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Pyrazolonaphthyridine derivatives


Title: Pyrazolonaphthyridine derivatives.
Abstract: wherein A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may be unsubstituted or optionally substituted with one or more members selected from the group consisting of hydroxyl, halogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl, lower alkoxy-carbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-lower alkylene, lower alkylsulfonyl, lower alkylsulfonyl-amino, and ureido; R1 is a group selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and lower alkoxycarbonyl; R2 is hydrogen or lower alkyl; and m is an integer of 1 to 3; or a pharmaceutically acceptable salt thereof, possesses highly excellent PDE IV-specific inhibitory actions and is useful as an anti-asthmatic drug and/or a prophylactic/therapeutic drug for COPD with high safety. The target is to provide PDE IV inhibitors which have a highly potent anti-asthmatic and/or COPD-prophylactic/therapeutic profile with unexpectedly excellent safety. A compound of the formula (1): ...




USPTO Applicaton #: #20100093782 - Class: 514293 (USPTO) - 04/15/10 - Class 514 
Inventors: Hashime Kanazawa, Tomoji Aotsuka, Kentarou Kumazawa, Kouki Ishitani, Takashi Nose

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The Patent Description & Claims data below is from USPTO Patent Application 20100093782, Pyrazolonaphthyridine derivatives.

FIELD OF THE INVENTION

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The present invention relates to novel condensed naphthyridine derivatives that inhibit phosphodiesterase (hereinafter, referred to as “PDE”) IV, or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION

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PDEs are enzymes which hydrolyze intracellular cyclic AMP (cAMP) and intracellular cyclic GMP (cGMP) and widely distributed in vivo in various tissues and organs. Up to now, it has been known that PDEs are classified into 7 isoenzyme families, i.e., type I to VII PDEs (PDE I to VII), according to their properties. Among them, PDE IV is known to be an enzyme which is predominantly present in airway smooth muscle cells and a wide variety of inflammatory cells, i.e., neutrophils, eosinophils, lymphocytes, etc. and selectively breaks down cAMP.

In addition, it has been known that an elevation of cAMP levels in airway smooth muscle cells leads to relaxation of the airway smooth muscles. An increase of cAMP levels in inflammatory cells has also been known to suppress an activation of inflammatory cells, including, for example, a release of cytotoxic proteins from eosinophils, etc.

Therefore, if PDE IV predominantly located in airway smooth muscle cells and inflammatory cells is inhibited by inhibitors selective for said isozyme form, an elevation of cAMP levels would be induced in such cells. As a result, it would be expected to elicit bronchodilator actions via relaxing airway smooth muscles and anti-inflammatory actions through suppressing inflammatory cell activation. As seen, for example, in Barnette, PROGRESS IN DRUG RESEARCH, USA, Vol. 53, pp. 193-229 (1999) (non-patent document No. 1), such selective inhibitors of PDE IV would be expected to become excellent anti-asthmatic agents and therapeutic agents for chronic obstructive pulmonary disease (COPD).

Up to now, it has been known that theophylline which is a xanthine derivative, rolipram, which is a catechol derivative, etc., are inhibitors of PDE IV. Theophylline inhibits PDE in various tissues due to its non-selectivity for individual isozymes, thereby exerting not only a bronchodilator activity to be targeted but also extra actions on heart, CNS, etc. Although rolipram is observed to be selective for PDE IV, it is easily transferred into the CNS due to its property of being absorbed. Therefore, rolipram has a drawback that it induces adverse central side-effects such as an emetic action.

Over the past decade, many pharmaceutical companies have focused on the inhibition of PDE IV for the treatment of asthma. The biological studies on the PDE IV isozyme and the structure-activity relationship of said inhibitors have recently been reviewed in the literature. In such processes, it has been pointed out that in general the therapeutic utility of selective PDE IV inhibitors, such as the prototypical agent rolipram, have been hampered by nausea and emesis limiting their therapeutic potential (J. Med. Chem., 41: 2268 to 2277 (1998): non-patent document No. 2).

It recently becomes known that PDE IV inhibitors produce inhibition of drug-metabolizing enzymes such as CYP2D6 and CYP3A4, thereby raising a variety of adverse side-actions. Therefore, there is still a desire to develop a PDE IV inhibitor free of affecting the drug-metabolizing enzymes.

