Benzothiazole compounds and their therapeutic use

• US 6,313,116 B1
• Filed: 02/09/2001
• Issued: 11/06/2001
• Est. Priority Date: 02/11/2000
• Status: Expired due to Fees

• Current Assignee: Darwin Discovery Ltd. (UCB SA)
• Original Assignee: Darwin Discovery Ltd. (UCB SA)
• Inventors: Richard, Marianna Dilani, Dyke, Hazel Joan, Buckley, George Martin, Sabin, Verity Margaret, Sharpe, Andrew, Haughan, Alan Findlay, Davenport, Richard John, Kendall, Hannah Jayne
• Primary Examiner(s): STOCKTON, LAURA LYNNE
• Application Number:
  US09/780,911
• Time in Patent Office: 270 Days
• Field of Search: 548/178, 546/198, 544/135, 544/368, 514/233.8, 514/254.02, 514/321, 514/367
• US Class Current: 514/233.8
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/18 : for HIV
• 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 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Compounds that are inhibitors of phosphodiesterase and have therapeutic utility, are of formula (i)

wherein R₁ is C_3-6 cycoalkyl, or C_1-3 alkyl optionally substituted with one or more fluorine atoms;

R₂ is C_1-6 alkyl, C_3-6 cycloalkyl, CF₃, CH₂CF₃, C₂F₅ or NR₄R₅;

R₃ is a pyrazole, imidazole or isoxazole group of partial formula (A), (B) or (C)

NR₄R₅ is a nitrogen-containing heterocyclic ring;

R₆ is C_1-3 alkyl; and

R₇ and R₈, which are the same or different, are each H, C_1-3 alkyl, halogen, CF₃ or CN, provided that both are not H;

or a pharmaceutically-acceptable salt thereof

Claims

1. A compound of the formula

wherein R₁ is C_3-6 cycloalkyl, or C_1-3 alkyl optionally substituted with one or more fluorine atoms;

R₂ is C_1-6 alkyl, C_3-6 cycloalkyl, CF₃, CH₂CF₃, C₂F₅ or NR₄R₅;

R₃ is a pyrazole, imidazole or isoxazole group of partial formula (A), (B) or (C)

NR₄R₅ is a nitrogen-containing heterocyclic ring;

R₆ is C_1-3 alkyl; and

R₇ and R₈, which are the same or different, are each H, C_1-3 alkyl, halogen, CF₃ or CN, provided that both are not H;

or a pharmaceutically-acceptable salt thereof.

2. The compound of claim 1, wherein R₃ is a pyrazole or isoxazole group.

3. The compound of claim 2, wherein R₃ is a pyrazole group, R₆ is CH₃ and R₇ is CN, CH₃ or CF₃.

4. The compound of claim 2, wherein R₃ is an isoxazole group and R₇ and R₈ are independently selected from CH₃, CF₃ and CN.

5. The compound of claim 1, wherein R₁ is optionally F-substituted alkyl and R₂ is alkyl, cycloalkyl, CF₃ or NR₄R₅.

6. The compound of claim 5, wherein R₁ is CH₃ or CHF₂.

7. The compound of claim 5, wherein R₂ is CF₃, ethyl or cyclopropyl.

8. The compound of claim 6, wherein R₂ is CF₃, ethyl or cyclopropyl.

9. The compound of claim 1, selected from the group consisting of

2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (3,5-dimethylisoxazol-4-yl) amide,

4-methoxy-2-(morpholin-4-yl)-benzothiazole-7-carboxylic acid (3,5-dimethylisoxazol-4-yl)amide,

2-cyclopropyl-4-methoxybenzothiazole-7-caboxylic acid (3,5-dimethylisoxazol-4-yl)amide,

4-methoxy-2-(piperidin-1-yl)-benzothiazole-7-carboxylic acid (3,5-dimethylisoxazol-4-yl)amide,

2-ethyl-4-methoxybenzothiazole-7-carboxylic acid (2-methyl-2H-pyrazol-3-yl)amide,

2-(4-tert-butoxycarbonylpiperazin-1-yl)-4-methoxybenzothiazole-7-caboxylic acid (3,5-dimethylisoxazol-4-yl)amide,

2-ethyl-4-methoxybenzothiazole-7-caboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide

4-methoxy-2-(morpholin-4-yl)-benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)-amide,

4-methoxy-2-(piperidin-1-yl)benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide,

2-(4-tert-butoxycarbonylpiperazin-1-yl)-4-methoxyenzothiazole-7-oxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide,

4-methoxy-2-(piperazin-1-yl)benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide, trifluoroacetic acid salt,

4-methoxy-2-(piperazin-1-yl)benzothiazole-7-carboxylic acid (3,5-dimethylisoxazol-4-yl)amide, trifluoroacetic acid salt, and

4-methoxy-2-(4-methylpiperazin-1-yl)benzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide.

10. The compound of claim 1, selected from the group consisting of

4-methoxy-2-trifluoromethylbenzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide and

2-cyclopropyl-4-methoxybenzothiazole-7-carboxylic acid (4-cyano-2-methyl-2H-pyrazol-3-yl)amide.

11. A composition for use in therapy, comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

12. A method for the treatment of a disease state that is capable of being modulated by inhibition of phosphodiesterase IV or Tumour Necrosis Factor, or that is a pathological condition associated with a function of phosphodiesterase IV, eosinophil accumulation or a function of the eosinophil, said method comprising administering to a person or animal an effective amount of the compound of claim 1.

13. The method of claim 12, wherein the disease state is an inflammatory disease or autoimmune disease.

14. The method of claim 12, wherein the disease state is selected from the group consisting of asthma, chronic bronchitis, chronic pulmonary inflammatory disease, chronic obstructive airways disease, atopic dermatitis, allergic rhinitis, psoriasis, arthritis, rheumatoid arthritis, joint inflammation, ulcerative colitis, Crohn'"'"'s disease, atopic eczema, stroke, bone resorption disease, multiple sclerosis and inflanmmatory bowel disease.

15. The method of claim 12, wherein the disease state is selected from the group consisting of urticaria, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, gouty arthritis and other arthritic conditions, adult respiratory distress syndrome, diabetes insipidus, keratosis, cerebral senility, multi-infarct dementia, senile dementia, memory impairment associated with Parkinson'"'"'s disease, depression, cardiac arrest, intermittent claudication, rheumatoid spondylitis, osteoarthritis, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, acute respiratory distress syndrome, cerebral malaria, silicosis, pulmonary sarcoidosis, reperfusion injury, graft vs host reaction, allograft rejection, infection-related fever or myalgia, malaria, HIV, AIDS, ARC, cachexia, keloid formation, scar tissue formation, pyresis, systemic lupus erythematosus, type 1 diabetes mellitus, Bechet'"'"'s disease, anaphylactoid purpura nephritis, chronic glomerulonephritis, leukaemla, tarditive dyskinesia, yeast or fungal infection, conditions requiring gastroprotection, and neurogenic inflammatory disease associated with irritation and pain.

16. The method of claim 12, wherein the disease state is asthma.

17. The method of claim 12, wherein the disease state is chronic obstructive airways disease or chronic bronchitis.