HK1036989A - Aryl alkanoylpyridazines - Google Patents

Description

Arylalkanoylpyridazine compounds

The invention relates to arylalkanoyl pyridazine derivatives of formula (I) and physiologically acceptable salts and solvates thereof,wherein B is unsubstituted or substituted by R³A mono-or polysubstituted phenyl ring, Q is absent or an alkylene group having 1 to 4 carbon atoms, R¹、R²Independently of one another are-OR⁴、-S-R⁴、-SO-R⁴、-SO₂-R⁴Or Hal, R¹And R²Taken together may also be-O-CH₂-O-,R³Is R⁴、Hal、OH、OR⁴、OPh、NO₂、NHR⁴、N(R⁴)₂、NHCOR⁴、NHSO₂R⁴

Or NHCOOR⁴,R⁴Is A, cycloalkyl having 3 to 7 carbon atoms, alkylene having 5 to 10 carbon atoms

Cycloalkyl or alkenyl having 2 to 8 carbon atoms, A is alkyl having 1 to 10 carbon atoms which may be substituted by 1 to 5F and/or Cl atoms, and Hal is F, Cl, Br or I.

1-benzoyltetrahydropyridazine compounds useful as ligands for the progesterone receptor are described, for example, in journal of pharmaceutical chemistry (J.Med.chem.)38,4878 (1995).

Similar compounds are also disclosed in DE19632549a 1.

The object of the present invention was to find new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has now been found that the compounds of formula i and their salts and solvates have very valuable pharmacological properties and good tolerability.

In particular, they show a selective inhibition of phosphodiesterase IV, which is accompanied by an increase in intracellular cAMP (N. Sommer et al, Nature medicine, 1,244-248 (1995)).

The inhibition of PDE IV can be demonstrated in a similar manner to that described, for example, in C.W.Davis, journal of biochemistry and biophysics (Biochim. Biophys. acta)797,354-362 (1984).

The compounds of the invention are useful in the treatment of asthma. The anti-asthmatic effects of PDE IV inhibitors are described, for example, in T.J.Torphy et al, thoracic (Thorax),46,512-523(1991) and can be determined, for example, by the methods described in T.Olsson, the report on allergy science (Acta allergologica)26,438-447 (1971).

Since cAMP inhibits osteoclasts and stimulates osteoblasts (s. kasugai et al, M68l and k. miyamoto, M682, abstract of the american society for bone and mineral research 18's annual meeting, 1996), the compounds of the invention are useful in the treatment of osteoporosis.

In addition, the compounds show an antagonistic effect on the production of TNF (tumor necrosis factor) and can therefore be used for the treatment of allergic and inflammatory diseases, autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, Crohn's disease, diabetes or ulcerative colitis, graft rejection, cachexia and sepsis.

The anti-inflammatory effects of the substances of the invention and their effectiveness in the treatment of, for example, autoimmune diseases such as multiple sclerosis or rheumatoid arthritis can be determined in a manner analogous to that of N.Sommer et al, Nature Medicine 1,244-248(1995) or L.Sekut et al, immunology of clinical experiments 100,126-132 (1995).

The compounds are useful for the treatment of cachexia. Anti-cachexia effects can be tested in THF-dependent cachexia models (p. costelli et al, journal of clinical research (j. clin. invest.)95,2367 et al (1995); j.m. argels et al, reviews of drug research (med. res. rev.)17,477 et al (1997)).

PDE IV inhibitors also inhibit the growth of tumor cells and are therefore useful in the treatment of tumors (D. Marko et al, Cell biochemistry and biophysics (Cell biochem. Biophys.)28, p.75 et al (1998)). The role of PDE IV inhibitors in the treatment of tumours is described, for example, in WO9535281, WO9517399 or WO 9600215.

PDE iv inhibitors can reduce mortality in models of sepsis and are therefore useful in the treatment of sepsis (w. fischer et al, biochem. pharmacol. (1993)) 45,2399.

In addition, they are useful for the treatment of memory disorders, atherosclerosis, atopic dermatitis and AIDS.

