SK4922002A3 - Imidazole derivative as phosphodiesterase vii inhibitor, use thereof and pharmaceutical composition containing the same - Google Patents

Abstract

The invention relates to imidazole derivatives of formula (I), wherein R<1> means H, A, benzyl, indane-5-yl, 1,2,3,4-tetrahydro-naphthaline-5-yl, dibenzothiophene-2-yl or phenyl that is unsubstituted or substituted once, twice or three times by means of Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA, R<2> means H or A, X means O or S, Hal means F, Cl, Br or I and A means alkyl with 1 to 6 C-atoms. The invention also relates to the physiologically acceptable salts and/or solvates thereof acting as phosphodiesterase VII inhibitors. The invention further relates to the use thereof for producing a medicament.

Description

An imidazole derivative as a phosphodiesterase VII inhibitor, its use and a pharmaceutical composition containing it

Technique ??

The invention relates to imidazole derivatives of the formula I

where it means

R ^{@ 1} is hydrogen, A, benzyl, indan-5-yl,

1,2,3,4-tetrahydronaphthalen-5-yl, dibenzothiophen-2-yl or phenyl which is unsubstituted or is monosubstituted, disubstituted or trisubstituted with Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA

R ² is H or A,

X is an oxygen or sulfur atom,

Hal is fluorine, chlorine, bromine or iodine,

And an alkyl group having 1 to 6 carbon atoms, and physiologically acceptable salts and / or solvates thereof, as well as phosphodiesterase VII inhibitors.

BACKGROUND OF THE INVENTION

Benzopyranoimidazoles have been described, for example, by M. Trkovnik et al. (Org. Prep. Proced. Int. 19 (6): 450-455, 1987) or V.L. Savelev et al. (Khin. Farm. Zh. 17 (6): 697-700 (1983)). Benzopyranoimidazole derivatives have been described, for example, by V.L. Savelev et al. (Khim. Geterotsikl. Soedin. (4), pp. 479-483, 1980).

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds with valuable properties, in particular compounds which can be used for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention provides imidazole derivatives of the formula I as defined above and their physiologically acceptable salts or solvates as well as phosphodiesterase VII inhibitors.

The invention further relates to the use of the compounds of formula I for the manufacture of a medicament for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory disorders, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes. or ulcerative colitis, for the treatment of osteoporosis, transplant rejection, disease weight loss, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

It has been surprisingly found that the compounds of the formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they exhibit specific inhibition of rolipram insensitive cAMP phosphodiesterase (PDE VII).

The biological activity of the compounds of formula I can be determined by methods described, for example, by M.A, Giembycz et al. (Br. J. Pharmacol. 118: 1945-1958, 1996). The affinity of compounds for αAMP phosphodiesterase (PDE VII) is determined by measuring their IC 50 values (inhibitor concentration required to achieve 50% inhibition of enzyme activity).

The assay is performed using homogenized SK-N-SH neuroblastoma cells instead of T cells and CI930 is used to inhibit PDE III. CI-930 is a selective PDE III inhibitor (J.A. Bristol et al., J. Med. Chem. 27 (9), pp. 1099-1101, 1984).

The compounds of formula I can be used to treat asthmatic diseases. The antiasthmatic effect can be determined, for example, in a manner similar to that described by T. Olson (Acta allergologica 26, 438-447, 1971).

Since aAMP inhibits osteoclast cells and stimulates osteoblast cells (S. Kasugai et al., M 681 and K. Miyamoto, M 682 in Abstracts of the American Soil for Bone and Mineral Research 18th Annual Assembly 1996), the compounds of formula I may be used to treat osteoporosis.

The compounds further show an antagonistic effect on the production of TNFα (tumor necrosis factor) and are thus suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis,

Crohn's disease, diabetes mellitus or ulcerative colitis, for graft rejection, for the treatment of disease weight loss and sepsis.

The anti-inflammatory activity of the compounds of formula I and their efficacy in the treatment of, for example, autoimmune diseases such as multiple sclerosis and rheumatoid arthritis can be ascertained by the methods described by N.Sommer et al. (Nature

Medicine 1, p. 244-248 (1995) or L. Sekut et al. (Clin. Exp. Immunol. 100: 126-132, 1995).

The compounds may be used to treat diseased debilitating (cachexia). The efficacy against disease exhaustion can be tested in TNF-dependent cachexia models (P. Costelli et al., J. Clin. Invest 95, from p. 2367, 1995; JM Arailes et al., Med. Res. Rev. 17, p. 477 (1997).

