JP2002532411A - Tricyclic nitrogen heterocyclic compounds as PDEIV inhibitors - Google Patents

Abstract

(57) Abstract: The present invention relates to the use of a tricyclic nitrogen heterocyclic compound of the general formula (I) as a drug having a PDE IV inhibitory effect, wherein the groups R ¹ , R ² and R ³ are described in the description and claims. It has the meaning indicated in the range. Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the use of a tricyclic nitrogen heterocyclic compound of the general formula (I) as a pharmaceutical composition having an inhibitory effect on PDE IV.

[0002]

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In the formula, the radicals R ¹ , R ² and R ³ have the meaning given in the following description and claims. BACKGROUND OF THE INVENTION Cyclic nucleotide phosphodiesterases (PDEs) degrade second messengers cAMP and cGMP to 5'-AMP and 5'-GMP. Second messenger cAMP and cGMP
Causes activation of protein kinases, thereby causing protein phosphorylation. By hydrolyzing cAMP and cGMP, the inactive nucleotide 5'-A
Forming MP and 5'-GMP, PDEs prevent activation of protein kinases. Phosphodiesterases are split into different classes of PDE isozymes, inter alia depending on their different substrate specificities, different kinetic properties, and the like. PDE I isoenzyme family are activated by intracellular receptor protein for Ca ^{2 +} ions calmodulin (Ca ²⁺ / calmodulin-stimulated PDE). PDE II isoenzymes are cGMP-stimulated phosphodiesterases that have no affinity for cAMP and cGMP. The PDE III isozyme family (cGMP repression) is characteristically characterized by a high affinity for cAMP and cGMP. Type IV
Phosphodiesterase (PDE IV) refers to cAMP-specific PDEs that have a high affinity for cAMP but a low affinity for cGMP. The PDE V isoenzyme is a cGMP specific with low affinity for cAMP.

[0004] PDE inhibitors affect intracellular cAMP and cGMP levels. Of particular interest are:
Selective suppression of type IV phosphodiesterase that results in increased intracellular cAMP levels. Type IV phosphodiesterase (PDE) inhibitors are already known. One of the most prominent examples of compounds that selectively inhibit PDE IV isoenzymes is rolipram, which has the following chemical structure:

[0005]

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[0006] PDE IV inhibitors cause vasodilation (reduction of smooth muscle tone), have a partial positive inotropic effect, and are also anti-inflammatory. Therefore, P
DE IV inhibitors are expected to have the above effects caused by increased cAMP levels and will have a therapeutic effect in treating and preventing the desired disease.

DETAILED DESCRIPTION OF THE INVENTION Surprisingly, the tricyclic heterocyclic compounds of the general formula (I) in which the groups R ¹ , R ² and R ³ are as defined above Is a selective inhibitor of type IV phosphodiesterase. Accordingly, the present invention provides a pharmaceutical composition having PDE IV inhibitory activity, which comprises a tricyclic nitrogen heterocyclic compound of the general formula (I) (optionally, a racemate thereof, an enantiomer thereof, a diastereomer thereof and a mixture thereof). , Their tautomers, and their pharmacologically acceptable addition salts).

[0008]

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Wherein R ¹ is saturated, optionally containing one or two heteroatoms selected from the group comprising C _1-5 -alkyl, C _5-6 -cycloalkyl, phenyl, benzyl or oxygen and nitrogen. Or an unsaturated 5- or 6-membered heterocyclic ring, R ² represents C _1-5 -alkyl or C _2-4 -alkenyl, R ³ is C _1-4 -alkoxy, C _{5- 6} -cycloalkyl, phenoxy or C ₁ optionally substituted by a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain one or two heteroatoms selected from the group comprising oxygen and nitrogen _-5 -alkyl; C _5-6 -cycloalkyl; or phenyl or benzyl optionally substituted by C _1-4 -alkoxy.

