Substituted &bgr; diketones and their use

Details Substituted &bgr; diketones and their use Substituted &bgr; diketones and their use

1999-07-01

2001-03-13

Vollano, Jean F (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Sulfur, selenium or tellurium compound

C514S675000, C514S709000, C568S028000, C568S031000

Reexamination Certificate

active

06201027

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to new and known substituted &bgr;-diketones, more precisely, phenyl-methylene-2,4-pentanedione derivatives, to their preparation and use in the prevention and the treatment of respiratory diseases, especially asthma, ARDS (Acute Respiratory Distress Syndrome), COPD (chronic obstructive pulmonary diseases), allergic rhinitis and related inflammatory conditions. More specifically, the invention relates to the use of said compounds in the prevention and the treatment of asthma in steroid-resistant patients. The invention also relates to pharmaceutical formulations used in the treatment of said diseases.
BACKGROUND OF THE INVENTION
Asthma is a chronic inflammatory disease of the airways characterized by eosinophil accumulation into the lung and hyperreactivity of the airways. The disease has a wide spectrum from mild symptoms to deaths. Atopic asthma is an allergic disease where the airways-hyperreactivity is the most typical feature and occurs most often in children. When the disease occurs in older people it is very often so called intrinsic asthma. Characteristic for this subtype of asthma is a more prominent inflammation of the airways than in atopic asthma.
The most effective drugs for asthma today are inhaled corticosteroids. All currently available inhaled steroids are absorbed systemically from the lungs. The most important adverse effect of long term treatment with corticosteroids is the suppression of endogenous cortisol production by adrenals. An ideal drug for asthma would have a powerful anti-inflammatory effect locally at the airways but no systemic effects. A subset of patients with asthma are steroid-resistant. For these patients there is a need for a new drug, which does not act through the same mechanism as corticosteroids but has the same inhibitory effect on the inflammatory cells. Today methotrexate, cyclosporin and immunoglobulin are used for treatment of steroid resistant asthma. These drugs are systemically acting and thus cause serious adverse effects.
EP-A-0 440 324 discloses substituted &bgr;-diketones which are suggested to be useful in the treatment of inflammatory bowel disease (IBD). The compounds of EP-A-0 440 324 were tested using the so called TNB-induced chronic colitis model in rats. The most promising compound OR 1364 (3-[(3-cyanophenyl)methylene]-2,4-pentanedione) has been extensively studied in the treatment of IBD and taken to clinical trials. Unfortunately, the trials had to be discontinued because the compound was found to be irritating.
SUMMARY OF THE INVENTION
The invention is directed to a new type of locally acting, nontoxic, medicament for the prevention and treatment of respiratory diseases, especially asthma. The compounds of the invention are new, except for 3-[(4-methylsulfonylphenyl)methylene]-2,4-pentanedione), the use of which in the treatment of inflammatory bowel disease has been disclosed earlier in EP-A-0440324.
Accordingly, the invention provides a compound of general formula I:
wherein one of X
1
and X
2
is MeSO
2
and the other one is halogen and X
3
is hydrogen or halogen.
The invention further provides a method for the use of compounds of general formula I′ to prevent or treat respiratory diseases:
wherein, in formula I′, one of X
1
and X
2
is MeSO
2
and the other one is hydrogen or halogen and X
3
is hydrogen or halogen. Most preferable in this indication are the compounds of formula I (I′) wherein X
1
is halogen, X
2
is MeSO
2
and X
3
is hydrogen. Especially preferably X
1
is chloro.
The invention further provides a method for the manufacture of a medicament for use in the treatment of respiratory diseases.
The invention also provides new, valuable intermediates having formula II′:
wherein one of X
1
and X
2
is MeSO
2
and the other one bromo or fluoro and X
3
is hydrogen or halogen, and methods for their use.