The role of PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes, atopic dermatitis, psoriasis, AIDS, cachexia, tumor growth or tumor metastasis is described, for example, in EP 779291.

The compounds of formula I can be used as pharmaceutically active compounds in human and veterinary medicine. They are also useful as intermediates for the preparation of other pharmaceutically active compounds.

The invention therefore relates to a process for the preparation of compounds of the formula I and of the salts and solvates thereof as claimed in claim 1, characterized in that a compound of the formula II is reactedWherein R is¹And R²Having the above-mentioned meaning, with a compound of the formula III,wherein B and Q have the abovementioned meanings and L is Cl, Br, OH or a reactive esterified OH group, or else compounds of the formula IVWherein R is¹、R²And Q has the abovementioned meaning, with compounds of the formula V,

B-CO-L V in which B has the abovementioned meaning and L is Cl, Br, OH or a reactive esterified OH group, and/or basic compounds of the formula I are converted into salts thereof by treatment with acids.

Solvates of compounds of formula i refer to adducts of inert solvent molecules with compounds of formula i, which solvates are formed as a result of their mutual attractive forces. Solvates are, for example, mono-or dihydrate or alcoholates.

The radicals R unless otherwise stated hereinbefore or hereinafter¹、R²B, Q and L have the meanings given in formulae I, II, III, IV and V.

A is preferably an alkyl group, and preferably an alkyl group is substituted with 1 to 5 fluorine and/or chlorine atoms.

In the above formula, the alkyl group is preferably an unbranched alkyl group having 1,2, 3,4, 5,6, 7, 8, 9 or 10 carbon atoms, preferably 1,2, 3,4, 5 or 6 carbon atoms, preferably a methyl group, an ethyl group, a trifluoromethyl group, a pentafluoroethyl group or a propyl group, further preferably an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, and an n-pentyl group, a neopentyl group, an isopentyl group or an n-hexyl group; particular preference is given to methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, n-pentyl, n-hexyl or n-decyl.

Cycloalkyl preferably contains 3 to 7 carbon atoms, preferably cyclopropyl or cyclobutyl, furthermore preferably cyclopentyl or cyclohexyl, and cycloheptyl; cyclopentyl is particularly preferred.

Alkenyl is preferably allyl, 2-or 3-butenyl, isobutenyl, sec-butenyl; preference is furthermore given to 4-pentenyl, isopentenyl or 5-hexenyl.

The alkylene group is preferably linear, preferably methylene or ethylene, and furthermore preferably propylene or butylene.

The cycloalkylene radical preferably has 5 to 10 carbon atoms, preferably a methylenecyclopropyl, methylenecyclobutyl, furthermore preferably a methylenecyclopentyl, methylenecyclohexyl or methylenecycloheptyl radical, and also preferably an ethylenecyclopropyl, ethylenecyclobutyl, ethylenecyclopentyl, ethylenecyclohexyl or ethylenecycloheptyl radical, propylenylcyclopentyl, propylenylcyclohexyl, butylenecyclopentyl or butylenecyclohexyl radical.

Hal is preferably F, Cl or Br, and I is furthermore preferred.

Radical R¹And R²May be the same or different and is located at the 3-or 4-position of the phenyl ring. They are, independently of one another, for example hydroxy, -S-CH₃、-SO-CH₃、-SO₂CH₃F, Cl, Br or I, or taken together are methylenedioxy. However, preferably they are each methoxy, ethoxy, propoxy, cyclopentyloxy, or are fluoro-, difluoro-or trifluoromethoxy, or 1-fluoro-, 2-fluoro-, 1, 2-difluoro-, 2, 2-difluoro-, 1,2, 2-trifluoro-or 2,2, 2-trifluoroethoxy.

Radical R¹Methoxy, ethoxy, cyclopentyloxy or isopropoxy are particularly preferred.

Radical R²Methoxy or ethoxy is particularly preferred.