Under these circumstances, in order to find out pharmaceutical drugs having an excellent anti-asthmatic efficacy and/or a prophylactic or therapeutic efficacy on COPD via minimizing undesirable side-effects in tissues and organs other than bronchial smooth muscles and inflammatory cells, various PDE IV inhibitors have been screened and examined.

For instance, with an aim at such inhibitors with improved selectivity for PDE IV, various compounds have been proposed including naphthalene derivatives (e.g., Patent document No. 1: JP, A, 10-226647 (1998)), catechol diethers derivatives (e.g., Patent document No. 2: JP, A, 2001-527508), 2,3-di-substituted pyridine derivatives (e.g., Patent document No. 3: JP, A, 2001-354655), etc. Further, for the purpose of developing not only anti-asthmatic agents but also pharmaceutical agents for preventing and treating a wide range for diseases, PDE IV-inhibitory compounds having a naphthyridine ring have been proposed (for example, Patent document No. 4: JP, A, 7-10875 (1995); Patent document No. 5: WO, A, 96/06843; Patent document No. 6: JP, A, 11-106385 (1999); Patent document No. 7: JP, A, 2002-138089; Patent document No. 8: WO, A, 99/02527; Patent document No. 9; WO, A, 99/38867; Patent document No. 10; WO, A, 01/42244; etc.).

Whereas, in connection with compounds where a heterocyclic ring is condensed to a naphthyridine ring are disclosed compounds having anti-inflammatory, immunoregulatory, analgesic, and antipyretic actions (for example, Patent document No. 11: JP, A, 5-132484 (1993), Patent document No. 12: JP, A, 6-100561 (1994)) and compounds having anti-inflammatory, immunoregulatory, bronchodilator, and hair-growing actions (for example, Patent document No. 13: JP, A, 5-194515 (1993), Patent document No. 14: JP, B2, 3016905); however, no inhibitory action on PDE IV is indicated in these prior art compounds.

[Patent document No. 1] JP, A, 10-226647 (1998)
[Patent document No. 2] JP, A, 2001-527508
[Patent document No. 3] JP, A, 2001-354655
[Patent document No. 4] JP, A, 7-10875 (1995)
[Patent document No. 5] WO, A, 96/06843
[Patent document No. 6] JP, A, 11-106385 (1999)
[Patent document No. 7] JP, A, 2002-138089
[Patent document No. 8] WO, A, 99/02527
[Patent document No. 9] WO, A, 99/38867
[Patent document No. 10] WO, A, 01/42244
[Patent document No. 11] JP, A, 5-132484 (1993)
[Patent document No. 12] JP, A, 6-100561 (1994)
[Patent document No. 13] JP, A, 5-194515 (1993)
[Patent document No. 14] JP, B2, 3016905
[Non-patent document No. 1] PROGRESS IN DRUG RESEARCH, (USA), 53, pp. 193-229 (1999)
[Non-patent document No. 2] JOURNAL OF MEDICINAL CHEMISTRY, (USA), 41, pp. 2268-2277 (1999)

SUMMARY

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OF THE INVENTION

The aforementioned compound groups are still unsatisfactory in view of solving the problems, i.e., of minimizing unfavorable side effects in other tissues/organs than airway smooth muscle cells and inflammatory cells, in order to develop and provide drugs with excellent anti-asthmatic and/or COPD-preventing/treating profiles.

There is a great desire to find an advantageously safe drug having not only a highly specific-inhibitory action on PDE IV but also an excellent anti-asthmatic and/or COPD-preventing/treating action.

The present inventors have conducted an extensive research on various compounds in order to solve the above problems. As a result, the present inventors have succeeded in producing unique pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives which are derived from the compound having a naphthyridine skeleton (disclosed in WO, A, 01/42244) by condensing a imidazole ring to a specific site of the naphthyridine ring thereof and finding that these novel pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives are not only pharmacologically advantageous over the conventional PDE IV inhibitors, but also qualified as excellently safer drugs than the conventional PDE IV inhibitors because it is perceivable that there is a great difference between their pharmacologically-effective dose and their effective dose for inhibiting drug-metabolizing enzymes. Thus, the present inventors have succeeded in accomplishing this invention.

The present invention, as described herein below, encompasses 1-unsubstituted or optionally 1-substituted pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one derivatives having an unsubstituted or optionally substituted phenyl, pyridyl, 1-oxypyridyl or thienyl group via 1 to 3 methylene chains on the 3 position of the pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one nucleus.