REFERENCES:
patent: 4741769 (1988-05-01), Lee
patent: 5292771 (1994-03-01), Backstrom et al.
patent: 5804532 (1998-09-01), Cain et al.
patent: 37 40 383 A1 (1988-06-01), None
patent: 0 323 162 A2 (1989-07-01), None
patent: 0 440 324 A2 (1991-08-01), None
patent: 0 357 403 B1 (1994-12-01), None
patent: 62-30767 (1987-02-01), None
CA:130:234068 abs of WO9915168, Apr. 1999.
CA:128:289576 ags of Drugs Future by Wrobleski et al, 23(1) pp. 28-31, 1998.
Aho, P. et al., abstract of presentation entitled “Protection in Rat Colitis Models by the Sulfhydryl Modulating Compound OR-1364,” Falk Symposium No. 67, “Inflammatory Bowel Diseases—Pathophysiology as Basis of Treatment”, in Regensburg, Germany, Jun. 25-27, 1992.
Aho, P. et al., poster presentation entitled “Protection in Rat Colitis Models by the Sulfhydryl Modulating Compound OR-1364,” Falk Symposium No. 67, “Inflammatory Bowel Diseases—Pathophysiology as Basis of Treatment”, in Regensburg, Germany, Jun. 25-27, 1992.
Aho, P. et al., abstract of presentation entitled “The Sulfhydryl Modulating Compound OR-1364 Protects Against Free Radical Induced Colitis in Rats,” American Gastroenterological Association Conference in Boston, MA, May 15-19, 1993.
Aho, P. et al., poster presentation entitled “The Sulfhydryl Modulating Compound OR-1364 Protects Against Free Radical Induced Colitis in Rats,” American Gastroenterological Association Conference in Boston, MA, May 15-19, 1993.
Aho, P. et al., abstract of presentation entitled “Protection in Rat Colitis Models by the Sulfhydryl Modulating Compound OR-1364,” 26thNordic Meeting of Gastroenterology in Tampere, Finland, May 26-29, 1993.
Aho, P. et al., abstract of presentation entitled “OR-1364 inhibits the Development of Immune Complex Colitis in Rabbits,” American Gastroenterology Association Digestive Disease Week in New Orleans, LA, May 15-18, 1994.
Aho, P. et al., poster presentation entitled “OR-1364 Inhibits the Development of Immune Complex Colitis in Rabbits,” American Gastroenterology Association Digestive Disease Week in New Orleans, LA, May 15-18, 1994.
Aho, P., et al., abstract of presentation entitled “Protection Against Immune Complex-Induced Colitis in Rabbits by OR-1364,” 3rdUnited European Gastroenterology Week in Oslo, Norway, Jun. 25-29, 1994.
Aho, P., et al., poster presentation entitled “Protection Against Immune Complex-Induced Colitis in Rabbits by OR-1364,” 3rdUnited European Gastroenterology Week in Oslo, Norway, Jun. 25-29, 1994.
Aho, P. et al., abstract of presentation entitled “OR-1364, A Novel Locally Acting Compound for the Treatment of Inflammatory Bowel Diseases,” Falk Symposium No. 85, “Inflammatory Bowel Diseases,” in Den Haag, The Netherlands, Jun. 29-Jul. 1, 1995.
Aho, P. et al., “Hapten-Induced Murine Colitis—A Useful Model For Studying Tissue Levels of Cytokines,”Gastroenterology110:A852 (1996).
Aho, P. et al., abstract of presentation entitled “OR-1384, A Novel Locally Acting Immunomodulating Agent, Protects Against Experimental Colitis,” Annual Meetings of the American Gastroenterological Association, American Association for the Study of Liver Diseases, May 11-14, 1997.
Heinonen, T. et al., abstract of presentation entitled “Simulation of In Vivo Conditions in Cell Culture by Coculturing Techniques,” The 15thAnniversary Meeting of the Finnish Society of Toxicology in Kuopio, Finland, Apr. 22-23, 1994.
Heinonen, T. et al., poster presentation entitled “Simulation of In Vivo Conditions in Cell Culture: Epithelial Cell Monolayers Cultured on Permeable Support,” The 15thAnniversary Meeting of the Finnish Society of Toxicology in Kuopio, Finland, Apr. 22-23, 1994.
Koponen, A. et al., abstract of presentation entitled “Protection Against Immune Complex-Induced Colitis in Rabbits by OR-1364,” Falk Symposium No. 76, “Inflammatory Bowel Diseases: New Insights into Mechanisms of Inflammation and Challenges in Diagnosis and Treatment,” in Cascais, Portugal, May 5-7, 1994.
Koponen, A. et al., poster presentation entitled “Protection Against Immune Complex-Induced Colitis in Rabbits by OR-1364,” Falk Symposium No. 76, “Inflammatory Bowel Diseases: New Insights into Mechanisms of Inflammat

Affiliated with

Also associated with

Rating

Substituted &bgr; diketones and their use does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted &bgr; diketones and their use, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted &bgr; diketones and their use will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2442761