R³Preferably R is⁴F, Cl, Br or I, hydroxy, Oalkyl, OPh, NO₂Alkylamino, cycloalkylamino, dialkylamino, alkylcycloalkylamino, NHCO alkyl, NHCO cycloalkyl, NHSO₂Alkyl, NHSO₂Cycloalkyl, nhcooalkyl or nhcoocycloalkyl, wherein alkyl and cycloalkyl may have the above-mentioned meanings. Particular preference is given to R³Is NO₂Methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy or decyloxy, Cl or F, NCOOCH₃、NCOOC₂H₅、NSO₂CH₃、NCOCH₃Or NCOCH (CH)₃)₂. Radical R³Particularly preferably in the 3-or 4-position of the phenyl ring.

R⁴Preferably alkyl, cycloalkyl, alkenyl or alkylenecycloalkyl having the above-mentioned meanings; alkyl or cycloalkyl groups are particularly preferred.

The radical B is preferably an unsubstituted phenyl ring or a substituted or unsubstituted phenyl ring³A mono-or polysubstituted phenyl ring, wherein R is³Have the meaning indicated above. B is also preferably phenyl, o-, m-or p-methylphenyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-N, N-dimethylaminophenyl, o-, m-or p-nitrophenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-methoxyphenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-isopropoxyphenyl, o-, m-or p-butoxyphenyl, M-or p-pentyloxyphenyl, o-, m-or p-hexyloxyphenyl, o-, m-or p-decyloxyphenyl, o-, m-or p-trifluoromethylphenyl, o-, m-or p-fluorophenyl, o-, m-or p-chlorophenyl, o-, m-or p-bromophenyl, o-, m-or p-acetamidophenyl, o-, m-or p-isopropylcarbonylaminophenyl, o-, m-or p-methylsulfonylaminophenyl, o-, m-or p-ethylsulfonylaminophenyl, o-, m-or p-methoxycarbonylaminophenyl, o-, m-or p-ethoxycarbonylaminophenyl, preference is furthermore given to 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dihydroxyPhenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3, 4-or 3, 5-dimethoxyphenyl.

The group Q is preferably absent or alkylene having the preferred meanings indicated above. It is particularly preferred that Q is absent.

In the present invention, when the groups are present plural times, these groups may be the same or different, that is, they are independent of each other.

The 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 given above. Certain preferred groups of compounds can be represented by the following formulae Ia to Ib, which correspond to formula I and in which the radicals not specified have the meanings given in formula I, but in which, in Ia, R¹And R²Independently of one another OA, Q is absent and B is unsubstituted or substituted by R³Substituted phenyl ring, in Ib, R¹And R²Independently of one another OA, Q is methylene and B is unsubstituted or substituted by R³Substituted phenyl ring, in ic, R¹And R²Taken together are-O-CH₂-O-,

Q is absent, and

b is unsubstituted or substituted by R³A substituted phenyl ring.

The compounds of the formula I and the starting materials for their preparation can be prepared by known Methods, for example those described in the literature (for example Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart), i.e.under known reaction conditions which are suitable for the abovementioned reactions. In this case, other methods known per se may also be used, but are not described in detail here.

In the compounds of the formulae II to IV, R¹And R²Have the meanings indicated above, in particular the preferred meanings given.

In the compounds of the formulae III and IV, Q is absent or is preferably methylene or ethylene, furthermore preferably propylene or butylene.

In the compounds of the formulae III and IV, B has the preferred meanings given and L is Cl, Br, OH or a reactive esterified OH group.

If L is a reactive esterified OH, it is preferably an alkylsulfonyloxy radical having from 1 to 6 carbon atoms, preferably a methylsulfonyloxy radical, or an arylsulfonyloxy radical having from 6 to 10 carbon atoms, preferably a phenyl or p-tolylsulfonyloxy radical, and furthermore preferably a 2-naphthalene-sulfonyloxy radical.

If desired, the starting materials can also be formed in situ, so that they can be reacted further without isolation to give the compounds of the formula I.

On the other hand, the reaction may be carried out stepwise.

The compounds of the formula I are preferably obtained by reacting compounds of the formula II with compounds of the formula III.

Some starting materials of the formulae II and III are known. If they are unknown, they can be prepared by known methods.