The present invention provides the following:

1) A compound of the formula (1):

wherein:

A is phenyl, pyridyl, 1-oxypyridyl, or thienyl, which may be unsubstituted or optionally substituted with one or more members selected from the group consisting of hydroxyl, halogen, cyano, nitro, lower alkyl, lower alkoxy, lower alkylcarbonyloxy, amino, carboxyl, lower alkoxycarbonyl, carboxy-lower alkylene, lower alkoxycarbonyl-lower alkylene, lower alkylsulfonyl, lower alkylsulfonylamino, and ureido;

R1 is a group selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, nitro, lower alkoxy, amino, carboxyl, and lower alkoxycarbonyl;

R2 is hydrogen or lower alkyl; and

m is an integer of 1 to 3;

or a pharmaceutically acceptable salt thereof.

2) The compound according to the above 1), wherein A is phenyl; or a pharmaceutically acceptable salt thereof.

3) The compound according to the above 1), wherein A is pyridyl or 1-oxypyridyl; or a pharmaceutically acceptable salt thereof.

4) A compound, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of 3-benzyl-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 5-phenyl-3-[2-(1-oxypyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 5-(3-nitrophenyl)-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one, 3-(4-carboxymethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-(2-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-(2-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-(2,5-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-(4-ethoxycarbonylmethylbenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-benzyl-5-(3-cyanophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, 3-benzyl-5-(3-nitrophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one, and 3-benzyl-5-(3-fluorophenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one.

5) A pharmaceutical composition which comprises an effective amount of a compound according to any of the above 1) to 4) or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable carrier.

6) A phosphodiesterase IV inhibitor comprising an effective amount of a compound according to any of the above 1) to 4) or a pharmaceutically acceptable salt thereof.

7) A drug for the prophylaxis and/or treatment of at least one member selected from diseases or abnormal conditions directly or indirectly related to phosphodiesterase IV, said drug comprising an effective amount of a compound according to any of the above 1) to 4) or a pharmaceutically acceptable salt thereof.

8.) A drug comprising an effective amount of a compound according to any of the above 1) to 4) or a pharmaceutically acceptable salt thereof,

said drug for preventing and/or treating at least one respiratory disease selected from the group consisting of: bronchial asthma including chronic bronchial asthma and atopic asthma; acute bronchitis; chronic bronchitis; asthmatic bronchitis; pneumonic diseases; pulmonary emphysema; chronic obstructive pulmonary disease (COPD); and acute respiratory distress syndrome (ARDS).

9) An anti-asthmatic comprising an effective amount of a compound according to any of the above 1) to 4) or a pharmaceutically acceptable salt thereof.

The aforementioned diseases or abnormal conditions directly or indirectly related to phosphodiesterase IV may include, for example, the following:

(1) inflammatory diseases, including atopic dermatitis, conjunctivitis, urticaria, acquired immunodeficiency syndrome (AIDS), keloid formation, rhinitis, iridocyclitis, gingivitis, periodontitis, dentoalveolitis, gastritis, ulcerative colitis, Crohn\'s disease, gastrointestinal ulcer, esophagitis, myositis, encephalitis, myasthenia gravis, multiple sclerosis, neuritis, hepatitis, scar tissue formation, nephritis (including proliferative nephritis), peritonitis, pleurisy, scleritis, scleroderma, scalds or burns, and the like;

(2) systemic or local joint diseases, including osteoarthritis, gouty arthritis, rheumatoid arthritis, malignant rheumatism, psoriatic arthritis, and the like;

(3) inflammatory conditions associated with organ transplantation, etc., including reperfusion injury, graft versus-host reaction, and the like;

(4) diseases related to urination, including diabetes insipidus, urethritis, urinary incontinence, cystitis, irritable bladder, neurogenic bladder, uremia, uriniferous tubular disorder, pollakiuria, ischuria, and the like;




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stats Patent Info
Application #
US 20100093782 A1
Publish Date
04/15/2010
Document #
12585430
File Date
09/15/2009
USPTO Class
514293
Other USPTO Classes
546 82
International Class
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Drawings
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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai   Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms   Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos   Tricyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos   Plural Hetero Atoms In The Tricyclo Ring System  

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