Benzocycloheptathiophene compounds

Details Benzocycloheptathiophene compounds Benzocycloheptathiophene compounds

1999-10-29

2001-03-27

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S202000

Reexamination Certificate

active

06207683

ABSTRACT:

TECHNICAL FIELD
This invention relates to new chemical entities as shown below and to methods of treatment of disease states modulated by allergic, inflammatory, or cholinergic activities in a mammal, using said new chemical entities.
The compounds of the invention include chemical entities of the following formula:
where
—A—B— is a moiety having the formula
—CO—CH
2
—  (a)
—CH
2
—CO—  (b)
—CH
2
—CH
2
—  (c)
—CHOH—CH
2
—  (d)
—CHOH—CHOH—  (e)
—CH
2
—CHOH—  (f)
or
—CO—CO—  (g) and
where
R is a hydroxyalkyl or a carboxyalkyloxyalkyl moiety, and the pharmaceutically acceptable salts thereof, and the optically active isomers of the racemic compounds.
The compounds of this inventions have pharmacological properties that render said compounds to be useful in preventing and treating allergies, inflammations, various types of ocular diseases, and different types of smooth muscle hyperreactivity (such as bronchial and uterine hyperreactivity, including drug-induced hyperreactivity).
More particularly, this invention relates to new chemical entities and to methods of treating allergic disorders (such as for example allergic rhinitis), pulmonary disorders (such as for example asthma, bronchitis, cough and bronchial hyperreactivity), skin disorders (such as for example urticaria, psoriasis and atopic dermatitis), gastro-intestinal disorders (such as hypersecretory syndromes including Zollinger-Ellison syndrome, gastric irritation and enteritis) and other inflammatory disorders and/or allergic disorders (such as for example ocular conjunctivitis and ocular keratitis), while avoiding side effects (such as sedation, cardiac arrhythmias and ocular irritation), using said new chemical entities.
The invention also refers to compositions, containing at least one of said new chemical entities and combination of the present compounds with various other chemical entities.
BACKGROUND OF THE INVENTION
This invention relates specifically to anti-inflammatory and anti-allergic compounds, having therapeutic use in various diseases, most importantly for patients suffering from hyperreactive airways and/or obstructive airways diseases, including asthma and bronchitis or from skin disorders and allergies, including urticaria, atopic dermatitis, allergic rhinitis and retinopathy or other small vessel diseases associated with diabetes mellitus or from ocular disorders, including conjunctivitis and keratitis.
The present compounds demonstrate chemical similarities to ketotifen (Zaditen®) and are not previously known to the applicants. Sedative side effects have severely limited the therapeutic usefulness of ketotifen and such side effects can been reduced or eliminated by using the compounds of the present invention.
The pharmacology, toxicology, metabolism and the clinical experience with ketotifen has been summarized by Sorkin et al. (Focus on Ketotifen. Ed. E. M. Sorkin.
In Drugs,
September 1990, Vol. 40, No. 3, pp. 412-448).
SUMMARY OF THE INVENTION
The present invention is concerned with certain new chemical entities as described below, methods of using said chemical entities for therapeutic purposes and compositions comprising one or more pharmaceutically acceptable inert carriers and as active ingredient a therapeutically effective amount of at least one compound, the pharmaceutically acceptable acid addition salts thereof and the stereochemically isomeric forms thereof, having the formula:
where
R is a member selected from the group consisting of hydroxy-C
2-6
alkyl or carboxy-C
1-6
alkyloxy-C
1-6
alkyl and
—A—B— is a moiety having the formula
—CO—CH
2
—  (a)
—CH
2
—CO—  (b)
—CH
2
—CH
2
—  (c)
—CHOH—CH
2
—  (d)
—CHOH—CHOH—  (e)
—CH
2
—CHOH—  (f)
or
—CO—CO—  (g)
Compounds of the present invention have been synthesized and studied pharmacologically. Significant pharmacological differences were found between the compounds of the present invention and ketotifen. Thus, ketotifen has profound sedative side effects while the present compounds have now been found to have reduced or no sedative activity. It has also been established that the new compounds have anti-histaminergic and anti-inflammatory properties. Of importance is that the new compounds have potent pulmonary anti-inflammatory effects and that they potently inhibit bronchial smooth muscle hyperreactivity.
Since pulmonary airway inflammation and bronchial smooth muscle hyperreactivity are the hallmarks of asthma, it is concluded that the new compounds—in additions to being potent antihistamines—will have clinical utility for the treatment of asthma and bronchitis, without concomitant sedative side effects.
DETAILED DESCRIPTION BIOLOGICAL STUDIES OF THE COMPOUNDS OF THE PRESENT INVENTION
As discussed above, it is now shown that the compounds of the present invention have beneficial pharmacological effects, useful in the treatment of various disorders, such as asthma, allergies and ocular disorders. The new findings are described in the following biological studies.
1. Binding to histaminergic receptors
The affinities of the test compounds for histamine H
1
-receptors were assessed using the [
3
H]pyrilamine binding assay, modified after Chang et al. Heterogeneity of Histamine H
1
-Receptors. J. Neurochem. 1979, 32: 1653-1663 Briefly, membranes from bovine cerebellum were incubated with [
3
H]pyrilamine and the test compound at increasing concentrations. The specific binding of the radioactive ligand to the receptor was defined as the difference between total binding and nonspecific binding, determined in the presence of an excess of unlabelled ligand. IC
50
values (concentration required to inhibit 50% of specific binding of [
3
H]pyrilamine) were determined by non linear regression analysis of the competition curves.
IC50 (M)
KETOTIFEN
8.15 × 10−9
NORKETOTIFEN
4.36 × 10−8
10-OH-NORKETOTIFEN
1.13 × 10−7
EXAMPLE 2, where n = 2
5.85 × 10−9
EXAMPLE 5, where n = 2
6.95 × 10−8
TRIPROLIDINE HCl
1.41 × 10−8
(reference compound)
2. Binding to muscarinic receptors
The affinities of the test compounds for muscarinic M
1
-receptors were assessed using the [
3
H]pirenzepine binding assay, modified after Luthin et al. [
3
H]Pirenzepine and [
3
H]QNB binding to brain muscarinic cholinergic receptors. Molec. Pharmac. 1984, 26: 164-169. Briefly, the experiments were carried out on bovine striatal membranes expressing muscarinic M
1
-receptors. After incubation with the test article and the proper radioligand and washing, bound radioactivity is determined with a ligand scintillation counter, using a commercial scintillation cocktail. The specific radioligand binding to each receptor is defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabelled ligand. IC
50
values (concentrations required to inhibit 50% of specific binding) were determined by non linear regression analysis of the competition curves.
IC 5O (M)
KETOTIFEN
7.11 × 10−8
NORKETOTIFEN
2.61 × 10−7
EXAMPLE 2, where n = 2
2.35 × 10−7
EXAMPLE 5, where n = 2
8.80 × 10−7
ATROPINE Sulfate
5.74 × 10−10
(reference compound)
3. Studies on sedative effects
The physostigmine-induced lethality test used in these tests is a modification of the sedation test technique reported by COLLIER et al., in Br. J. Pharmac., 1968, 32: 295-310. In short, physostigmine (1.9 mg/kg s.c.) produces 100% lethality when given to grouped mice with 10 animals in each plastic cage (approx. 11×26×13 cm). Mice administered a sedating antihistamine prior to physostigmine are protected and survive. In the present study, test compounds were administered orally 60 minutes prior to physostigmine. The number of survivors were counted 30 minutes after physostigmine administration. The doses in the

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