HK1051364A - Imidazole compounds used as phosphodiesterase vii inhibitors - Google Patents

Description

Imidazoles as phosphodiesterase VII inhibitors

The present invention relates to imidazole compounds of formula I and physiologically acceptable salts and/or solvates thereof.Wherein R is¹And R²Independently of one another, each represents A¹、OA¹、SA¹Or Hal, A¹Represents H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A represents alkyl having 1 to 10 carbon atoms, Hal represents F, Cl, Br or I, and X represents O, S, SO or SO₂

Other imidazole derivatives have been disclosed, for example, by m.trkovnik et al in org.prep.proced.int. (1987), 19(6), 450-5, or by v.l.savel' ev et al in khim. -farm.zh. (1983), 17(6), 697-700. Benzothiopyrazole derivatives have been disclosed, for example, by V.L.Savel' ev et al in Khim.Getertisikl.Soedin. (1980), (4), 479-83.

The object of the present invention is to find new compounds with useful properties, in particular those which can be used for the preparation of medicaments.

It has been found to date that the compounds of formula I and their salts have very valuable pharmacological properties and are well tolerated. In particular, they show a specific inhibition of "rolipril (Rolipram) insensitive" cAMP phosphodiesterase (PDE VII).

The biological activity of the compounds of formula I can be determined, for example, by the methods described in m.a.giembycz et al, br.j.pharmacol. (1996), 118, 1945-1958. The affinity of said compounds for cAMP-phosphodiesterase (PDE VII)The sum force can be measured by measuring its IC₅₀Values (inhibitor concentration required to obtain 50% inhibition of enzyme activity). For the assay, homogenized SK-N-SH neuroblastoma cells were used in place of T lymphocytes and PDE III inhibition was performed using CI-930. This is a selective PDE III inhibitor (j.a. bristol et al, j.med. chem.1984, 27(9), 1099-1101). Alternatively, the SK-N-SH is replaced by HUT-78 and the CI-930 is replaced by Ququizalin (trequestin) for inhibition (D.Ruppert et al, Life Sci.31: 2037, 1982).

The compounds of formula I are useful for the treatment of asthma. Anti-asthmatic effects can be determined, for example, according to a method similar to that described by T.Olsson in Acta allergologica 26, 438-447 (1971).

Since cAMP inhibits osteoclasts and stimulates osteoblasts (S.Kasugai et al, M681)&Miyamoto, M682, published in Abstracts of the American Society for Bonneand Mineral Research, 18^thAnnual Meeting, 1996), the compounds of formula I can be used to treat osteoporosis.

The compounds also exhibit an antagonistic effect on the production of TNF α (tumour necrosis factor) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, crohn's disease, diabetes or ulcerative colitis, transplant rejection, cachexia and sepsis.

The anti-inflammatory effects of the substances of formula I and their effectiveness in the treatment of, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis, can be determined according to methods similar to N.Sommer et al, Nature medicine 1, 244-248(1995), or L.Seku et al, Clin.exp.Immunol.100, 126-132 (1995).

The compounds may be used to treat cachexia. Anti-cachexia effects can be tested in a TNF-dependent cachexia model (p. costelli et al, j. clin. invest.95, 2367ff. (1995); j.m. arms et al, med. res. rev.17, 477ff. (1997)).

PDE VII inhibitors may also inhibit the growth of tumor cells and are thus suitable for tumor therapy (for PDE IV inhibitors see d. marko et al, Cell biochem. biophysis.28, 75ff. (1998)).

They can further be used in the treatment of sepsis and in the treatment of memory disorders, atherosclerosis, atopic dermatitis and AIDS, but also in the treatment of T-cell dependent diseases (L.Li et al, Science, 1999, 283, 848-851).

The compounds of formula I can be used as pharmaceutically active ingredients in human and veterinary medicine. They can also be used as intermediates for the preparation of other pharmaceutically active ingredients. In particular, the compounds of formula I can be used as pharmaceutically active ingredients for the inhibition of PDE VII in humans and veterinary medicine.

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

A represents an alkyl group having 1 to 10 carbon atoms and having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably represents a methyl, ethyl or propyl group, more preferably an isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group, and may also represent an n-pentyl, neopentyl, isopentyl or hexyl group. In these radicals, 1 to 7H atoms can also be replaced by F and/or Cl. Thus A also represents, for example, trifluoromethyl or pentafluoroethyl. Cycloalkyl has 3 to 9 carbon atoms and preferably represents, for example, cyclopentyl or cyclohexyl. Alkenyl has 2 to 10 carbon atoms, is straight-chain or branched and preferably represents ethenyl, propenyl or butenyl. The alkylenecycloalkyl group has 4 to 10 carbon atoms and represents, for example, methylenecyclopentyl, ethylenecyclopentyl, methylenecyclohexyl or ethylenecyclohexyl. R¹And R²In each case independently of one anotherIs selected from H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, methylthio, cyclopentyl or cyclohexyl.

The invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the following formulae Ia to Ig, which correspond to formula I and in which the radicals not specified in more detail have the meanings indicated in formula I, but in which: x in Ia represents S; in Ib X represents S, and the formula I is shown in the specification,

R¹represents H; in Ic X represents S, and in Ic,

R¹represents F or Cl; in Id, X represents S and X represents S,

R²represents H; in Ie X represents S and X represents S,

R²represents F or Cl; in If X represents S, the ratio of X to S,

R¹represents a compound of formula (I) or (II),

R²represents F or Cl; in Ig, X represents S, and X represents S,

R¹represents F or Cl;

R²represents H; in Ih X represents S,

A¹represents a group of formula (I) wherein R represents H or A,

a represents an alkyl group having 1, 2, 3 or 4 carbon atoms; in Ii X represents S and X represents S,

R¹and R²Independently of one another, each represents A¹Or a Hal (hydrogen-to-oxygen) compound,

A¹represents a group of formula (I) wherein R represents H or A,

a represents an alkyl group having 1, 2, 3 or 4 carbon atoms,

hal represents F or Cl; and their physiologically acceptable salts or solvates.

The present invention relates to compounds of formula I and a process for the preparation of compounds of formula I as claimed in claim 1And salts thereof, characterized in that a compound of formula II:wherein R is¹，R²And X is as defined above, and L represents Cl, Br, OH, SCH₃Or reacting the reactive esterified OH group with imidazole and/or converting the compound of formula I into one of its salts.

Furthermore, the compounds of the formula I and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example in standard works, such as Houben-Weyl, methods of organic chemistry (Methoden der organischen Chemie), Georg-Thieme-Verlag, Stuttgart), precisely under conditions which are known and suitable for this reaction. Modifications of these schemes, which are known per se but not described in detail herein, may also be employed.

In the compounds of the formula II, R¹，R²And X has the stated meanings, in particular the preferred meanings stated.

If L represents a reactive esterified OH group, this is preferably an alkylsulfonyloxy group having from 1 to 6 carbon atoms (preferably a methylsulfonyloxy group) or an arylsulfonyloxy group having from 6 to 10 carbon atoms (preferably a phenyl-or p-tolylsulfonyloxy group, and also a 2-naphthalenesulfonyloxy group).

The starting compounds of the formula II are generally known compounds. If they are unknown compounds, they can be prepared by methods known per se.

The compounds of the formula II can be prepared by methods known from the literature, for example by reduction of the corresponding carbonyl precursors using complex metal hydrides.

In detail, the reaction of the compound of formula II with imidazole is carried out at a temperature of about-20 ℃ to about 150 ℃, preferably 20 ℃ to 100 ℃, with or without an inert solvent.

The addition of an acid binding agent, such as an alkali or alkaline earth metal hydroxide, an alkali or alkaline earth metal carbonate or bicarbonate or another salt of a weak acid, preferably potassium, sodium or calcium; or the addition of an organic base, such as triethylamine, dimethylamine, pyridine or quinoline, is advantageous.

Examples of suitable inert solvents are: hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, isopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, ethylene glycol monomethyl ether or monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone or Dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; or mixtures of said solvents.

The base of formula I may be converted to the relevant acid addition salt with an acid, for example by reaction of an equivalent amount of the base with the acid in a suitable solvent such as ethanol, followed by evaporation. Acids suitable for this reaction are in particular those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, cycloaliphatic, araliphatic, aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and naphthalenedisulfonic acid, dodecylsulfuric acid. Salts with physiologically unacceptable acids, such as picrates, can be used to isolate and/or purify the compounds of formula I.

The invention also relates to the use of the medicaments of formula I and the physiologically acceptable salts thereof as phosphodiesterase VII inhibitors.

The invention further relates to pharmaceutical preparations containing at least one phosphodiesterase VII inhibitor of the formula I and/or one of its physiologically acceptable salts and/or solvates for the treatment of allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes or ulcerative colitis, osteoporosis, transplant rejection, cachexia, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

The substances according to the invention are generally suitable for administration in a dosage of about 1 to 500mg, in particular 5 to 100mg, per dosage unit. The daily dosage is preferably about 0.02-10mg/kg body weight. However, the specific dose for each patient will depend upon a variety of factors such as the potency of the specific compound employed, the age, body weight, general health, sex, diet, time and method of administration, rate of excretion, drug combination and the severity of the particular disease for which the treatment is intended. Oral administration is preferred.

