DE19858331A1 - Tricyclic nitrogen heterocycles as PDE IV inhibitors - Google Patents

Abstract

The invention relates to the use of tricyclic nitrogen heterocycles of the general formula I DOLLAR F1 as a medicament with PDE IV inhibiting action, wherein the radicals R · 1 ·, R · 2 · and R · 3 · have the meaning given in the description and in the claims ,

Description

The invention relates to the use of tricyclic nitrogen heterocycles of the general formula I.

as a drug with PDE IV inhibitory activity, wherein the radicals R ¹ , R ² and R ^{3 may have} the meaning given in the following part of the description and in the claims.

Background of the invention

Cyclic nucleotide phosphodiesterases (PDEs) cause degradation of the second cAMP and cGMP to 5'-AMP and 5'-GMP. The second messenger cAMP and cGMP trigger the activation of protein kinases and thus phosphorylation of proteins. By the hydrolysis of cAMP and cGMP to the inactive Nucleotides 5'-AMP and 5'-GMP thus prevent PDEs from activating Protein kinases.

Due to different substrate specificity, different kinetic properties, etc., phosphodiesterases are divided into different PDE-isoenzyme classes. The family of PDE i isoenzymes is activated via the intracellular receptor protein for Ca ²⁺ ions kalmodulin (Ca ²⁺ / kalmodulin-stimulated PDE). PDE II isoenzymes are cGMP-stimulated phosphodiesterases with low affinity to cAMP and cGMP. The family of PDE III isoenzymes (cGMP-inhibited) is characterized by a high affinity for cAMP and cGMP. The phosphodiesterases type IV (PDE IV) cAMP-specific PDEs are understood that have low affinity for cGMP high affinity for cAMP.

PDE V isoenzymes are cGMP-specific with low affinity to cAMP.

PDE inhibitors influence the concentration of intracellular cAMP and cGMP. Of particular interest is the selective inhibition of Phosphodiesterase type IV, which leads to an increase in the concentration of intracellular cAMP leads.  

Phosphodiesterase (PDE) Type IV inhibitors are known in the art. One of the most prominent representatives of PDE IV isoenzyme selective inhibitory compounds is the following chemical structure having rolipram.

PDE IV inhibitors cause vasodilation (tonus reduction of smooth Musculature), have partially positive inotropic and anti-inflammatory Properties on. Accordingly, PDE IV inhibitors can be used in the treatment and prophylaxis of diseases in which by increasing the cAMP concentration The above effects are desirable and expected to have a therapeutic effect unfold.

Detailed description of the invention

Surprisingly, it has been found that tricyclic heterocycles of the general formula (I) whose radicals R ¹ , R ² and R ^{3 are} as defined below are selective inhibitors of phosphodiesterase type IV.

The invention accordingly relates to the use of tricyclic nitrogen heterocycles of the general formula I.

as a drug with PDE IV inhibitory activity, wherein
R ^{1 is} C ₁ -C ₅ alkyl, C ₅ -C ₆ cycloalkyl, phenyl, benzyl or a 5- or 6-membered saturated or unsaturated heterocyclic ring which may contain one or two heteroatoms selected from the group consisting of oxygen and nitrogen ;
R ^{2 is} C ₁ -C ₅ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₅ -alkyl optionally substituted by C ₁ -C ₄ -alkoxy, C ₅ -C ₆ -cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring containing one or two Heteroatoms selected from the group consisting of oxygen and nitrogen may be substituted,
C ₅ -C ₆ -cycloalkyl or phenyl optionally substituted by C ₁ -C ₄ -alkoxy or benzyl, may optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally their pharmacological harmless acid addition salts.

Preference is given to the abovementioned use of the compounds of the general formula (I) in which
R _{1 is} C ₁ -C ₄ -alkyl, C ₅ -C ₆ -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;
R ^{2 is} C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₄ -alkyl, which may optionally be substituted by C ₁ -C ₄ -alkoxy, C ₅ -C ₆ -cycloalkyl, phenoxy, (C ₁ -C ₄ -alkoxy) -phenyloxy, piperazine or pyrrole, C C ₅ -C ₆ -cycloalkyl or phenyl or benzyl optionally substituted by C ₁ -C ₄ -alkoxy may optionally be in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, optionally in the form of their tautomers and optionally their pharmacologically acceptable acid addition salts.