PDE VII inhibitors may also inhibit the growth of tumor cells and will therefore go on to tumor therapy (for PDE IV inhibitors, D. Marko et al., Cell Biochem. Biophys, 28, p. 75, 1998).

Further, they can be used to treat sepsis and to treat memory disorders, atherosclerosis, atopic dermatitis and AIDS as well as to treat T-cell dependent diseases (L. Li et al. Science 283, 848-851, 1999).

The invention further relates to the use of phosphodiesterase YII inhibitors for the manufacture of a medicament for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory disorders, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, diabetes mellitus or Crohn's disease. ulcerative colitis, osteoporosis, transplant rejection, disease weight loss, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

The compounds of formula I can be used as pharmaceutical active ingredients for inhibiting PDE VII in human and veterinary medicine.

In formula (I), A is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms and preferably methyl, ethyl or propyl, also preferably isopropyl, butyl, isobutyl, sec-butyl, tert-butyl but also an n-pentyl, neopentyl, isopentyl or hexyl group. A also represents a cycloalkyl group, for example a cyclohexyl group.

Alkoxy is preferably methoxy, ethoxy, propoxy or butoxy.

The symbol Hai is preferably a fluorine or chlorine atom.

The A-CO-NH group is preferably acetamido.

The base of formula (I) can be converted into the appropriate acid addition salt by acid, for example by reaction of an equivalent amount of base and acid in an inert solvent such as ethanol and subsequent evaporation of the solvent. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids may be used, especially aliphatic, alicyclic, araliphatic, aromatic or heteroaryl monohydric or polybasic carboxylic, sulfonic acids or sulfuric acids such as formic, acetic, propionic, succinic, pimelic, malic, citric, pivalic, diethylootic, malonic, fumaric, maleic, lactic, tartaric, gluconic, ascorbic, nicotinic, isonicotinic, ethanesulfonic, methanesulfonic, methanesulfonic, -hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I.

The invention further relates to pharmaceutical compositions comprising as well as at least one phosphodiesterase VII inhibitor a compound of the formula I or a physiologically acceptable salt and / or solvate thereof for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory disorders, autoimmune diseases. diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, for the treatment of osteoporosis, transplant rejection, disease loss, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and

AIDS.

The compounds of the formula I according to the invention are generally administered in a dose of approximately 1 to 500 mg, in particular 5 to 100 mg per dosage unit. The daily dose is preferably about 0.02 to 10 mg / kg body weight. The specific dose for each individual depends on a variety of factors, such as the efficacy of a particular compound used, age, body weight, general health, sex, diet, time and route of administration, excretion rate, drug combination and severity of the disease. . Oral administration is preferred.

The pharmaceutical compositions can be used as well as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration or for administration in the form of inhalation sprays and which do not react with compounds of formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, suspensions or drops, suppositories for rectal use, solutions for parenteral use, especially oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents or one or more other active ingredients. such as vitamins.

In particular, the invention relates to the compounds of the formula I shown in the following examples and their physiologically acceptable salts or solvates as well as PDE VII inhibitors and their use for the manufacture of pharmaceutical compositions for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases. inflammatory disorders, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, for the treatment of osteoporosis, graft rejection, disease weight loss, tumor growth or tumor metastasis, and sepsis, sepsis, sepsis, sepsis.

The invention is illustrated by the following examples.

Examples

1-phenyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one

1-benzyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one

1-Cyclohexyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1-Cyclopentyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1-Butyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1-isopropyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one

1-propyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one

1-ethyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one

1-Methyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

2-Methyl [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1-phenyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

1-benzyl [1] benzothiopyran [3,4-d] imidazol-4- (1H) -one

1-Cyclohexyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1-cyclopentyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one, 1- butyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

1-isopropyl [l] benzothiopyran [3,4-d] imidazol-4- (1H) -one

1-propyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

1-Ethyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

1-Methyl [1] benzothiopyrano [3,4-d] imidazole-4- (1H), [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

2-Methyl [1] benzothiopyrano [3,4-d] imidazol-4- (1H) -one,

1- (2-chlorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1 H) -one,

1- (4-Methylphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1- (4-fluorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1 H) -one,

1- (2,4-Dimethylphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (3-chlorophenyl) [1] benzopyrano [3,4-d] imidazole- 4 (1H) -one

1- (2,4-Dichlorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,5-dichlorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-acetamidophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2-fluorophenyl) [1] benzopyrano [ 3,4-d] imidazol-4- (1H) -one