In particular, the reaction of the compound of formula II with the compound of formula III is carried out in the presence or absence of an inert solvent at a temperature of from about-20 to about 150 deg.C, preferably from 20 to 100 deg.C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether (methyl or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides such as acetamide, dimethylacetamide 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 the above solvents.

The compounds of formula I may also be prepared by reacting a compound of formula IV with a compound of formula V.

In general, the starting compounds of the formulae IV and V are known. Compounds of the formula IV are described, for example, in DE 19632549. If they are unknown, they can be prepared by known methods. The preparation of 1-benzoyltetrahydropyridazine is described, for example, in journal of medicinal chemistry (J.Med.chem.)38,4878 (1995).

In the compounds of the formula V, the radical-CO-L is a previously activated carboxylic acid, preferably an acid halide.

The reaction of the compound of formula iv with the compound of formula v is carried out under the same conditions, i.e. under the same reaction time, temperature and solvent, as described for the reaction of the compound of formula ii and the compound of formula iii.

The base of formula i may be converted to the corresponding acid addition salt with an acid, for example by reacting equal amounts of the base and acid in an inert solvent such as ethanol and then evaporating. Suitable acids for this reaction are those which can form physiologically acceptable salts. For this purpose, use may be made of 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, arylaliphatic, 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, methanesulfonic acid or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid or naphthalenedisulfonic acid, dodecylsulfuric acid. Salts with physiologically unacceptable acids, such as picrates, can be used for the isolation and/or purification of compounds of formula I.

Alternatively, if desired, a base (e.g., sodium or potassium hydroxide, sodium or potassium carbonate) may be used to liberate the free base of formula I from the salt.

The invention also relates to the use of the compounds of formula (I) and their physiologically acceptable salts and solvates as medicaments.

The invention also relates to the use of the compounds of formula (I) and their physiologically acceptable salts and solvates as phosphodiesterase IV inhibitors.

The invention also relates to the use of compounds of the formula I and/or physiologically acceptable salts and/or solvates thereof for producing pharmaceutical preparations, in particular non-chemically. For this purpose, they can be combined with at least one solid, liquid and/or semi-liquid excipient or adjuvant, if desired, with one or more other active ingredients in a suitable dosage form.

The invention also relates to pharmaceutical preparations containing at least one compound of the formula I and/or one of its physiologically acceptable salts and/or solvates.

These formulations are useful as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration or topical application and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, triacetin, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and vaseline. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices, drops are used for oral administration; suppositories for rectal administration; solutions, preferably oily or aqueous solutions, and suspensions, emulsions or implants for parenteral administration; ointments, creams or powders are used for topical administration. The novel compounds can also be freeze-dried and the lyophilizates obtained can be used, for example, for the production of injection preparations. The formulations may be sterile and/or may contain adjuvants, such as lubricating, preserving, stabilizing and/or wetting agents, emulsifying agents, salts for regulating the osmotic pressure, buffer substances, coloring, flavoring and/or one or more other active compounds, for example one or more vitamins.

The compounds of formula (I) and their physiologically acceptable salts and solvates are useful in the control of diseases in which increased cAMP (cyclic adenosine monophosphate) levels inhibit or prevent inflammation and cause muscle relaxation. The PDE iv inhibitors of the invention are useful, inter alia, 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.

In this connection, it is generally preferred to administer the substances according to the invention in a dose corresponding to 1 to 500mg of the compound cyclopentapyrazine, in particular in a dose unit of 5 to 100 mg. The daily dosage is preferably about 0.02 to 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 route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Oral administration is preferred.

Herein, all temperatures are expressed in ° c. In the following examples, "conventional work-up" means that, if desired, water is added and, if desired, the pH of the mixture is adjusted to 2 to 10, depending on the structure of the end product, and then extraction is carried out with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and then evaporated, and the residue is purified by chromatography on silica gel and/or crystallization.

Example 1

1.1g of 1- (3-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine (m.p.180 ℃ C.) [ obtainable by catalytic hydrogenation of 1- (3-nitrobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine (m.p.173 ℃ C.) in 150ml of tetrahydrofuran in the presence of 3.5g of Raney nickel (Raney nickel) ] and a solution of 0.6ml of pyridine in 50ml of acetonitrile are treated with 0.5g of 4-chlorobenzoyl chloride and stirred for 2 hours. The solvent is distilled off and the residue is worked up in a conventional manner. After recrystallization N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-chlorobenzoyl-3-carboxamide was obtained, m.p.236 ℃.

