Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-07
2003-04-08
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06544983
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of diazepinoindoles for the treatment of chronic obstructive pulmonary disease (hereinafter COPD).
TECHNICAL BACKGROUND OF THE INVENTION
COPD is a chronic, slowly progressive disorder characterized by airflow obstruction (associated with airways inflammation and an important neutrophil content). Most of the lung function impairment is fixed (although some reversibility can be produced by bronchodilator therapy). This disease will be referred to as COPD, although a number of clinical terms have been used in the past, either alone or in combination. These terms include emphysema, chronic bronchitis, chronic airflow limitation, chronic airways obstruction, non-reversible obstructive airways disease, chronic obstructive airways disease and chronic obstructive lung disease.
The clinical presentation of COPD can vary in severity from simple chronic bronchitis without disability to the severely disabled state with chronic respiratory failure. The major clinical features of patients suffering from COPD are chronic bronchitis and/or emphysema (associated with airways inflammation and/or an important neutrophil content).
Although the known prevalence of COPD is not complete, it can be ascertained that COPD is the fourth leading cause of death in developed countries, especially in the USA. Also, the problem of COPD is expected to grow, both in the developed western countries and in other countries in the coming years. A 3-fold increase is predicted to occur in the next ten years in the East Asia countries, as a large proportion of the male population is smoking.
Thus, there is a need for an efficient treatment of COPD.
In the past years, second-generation selective phosphodiesterase 4 inhibitors (PDE4 inhibitors) have been proposed as a potentially efficient treatment in COPD. See inter alia Doherty,
Current Opinion in Chemical Biology
1999, 3:466-473; Mohammed et al,
Anti
-
inflammatory
&
Immunomodulatory Investigational
Drugs 1999 1(1):21-28; Schmidt et al.,
Clinical and Experimental Allergy,
29, supplement 2, 99-109.
Cilomilast (Ariflo®), an orally active PDE4 inhibitor, has been proposed as a treatment for COPD. See inter alia: Nieman et al,
Am J Respir Crit Care Med
1998, 157:A413; Underwood et al,
Eur Respir J
1998, 12:86s; Compton et al,
Am J Respir Crit Care Med
1999, 159:A522. See also the oral presentations at the European Respiratory Society Meeting, Madrid, Oct. 12, 1999, by Compton, and at the 4
th
World Congress on Inflammation, Paris, Jun. 27-30, 1999, by Torphy and Underwood. This compound is currently in phase III clinical trials for COPD.
However, the use of cilomilast for treating COPD presents some drawbacks. It has been reported that when cilomilast is given at a single dose of 20 mg, relevant side effects such as nausea and vomiting occurred. See Murdoch et al,
Am J Respir Crit Care Med
1998, 157:A409. Side effects appearing at such low dose will limit the application of cilomilast and will prevent daily single dosage forms, thus leading to patient discomfort.
SUMMARY OF THE INVENTION
The present invention proposes the use of a certain class of diazepinoindoles known as PDE4 inhibitors for the treatment of COPD. These compounds are devoid of adverse side effects, notably on the heart or digestive system (see Burnouf et al,
Journal of medicinal chemistry
(2000), 43:4850-4867), and are more efficient than cilomilast at lower doses.
The invention relates to the use of [1,4]diazepino[6,7,1-hi]indoles of formula (I)
in which:
A is aryl or nitrogen-containing heteroaryl, each optionally being substituted with one to three groups chosen independently from halogen, lower alkyl, lower haloalkyl, lower alkoxy, cycloalkyloxy, amino and lower alkylcarbonyl-amino or alkyloxycarbonylamino;
B is a hydroxyl or amino radical, itself optionally substituted,
or a pharmaceutically acceptable salt thereof,
for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease or COPD.
The invention also provides a method for the treatment of COPD comprising administering to a human in need thereof an effective amount of a diazepinoindole of formula I.
These compounds, their use as PDE4 inhibitors and their preparation processes are disclosed in WO 97/36905, the content of which is incorporated herein by reference. These diazepinoindoles will be used in the invention as the active ingredient.
REFERENCES:
patent: 5082937 (1992-01-01), Calvet et al.
patent: 5852190 (1998-12-01), Pascal et al.
patent: 5972927 (1999-10-01), Pascal et al.
patent: 6239130 (2001-05-01), Pascal et al.
patent: WO 97/36905 (1997-10-01), None
Doherty, “Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents”,Current Opinion in Chemical Biology, vol. 3, 1999, pp 466-473.
Mohammed and Young, “Clinical aspects and treatment of chronic obstructive pulmonary disease”,Current Opinion in Anti-inflammatory&Immunomodulatory Investigational Drugs, vol. 1, No. 1, 1999, pp 21-28.
Schmidt et al., “Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease”,Clinical and Experimental Allergy, vol. 29, Supplement 2, 1999, pp 99-109.
Nieman et al., “SB 207499 (Ariflo™), A Second-Generation, Selective Oral Phosphodiesterase Type 4 (PDE4) Inhibitor, Attenuates Exercise Induced Bronchoconstriction in Patients With Asthma”,Am. J. Respir. Crit. Care Med., vol. 157, No. 3, 1998, p A413.
Underwood et al., “The Second Generation Phosphodiesterase (PDE)4 Inhibitor, SB 207499, Inhibits Antigen-Induced Bronchoconstriction and Eosinophilia and LPS-Induced Airway Neutrophilia and Edema in the Guinea Pig”,Eur. Respir. J., vol. 12, Suppl. 29, 1998, p 86s.
Compton et al., “Ariflo™(SB 207499), A Second Generation, Oral PDE4 Inhibitor, Improves Quality of Life in Patients with COPD”,Am. J. Respir. Crit. Care Med., vol. 159, No. 3, 1999, p A522.
Murdoch et al., “The Safety and Tolerability of Ariflo™(SB 207499), A Novel & Selective Phosphodiesterase 4 Inhibitor, in Healthy Male Volunteers”,Am. J. Respir. Crit. Care Med., vol. 157, No. 3, 1998, p A409.
Burnouf et al., “Synthesis Structure-Activity Relationships, and Pharmacological Profile of 9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indoles: Discovery of Potent, Selective Phosphodiesterase Type 4 Inhibitors”,J. Med. Chem., vol. 43, No. 25, 2000, pp 4850-4867.
Barnes, “Chronic obstructive pulmonary disease: new opportunities for drug development”,TIPS, vol. 19, 1998, pp 415-423.
Leckie et al., “Novel therapy for COPD”,Expert Opinion on Investigational Drugs, vol. 9, No. 1, 2000, pp 3-23.
Pruniaox, “Novel Generation Phosphodiesterase 4 Inhibitors for the Treatment of Asthma”PDE Inhibitors: Drugs with an expanding range of therapeutic uses (Nice, France), William Harvey Research Conference Abstract, vol. 21, p. 20 (1999).
Benson Gregg C.
Henley III Raymond
Pfizer Inc
Richardson Peter C.
Ronau Robert T.
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