Also preferred is the above-mentioned use of compounds of general formula (I) wherein
R ^{1 is} ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, N-morpholinyl or phenyl;
R ^{2 is} ethyl, propyl, allyl or butenyl;
R ^{3 may be} ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrolylmethyl, optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally their pharmacologically acceptable acid addition salts.

Particularly preferred is the above-mentioned use of compounds of general formula (I) wherein
R ^{1 is} ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;
R ^{2 is} ethyl or n-propyl;
R ^{3 may be} ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl, optionally in the form of their racemates, their enantiomers, in Form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally their pharmacologically acceptable acid addition salts.

Optionally, the compounds of general formula (I) may be incorporated in their salts, especially for the pharmaceutical application, in their physiological compatible salts with an inorganic or organic acid become. As acids for example succinic acid, Hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulfonic acid, Lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid or Citric acid into consideration. Furthermore, mixtures of the aforementioned acids be used.

As alkyl groups (even if they are part of other radicals) are considered branched and unbranched alkyl groups with 1 to 5 carbon atoms, For example: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso Butyl, sec. Butyl, tert-butyl, n-pentyl, iso-pentyl or neo-pentyl. Possibly For the groups mentioned above, the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. used.

As cycloalkyl radicals having 5 or 6 carbon atoms are cyclopentyl or Called cyclohexyl. As examples 5- or 6-membered, saturated or  unsaturated heterocyclic rings containing one or two heteroatoms selected from the group containing oxygen and nitrogen may be called: furan, Tetrahydrofuran, tetrahydrofuranone, γ-butylrolactone, α-pyran, γ-pyran, dioxolane, Tetrahydropyran, dioxane, pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, Imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, Morpholine, oxazole, isoxazole, oxazine, pyrazolidine.

The preparation of the compounds of general formula (I) can be carried out in analogy to by the prior art for some representatives of those defined above Compounds of general formula (I) (Tenor et al., Chem. Ber. Vol. 97 (1964) p. 1373-1382), to which reference is made at this point content is referred to.

The present invention aims in addition to the purpose mentioned above to the use of the previously defined compounds of general formula (I) for the preparation of medicaments for the treatment or prophylaxis of diseases, in which selective inhibition of the PDE IV enzyme is indicated. The present invention further aims at the use of compounds of the general formula (1) for the treatment or prophylaxis of diseases in which by therapeutically increasing the concentration of intracellular cAMP desired effect can be achieved. Accordingly, the present aims Invention to the use of compounds of general formula (I) according to the above definitions for increasing the concentration of intracellular cAMP. The use of the compounds of general formula (I) according to the o. g. Definitions for the preparation of a medicament for increasing the concentration of intracellular cAMP is another aspect of the present invention.

PDE IV inhibitors have a bronchodilatory or even an anti-inflammatory Effect in the lung. The compounds of general formula (I) according to the o. G. Definitions may therefore be use for the treatment of asthma or C.O.P.D. (chronic obstructive pulmonary disease).

PDE IV inhibitors inhibit eosinophil influx after allergic Irritation. The compounds of the general formula (I) according to the above Consequently, definitions can be used in the treatment of allergic diseases such as z. Allergic rhinitis, allergic conjunctivitis and allergic Eye diseases are used.  

Since PDE IV inhibitors also release cytokines such as TNF-alpha from Inhibiting macrophages is an efficacy of the compounds defined above general formula (I) in the treatment of diseases such. B. Adult Respiratory Distress Syndrome or Inflammatory Arthritis, where TNF release is a Role plays, to be expected.

Also for the treatment and prophylaxis of the diseases mentioned below may be the compounds of the general formula (I) of therapeutic benefit: asthma, especially asthma in inflammation of the Lungs, Inflammations of the Lungs and Respiratory Tract, C.O.P.D. (chronic obstructive pulmonary disease), cystic fibrosis, chronic bronchitis, eosinophilic granuloma, inflammatory skin diseases such as Psoriasis, ischemia, endotoxic or septic shock, ulcerative colitis, Crohn's disease, rheumatoid arthritis, chronic glomerulonephritis, urticaria, Vernal conjunctivitis, multiple sclerosis or arteriosclerosis.  

Table 1 summarizes the pharmacological data obtained for the compounds of general formula (I). These were based on Torphy et al. (1992) J. Pharmacol. Exp. Ther. 263: 1195 certainly.