The following compounds were prepared by reacting 1- (3-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine with the starting materials in an analogous manner: reacting with 3-nitrobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-nitrobenzoyl-3-carboxamide, m.p.160 ℃; reacting with 4-nitrobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-nitrobenzoyl-3-carboxamide, m.p.255 ℃; reacting with 4-methoxybenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-3-carboxamide, m.p.206 ℃; reaction with 4-methylbenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methylbenzoyl-3-carboxamide, m.p.219 ℃; reaction with benzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) benzoyl-3-carboxamide, m.p.203 ℃; reacting with 3, 4-dichlorobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3, 4-dichlorobenzoyl-3-carboxamide, m.p.177 ℃; reaction with 4-trifluoromethylbenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-trifluoromethylbenzoyl-3-carboxamide, m.p.207 ℃; reaction with 3-chlorobenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-chlorobenzoyl-3-carboxamide, m.p.121 ℃; reaction with 4-fluorobenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-fluorobenzoyl-3-carboxamide, m.p.236 ℃; reaction with 4-butoxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-3-carboxamide, m.p.123 ℃; reaction with 4-pentyloxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-pentyloxybenzoyl-3-carboxamide, m.p.145 ℃; reaction with 4-ethoxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-3-carboxamide, m.p.174 ℃; reacting with 3, 4-dimethoxybenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3, 4-dimethoxybenzoyl-3-carboxamide, m.p.160 ℃; reaction with 3-methylbenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methylbenzoyl-3-carboxamide, m.p.115 ℃; reacting with 3-methoxybenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methoxybenzoyl-3-carboxamide, m.p.161 ℃.

Example 2

1.1g of 1- (4-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine (m.p.150 ℃ C.) [ prepared by catalytic hydrogenation of 1- (4-nitrobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine (m.p.159 ℃ C.) in 150ml of tetrahydrofuran in the presence of 3.5g of Raney nickel at room temperature ] and 0.6ml of a solution of pyridine in 50ml of acetonitrile are treated with 0.5g of 4-nitrobenzoyl chloride and stirred for 2 hours. The solvent is removed and the residue is worked up in a conventional manner. After recrystallization N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine-1-carbonyl) phenyl) -4-nitrobenzoyl-4-carboxamide was obtained, m.p.233 ℃.

The following compounds were prepared by reacting 1- (4-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine with the starting materials in an analogous manner: reacting with 4-methoxybenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-4-carboxamide, m.p.201 ℃; reaction with 4-fluorobenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-fluorobenzoyl-4-carboxamide, m.p.193 ℃; reaction with benzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) benzoyl-4-carboxamide, m.p.186 ℃; reaction with 4-chlorobenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-chlorobenzoyl-4-carboxamide, m.p.200 ℃; reacting with 3-nitrobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-nitrobenzoyl-4-carboxamide, m.p.233 ℃.

Example 3:

a suspension of 4.70g of 3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazine in 150ml of THE is treated with 2.24g of potassium tert-butoxide and stirred for 30 minutes. 5.44g of 3-benzoylaminobenzoyl chloride were added and the mixture was stirred at room temperature for 10 hours. The solvent is distilled off and the residue is worked up in a conventional manner. N- (3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl-3-benzoyl-3-carboxamide is obtained at m.p.196 ℃.

The following compounds were prepared by reacting 3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazine with the starting materials in an analogous manner: reacting with 3- (3, 4-dimethoxy benzoyl) aminobenzoyl chloride to obtain

N- (3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3, 4-dimethoxybenzoyl-3-carboxamide, m.p.183 ℃ reaction with 3- (3-methylbenzoyl) aminobenzoyl chloride to give

N- (3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methylbenzoyl-3-carboxamide, m.p.171 ℃, with 3- (3-chlorobenzoyl) aminobenzoyl chloride to give

N- (3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-chlorobenzoyl-3-carboxamide, m.p.172 ℃ with 3- (4-methoxybenzoyl) aminobenzoyl chloride to give

N- (3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-3-carboxamide, m.p.203 ℃.

