KR20020000550A - Use of arylalkanoylpyridazines - Google Patents

Abstract

The present invention provides a compound of formula 1 for the preparation of a medicament for the treatment of osteoporosis, tumors, arteriosclerosis, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis and AIDS:

[Formula 1]

Wherein R ¹ , R ² , Q and B have the meaning given in claim 1, and / or the use of physiologically acceptable salts thereof.

Description

Uses of arylalkanoylpyridazines {USE OF ARYLALKANOYLPYRIDAZINES}

Such compounds are known from WO 98/06704.

The present invention provides a compound of formula 1 for the manufacture of a medicament for treating osteoporosis, tumors, arteriosclerosis, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis and AIDS:

(Wherein

B is A, OA, NH ₂ , NHA, NAA 'or 1-4 N, O and / or S atoms which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and / or OA Branch is an aromatic heterocycle,

Q is absent or is alkylene having 1 to 6 carbon atoms,

R ¹ , R ² are each independently of each other -OH, OR ⁵ , -SR ⁵ , -SO-R ⁵ , -SO ₂ -R ⁵ , Hal, -NO ₂ , -NH ₂ , -NHR ⁵ or -NR ⁵ R ⁶ ,

R ¹ and R ² together are —O—CH ₂ —O—,

R ⁵ and R ⁶ are each independently of each other A, cycloalkyl having 3 to 7 carbon atoms, methylenecycloalkyl having 4 to 8 carbon atoms, or alkenyl having 2 to 8 carbon atoms,

A and A 'are each independently alkyl having 1 to 10 carbon atoms which may be substituted by 1 to 5 F and / or Cl atoms,

Hal is F, Cl, Br or I)

And / or the use of physiologically acceptable salts thereof.

The present invention is based on the discovery of new uses for the compounds of formula (1), in particular the use of enabling the preparation of medicaments.

It has been found that the compound of formula 1 and salts thereof have very useful pharmacological properties with good tolerance.

In particular, they have been shown to selectively inhibit phosphodiesterase IV, increasing intracellular cAMP (N. Sommer et al., Nature Medicine, 1 , 244-248 (1995)). For example, similar to CW Davis in Biochim. Biophys. Acta 797 , 354-362 (1984), the inhibition of PDE IV can be confirmed.

The compounds according to the invention can be used in the treatment of asthma diseases. The anti-asthmatic action of PDE IV inhibitors is described in TJ Torphy et al., In Thorax, 46, 512-523 (1991), and in T. Olson, Acta allergologica 26, 438-447 (1971)).

cAMP inhibits osteoblasts and stimulates osteoblasts (S. Kasugai et al., M681, and K. Miyamoto, M682, in Abstract of the American Society for Bone and Mineral Research 18 ^th annual meeting, 1996) The compounds according to the invention can be used for the treatment of osteoporosis.

The compounds also antagonize the production of Tumor Necrosis Factor (TNF) and are therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases and transplant rejection. They can be used to treat memory disorders, tumors, arteriosclerosis, rheumatoid arthritis, multiple sclerosis, Crohn's disease, atopic dermatitis, diabetes, ulcerative colitis and AIDS.

The action of PDE IV inhibitors in the treatment of asthma, inflammatory diseases, diabetes, atopic dermatitis, psoriasis, AIDS, tumor growth or tumor metastasis is described, for example, in EP 77 92 91.

The anti-inflammatory action of the substances according to the invention and their efficacy in the treatment of, for example, autoimmune diseases, multiple sclerosis or rheumatoid arthritis are described in N. Sommer et al., Nature Medicine, 1 , 244-248 ( 1995) or L. Sekut et al., Clin. Exp. Immunol., 100 , 126-132 (1995)).

The action of PDE IV inhibitors in the treatment of tumors is disclosed for example in WO 95 35 281, WO 95 17 399 or WO 96 00 215.

The compound of formula 1 may be used as a pharmaceutically active ingredient in human and animal pharmaceuticals. They can also be used as intermediates for preparing other pharmaceutically active compounds.

The compound of formula 1 may have a chiral center and therefore may exist in various stereoisomeric forms. Both of these forms (eg R and S forms) and mixtures thereof (eg R and S forms) are included in Formula 1.

The preparation of such compounds is disclosed in WO 98/06704.

A and A 'are preferably alkyl, more preferably alkyl substituted with 1 to 5 fluorine and / or chlorine atoms.

Alkyl is preferably not branched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1, 2, 3, 4 or 5 carbon atoms, preferably Methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, also preferably isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, n-pentyl, neopentyl or isopentyl.

