Phenylpyridazine compounds and medicines containing the same

• US 6,664,256 B1
• Filed: 07/10/2000
• Issued: 12/16/2003
• Est. Priority Date: 07/10/2000
• Status: Expired due to Fees

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Ohkuchi, Masao, Kotaki, Kyoko, Matsuda, Takayuki, Koshi, Tomoyuki, Ohgiya, Tadaaki, Kyotani, Yoshinori, Shigyo, Hiromichi, Kumai, Natsuyo
• Primary Examiner(s): BERNHARDT, EMILY A
• Application Number:
  US09/612,953
• Time in Patent Office: 1,254 Days
• Field of Search: 544/238, 544/239, 544/114, 544/224, 514/252.03, 514/247, 514/236.5
• US Class Current: 514/236.5
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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 237/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 237/12 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07D 237/18 Sulfur atoms
• CPC Class Codes: C07D 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond

Abstract

Phenylpyridazine compounds represented by the following formula (I):

are provided, wherein R¹, R², R³, R⁴, and n are as defined herein having excellent inhibitory activity against interleukin-1β production, and useful in the treatment of prevention of diseases caused by stimulation of interleukin-1β production, such as immune system diseases, inflammatory diseases, and ischemic diseases.

Claims

1. A phenylpyridazine compound represented by the following formula (I):

wherein

R¹ represents phenyl, pyridyl, substituted phenyl or substituted pyridyl, wherein the substituents are selected from the group consisting of halogen, hydroxyl, alkyl, lower alkoxy and phenylthio;

R² represents lower alkoxy, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl;

R³ represents hydrogen or lower alkoxy;

or R² and R³ may be fused together to form an alkylenedioxy group;

R⁴ represents hydrogen, halogen, cyano, carboxy, lower alkyl, lower alkyl substituted by halogen, hydroxy, cyano, nitro, amino, carboxy, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl or lower alkyl substituted aminocarbonyl;

lower alkenyl, halogen or phenyl substituted lower alkenyl, lower alkylthio, phenyl substituted lower alkylthio, lower alkylsulfinyl, phenyl substituted lower alkylsulfinyl, lower alkylsulfonyl, phenyl substituted lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl substituted lower alkylsulfonyloxy, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro, or amino;

pyridyl, pyridyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenoxy, phenoxy substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenylthio, phenylthio substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenylsulfinyl, phenylsulfinyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenylsulfonyl, phenylsulfonyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyloxy, pyridyloxy substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

morpholino, morpholino substituted by halogen, lower alkyl, lower alkoxy, cyano or nitro;

morpholinocarbonyl, morpholinocarbonyl substituted by halogen, lower alkyl, lower alkoxy, cyano or nitro;

piperidinocarbonyl, piperidinocarbonyl substituted by halogen, lower alkyl, lower alkoxy, cyano or nitro;

1-piperazinylcarbonyl, 1-piperazinylcarbonyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

amino substituted by phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl or lower alkoxy, or benzyl; and

n is 0 or 1,

with the proviso that when R¹ is 4-methoxyphenyl, R² is methoxy and R³ is hydrogen, R⁴ can not be hydrogen or halogen and with the proviso that R¹ can not be 4-(methylsulfonyl)phenyl or 4-(aminosulfonyl)phenyl and with the proviso that when R⁴ is halogen, R¹ can not be lower alkoxyphenyl and R² can not be lower alkoxy;

or a salt thereof.

2. The phenylpyridazine compound or a salt thereof of claim 1, wherein

R¹ represents pyridyl, phenyl or phenyl substituted by halogen, hydroxyl, alkyl, lower alkoxy or phenylthio;

R² represents lower alkoxy, lower alkylthio or lower alkylsulfonyl;

R³ represents hydrogen or lower alkoxy;

or R² and R³ may be fused together to form an alkylenedioxy group;

R⁴ represents hydrogen, halogen, cyano, carboxy, lower alkyl, lower alkyl substituted by halogen, hydroxy, cyano, nitro, amino, carboxy, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl or lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyl, pyridyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenoxy, phenoxy substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenylthio, phenylthio substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl, 1-piperazinylcarbonyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

amino substituted by phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl or lower alkoxy, or benzyl; and

n is 0 or 1.

3. The phenylpyridazine compound or a salt thereof according to claim 1, wherein

R¹ represents pyridyl, or phenyl which is substituted by one or more members selected from the group consisting of hydrogen, halogen, lower alkoxy and phenylthio groups.

