Quinoline sulfonamides and their therapeutic use

• US 5,834,485 A
• Filed: 05/20/1997
• Issued: 11/10/1998
• Est. Priority Date: 05/20/1996
• Status: Expired due to Fees

• Current Assignee: Darwin Discovery Ltd. (UCB SA)
• Original Assignee: Chiroscience Limited
• Inventors: Montana, John Gary, Dyke, Hazel Joan
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): Rao, Deepak R.
• Application Number:
  US08/858,969
• Time in Patent Office: 539 Days
• Field of Search: 546/154, 546/155, 546/156, 546/157, 546/160, 546/162, 546/172, 514/311, 514/312, 514/313, 514/314
• US Class Current: 514/311
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/36 Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 215/48 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 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The subject invention pertains to quinolinesulfonamides. The subject compounds can be used to treat disease states, such as those that are associated with proteins that mediate cellular activity, for example, by inhibiting phosphodiesterase IV (PDE IV) or tumor necrosis factor (TNF). The invention also pertains to methods of treating disease states, including those states capable of being modulated by inhibition of PDE IV or TNF.

Claims

1. A compound of the general formula (i) ##STR5## wherein R is selected from the group consisting of H, halogen, and alkyl;

R₁ is selected from the group consisting of OH, alkoxy optionally substituted with one or more halogens, and thioalkyl;

R₂, R₃, and R₄ are the same or different and are each selected from the group consisting of H, R₇, OR₁₁, COR₇, C(═

NOR₇)R₇, alkyl-C(═

NOR₇)R₇ alkyl-C(═

NOR)R₇, C(═

NOH)R₇, halogen, CF₃, CN, CO₂ H, CO₂ R₁₁, CONH₂, CONHR₇, CON(R₇)₂, NR₉ R₁₀, and CONR₁₂ R₁₃ where NR₁₂ R₁₃ is a heterocyclic ring optionally substituted with one or more R₁₅ ;

R₅ is selected from the group consisting of arylalkyl, heteroarylalkyl, S(O)_m R₁₁, and alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, CO₂ R₈, SO₂ NR₁₂ R₁₃, CONR₁₂ R₁₃, CN, NR₉ R₁₀, COR₁₁, and S(O)_n R₁₁ ;

for R₅ and/or R₆, the aryl/heteroaryl portion is optionally substituted with one or more substituents alkyl-R₁₄ or R₁₄ ;

R₆ is selected from the group consisting of aryl, heteroaryl, arylalkyl, and heteroarylalkyl;

R₇ represents R₁₁ optionally substituted at any position with one or more R₁₆ ;

R₈ is selected from the group consisting of H, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl;

R₉ is selected from the group consisting H, aryl, heteoaryl, heterocyclo, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, heterocyclalkyl, alkylcarbonyl, alkoxycarbonyl, arylsulphonyl, heteroarylsulphonyl, heterocyclosulphonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, and alkylsulphonyl;

R₁₀ is selected from the group consisting of H, aryl, heteroaryl, heterocyclo, alkyl, cycloalkyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl;

R₁₁ is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, and heterocycloalkyl;

R₁₂ and R₁₃ are the same or different and are each selected from the group consisting of H and R₁₁, or NR₁₂ R₁₃ represents a heterocyclic ring as defined above;

Rhd 14 is selected from the group consisting of alkyl (optionally substituted by one or more halogens), cycloalkyl, aryl, heteroaryl, heterocyclo, hydroxy, alkoxy (optionally substituted by one or more halogens), thioalkyl, aryloxy, heteroaryloxy, heterocyclooxy, arylalkyloxy, heteroarylalkyloxy, heterocycloalkyloxy, CO₂ R₄, CONR₁₂ R₁₃, SO₂ NR₁₂ R₁₃, halogen, --CN, --NR₉ R₁₀, COR₁₁, S(O)_n R₁₁, and carbonyl oxygen;

R₁₅ is selected from the group consisting of alkyl, arylalkyl, and heteroarylalkyl;

R₁₆ is selected from the group consisting of alkyl, OH, OR₁₁, NR₉ R₁₀, CN, CO₂ H, CO₂ R₁₁, CONR₁₂ R₁₃, and COR₁₁ ;

m is an integer of up to 2; and

n=0-2;

or a pharmaceutically acceptable salt thereof.

2. The compound, according to claim 1, wherein R is H or halogen.

3. The compound, according to claim 1, wherein R₁ is alkoxy optionally substituted with one or more halogens.

4. The compound, according to claim 1, wherein R₂, R₃, and R₄ are the same or different and are each selected from the group consisting of H, CF₃, COR₇, C(═

NOR₇)R₇, C(═

NOH)R₇, CN, R₇, alkyl-C(═

NOH)₇, and alkyl-C(═

NOR₇)R₇.