[0010] R¹Is C_1-4-Alkyl, C_5-6-Cycloalkyl, tetrahydrofuranyl, tetrahi
Represents dropranyl, piperazinyl, morpholinyl or phenyl, R^TwoIs C_1-4-Alkyl or C_2-4-Represents alkenyl, R^ThreeNeed as C_1-4-Alkoxy, C_5-6-Cycloalkyl, phenoxy, (C_1-4-
(Alkoxy) C optionally substituted with phenyloxy, piperazine or pyrrole _1-4 -Represents alkyl, or R^ThreeIs C_5-6-Cycloalkyl or optionally C_1-4-Arco
In the above general formula (I) representing phenyl or benzyl which may be substituted by xy
Compounds (where necessary, their racemates, their enantiomers, their diastereomers
And their mixtures, their tautomers and their pharmacologically acceptable additions
(Which may be in the form of a salt).

R ¹ represents ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, N-morpholinyl or phenyl; R ² represents ethyl, propyl, allyl or butenyl; R ³ represents ethyl, propyl , Butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrrolylmethyl, a compound of the above-mentioned general formula (I) (where necessary, their racemates, their enantiomers, their diastereomers) And their mixtures, their tautomers, and their pharmacologically acceptable addition salts). R ¹ represents ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl, R ² represents ethyl or n-propyl, R ³ represents ethyl, i-propyl, n- A compound of the above general formula (I) representing propyl, n-butyl, t-butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrrolylmethyl (optionally a racemate thereof, It is particularly preferred to use their enantiomers, their diastereomers and their mixtures, which may be in the form of their tautomers and their pharmaceutically acceptable addition salts).

If desired, the compounds of the general formula (I) may be converted into their salts, in particular the pharmaceutically acceptable salts thereof with inorganic or organic acids, for use in medicine. Suitable acids for this purpose include, 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. It is also possible to use mixtures of the above-mentioned acids. Suitable alkyl groups (including those that are part of other groups) are branched and unbranched alkyl groups of 1 to 5 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n -Butyl, iso-butyl, sec. Butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl and the like. Abbreviations Me, Et, n-
Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. are used for the above groups. Examples of C5 or C6 cycloalkyl groups include cyclopentyl or cyclohexyl. Examples of a saturated or unsaturated 5- or 6-membered heterocycle that may contain one or two heteroatoms selected from the group containing oxygen and nitrogen are furan, tetrahydrofuran, tetrahydrofuranone, γ-butyrolactone, α-pyran, γ-pyran, dioxolan, tetrahydropyran, dioxane, pyrrole,
Examples include pyrroline, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, pyridine, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, morpholine, oxazole, isoxazole, oxazine, and pyrazolidine.

The compounds of the general formula (I) can be prepared according to the method described in the prior art (Chem. Ber. Vol. 97 (1964) S. 1373-1382)
And the contents of this document are included in the present specification. The invention relates not only to the applications mentioned at the outset, but also to the use of the abovementioned compounds of general formula (I) for preparing pharmaceutical compositions for the treatment or prevention of diseases in which the selective control of the PDE IV enzyme is required. The present invention also relates to the use of the compounds of the general formula (I) for treating or preventing diseases in which a favorable therapeutic effect is exerted by increasing the intracellular cAMP concentration.
Accordingly, the present invention provides a compound of the general formula (I
)). The use of a compound of general formula (I) as defined above for preparing a pharmaceutical composition for increasing intracellular cAMP concentration is a further aspect of the present invention.

