Benzenesulfonamide inhibitors of PDE-IV and their therapeutic us

Details Benzenesulfonamide inhibitors of PDE-IV and their therapeutic us Benzenesulfonamide inhibitors of PDE-IV and their therapeutic us

2000-02-07

2000-12-19

Reamer, James H.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

514538, 514523, 514315, 514427, A61K 3118

Patent

active

061628301

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates to known and novel sulfonamide compounds and pharmaceutically acceptable salts thereof, processes for their production, formulation, and use as pharmaceuticals in the treatment of asthma, allergic diseases, rheumatoid arthritis, osteoarthritis, septic shock, and other diseases treatable by the inhibition of phosphodiesterase-IV (PDE-IV) or Tumour Necrosis Factor (TNF).


SUMMARY OF THE RELATED ART

Phosphodiesterases regulate cyclic AMP concentrations. Phosphodiesterase IV has been demonstrated to be a principal regulator of cyclic AMP in respiratory smooth muscle and inflammatory cells (Trophy and Creslinski, Molecular Pharmacology 37:206 (1990); Dent, et al.: British Journal of Pharmacology, 90:163 (1990)). Inhibitors of PDE-IV have been implicated as being bronchodilators and asthma-prophylactic agents and as agents for inhibiting eosinophil accumulation and the function of eosinophils (for example, Giembycz and Dent, Clinical and Experimental Allergy, 22:237 (1992)) and for treating other diseases and conditions characterized by, or having an etiology including, morbid eosinophil accumulation. Inhibitors of phosphodiesterase-IV are also implicated in treating inflammatory diseases, proliferative skin disease and conditions associated with cerebral metabolic inhibition.
Excessive or unregulated production of Tumour Necrosis Factor (TNF), a serum glycoprotein, has been implicated in mediating, or exacerbating a number of diseases including, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, reperfusion injury, graft versus host reaction, allograft rejections, fever, and myalgias due to infection, such as influenza, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS-related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis, in addition to a number of autoimmune diseases, such as multiple sclerosis, autoimmune diabetes, and systemic lupus erythematosis.
TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus, adenovirus, and the herpes virus.
TNF is also associated with yeast and fungal infections. Specifically Candida albicans has been shown to induce TNF production in vitro in human monocytes and natural killer cells [see Riipi, et al., Infection and Immunity, 58(9):2750-54 (1990); and Jafari, et al., Journal of Infectious Diseases, 162:211-214 (1990)].
Benzenesulfonamide inhibitors of PDE-IV and TNF of the general formula: ##STR1## have been disclosed:
International Patent Application WO 94/02465 discloses, inter alia, compounds of Formula I wherein R.sub.1 represents alkyl; R.sub.2 represents alkyl or cycloalkyl; R.sub.3 represents H; and R.sub.4 represents aryl or heteroaryl.
International Patent Application WO 95/35283 discloses compounds of Formula I wherein R.sub.1 represents H or alkyl; R.sub.2 represents optionally substituted heterocycloaliphatic or an optionally substituted moncyclic or bicyclic aryl group; R.sub.3 is alkyl; and R.sub.4 represents (Alk).sub.t (X).sub.n Ar, where Alk is an optionally substituted straight or branched alkyl chain, optionally interrupted by an atom or group X, where X is --O--, --S(O).sub.m, or --N(R.sup.b)--, (where R.sup.b is a hydrogen atom or an optionally substituted alkyl group, and m is zero or an integer of value 1 or 2), and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulfur, or nitrogen atoms.
International Patent Application WO 96/36611 discloses compounds of Formula I, wherein R.sub.1 represents C.sub.1-3 alkyl optionally substituted with halogen; R.sub.2 represents optionally substituted C.sub.1

REFERENCES:
patent: 5283352 (1994-02-01), Backstrom et al.

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