HK1050366A - Imidazopyridine derivatives used as phosphodiesterase vii inhibitors - Google Patents

Description

Imidazopyridine derivatives as phosphodiesterase VII inhibitors

The present invention relates to compounds of formula I:

wherein

R¹Represents CONR⁴R⁵，

R²Represents a group of a compound represented by the formula H or A,

R⁴and R⁵Each independently represents H or A¹，

R³The expression Hal is given to the expression,

hal represents F, Cl, Br or I,

a represents an alkyl group having 1 to 4 carbon atoms,

A¹represents an alkyl group having 1 to 10 carbon atoms

X represents an alkylene group having 1 to 4 carbon atoms, wherein the ethylene group may be further substituted by a double bond or a triple bond,

and physiologically acceptable salts and/or solvates thereof.

Other imidazopyridine derivatives having GABA agonistic effects are disclosed, for example, in EP 82369.

The present invention has for its object to find novel compounds having valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of formula I and their salts have valuable pharmacological properties and are well tolerated.

In particular, they exhibit a specific inhibitory action of the "rolipram insensitive" cAMP phosphodiesterase (PDE VII).

The biological activity of the compounds of formula I can be determined, for example, by the method described by m.a.giembycz et al, br.j.pharmacol, (1996), 118, 1945-1958.

The affinity of compounds for cAMP phosphodiesterase (PDE VII) is determined by measuring their IC50 values (concentration of inhibitor required to achieve 50% inhibition of enzyme activity). To perform this 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). In addition, SK-N-SH was replaced with HUT-78 and treequein using CI-930 for inhibition (D.Ruppet et al, life Sci.31: 2037, 1982).

The compounds of formula I can be used for the treatment of asthma diseases. Antiasthmatic effects can be determined analogously to the method of T.Olsson, Acta allergologica 26, 438-447(1971), for example.

Because cAMP inhibits osteoclasts and mimics osteoblasts (S.Kasugai et al, M681, and K.Miyamoto, M682, in Abstract of American Society for bone and Mineral Research, 18)^thAnnual Meeting, 1996), the compounds of formula I can be used for the treatment of osteoporosis.

These compounds also exhibit antagonism against 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 (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 treating, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis can be determined analogously to the method of N.Sommer et al, Nature medicine 1, 244-248(1995), or L.Sekut et al, Clin.exp.Immunol.100, 126-132 (1995).

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

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

They can therefore also be used for the treatment of sepsis and for the treatment of memory disorders, atherosclerosis, atopic dermatitis and AIDS, and furthermore for 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 pharmaceutical active ingredients in human and veterinary medicine. They can furthermore 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 PDE VII inhibition in human and veterinary medicine.

The invention furthermore relates to the use of compounds of the formula I for preparing 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 alkyl having 1 to 4 carbon atoms, and having 1, 2, 3 or 4 carbon atoms, preferably methyl, ethyl or propyl, furthermore preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl. The 1-7H atoms in the radical may also be substituted by F and/or Cl. A therefore also denotes, for example, trifluoromethyl or pentafluoroethyl.

A¹Represents having 1 to 10 carbonsAn alkyl group of atoms, and having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably representing methyl, ethyl or propyl, furthermore more preferably isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also n-pentyl, neopentyl, isopentyl or hexyl. The 1-7H atoms in these groups may also be substituted by F and/or Cl. A. the¹Thus also for example trifluoromethyl or pentafluoroethyl.

X represents an alkylene group having 1 to 4 carbon atoms, preferably a methylene, ethylene, propylene or butylene group, wherein one ethylene group may also be replaced by a double or triple bond. X thus also represents for example-CH₂-CH＝CH-CH₂-or-C ≡ C-.

The present invention therefore relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred families of compounds can be represented by the following sub-formulae Ia to Ic, which correspond to formula I, in which sub-formulae the radicals not specified in more detail have the meanings stated in formula I, but in which

In Ia, R³Represents Cl;

in Ib, R³Represents a compound represented by the formula (I) Cl,

x represents an alkylene group having 1 to 4 carbon atoms;

in Ic, R³Represents a compound represented by the formula (I) Cl,

x represents an alkylene group having 1, 2, 3 or 4 carbon atoms,

A¹represents an alkyl group having 1, 2, 3 or 4 carbon atoms.

The compounds of the formula I and the starting materials for their preparation can be prepared in particular analogously as described on page 3, left-hand column 18 line to page 4, column 6, line 16 of EP 82369 or in example 1.