[0014] PDE IV inhibitors have bronchodilator capacity or also have anti-inflammatory effects in the lungs.
Thus, the compounds of general formula (I) as defined above can be used for treating asthma or COPD (chronic obstructive pulmonary disease). PDE IV inhibitors suppress eosinophil influx following allergic stimuli. Accordingly, the compounds of general formula (I) as defined above may be used for treating allergic diseases, such as allergic rhinitis, allergic conjunctivitis and allergic eye diseases. In addition, since the PDE IV inhibitor suppresses the release of cytokines such as TNF-α by macrophages, the above compound of the general formula (I) can be used for treating diseases associated with TNF release such as adult respiratory distress syndrome or inflammatory arthritis. It is expected to be effective. Also, the compounds of general formula (I) as defined above may be therapeutically useful in the treatment and prevention of the diseases described below. Asthma, especially pneumonia asthma, pneumonia and airway inflammation, CO
PD (chronic obstructive pulmonary disease), cystic fibrosis, chronic bronchitis, eosinophilic granuloma,
Inflammatory skin diseases such as psoriasis, ischemia, endotoxin or septic shock, ulcerative colitis,
Crohn's disease, rheumatoid arthritis, chronic glomerulonephritis, hives, spring conjunctivitis (conjun
ctivitis vernalis), multiple sclerosis or arteriosclerosis. Table 1 contains the pharmacological data obtained for the compounds of general formula (I). Data was obtained by the method of Torphy et al., J. Pharmacol. Exp. Ther. 263: 1195 (1992).

[0015]

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[0016]

[Table 1] ^* Experimental conditions-enzyme: purified from human monocytes (U937-cell); final volume of assay:
0.1 ml; protein: range from 2 μg / measurement point to 6 μg / measurement point (depending on enzyme purification degree); incubation buffer: 40 mM Tris-HCl (pH 7.8), 3 mM MgCl ₂ ;
Radioligand: 1 μCi / ml [3H] cAMP; Incubation: 30 ° C. for 30 minutes; Comparative inhibitor: Rolipram

The compounds of the general formula (I) may be used on their own or together with other active substances according to the invention and, if necessary, together with other pharmacologically active substances. Is also good. Suitable formulations include, for example, tablets, capsules, suppositories, solutions, elixirs, emulsions or dispersible powders. Suitable tablets are, for example, active substances and known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, stearin. It can be obtained by mixing a lubricant such as magnesium acid or talc and / or a delayed release agent such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also contain several layers.

Coated tablets are prepared by coating cores made in a manner similar to tablets with materials commonly used as tablet coatings, such as kollidone or shellac, gum arabic, talc, titanium dioxide or sugar. Is also good. Also, the core may consist of several layers to achieve delayed release or to avoid compounding contraindications. Similarly, using the above-mentioned excipients for tablets, the tablet coating may also consist of several layers to achieve delayed release. Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetening agent such as saccharin, cyclamate, glycerol or sugar and a flavor enhancer, eg a flavoring such as vanillin or orange extract. Also, they
Suspension adjuvants or thickeners, such as sodium carboxymethyl cellulose, may be included, for example, wetting agents, such as the condensation products of fatty alcohols and ethylene oxide, or preservatives, such as p-hydroxybenzoate.

Solutions for injection are prepared in the usual manner, by adding a preservative such as p-hydroxybenzoate or a stabilizer such as the alkali metal salt of ethylenediaminetetraacetic acid, and transferred to an injection vial or ampoule. Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol, and filling them in gelatin capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof. The therapeutically effective daily dosage is 1 to 800 mg per adult, preferably 10 to 300 mg. The present invention will be described specifically with reference to the following examples, but the scope is not limited.

(Example of Pharmaceutical Formulation) The finely ground active substance, lactose and a portion of the corn starch were mixed together. Sieving the mixture and then moistening with an aqueous solution of polyvinylpyrrolidone,
Kneaded, wet granulated and dried. The granules, remaining corn starch and magnesium stearate were sieved and mixed together. The mixture was compressed to produce tablets of suitable shape and size.

[0021] The finely ground active substance, a portion of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is sieved and treated with the remaining corn starch and water to form a granulate, which is then granulated. Dried and sieved. Add sodium carboxymethyl starch and magnesium stearate,
After mixing, the mixture was compressed to form tablets of a suitable size.