4. The phenylpyridazine compound or a salt thereof according to claim 1, wherein R⁴ is hydrogen, halogen, cyano, carboxy, lower alkyl which is substituted by one or more members selected from the group consisting of hydroxyl, carboxyl, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl and lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenoxy which is substituted by one or more members selected from the group consisting of halogen, cyano, nitro and lower alkoxy;

phenylthio which is substituted by at least one halogen atom;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl which is substituted by one or more alkyl groups;

or amino which is substituted by one or more members selected from the group consisting of phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl, and lower alkoxy, or benzyl.

5. The phenylpyridazine compound or a salt thereof according to claim 1, wherein the compound is a member selected from the group consisting of 3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,5-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,6-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetrafluorophenoxy)pyridazine, 3,4-bis(4methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenylthio)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2-cyanophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3-cyanophenoxy)pyridazine, 6-(2,4-difluorophenoxy)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine, 6-(2,3-difluorophenoxy)-3-(4-methoxyphenyl)-4-phenylpyridazine, 6-(2,4-difluorophenoxy)-3(4-methoxyphenyl)-4-phenylpyridazine, 3-(4-methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpyridazine, 3-[4-(methylthio)phenyl]-6-phenylthio-4-[4(phenylthio)phenyl]pyridazine, 4-(4-chlorophenyl)-6-(2,4-difluorophenoxy)-3-[4-(methylthio)phenyl]pyridazine, 3,4-bis(4-methoxyphenyl)-6-cyanopyridazine, 6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazine, and salts thereof.

6. The phenylpyridazine compound or a salt thereof as claimed in claim 1, wherein the salt is a member selected from the group consisting of hydrochloride, nitrate, hydrobromide, acetate, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, methylammonium salt, dimethylammonium salt, and trimethylammonium.

7. A pharmaceutical composition comprising, as active ingredient, a phenylpyridazine compound as claimed in claim 1, or a pharmacologically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, wherein said composition further comprises one or more members selected from the group consisting of pharmaceutically acceptable excipients, binders, extenders, disintegrators, surfactants, lubricants, dispersants, buffers, preservatives, corrigents, perfumes, coating agents, vehicles, diluents and carriers.

9. The pharmaceutical composition according to claim 7, wherein said phenylpyridazine compound is a salt selected from the group consisting of hydrochloride, nitrate, hydrobromide, acetate, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, methylammonium salt, dimethylammonium salt, and trimethylammonium.

10. The pharmaceutical composition according to claim 7, wherein

R¹ represents pyridyl, phenyl or phenyl substituted by halogen, hydroxyl, alkyl, lower alkoxy or phenylthio;

R² represents lower alkoxy, lower alkylthio or lower alkylsulfonyl;

R³ represents hydrogen or lower alkoxy;

or R² and R³ may be fused together to form an alkylenedioxy group;

R⁴ represents hydrogen, halogen, cyano, carboxy, lower alkyl, lower alkyl substituted by halogen, hydroxy, cyano, nitro, amino, carboxy, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl or lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyl, pyridyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenoxy, phenoxy substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro, or amino;

phenylthio, phenylthio substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl;

1-piperazinylcarbonyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

or amino substituted by phenyl;

phenyl substituted by halogen, cyano, nitro, amino, lower alkyl, or lower alkoxy, or benzyl; and

n is 0 or 1.

11. The pharmaceutical composition according to claim 7, wherein R¹ is pyridyl, or phenyl which may be substituted by one or more members selected from the group consisting of halogen, lower alkoxy and phenylthio.

12. The pharmaceutical composition according to claim 7, wherein R⁴ is hydrogen, halogen, cyano, carboxy, lower alkyl which is substituted by one or more members selected from the group consisting of hydroxyl, carboxyl, aminocarbonyl, N-hydroxy, N-loweralkylaminocarbonyl and lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenoxy which is substituted by one or more members selected from the group consisting of halogen, cyano, nitro and lower alkoxy;

phenylthio which is substituted by at least one halogen atom;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl which is substituted by one or more hydrogen or alkyl groups;

or amino which is substituted by one or more members selected from the group consisting of phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl, and lower alkoxy, or benzyl.

13. The pharmaceutical composition according to claim 7, wherein said phenylpyridazine compound is a member selected from the group consisting of 3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,5-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,6-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetrafluorophenoxy)pyridazine, 3,4-bis(4methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)pyridazine, 3,4-.bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenylthio)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2-cyanophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3-cyanophenoxy)pyridazine, 6-(2,4-difluorophenoxy)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine, 6-(2,3-difluorophenoxy)-3-(4-methoxyphenyl)-4-phenylpyridazine, 6-(2,4-difluorophenoxy)-3(4-methoxyphenyl)-4-phenylpyridazine, 3-(4-methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpyridazine, 3-[4-(methylthio)phenyl]-6-phenylthio-4-[4(phenylthio)phenyl]pyridazine, 4-(4-chlorophenyl)-6-(2,4-difluorophenoxy)-3-[4-(methylthio)phenyl]pyridazine, 3,4-bis(4-methoxyphenyl)-6-cyanopyridazine, 6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazine, and salts thereof.

