Water-soluble phenylpyridazine compounds and compositions containing the same

• US 20050085480A1
• Filed: 10/12/2004
• Published: 04/21/2005
• Est. Priority Date: 09/26/2001
• Status: Active Grant

• Current Assignee: KOWA Company Limited
• Original Assignee: KOWA Company Limited
• Inventors: Takemura, Shunji, Yasuoka, Kyoko, Totsuka, Junko, Sato, Seiichi, Koshi, Tomoyuki, Kitamura, Takahiro, Yoshizaki, Hideo, Kyotani, Yoshinori, Shigyo, Hiromichi
• Granted Patent: US 7,087,606 B2
• Time in Patent Office: Days
• US Class Current: 514/247
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• 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 13/12 of the kidneys
• 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 25/00 Drugs for disorders of the nervous system
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• 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 9/10 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 237/14 Oxygen atoms
• CPC Class Codes: C07D 237/24 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Abstract

Compounds having the formula (1):
wherein R¹ represents an alkyl or alkenyl group, R² and R³ each independently represent a hydrogen atom or an alkyl, hydroxyalkyl, dihydroxyalkyl or alkynyl group, or R² and R³ may be fused together with the adjacent nitrogen atom to form a substituted or unsubstituted, nitrogen-containing, saturated heterocyclic group, X, Y and Z each independently represent a hydrogen atom, an alkyl group, a halogen atom or the like, and n stands for an integer of from 1 to 5; and also to medicinal compositions containing them. These compounds have inhibitory activity against IL-1β production, high water solubility and good oral absorbability.

Claims

1. A phenylpyridazine compound having the formula (1):

2. The compound of claim 1, wherein R¹ is substituted or unsubstituted alkyl having 1 to 7 carbon atoms or substituted or unsubstituted alkenyl having 2 to 7 carbon atoms.

3. The compound of claim 2, wherein one or more substituents on said alkyl or alkenyl group represented by R¹ are each independently an aryl group having 6 to 14 carbon atoms or a 5- or 6-membered heteroaryl group having 1 to 3 nitrogen atoms;

and said aryl or heteroaryl group are each unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of halogen atoms, alkyl groups and alkoxy groups.

4. The compound of claim 1, wherein R² and R³ each independently represents hydrogen, alkyl, hydroxyalkyl, dihydroxyalkyl or alkynyl;

or R² and R³ are fused together with the adjacent nitrogen atom to form a 5- or 7-membered, nitrogen-containing, saturated heterocyclic group, said heterocyclic group being unsubstituted or substituted with one or more halogen atoms, or alkyl, alkoxycarbonyl or aralkyl groups.

5. The compound of claim 1, wherein X, Y and Z each independently are hydrogen, halogen, alkyl which is unsubstituted or substituted by one or more halogen atoms, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, or C₆-C₁₄ aryl groups which are unsubstituted or substituted by one or more of halogen, alkyl and alkoxy.

6. The compound of claim 1, wherein

R¹ is isobutyl, cyclopropylmethyl, cyclopentylmethyl, cinnamyl, halogenocinnamyl, benzyl, halogenobenzyl, dihalogenobenzyl or (halogenophenyl)propyl;

R² and R³ are each independently hydrogen, C_1-7 alkyl, C_1-7 hydroxyalkyl or propargyl;

said heterocyclic group formed by R² and R³ is substituted with C_1-7 alkyl or is piperazinyl, piperidino, pyrrolidino or morpholino which is unsubstituted or substituted by one or more benzyl;

X is methyl, methoxy, methylthio or halogen;

Y is hydrogen or halogen;

Z is hydrogen; and

n is 1 or 3.

8. A pharmaceutical composition comprising at least one of the phenylpyridazine compound, or a salt thereof, of claim 1, and a pharmaceutically-acceptable carrier.

9. A method of using a phenylpyridazine compound, or a salt thereof, the method comprising inhibiting interleukin-1β

production in a mammal by administering at least one of the phenylpyridazine compound, or a salt thereof, of claim 1 to the mammal.

11. The method of claim 9, wherein the administering prevents or treats rheumatism in the mammal.

12. The method of claim 9, wherein the administering prevents or treats arthritis in the mammal.

14. The method of claim 9, wherein the mammal is a human.

15. The method of claim 9, wherein the administering is by oral administration.

16. The method of claim 9, wherein the administering is by parenteral administration.

17. A The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is in a form suitable for oral administration.

18. The pharmaceutical composition of claim 17, wherein the form suitable for oral administration is a tablet.

7. (canceled)

10. (canceled)

13. (canceled)