Example 4:

in analogy to example 2, 1- (4-aminobenzoyl) -3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-butoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-4-carboxamide, m.p.161 ℃; reaction with 4-ethoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-4-carboxamide, m.p.171 ℃; reaction with benzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -benzoyl-4-carboxamide, m.p.220 ℃; reaction with 3-methylbenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methylbenzoyl-4-carboxamide, m.p.196 ℃; reaction with 4-cyclopentyloxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-cyclopentyloxybenzoyl-4-carboxamide, m.p.163 ℃; reaction with 4-isopropoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-isopropoxybenzoyl-4-carboxamide, m.p.183 ℃; reaction with 4-propoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-propoxybenzoyl-4-carboxamide, m.p.171 ℃.

Example 5:

in a similar manner to example 1, 1- (3-aminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 3-methylbenzoyl chloride to give

N- (3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methylbenzoyl-3-carboxamide, m.p.144 ℃; reacting with 4-methoxybenzoyl chloride to obtain

N- (3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-3-carboxamide, m.p.194 ℃; reaction with 4-phenylbenzoyl chloride to give

N- (3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-phenylbenzoyl-3-carboxamide, m.p.140 ℃.

Example 6:

in a similar manner to example 1, 1- (3-aminobenzoyl) -3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-chlorobenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-chlorobenzoyl-3-carboxamide, m.p.152 ℃; reacting with 3-nitrobenzoyl chloride to obtain

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-nitrobenzoyl-3-carboxamide, m.p.105 ℃; reaction with 4-butoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-3-carboxamide, m.p.103 ℃; reaction with 4-ethoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-3-carboxamide, m.p.181 ℃.

Example 7:

in a similar manner to example 2, 1- (4-aminobenzoyl) -3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-chlorobenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-chlorobenzoyl-4-carboxamide, m.p.195 ℃; reacting with 3-nitrobenzoyl chloride to obtain

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-nitrobenzoyl-4-carboxamide, m.p.218 ℃; reaction with 4-butoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-4-carboxamide, m.p.103 ℃; reaction with 4-ethoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-4-carboxamide, m.p.176 ℃; reacting with 4-methoxybenzoyl chloride to obtain

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-4-carboxamide, m.p.192 ℃.

Example 8:

in analogy to example 1, 1- (3-aminobenzoyl) -3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-ethoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-3-carboxamide, m.p.160 ℃; reaction with 4-butoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-3-carboxamide, m.p.160 ℃; reacting with 4-methoxybenzoyl chloride to obtain

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-3-carboxamide, m.p.161 ℃; reaction with 4-isopropoxybenzoyl chloride to give

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-isopropoxybenzoyl-3-carboxamide, m.p.168 ℃; reacting with 3-nitrobenzoyl chloride to obtain

N- (3- (3-isopropoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-nitrobenzoyl-3-carboxamide, m.p.194 ℃.

Example 9:

in a similar manner to example 1, 1- (3-aminobenzoyl) -3- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting material to give the following compound: reaction with 4-ethoxybenzoyl chloride to give

N- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxybenzoyl-3-carboxamide, m.p.176 ℃; reaction with 4-butoxybenzoyl chloride to give

N- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-butoxybenzoyl-3-carboxamide, m.p.143 ℃; reaction with 4-pentyloxybenzoyl chloride to give

N- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-pentyloxybenzoyl-3-carboxamide, m.p.140 ℃; reaction with 3-propoxybenzoyl chloride to give

N- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-propoxybenzoyl-3-carboxamide, m.p.153 ℃; reaction with 4-hexyloxybenzoyl chloride to give

N- (3, 4-dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-hexyloxybenzoyl-3-carboxamide, m.p.162 ℃; reaction with 4-decyloxybenzoyl chloride to give

N- (3, 4-Dimethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-decyloxybenzoyl-3-carboxamide, m.p.130 ℃.

