet aggregation are exhibited.
Moreover, it has been reported that such cGMP specific PDE inhibitors (i.e., PDE V inhibitors) are useful in the treatment of diseases caused by a functional disorder of cGMP-signaling, including hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, pulmonary hypertension, etc. (cf., PCT Patent Publication WO 96/05176, etc.), and prostatic hyperplasia (Australian Patent Publication No. 9955977). It has also been reported that PDE V inhibitors may be useful in the treatment of female sexual dysfunction (Vemulapalli et al., Life Sciences, 67, 23-29 (2000)), diabetic gastroparesis (Watkins et al., J. Clin. Invest. 106: 373-384 (2000)), achalasia (Bortolotti et al., Gastroenterology; 118: 253-257 (2000)), diarrhea (Mule et al., Br. J. Pharmacol., 127, 514-520 (1999)), constipation (Bakre et al., J. Cell. Biochem. 77: 159-167 (2000)) and asthma (Turner et al., Br. J. Pharmacol., 111, 1198-1204 (1994)).
Furthermore, it has been also reported that 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methylpiperazine [general name: Sildenafil] having PDE V inhibitory activity is useful in the treatment of diseases such as penile erectile dysfunction (copulative impotence), etc. (cf., Boolell et al., The Journal of Urology, Supplement, vol. 155, no. 5, p. 495A739 (1996); Terrett et al., Bioorganic & Medicinal Chemistry Letters, vol. 6, no. 15, p. 1819 (1996); and Ballard et al., British Journal of Pharmacology, Proceeding Supplement, vol. 118, p. 153 (1996)).
However, sildenafil has been reported to have side effects such as headache, facial suffusion, gut disorder, rhinitis, color sense disorder, penile erectile continuance, etc. (Irwin et al., The New England Journal of Medicine, vol. 338, no. 20, p. 1397-1404 (1998); Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998); and Goldenberg, Clinical Therapeutics, vol. 20, no. 6, p. 1033-1048 (1998)).
In addition, sildenafil has also been reported that the effects of sildenafil on light response of retina tissues and its PDE VI inhibitory activity correlate each other in the experiments on dogs (Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998)), while it has been reported that PDE VI on retina plays an importance role in the sensation of light (Morrales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69-73 (1998); Estrade et al., European Journal of Pharmacology, vol. 352, p. 157-163 (1998)).
DISCLOSURE OF INVENTION
An object of the present invention is to provide a novel aromatic nitrogen-containing 6-membered cyclic compound showing an excellent phosphodiesterase V (PDE V) inhibitory activity, and being useful as a remedy for the prophylaxis or treatment of penile erectile dysfunction with few side effects. Another object of the present invention is to provide a process for preparing such a novel aromatic nitrogen-containing 6-membered cyclic compound.
The present invention relates to an aromatic nitrogen-containing 6-membered cyclic compound of the formula (I):
wherein Ring A is a substituted or unsubstituted nitrogen-containing heterocyclic group; R
1
is a substituted or unsubstituted lower alkyl group, a group of the formula: —NH—Q—R
3
(in which R
3
is a substituted or unsubstituted nitrogen-containing heterocyclic group, and Q is a lower alkylene group or a single bond), or a group of the formula: —NH—R
4
(in which R
4
is a substituted or unsubstituted cycloalkyl group); R
2
is a substituted or unsubstituted aryl group; one of Y and Z is a group of the formula: ═CH—, and the other is a group of the formula: ═N—, or a pharmaceutically acceptable salt thereof, and a process for preparing the same.
Among the compounds (I) of the present invention, the nitrogen-containing heterocyclic group of the “substituted or unsubstituted nitrogen-containing heterocyclic group” for Ring A is a 5- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclic group, more particularly, a 5- or 6-membered nitrogen-containing heteromonocyclic group and a 8- to 10-membered nitrogen-containing heterobicyclic group, and most particularly, a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group such as pyrrolidinyl group, piperazinyl group, piperidyl group, morpholino group, etc., a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group such as imidazolyl group, pyrrolyl group, etc., and a nitrogen-containing heterobicyclic group such as 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl group, 5,6,7,8-tetrahydroimidazo[1,2-a]-pyrazin-7-yl group, 5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl group, 1,2,3,4-tetrahydro-2-isoquinolinyl group, 1H-2,3,4,5,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl group, 4,5,6,7-tetrahydrothiazolo[5,4-c]-pyridin-6-yl group, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl group, 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl group, etc.
The nitrogen-containing heterocyclic group of the “substituted or unsubstituted nitrogen-containing heterocyclic group” for R
3
is a 5- or 6-membered nitrogen-containing heteromonocyclic group or a 8- to 10-membered nitrogen-containing heterobicyclic group, for example, a 5- or 6-membered non-aromatic nitrogen-containing heteromonocyclic group such as morpholinyl group, piperazinyl group, piperidyl group, thiadiazolyl group, dihydropyrimidinyl group, dihydropyrazolyl group, a 5- or 6-membered aromatic nitrogen-containing heteromonocyclic group such as pyrimidinyl group, pyridazinyl group, pyridyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, pyrazinyl group, and a 8- to 10-membered nitrogen-containing heterobicyclic group such as benzothiazolyl group, quinolyl group, dihydrobenzoxazolyl group, etc.
The substituent of the “substituted or unsubstituted nitrogen-containing heterocyclic group” for Ring A and R
3
is, for example, (1) a lower alkyl group, (2) a hydroxy-substituted lower alkyl group, (3) a formyl group, (4) an oxo group, (5) an amino group, (6) a di-(lower alkyl)amino group, (7) a hydroxy group, (8) a lower alkoxy group, (9) a lower alkoxycarbonyl group, (10) a lower alkoxy-substituted lower alkanoyl group, (11) a lower alkanoyl group, (12) a cyano-substituted lower alkyl group, and (13) a pyrimidinyl group substituted by (i) a benzylamino group substituted by a halogen atom and a lower alkoxy group and (ii) a cycloalkylcarbamoyl group substituted by a hydroxy group, etc.
The aryl group of the “substituted or unsubstituted aryl group” for R
2
is, for example, a 5- to 10-membered monocyclic or bicyclic aromatic hydrocarbon group such as phenyl group, naphthyl group, etc.
The substituent of the “substituted or unsubstituted aryl group” for R
2
is, for example, a lower alkoxy group, a halogen atom, a cyano group, a nitro group, a hydroxy group, a lower alkyl group, etc.
The substituent of the “substituted or unsubstituted lower alkyl group” for R
1
and the substituent of the “substituted or unsubstituted cycloalkyl group” for R
4
are, for example, a lower alkoxy group, a hydroxy group, a morpholinyl group, a lower alkylsulfonyl group, a di-(lower alkyl)phosphino grou
Kikkawa Kohei
Matsuki Kenji
Omori Kenji
Yamada Koichiro
Balasubramanian Venkataraman
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Tanabe Seiyaku Co. Ltd.
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