[0022] The active substance, corn starch, lactose and polyvinylpyrrolidone were mixed well and moistened with water. Forcibly pass the wet paste through a sieve with a mesh size of 1 mm,
After drying at about 45 ° C., the granules were passed through the same sieve again. After addition of the magnesium stearate, a 6 mm diameter convex tablet core was compressed in a tablet machine. The tablet cores thus produced were coated in a known manner with a coating consisting essentially of sugar and talc. The final coated tablet was polished with wax.

[0023] The active substance and corn starch were mixed together and moistened with water. The wet mass was sieved and dried. The dried granules were sieved and mixed with magnesium stearate. The final mixture was packed into size 1 hard gelatin capsules.

[0024] The active substance was dissolved in water at its own pH or, if necessary, pH 5.5 to 6.5, and sodium chloride was added to make it isotonic. The resulting solution was filtered pyrogen-free and the filtrate was transferred under aseptic conditions to an ampoule, which was then sterilized and sealed by fusion. Ampoules contain 5 mg, 25 mg and 50 mg of active substance.

[0025] The hard fat was melted. The ground active substance was homogeneously dispersed at 40 ° C. Cooled to 38 ° C. and poured into slightly cooled suppository frames.

[0026] Distilled water was heated to 70 ° C. The hydroxyethyl cellulose was dissolved therein with stirring. After addition of the sorbitol solution and glycerol, the mixture was cooled to ambient temperature. At ambient temperature, sorbic acid, flavor and active substance were added. The suspension was degassed with stirring to remove air.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 11/00 A61P 11/00 11/02 11/02 11/06 11/06 13/12 13/12 17 / 06 17/06 19/02 19/02 25/00 25/00 27/02 27/02 29/00 29/00 101 101 35/00 35/00 37/08 37/08 43/00 111 43/00 111 (72) Inventor Küffner-Mühl Ulrique Germany Day 55218 Ingelheim am Rhein Blüder-Grim Strasse 37 Day (72) Inventor Mead Christopher John Montagu Germany Germany Day 55411 Bingen am Rhein Burgstrasse 104 F-term (Reference) 4C086 AA01 CB05 MA01 MA04 NA14 ZA02 ZA33 ZA34 ZA39 ZA45 ZA51 ZA59 ZA66 ZA81 ZA89 ZA96 ZB11 ZB13 ZB15 ZB21 ZB26 ZC20

Claims (12)