Example 10:

in a similar manner to example 1, 1- (3-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-isopropoxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-isopropoxybenzoyl-3-carboxamide, m.p.108 ℃; reaction with 3-ethoxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-ethoxybenzoyl-3-carboxamide, m.p.142 ℃; reaction with 3-butoxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-butoxybenzoyl-3-carboxamide, m.p.144 ℃; reaction with 3-hexyloxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-hexyloxybenzoyl-3-carboxamide, m.p.137 ℃; reaction with 4-decyloxybenzoyl chloride to give

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-decyloxybenzoyl-3-carboxamide, m.p.123 ℃; reacting with 3-methoxycarbonylaminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methoxycarbonylaminobenzoyl-3-carboxamide, m.p.193 ℃; reacting with 3-ethoxycarbonyl amino benzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-ethoxycarbonylaminobenzoyl-3-carboxamide, m.p.221 ℃; reacting with 3-methanesulfonyl aminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-methanesulfonylaminobenzoyl-3-carboxamide, m.p.174 ℃; reacting with 4-methoxycarbonylaminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxycarbonylaminobenzoyl-3-carboxamide, m.p.234 ℃; reacting with 4-ethoxycarbonyl amino benzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxycarbonylaminobenzoyl-3-carboxamide, m.p.221 ℃; reacting with 4-acetylaminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-acetylaminobenzoyl-3-carboxamide, m.p.244 ℃.

Example 11:

in analogy to example 2, 1- (4-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the stated starting materials to yield the following compounds: reacting with 4-acetylaminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-acetylaminobenzoyl-4-carboxamide, m.p. > 266 ℃; reacting with 4-isopropyl carbonyl amino benzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-isopropylcarbonylaminobenzoyl-4-carboxamide, m.p. > 260 ℃; reacting with 4-methoxycarbonylaminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxycarbonylaminobenzoyl-4-carboxamide, m.p.275 ℃; reacting with 4-ethoxycarbonyl amino benzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-ethoxycarbonylaminobenzoyl-4-carboxamide, m.p.246 ℃; reacting with 4-methanesulfonyl aminobenzoyl chloride to obtain

N- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methanesulfonylaminobenzoyl-4-carboxamide, m.p. > 260 ℃.

Example 12:

in a similar manner to example 1, 1- (3-aminobenzoyl) -3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazine was reacted with the starting materials to give the following compounds: reaction with 4-pentyloxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-pentyloxybenzoyl-3-carboxamide, m.p.145 ℃; reaction with 3-propoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-propoxybenzoyl-3-carboxamide, m.p.112 ℃; reaction with 3-butoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-butoxybenzoyl-3-carboxamide, m.p.120 ℃; reaction with 3-hexyloxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-hexyloxybenzoyl-3-carboxamide, m.p.151 ℃; reaction with 3-ethoxybenzoyl chloride to give

N- (3- (3, 4-diethoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-ethoxybenzoyl-3-carboxamide, m.p.141 ℃.

The following examples relate to pharmaceutical formulations:

example A: injection medicine bottle

A solution of 100g of the active compound of the formula I and 5g of disodium hydrogenphosphate in 3 l of double distilled water is brought to pH6.5 with 2N hydrochloric acid, sterile-filtered, dispensed into injection vials, freeze-dried under sterile conditions and then sterile-sealed. Each injection vial contained 5mg of active compound.

Example B: suppository

A mixture of 20g of the active compound of the formula I with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into moulds and then cooled. Each suppository contains 20mg of active compound.

Example C: solution preparation

Preparation of 1g of active Compound of formula I, 9.38g of NaH₂PO₄·2H₂O、28.48gNa₂HPO₄·12H₂A solution of O and 0.1g benzalkonium chloride in 940ml double distilled water. This was adjusted to pH6.8, made into 1 liter and then sterilized by radiation. The solution can be used in the form of eye drops.

Example D: ointment

500mg of active compound of the formula I are mixed with 99.5g of vaseline under sterile conditions. Example E: tablet formulation

A mixture of 1kg of active compound 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 to give tablets, each containing 10mg of active compound.