14. A method for treating a disease caused by stimulation of interleukin-1β

production, comprising;

administering to a subject suffering from rheumatism or arthritis an effective amount of the pharmaceutical composition according to claim 7.

15. The method according to claim 14, wherein said phenylpyridazine compound contained in said pharmaceutical composition is a salt selected from the group consisting of hydrochloride, nitrate, hydrobromide, acetate, sulfate, p-toluenesulfonate, methanesulfonate, fumarate, succinate, lactate, sodium salt, potassium salt, magnesium salt, calcium salt, ammonium salt, methylammonium salt, dimethylammonium salt, and trimethylammonium.

16. The method according to claim 14, wherein said phenylpyridazine compound contained in said pharmaceutical composition has the following substituents on formula (I):

R¹ represents pyridyl, phenyl or phenyl substituted by halogen, hydroxyl, alkyl, lower alkoxy or phenylthio;

R² represents lower alkoxy, lower alkylthio or lower alkylsulfonyl;

R³ represents hydrogen or lower alkoxy;

or R² and R³ may be fused together to form an alkylenedioxy group;

R⁴ represents hydrogen, halogen, cyano, carboxy, lower alkyl, lower alkyl substituted by halogen, hydroxy, cyano, nitro, amino, carboxy, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl or lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyl, pyridyl substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenoxy, phenoxy substituted by halogen, lower alkyl, lower alkoxy, cyano, nitro or amino;

phenylthio, phenylthio which is substituted by at least one or more members selected from the group consisting of halogen atoms, lower alkyl, lower alkoxy, cyano, nitro or amino;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl, 1-piperazinylcarbonyl substituted halogen, lower alkyl groups, lower alkoxy, cyano, nitro or amino;

amino which is substituted by phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl, or lower alkoxy, or benzyl; and

n is 0 or 1.

17. The method according to claim 14, wherein said phenylpyridazine compound contained in said pharmaceutical composition has the following substituents on formula (I):

R¹ is pyridyl or phenyl which is substituted by one or more members selected from the group consisting of halogen, lower alkoxy and phenylthio groups; and

R⁴ is hydrogen, halogen, cyano, carboxy, lower alkyl, which is substituted by one or more members selected from the group consisting of hydroxyl, carboxyl, aminocarbonyl, N-hydroxy,N-loweralkylaminocarbonyl and lower alkyl substituted aminocarbonyl;

lower alkenyl, lower alkylthio, lower alkylsulfonyl, lower alkylsulfonyloxy, phenyl, phenoxy which is substituted by one or more members selected from the group consisting of halogen, cyano, nitro and lower alkoxy;

phenylthio which is substituted by at least one halogen atom;

pyridyloxy, morpholino, morpholinocarbonyl, 1-piperazinylcarbonyl, which is substituted by one or more alkyl groups;

or amino, which is substituted by one or more members selected from the group consisting of phenyl, phenyl substituted by halogen, cyano, nitro, amino, lower alkyl, and lower alkoxy, or benzyl.

18. The method according to claim 14, wherein said phenylpyridazine compound contained in said pharmaceutical composition is a member selected from the group consisting of 3,4-bis(4-methoxyphenyl)-6-(phenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,5-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,6-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4-difluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2,3,5,6-tetrafluorophenoxy)pyridazine, 3,4-bis(4methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3,4,5-trichlorophenylthio)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-methoxyphenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(4-nitrophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(2-cyanophenoxy)pyridazine, 3,4-bis(4-methoxyphenyl)-6-(3-cyanophenoxy)pyridazine, 6-(2,4-difluorophenoxy)-3-(4-methoxyphenyl)-4-(4-pyridyl)pyridazine, 6-(2,3-difluorophenoxy)-3-(4-methoxyphenyl)-4-phenylpyridazine, 6-(2,4-difluorophenoxy)-3(4-methoxyphenyl)-4-phenylpyridazine, 3-(4-methoxyphenyl)-6-(2,3,4,5,6-pentafluorophenoxy)-4-phenylpyridazine, 3-[4-(methylthio)phenyl]-6-phenylthio-4-[4(phenylthio)phenyl]pyridazine, 4-(4-chlorophenyl)-6-(2,4-difluorophenoxy)-3-[4-(methylthio)phenyl]pyridazine, 3,4-bis(4-methoxyphenyl)-6-cyanopyridazine, 6-cyano-3-(4-methoxyphenyl)-4-phenylpyridazine, and salts thereof.