[Claims] 1. Use of a tricyclic nitrogen heterocyclic compound of the general formula (I) for preparing a pharmaceutical composition for inhibiting type IV phosphodiesterase (PDE IV), and optionally a racemate thereof, an enantiomer thereof, Use of said tricyclic nitrogen heterocyclic compounds which may be in the form of their diastereomers and their mixtures, their tautomers and their pharmaceutically acceptable addition salts. Embedded image Wherein R ¹ is saturated or unsaturated which may contain one or two heteroatoms selected from the group comprising C _1-5 -alkyl, C _5-6 -cycloalkyl, phenyl, benzyl or oxygen and nitrogen. Represents a saturated 5- or 6-membered heterocyclic ring, R ² represents C _1-5 -alkyl or C _2-4 -alkenyl, R ³ represents C _1-4 -alkoxy, C _5-6 -cyclo C _1-5- which may be substituted by a saturated or unsaturated 5- or 6-membered heterocyclic ring which may contain 1 or 2 heteroatoms selected from the group comprising alkyl, phenoxy or oxygen and nitrogen Alkyl; C _5-6 -cycloalkyl; or phenyl or benzyl optionally substituted with C _1-4 -alkoxy.) 2. A compound of the general formula (I) according to claim ¹ , wherein R ¹ is C _1-4 -alkyl, C _5-6 -cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl. , Morpholinyl or phenyl, R ² represents C _1-4 -alkyl or C _2-4 -alkenyl, R ³ is optionally C _1-4 -alkoxy, C _5-6 -cycloalkyl, phenoxy, (C _1-4 - alkoxy) phenyloxy, optionally substituted piperazine or pyrrole C _1-4 - alkyl, C _5-6 - cycloalkyl; - phenyl optionally substituted by alkoxy C _1-4 or necessary Or benzyl type IV phosphodiesterase (PDE IV)
Use of said compounds for preparing pharmaceutical compositions for inhibition and, if necessary, their racemates, their enantiomers, their diastereomers and their mixtures, their tautomers and their pharmacologically acceptable Use of the compound which may be in the form of an addition salt. 3. The general formula (I) according to any one of claims 1 and 2,
Wherein R ¹ represents ethyl, propyl, butyl, cyclopentyl, tetrahydrofuranyl, tetrahydropyranyl, N-morpholinyl or phenyl; R ² represents ethyl, propyl, allyl or butenyl; R ³ represents ethyl And use of a compound for the preparation of a pharmaceutical composition for inhibiting type IV phosphodiesterase (PDE IV), which represents propyl, butyl, cyclopentyl, cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, methoxybenzyl or N-pyrrolylmethyl By their racemic, their enantiomers,
Use of said compounds which may be in the form of their diastereomers and their mixtures, their tautomers and their pharmaceutically acceptable addition salts. 4. The general formula (I) according to any one of claims 1 to 3,
R ¹ represents ethyl, n-propyl, tert-butyl, cyclopentyl, 3-tetrahydrofuryl, N-morpholinyl or phenyl, R ² represents ethyl or n-propyl, and R ³ represents ethyl. , I-propyl, n-propyl, n-butyl, t-butyl, cyclopentyl,
Type IV phosphodiesterase (PDE representing cyclohexylmethyl, benzyl, phenylethyl, phenoxymethyl, 4-methoxybenzyl or N-pyrrolylmethyl)
IV) Use of the compounds to prepare pharmaceutical compositions for inhibition, and optionally their racemates, their enantiomers, their diastereomers and mixtures thereof,
Use of said compounds which may be in the form of their tautomers and their pharmacologically acceptable addition salts. 5. The general formula (I) according to any one of claims 1 to 4, for preparing a pharmaceutical composition for treating a disease in which use of a PDE IV inhibitor is required.
Use of compounds. 6. Use of the compound of the general formula (I) according to any one of claims 1 to 4 for preparing a pharmaceutical composition for increasing intracellular cAMP concentration. 7. The general formula (I) according to any one of claims 1 to 4, for preparing a pharmaceutical composition for treating a disease requiring an increase in intracellular cAMP concentration.
Use of compounds. 8. Use of the compound of the general formula (I) according to any one of claims 1 to 4 for preparing a pharmaceutical composition for suppressing TNF. 9. Use of a compound of general formula (I) according to any one of claims 1 to 4 for the preparation of a pharmaceutical composition for the treatment of a disease in which TNF suppression is required. . 10. Asthma, especially asthma of pneumonia, COPD, allergic rhinitis, allergic conjunctivitis, allergic eye disease, adult respiratory distress syndrome, inflammatory arthritis,
Pneumonia and airway inflammation, cystic fibrosis, chronic bronchitis, eosinophilic granuloma, psoriasis, ischemia, endotoxin or septic shock, ulcerative colitis, Crohn's disease, rheumatoid arthritis, chronic glomeruli The method according to any one of claims 1 to 4, for preparing a pharmaceutical composition for treating a disease selected from the group comprising nephritis, urticaria, spring conjunctivitis, multiple sclerosis or arteriosclerosis. Use of a compound of general formula (I) as described. 11. A method for preparing a pharmaceutical composition for treating asthma, comprising the steps of:
Use of the compound of the general formula (I) according to any one of the above items 4 to 7. 12. Use of a compound of general formula (I) according to any one of claims 1 to 4 for preparing a pharmaceutical composition for the treatment of COPD.