Nitrogen-containing bicyclic compounds and drugs containing the same as the active ingredient

• US 7,378,428 B2
• Filed: 01/30/2003
• Issued: 05/27/2008
• Est. Priority Date: 01/31/2002
• Status: Expired due to Fees

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Yamamoto, Susumu, Ohhata, Akira, Ogawa, Mikio, Takaoka, Yoshikazu, Nakai, Hisao, Ochiai, Hiroshi
• Primary Examiner(s): Habte; Kahsay T
• Application Number:
  US10/502,884
• Publication Number:
  US 20050222138A1
• Time in Patent Office: 1,944 Days
• Field of Search: 546/18, 546/146, 514/307
• US Class Current: 514/307
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4738 ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/536 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 : for peripheral neuropathies
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/14 : Decongestants or antiallergics
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Abstract

A nitrogen-containing bicyclic compound of formula (I) or a pharmaceutically acceptable salt thereof (wherein the symbols have the same meanings as described in the specification).

The compound of formula (I) has an inhibitory activity against PDE7 and it is useful for the prevention and/or treatment of various diseases, i.e. autoimmune diseases (ulcerative colitis, Crohn'"'"'s disease, rheumatism, psoriasis, multiple sclerosis, collagenosis, etc.), inflammatory diseases (obstructive pulmonary disease, sepsis, pancreatitis, sarcoidosis, nephritis, hepatitis, enteritis, etc.), allergic diseases (asthma, allergic rhinitis, allergic conjunctivitis, seasonal conjunctivitis, atopic dermatitis, etc.), rejection of organ transplants, serious graft versus host disease (GVHD), diabetic disease, osteoporosis, bone fracture, restenosis, atherosclerosis, obesity, ischemic reperfusion injury, depression, Parkinson'"'"'s disease, dementia, leukemia, etc.

Claims

1. A compound of formula (I)

2. The compound according to claim 1, in formula (I), wherein

(i) Z is —

CR³R⁴— and

at least either of R⁷ or R⁸ is (24) C1-8 alkyl substituted with 1-3 of halogen atom, (25) C1-8 alkoxy substituted with 1-3 of halogen atom, (26) C1-8 alkoxy substituted with Cyc2, (27) —

O-Cyc2, (28) —

OSO₂R⁶⁵, or (29) —

CH═

N—

OR¹³⁷, or

(ii) Z is —

CR³R⁴— and

at least one Cyc2 which is represented by R⁷, R⁸ or ring is substituted with at least one R^17′

or a pharmacologically acceptable salt thereof.

3. The compound according to claim 1, which is represented by formula (I′

)

4. The compound according to claim 2, which is (Z)-2-(7-bromomethyl-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one,

or a pharmacologically acceptable salt thereof.

5. The compound according to claim 3, which is

(1) (Z)-2-(7-t-butylsulfamoyl-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one,

(2) (Z)-2-(7-hydroxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cycloheptylethan-1-one,

(3) (Z)-2-(6-hydroxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cyclohexylethan-1-one,

(4) (Z)-2-(6-hydroxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cycloheptylethan-1-one,

(5) (Z)-2-(6-hydroxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one,

(6) (Z)-2-(7-hydroxy-3,3,6-trimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one,

(7) (Z)-2-(7-hydroxy-3,3,6-trimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cyclohexylethan-1-one,

(8) (Z)-2-(7-hydroxy-3,3,6-trimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cycloheptylethan-1-one,

(9) (Z)-2-(7-(1-hydroxy-1-methylethyl)-6-methoxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cycloheptylethan-1-one,

(10) (Z)-2-(7-(1-hydroxyethyl)-6-methoxy-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-cycloheptylethan-1-one,

(11) (Z)-2-(7-methoxymethyl-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one, or

(12) (Z)-2-(7-sulfamoyl-3,3-dimethyl-3,4-dihydro-(2H)-isoquinolin-1-ylidene)-1-(adamantan-1-yl)ethan-1-one, or a pharmacologically acceptable salt thereof.

or a pharmacologically acceptable salt thereof.

6. A pharmaceutical composition comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as active ingredient and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising the compound according to claim 2, or a pharmacologically acceptable salt as active ingredient and a pharmaceutically acceptable carrier.

8. A method for treating allergic diseases, rejection of an organ transplant, graft versus host disease (GVHD), osteoporosis, bone fracture, re-stenosis, arteriosclerosis, obesity, ischemic reperfusion injury, or depression, which comprises administering the compound according to claim 1 or a pharmacologically acceptable salt thereof.

9. A method for treating asthma, allergy rhinitis, atopic dermatitis, rheumatism, postoperative pain and/or carcinomatous pain, which comprises administering the compound according to claim 2, or a pharmacologically acceptable salt as active ingredient.