The compounds of the formula I and the starting materials for their preparation are furthermore prepared by processes known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemistry [ Methods of Organic Chemistry ], Georg-Thieme-Verlag, Stuttgart), in particular under reaction conditions which are known and suitable for the reaction in question.

The base of formula I can be converted into the relevant acid addition salt using an acid, for example by reacting equal amounts of base and acid in a suitable solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are in particular those which give physiologically acceptable salts. It is therefore 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, furthermore organic acids, especially 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, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemomono-and disulfonic acid, lauryl sulfuric 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 medicaments of formula I and their physiologically acceptable salts as phosphodiesterase VII inhibitors.

The invention furthermore relates to pharmaceutical preparations comprising 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.

These substances are generally preferably administered in a dose of between about 1 and 500mg, in particular between 5 and 100mg per dosage unit. The daily dosage is preferably between about 0.02 and 10mg/kg body weight. The specific dosage for each patient, however, will depend upon a variety of factors such as the potency of the particular 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 being effected. Oral administration is preferred.

These pharmaceutical preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical administration and which are unreactive with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, sugars, such as lactose or starch, magnesium stearate, talc, vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds can also be freeze-dried and the lyophilizates obtained can be used, for example, for the preparation of injectable preparations. The formulations may be sterilized and/or include adjuvants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for varying the osmotic pressure, buffer substances, dyes, fragrances and/or a number of other active ingredients, for example 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 to their use for preparing 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

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c)]Pyridin-4-ylsulfanyl) -N, N-dimethyl-acetamide

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) acetamide,

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) propionamide,

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) butanamide,

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) -N-hexylacetamide,

2- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) -N-octylacetamide,

4- (3-butyl-7-chloro-3H-imidazo [4, 5-c ] pyridin-4-ylsulfanyl) -but-2-enoic acid dimethylamide.

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 hydrogen phosphate in 3L of double distilled water is adjusted to pH6.5 using 2N hydrochloric acid, sterile-filtered, transferred to an injection vial, lyophilised under sterile conditions and sealed under sterile conditions. Each injection bottle contained 5mg of active ingredient.

Example B: suppository

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

Example C: solutions of

Preparation of 1g of phosphodiesterase VII inhibitor of the formula I, 9.38g NaH₂PO₄·2H₂O，28.48gNa₂HPO₄·12H₂O and 0.1g benzalkonium chloride in 940ml double distilled water. The pH was adjusted to 6.8 and the solution was made up to 1L and sterilized by radiation. The solution can be used in the form of eye drops.

Example D: ointment

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

Example E: tablet formulation

According to the usual method, a mixture of 1kg of phosphodiesterase VII inhibitor of formula I, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed in such a way that each tablet contains 10mg of active ingredient to obtain tablets.

Example F: film-coated tablet

Tablets were compressed analogously to example E and subsequently coated in the usual manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule

According to the usual method, 2kg of a phosphodiesterase VII inhibitor of formula I are introduced into hard gelatin capsules in such a way that each capsule contains 20mg of active ingredient.

Example H: ampoule (CN)

A solution of 1kg of the phosphodiesterase VII inhibitor of the formula I in 60L of double distilled water is sterile-filtered, transferred into ampoules, lyophilised 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 formula I are dissolved in 10L of isotonic NaCl solution and the solution is transferred mechanically by means of a pump to a commercially available spray container. The solution can be sprayed into the mouth or nose. The amount of one spray (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims (6)

1. A compound of formula I:

wherein

R¹Represents CONR⁴R⁵，

R²Represents a group of a compound represented by the formula H or A,

R⁴and R⁵Each independently represents H or A¹，

R³The expression Hal is given to the expression,

hal represents F, Cl, Br or I,

a represents an alkyl group having 1 to 4 carbon atoms,

A¹represents an alkyl group having 1 to 10 carbon atoms,

x represents an alkylene group having 1 to 4 carbon atoms, wherein the ethylene group may be further substituted by a double bond or a triple bond,

and physiologically acceptable salts and/or solvates thereof.

2. Imidazopyridine derivatives of formula I according to claim 1 and their physiologically acceptable salts and solvates as a medicament.

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

4. A medicament according to claim 3 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.

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

6. The use of compounds of the formula I according to claim 1 and/or their physiologically acceptable salts or solvates 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.