Cycloalkyl preferably has 3 to 7 carbon atoms, preferably cyclopropyl or cyclobutyl, more preferably cyclopentyl or cyclohexyl, and also cycloheptyl.

Methylenecycloalkyl preferably has 4 to 8 carbon atoms, preferably methylenecyclopropyl or methylenecyclobutyl, and also preferably methylenecyclopentyl or methylenecyclohexyl and also methylenecycloheptyl.

Alkenyl is preferably vinyl, 1- or 2-propenyl, 1-butenyl, isobutenyl, secondary butenyl, and more preferably 1-pentenyl, isopentenyl or 1-hexenyl.

The alkylene is preferably not branched, preferably methylene or ethylene, and also preferably propylene or butylene.

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

The radicals R ¹ and R ² may be the same or different and are in the 3- or 4-position of the phenyl ring. For example, they are independently of each other hydroxyl, -S-CH ₃ , -SO-CH ₃ , -SO ₂ CH ₂ , F, Cl, Br or I or together are methylenedioxy. However, particularly preferably they are methoxy, ethoxy, propoxy, cyclopentoxy, or fluoro-, difluoro-, trifluoromethoxy, 1-fluoro-, 2-fluoro-, 1,2 -Difluoro-, 2,2-difluoro-, 1,2,2-trifluoro- or 2,2,2-trifluoroethoxy.

The radical B is preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrroyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- Or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, more preferably 1,2,3-triazole-1-,- 4- or -5-yl, 1,2,4-triazol-1-,-3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazole-4- or -5-yl, 1,2,4-oxadiazole-3- or -5-yl, 1,3,4-thiadiazole-2- or -5-yl, 1,2,4-thiadiazole -3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5- , 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7- Indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6 -Or 7-benz Sazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6 Or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-shinolinyl , 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

The radical B is also preferably methyl, ethyl, propyl, n-butyl, methoxy, ethoxy, propoxy, N-methylamino, N, N-dimethylamino, N-ethylamino or N, N-diethylamino to be.

All radicals which occur multiple times in the present invention may be the same or different, ie are independent of each other.

Accordingly, the present invention particularly provides for the use of compounds of formula 1 in which one or more of the radicals mentioned have one of the preferred meanings indicated above. Some preferred groups of compounds may be represented by the following Formulas 1a to 1e, and these radicals corresponding to Formula 1 and not shown in detail have the meanings shown in Formula 1,

In 1a,

R ¹ and R ² are each independently OA,

Q is absent,

B is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl or isoxazolyl;

In 1b,

R ¹ and R ² are each independently OA,

Q is methylene,

B is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl or isoxazolyl;

In 1c,

R ¹ and R ² together are —O—CH ₂ —O—,

Q is absent or alkylene having 1 to 6 carbon atoms,

B is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl or isoxazolyl;

In 1d,

R ¹ and R ² are each independently OA,

Q is absent or alkylene having 1 to 6 carbon atoms,

B is A or OA;

In 1e,

R ¹ and R ² are each independently OA,

Q is absent or alkylene having 1 to 6 carbon atoms,

B is pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl, isoxazolyl, A, OA or NH ₂ .

Compounds of formula 1 and starting materials for their preparation are described in, for example, Houben-Weyl, Mothoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart By known methods, ie suitable for the above reactions and prepared under known reaction conditions. Although not described in detail herein, known modification methods may be used.

In the compounds of the formulas (2) and (4), R ¹ , R ² and Q have the indicated meanings, in particular the preferred meanings indicated.

In the compounds of the formulas (3) and (4), Q is preferably methylene or ethylene and also preferably propylene or butylene.

In formulas (3) and (5), B has the preferred meaning indicated and L is Cl, Br, OH or a reactive esterified OH group.

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

If necessary, the starting material may be formed in situ and reacted immediately to form the compound of formula 1 without being separated from the reaction mixture. The reaction can also be carried out step by step.

Preferably, the compound of formula 1 may be obtained by reacting a compound of formula 2 with a compound of formula 3.

Starting materials of formulas (2) and (3) are known in some cases. If they are not known, they can be prepared by known methods.

Specifically, the reaction of the compound of formula 2 with the compound of formula 3 is carried out in the presence or absence of an inert solvent at a temperature of about -20 to about 150 ° C, preferably 20 to 100 ° C.

Examples of suitable inert solvents include 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 glycol 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); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of these solvents.

The compound of formula 1 can also be obtained by reacting a compound of formula 4 with a compound of formula 5.