1- (3-fluorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1 H) -one,

1- (2-Benzyloxyphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,6-dimethylphenyl) [1] benzopyrano [3,4-d] imidazole- 4- (1H) -one, 1- (indan-5-yl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1- (2-Methoxyphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1- (2,3-Dimethylphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (2,3-dichlorophenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (3-chloro-4-methylphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one,

1- (2,5-dimethylphenyl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (4-chlorophenyl) [1] benzopyrano [3,4-d] imidazole- 4- (1H) -one, 1- (1,2,3,4-tetrahydronephthalen-5-yl) [1] benzopyrano [3,4d] imidazol-4- (1H) -one,

1- (dibenzothiophen-2-yl) [1] benzopyrano [3,4-d] imidazol-4- (1H) -one, 1- (3-methoxyphenyl) 11] benzopyrano [3,4-d] imidazole-4 - (1 H) -one

1- (4-carboxy-2-methylphenyl) [1] benzopyrano [3,4-d] imidazole-4 (1H) -one

The following examples illustrate pharmaceutical compositions:

Example A

Injection ampoules

A solution of 100 g of a phosphodiesterase VII inhibitor of formula I and 5 g of disodium hydrogen phosphate in 3 L of two times distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and filled into injection vials, lyophilized under sterile conditions and the sterile vials are sealed. Each vial contains 5 mg of active ingredient.

Example B

suppository

A mixture of 20 g of a phosphodiesterase VII inhibitor of formula I is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C

solution

A solution of 1 g of a compound of formula I as a phosphodiesterase VII inhibitor, 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double distilled water is prepared. The pH of the solution is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used as eye drops.

Example D.

ointment

500 mg of a phosphodiesterase VII inhibitor compound of formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

From a mixture of 1 kg of a compound of formula I as a phosphodiesterase VII inhibitor, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate, tablets are compressed in a conventional manner such that each tablet contains 10 mg of the active substance.

Example F

dragee

Analogously to Example E, tablets are compressed and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G

The capsules

In a manner known per se, 2 kg of a compound of formula I as a phosphodiesterase VII inhibitor are filled into hard gelatin capsules such that each capsule contains 20 mg of the active ingredient.

Example H

ampoules

A solution of 1 kg of a phosphodiesterase VII inhibitor compound of formula I in 60 L of double-distilled water is sterile filtered and filled into ampoules, lyophilized under sterile conditions and the ampoules sealed. Each ampoule contains 10 mg of active ingredient.

Example I

Inhalation spray

Dissolve 14 g of a compound of formula I as a phosphodiesterase VII inhibitor in 10 l of isotonic sodium chloride solution and fill into conventional commercial spray canisters with a pump mechanism. The solution may be sprayed into the mouth or nose. Each spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Industrial Applicability

The imidazole derivative and pharmaceutically acceptable salts and / or solvates thereof as phosphodiesterase VII inhibitors for the manufacture of pharmaceutical compositions.

Claims (4)

PATENT CLAIMS What is claimed is: 1. A compound of the formula (I) EMI3.0 wherein: is R ^{@ 1} is hydrogen, A, benzyl, indan-5-yl, 1,2,3,4-tetrahydronaphthalen-5-yl, dibenzothiophen-2-yl or phenyl which is unsubstituted or is monosubstituted, disubstituted or trisubstituted with Hal, A, A-CO-NH, benzyloxy, alkoxy, COOH or COOA. R ² is H or A, X is an oxygen or sulfur atom, Hal is fluorine, chlorine, bromine or iodine, And an alkyl group having 1 to 6 carbon atoms, and physiologically acceptable salts and / or solvates thereof as phosphodiesterase VII inhibitors. Pharmaceutical composition, characterized in that it contains as inhibitors of phosphodiesterase VII at least one compound of the formula I according to claim 1 and / or a physiologically acceptable salt thereof. Use of the compounds according to claim 1 and / or their physiologically acceptable salts and / or solvates for the manufacture of pharmaceutical compositions for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory disorders, autoimmune diseases such as are, for example, rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes mellitus or ulcerative colitis, for the treatment of osteoporosis, transplant healing, disease wasting, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS. 4. Use of phosphodiesterase VII inhibitors for the manufacture of pharmaceutical compositions for the treatment of allergic disorders, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory disorders, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis or diabetes mellitus, Crohn's disease colitis, for the treatment of osteoporosis, transplant healing, disease wasting, tumor growth or tumor metastasis, sepsis, memory impairment, atherosclerosis, and AIDS.