Example F: coated tablet

Tablets were compressed in a similar manner to example E and then coated in a conventional manner with a coating agent comprising sucrose, potato starch, talc, tragacanth and a coloring agent.

Example G: capsule

2kg of active compound of formula I are dispensed in conventional manner into hard gelatin capsules so that each capsule contains 20mg of active compound.

Example H: ampoule (CN)

1kg of a 60 l double-distilled aqueous solution of the active compound of the formula I are sterile-filtered, dispensed into ampoules, freeze-dried under sterile conditions and then sterile-sealed. Each ampoule contains 10mg of active compound.

Example I: inhalation spray

14g of the active compound of the formula I are dissolved in 10 l of isotonic sodium chloride solution and the solution is dispensed into commercially available spray containers with pump means. The solution may be sprayed into the oral cavity or into the nose. Each ejection (about 0.1ml) corresponds to a dose of about 0.14 mg.

Claims (10)

1. Compounds of formula (I) and physiologically acceptable salts and solvates thereof,

wherein

B is unsubstituted or substituted by R³A mono-or poly-substituted phenyl ring,

q is absent or an alkylene group containing 1 to 4 carbon atoms,

R¹、R²independently of one another are-OR⁴、-S-R⁴、-SO-R⁴、-SO₂-R⁴Or a Hal (hydrogen-to-oxygen) compound,

R¹and R²Taken together may also be-O-CH₂-O-,

R³Is R⁴、Hal、OH、OR⁴、OPh、NO₂、NHR⁴、N(R⁴)₂、NHCOR⁴、NHSO₂R⁴Or NHCOOR⁴,

R⁴Is A, cycloalkyl having 3 to 7 carbon atoms, alkylenecycloalkyl having 5 to 10 carbon atoms or alkenyl having 2 to 8 carbon atoms,

a is an alkyl radical having 1 to 10 carbon atoms which may be substituted by 1 to 5F and/or Cl atoms, and

hal is F, Cl, Br or I.

2. A compound of formula i according to claim 1, which is:

(a) n- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-chlorobenzoyl-3-carboxamide;

(b) n- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-pentyloxybenzoyl-3-carboxamide;

(c) n- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -4-methoxybenzoyl-3-carboxamide;

(d) n- (3- (3-ethoxy-4-methoxyphenyl) -1,4,5, 6-tetrahydropyridazin-1-ylcarbonyl) phenyl) -3-chlorobenzoyl-3-carboxamide.

3. A process for the preparation of the compounds of formula I and their salts as claimed in claim 1, characterized in that compounds of formula II are reactedWherein R is¹And R²Having the above-mentioned meaning, with a compound of the formula III,wherein B and Q have the abovementioned meanings and L is Cl, Br, OH or a reactive esterified OH group, or else the conversion of the formula IVCompound (I)Wherein R is¹、R²And Q has the abovementioned meaning, with a compound of the formula V, B-CO-L V in which B has the abovementioned meaning and L is Cl, Br, OH or a reactive esterified OH group, and/or a basic compound of the formula I is converted into a salt of this compound by treatment with an acid.

4. A compound of the formula i as claimed in claim 1 and the physiologically acceptable salts and solvates thereof for use as a medicament.

5. Compounds of formula i according to claim 1 and their physiologically acceptable salts and solvates as phosphodiesterase iv inhibitors.

6. Pharmaceutical preparation, characterized in that it contains at least one compound of the formula i according to claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates.

7. Process for the production of pharmaceutical preparations, characterized in that a compound of the formula i according to claim 1 and/or one of its physiologically acceptable salts and/or one of its solvates is brought into a suitable dosage form together with at least one solid, liquid and/or semi-liquid excipient or adjuvant.

8. Compounds of formula i as claimed in claim 1 and their physiologically acceptable salts and solvates for use in the control 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.

9. The use of a compound of the formula i as claimed in claim 1 and/or of a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the control of 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, tumour growth or tumour metastasis, sepsis, memory disorders, atherosclerosis and AIDS.

10. The use of a compound of the formula i as claimed in claim 1 and/or physiologically acceptable salts and/or solvates thereof for the control of diseases.