The pharmaceutical formulation may be used as a medicament in humans or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and with which the novel compounds are not reactive, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates (e.g. lactose or starch), magnesium stearate, talc, vaseline. Particularly suitable for oral administration are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops; suitable for rectal administration are suppositories; suitable for parenteral administration are solutions, preferably oil or aqueous solutions, and suspensions, emulsions or implants; suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilized, the resulting lyophilizates being used, for example, for the preparation of injectable preparations. The formulations may be sterilized and/or contain adjuvants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for regulating the osmotic pressure, buffer substances, dyes, flavorings and/or various other active ingredients, such as one or more vitamins.

The invention relates in particular to the compounds of the formula I and their physiologically acceptable salts and/or solvates, which are listed in the examples below, as PDE VII inhibitors and their use for the preparation of a medicament against: allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes or ulcerative colitis, osteoporosis, transplant rejection, cachexia, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

Examples 10-chloro-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 4-chloro-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-methoxy-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-propoxy-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-methylthio-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-fluoro-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 4, 10-dichloro-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-trifluoromethyl-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 4-cyclopentyloxy-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine, 10-chloro-3-imidazol-1-yl-2, 3-dihydro-1H-7-oxa-11 b-azabenzo [ de ] anthracene, 10-chloro-3-imidazol-1-yl-2, 3-dihydro-1H-pyrido [3, 2, 1-kl ] phenothiazine 7, 7-dioxide. Preparation examples:

the compounds of formula I are prepared according to a reaction scheme analogous to that below:the following examples relate to pharmaceutical formulations:

example A: injection bottle

A solution of 100g of the phosphodiesterase VII inhibitor of the formula I and 5g of disodium hydrogenphosphate in 3L of double distilled water is brought to pH 6.5 with 2N hydrochloric acid, sterile-filtered, transferred to an injection vial, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection bottle contains 5mg of active ingredient.

Example B: suppository

20g of a mixture of phosphodiesterase VII inhibitors of the formula I are melted together with 100g of soya lecithin and 1400g of cocoa butter, poured into a mould and allowed to cool. Each suppository contains 20mg of active ingredient.

Example C: solutions of

1g of phosphodiesterase VII inhibitor of the formula I, 9.38g of NaH₂PO₄·2H₂O、28.48g Na₂HPO₄·12H₂O and 0.1g benzalkonium chloride were dissolved in 940ml double distilled water to prepare a solution. The pH was adjusted to 6.8 and the solution was brought to 1L and sterilized by irradiation. The solution may be used in the form of eye drops.

Example D: ointment

500mg of a phosphodiesterase VII inhibitor of the formula I are mixed under sterile conditions with 99.5g of vaseline.

Example E: tablet formulation

A mixture of 1kg of a phosphodiesterase VII inhibitor of the formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in the usual manner into tablets, each containing 10mg of active ingredient. Example F: coated tablet

Tablets were compressed in a manner analogous to example E and subsequently coated in a conventional manner with sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule

2kg of the phosphodiesterase VII inhibitor of the formula I are placed in hard gelatin capsules in a conventional manner, each capsule containing 20mg of active ingredient.

Example H: ampoule (CN)

1kg of a 60L double distilled aqueous solution of a phosphodiesterase VII inhibitor of the formula I is sterile filtered, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active ingredient.

Example I: inhalation spray

14g of the phosphodiesterase VII inhibitor of the formula I are dissolved in 10L of isotonic NaCl solution and the solution is transferred to a commercially available spray container with a pump device. The solution can be sprayed into the mouth or nose. One puff (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims (7)

1. Imidazole compounds of formula I and physiologically acceptable salts and/or solvates thereof.Wherein R is¹And R²Independently of one another, each represents A¹、OA¹、SA¹Or Hal, A¹Represents H, A, alkenyl, cycloalkyl or alkylenecycloalkyl, A represents alkyl having 1 to 10 carbon atoms, Hal represents F, Cl, Br or I, and X represents O, S, SO or SO₂

2. Imidazole compounds of formula I according to claim 1 and their physiologically acceptable salts and solvates as medicaments.

3. A medicament according to claim 2 for the inhibition of phosphodiesterase VII.

4. A medicament according to claim 3 for combating: allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes or ulcerative colitis, osteoporosis, transplant rejection, cachexia, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

5. Pharmaceutical formulation comprising at least one medicament according to one of claims 3 and 4 and optionally excipients and/or auxiliaries and optionally further active ingredients.

6. The use of a compound of the formula I according to claim 1 and/or of a physiologically acceptable salt or solvate thereof for the preparation of a medicament for the treatment of allergic diseases, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases, inflammatory diseases, autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, crohn's disease, diabetes or ulcerative colitis, osteoporosis, graft rejection, cachexia, tumor growth or tumor metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

7. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that a compound of formula II:wherein R is¹，R²And X is as defined above, L represents Cl, Br, OH, SCH₃Or reactive esterified OH groups, reacted with imidazole,

and/or converting a compound of formula I into one of its salts.