Table 1

The compounds of general formula (I) may be used alone or in combination with other active compounds according to the invention, if appropriate also in combination with other pharmacologically active agents, are used. suitable Examples of applications are tablets, capsules, suppositories, solutions, Juices, emulsions or dispersible powders. Appropriate tablets can for example, by mixing the active substance (s) with known excipients, for example, inert diluents such as calcium carbonate, calcium phosphate or milk sugar, disintegrants such as corn starch or alginic acid, binders such as Starch or gelatin, lubricants, such as magnesium stearate or talc, and / or Means for achieving the depot effect, such as carboxymethylcellulose, Cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers.

Coated tablets can be coated analogously to the tablets manufactured cores with commonly used in dragee coatings, For example Kollidon or shellac, gum arabic, talc, titanium dioxide or Sugar, to be produced. To achieve a depot effect or to avoid of incompatibilities, the core can also consist of several layers. Similarly, the dragee cover to achieve a depot effect from consist of several layers, those mentioned above in the tablets Excipients can be used.

Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetener, such as saccharin, cyclamate, glycerol or Sugar as well as a taste-improving agent, e.g. B. flavorings, such as vanillin or orange extract. You can also use suspension aids or Thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example Condensation products of fatty alcohols with ethylene oxide, or protective substances such as Hydroxybenzoates.

Injection solutions are in the usual manner, for. B. with the addition of Preservatives, such as p-hydroxybenzoates, or stabilizers, such as Alkali salts of ethylenediaminetetraacetic acid and in injection bottles or ampoules bottled.

The one or more active substances or combinations of active substances containing capsules can be prepared, for example, by the Ingredients with inert carriers, such as lactose or sorbitol, and mixes in Encapsulating gelatin capsules.  

Suitable suppositories can be, for example, by mixing with it provided carriers, such as neutral fats or polyethylene glycol or its derivatives.

A therapeutically effective daily dose is between 1 and 800 mg, preferably 10-300 mg per adult.

However, the following examples illustrate the present invention without them to be limited in scope:

Pharmaceutical Formulation Examples

A) tablets per tablet active substance 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg           500 mg         

The finely ground active ingredient, lactose and part of the corn starch will be mixed together. The mixture is sifted, followed by a solution of polyvinylpyrrolidone in water moistened, kneaded, wet granulated and dried. The granules, the remainder of the corn starch and the magnesium stearate are sieved and mixed together. The mixture becomes tablets of suitable form and Size pressed.

B) tablets per tablet active substance 80 mg corn starch 190 mg lactose 55 mg Microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl 23 mg magnesium stearate 2 mg           400 mg         

The finely ground active ingredient, part of the corn starch, lactose, microcrystalline Cellulose and polyvinyl pyrrolidone are mixed together, the mixture sieved and processed into granules with the remainder of the corn starch and water, which is dried and sieved. Add the sodium carboxymethyl starch and the magnesium stearate, mixed and compressed Mixture to tablets of appropriate size.

C) Dragées per dragée active substance 5 mg corn starch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesium stearate 0.5 mg           80 mg         

The active ingredient, corn starch, lactose and polyvinylpyrrolidone will be good mixed and moistened with water. The moist mass is pressed through a sieve with 1 mm mesh, dries at about 45 ° C and hits the granules then through the same sieve. After admixing magnesium stearate on a tableting machine, arched dragoe kernels become one Diameter of 6 mm pressed. The Dragoe kernels thus produced are opened known manner coated with a layer consisting essentially of sugar and Talc exists. The finished dragees are polished with wax.

D) capsules per capsule active substance 50 mg corn starch 268.5 mg magnesium stearate 1.5 mg           320 mg         

Substance and cornstarch are mixed and moistened with water. The moist mass is sieved and dried. The dry granules are sieved and mixed with magnesium stearate. The final mixture is in Hard gelatine capsules size 1 bottled.  

E) Ampoule solution active substance 50 mg sodium chloride 50 mg Aqua pro inj. 5 ml

The active ingredient is at intrinsic pH or optionally at pH 5.5 to 6.5 in water dissolved and treated with sodium chloride as isotonan, the resulting solution is filtered pyrogen-free and the filtrate under aseptic conditions in ampoules bottled, which are then sterilized and sealed. The ampoules contain 5 mg, 25 mg and 50 mg active substance.

F) Suppositories active substance 50 mg Adeps solidus 1650 mg           1700 mg         

The hard fat is melted. At 40 ° C, the ground active substance homogeneously dispersed. It is cooled to 38 ° C and slightly pre-cooled Suppository forms poured out.