5. The compound, according to claim 1, wherein R₅ is selected from the group consisting of arylalkyl, heteroarylalkyl, S(O)_m R₁₁, and alkyl.

6. The compound, according to claim 1, wherein R₆ is arylalkyl or heteroaryl in which the aryl and heteroaryl portions may be optionally substituted with one or more substituents alkyl-R₁₄ or R₁₄.

7. The compound, according to claim 1, wherein:

R is H;

R₁ is optionally-substituted alkoxy;

R₂, R₃, and R₄ are independently selected from the group consisting of H, R₇, and alkyl-R₇ ;

R₇ is selected from the group consisting of H, OH, alkoxy, aryloxy, heteroaryloxy, heterocyclooxy, arylalkoxy, heteroarylalkoxy, heterocycloalkyoxy, alkylamino, CF₃, and R₁₁ ;

R₈ is selected from the group consisting of H, alkyl, arylalkyl, heteroarylalkyl, and heterocycloalkyl;

R₉ is not cycloalkyl;

R₁₀ is not cycloalkyl;

R₁₁ is not cycloalkyl; and

R₁₄ is not alkyl, substituted alkoxy, thioalkyl, or cycloalkyl.

8. The compound, according to claim 1, which is 8-methoxyquinoline-5-(N-benzyl-N-methanesulphonyl)sulphonamide.

9. The compound, according to claim 1, which is 8-methoxyquinoline-5-(N-benzyl-N-propyl)sulphonamide.

10. The compound, according to claim 1, which is in the form of an enantiomer or mixers of enantiomers.

11. A pharmaceutical composition for therapeutic use comprising a compound of claim 1 and a pharmaceutically-acceptable carrier or excipient.

12. A method for treating a disease state capable of being modulated by inhibition of phosphodiesterase IV or Tumour Necrosis Factor, wherein said method comprises administering an effective amount of a compound of claim 1.

13. The method, according to claim 12, wherein said disease state is a pathological condition associated with the function of phosphodiesterase IV, eosinophil accumulation, or a function of the eosinophil.

14. The method, according to claim 13, wherein said pathological condition is selected from the group consisting of asthma, chronic bronchitis, chronic obstructive airways disease, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, rheumatoid arthritis, gouty arthritis or other arthritic conditions, ulcerative colitis, Crohn'"'"'s disease, adult respiratory distress syndrome, diabetes insipidus, keratosis, atopic eczema, atopic dermatitis, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson'"'"'s disease, depression, cardiac arrest, stroke, and intermittent claudication.

15. The method, according to claim 13, wherein said pathological condition is selected from the group consisting of chronic bronchitis, allergic rhinitis, and adult respiratory distress syndrome.

16. The method, according to claim 12, wherein said disease state is capable of being modulated by TNF inhibition.

17. The method, according to claim 16, wherein said disease state is an inflammatory disease or autoimmune disease.

18. The method, according to claim 17, wherein said disease state is selected from the group consisting of joint inflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis and osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, asthma, bone resorption disease, reperfusion injury, graft vs host reaction, allograft rejection, malaria, myalgias, HIV, AIDS, ARC, cachexia, Crohn'"'"'s disease, ulcerative colitis, pyresis, systemic lupus erythematosis, multiple sclerosis, type I diabetes mellitus, psoriasis, Bechet'"'"'s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, inflammatory bowel disease, and leukemia.

19. The method, according to claim 18, wherein said disease state is asthma.

20. The method, according to claim 14, wherein said pathological condition is asthma.

21. The method, according to claim 18, wherein said disease state is selected from the group consisting of acute respiratory distress syndrome, pulmonary inflammatory disease, and pulmonary sarcoidosis.

22. The method, according to claim 18, wherein said disease state is joint inflammation.

23. The method, according to claim 13, wherein said disease state is a disease or disorder of the brain.

24. The method, according to claim 23, wherein said disease state is selected from the group consisting of brain trauma, stroke, ischaemia, Huntingdon'"'"'s disease, and tardive dyskinesia.

25. The method, according to claim 16, wherein said disease state is a yeast or fungal infection.

26. A method for providing gastroprotection, wherein said method comprises administering an effective amount of a compound of claim 1.

27. A method for providing an analgesic, an anti-tussive, or an anti-hyperalgesic in the treatment of neurogenic inflammatory disease associated with inflammation and pain, wherein said method comprises administering an effective amount of a compound of claim 1.

28. A method for treating asthma which comprises administering an effective amount of a compound of claim 1, in coadministration with a drug selected from the group consisting of bronchodilators, steroids, and xanthines.