G) oral suspension active substance 50 mg hydroxyethyl 50 mg sorbic acid 5 mg Sorbitol (70%) 600 mg glycerin 200 mg Aroma 15 mg Water ad 5 ml

Distilled water is heated to 70 ° C. Herein is stirring Hydroxyethyl cellulose dissolved. After adding sorbitol solution and glycerin is added Room temperature cooled. At room temperature, sorbic acid, flavor and substance added. To vent the suspension is stirred evacuated.

Claims (12)

1) Use of tricyclic nitrogen heterocycles of the general formula I.
in which
R ^{1 is} C ₁ -C ₅ -alkyl, C ₅ -C ₆ -cycloalkyl, phenyl, benzyl or a 5- or 6-membered, saturated or unsaturated heterocyclic ring containing one or two heteroatoms selected from the group consisting of oxygen and nitrogen can;
R ^{2 is} C ₁ -C ₅ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₅ -alkyl optionally substituted by C ₁ -C ₄ -alkoxy, C ₅ -C ₆ -cycloalkyl, phenoxy or by a 5- or 6-membered, saturated or unsaturated heterocyclic ring containing one or two Heteroatoms selected from the group consisting of oxygen and nitrogen may be substituted,
C ₅ -C ₆ -cycloalkyl or optionally substituted by C ₁ -C ₄ -alkoxy-substituted phenyl or benzyl
optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally of their pharmacologically acceptable acid addition salts, for the manufacture of a medicament for the inhibition of phosphodiesterase type IV (PDE IV). 2) Use of the compounds of general formula (I) according to claim (I), wherein
R ^{1 is} C ₁ -C ₄ -alkyl, C ₅ -C ₆ -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholinyl or phenyl;
R ^{2 is} C ₁ -C ₄ alkyl or C ₂ -C ₄ alkenyl;
R ^{3 is} C ₁ -C ₄ -alkyl, which may optionally be substituted by C ₁ -C ₄ -alkoxy, C ₅ -C ₆ -cycloalkyl, phenoxy, (C ₁ -C ₄ -alkoxy) -phenyloxy, piperazine or pyrrole, C C ₅ -C ₆ -cycloalkyl or phenyl or benzyl optionally substituted by C ₁ -C ₄ -alkoxy,
optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally of their pharmacologically acceptable acid addition salts, for the manufacture of a medicament for the inhibition of phosphodiesterase type IV (PDE IV). 3) Use of compounds of the general formula (I) according to one of claims 1 or 2, wherein
R ^{1 is} ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, N-morpholinyl or phenyl;
R ^{2 is} ethyl, propyl, allyl or butenyl;
R ^{3 may be} ethyl, propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrolylmethyl,
optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally of their pharmacologically acceptable acid addition salts, for the manufacture of a medicament for the inhibition of phosphodiesterase type IV (PDE IV). 4) Use of compounds of general formula (I) according to any one of claims 1, 2 or 3, wherein
R ^{1 is} ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl;
R ^{2 is} ethyl or n-propyl;
R ^{3 may be} ethyl, i-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrollylmethyl,
optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and their mixtures, optionally in the form of their tautomers and optionally of their pharmacologically acceptable acid addition salts, for the manufacture of a medicament for the inhibition of phosphodiesterase type IV (PDE IV). 5) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of Diseases in which the application of PDE IV inhibitors is indicated. 6) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for increasing the Concentration of intracellular cAMP. 7) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of Diseases in which the increase in the concentration of intracellular cAMP is indexed. 8) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the preparation of a medicament for the inhibition of TNF. 9) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of Diseases in which TNF inhibition is indicated. 10) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of Diseases selected from the group of asthma, especially asthma Inflammations of the lungs, C.O.P.D., allergic rhinitis, allergic Conjunctivitis, allergic eye diseases, Adult Respiratory Distress Syndrome, inflammatory arthritis, inflammation of the lungs and respiratory, cystic Fibrosis, chronic bronchitis, eosinophilic granuloma, psoriasis, ischemia, endotoxic or septic shock, ulcerative colitis, Crohn's disease, rheumatoid  Arthritis, chronic glomerulonephritis, urticaria, conjunctivitis vernalis, multiple Sclerosis or arteriosclerosis. 11) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of Asthma. 12) Use of compounds of general formula (I) according to one of Claims 1, 2, 3 or 4 for the manufacture of a medicament for the treatment of C.O.P.D.