In general, starting compounds of formulas (4) and (5) are known. If they are not known, they can be prepared by known methods. Thus, for example, the preparation of 1-benzoyltetrahydropyridazine is described in J. Med. Chem. 38, 4878 (1995).

In the compound of formula 5, the radical -CO-L is a preactivated carboxylic acid, preferably a carboxylic acid halide.

The reaction of the compound of formula 4 with the compound of formula 5 takes place under the same conditions as described for the reaction of the compound of formula 2 with the compound of formula 3 with respect to reaction time, temperature and solvent.

The base of formula 1 can be converted to the related acid addition salt using acid, for example by reacting an equal amount of base with an acid in an inert solvent such as ethanol and then evaporating. Acids possible for this reaction are especially those that produce physiologically acceptable salts. Thus, halogenated acids such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho-phosphoric acid, inorganic acids such as sulfamic acid, and especially 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, isnicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p Aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic mono- or organic acids such as polybasic carboxyl, sulfone or sulfuric acid can be used -toluenesulfonic acid, naphthalene mono- and -disulfonic acid, and lauryl sulfate. Salts with physiologically unacceptable acids such as, for example, picrates may also be used for the separation and / or purification of the compounds of formula (1).

On the other hand, if necessary, the free base of formula (1) can be liberated from its salt using a base (e.g., sodium hydroxide or potassium hydroxide or sodium carbonate or potassium carbonate).

The compounds of formula 1 may be used as medicaments in human or veterinary medicine. Possible excipients are, for example, intestinal (eg, water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or wascelin Oral or organic or inorganic material suitable for parenteral administration or topical application and which does not react with the novel compound. Tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are used especially for oral administration, suppositories are used for rectal administration, solutions, preferably oils or aqueous solutions, also suspensions, emulsions or implants Is used for parenteral administration and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the resulting lyophilisate can be used, for example, to prepare injections. The formulation may be sterile and / or lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more vitamins, for example It may contain adjuvants such as one or more other active compounds.

Compounds of formula (1) and their physiologically acceptable salts can be used to control disease by increasing cAMP (cyclic adenosine monophosphate) levels, resulting in inhibition or prevention of inflammation and muscle relaxation. In particular, the compounds according to the invention can be used for the treatment of osteoporosis, tumors, asthma, chronic bronchitis, atopic dermatitis, psoriasis and other skin diseases and autoimmune diseases.

In this regard, in general, the substances according to the invention are preferably administered at a dosage of about 1 to 500 mg, in particular about 5 to 100 mg per dosage unit. The daily dosage is preferably about 0.02 to 10 mg / kg body weight. However, the specific dosage for each patient may vary with all kinds of factors, e.g., efficacy, age, weight, general health, sex, diet, time and route of administration, and rate of excretion, pharmaceutical combination of the specific compound used. And the severity of the particular disease to be treated. Oral administration is preferred.

The compound of formula 1 may comprise one or more chiral centers. In this case, they are generally present in racemic form. The racemates obtained can be separated physically or chemically into their enantiomers by known methods. It is preferred to react with an optically active separating agent to form diastereomers from the racemic mixture.

Of course, it is also possible to obtain an optically active compound of formula (I) by this method using already optically active starting materials.

Formula 1 includes all stereoisomers such as racemates and mixtures thereof.

All temperatures above and below are given in degrees Celsius. In the following examples, "normal reaction finishing" means: water is added if necessary, pH value is adjusted to 2-10 if necessary according to the composition of the final product, extracted with ethyl acetate or dichloromethane, and the organic phase is separated Dry, sodium sulfate, evaporate and purify the residue by chromatography on silica gel and / or by crystallization.

Mass spectrometer (MS)

EI (electron impact ionization) M ⁺

Fast Atom Bombardment (M + H) ⁺

Example 1

2.24 g of potassium tert-butoxide in suspension of 4.70 g of 3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine ("A") suspended in 150 mL THF. Mix with and stir the suspension for 30 minutes. 7.3 g of 4-nicotinoylaminobenzoyl chloride is added and the mixture is stirred at room temperature for 10 hours. The solvent is removed and the residue is finished with the usual reaction. 1- (4-nicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 239 ° C. (decomposition) is obtained.

Similarly, "A"

By reaction with 4-isonicotinoylaminobenzoyl chloride:

1- (4-isonicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 247 ° C. (decomposition) is obtained.

Example 2

1- (4-nitrobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5 in 150 ml tetrahydrofuran in the presence of 3.5 g Raney nickel at room temperature in [150 ml of acetonitrile] 2.0 g of 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridine obtained by catalytic hydrogenation of 6-tetrahydropyridazine Chopped, mp A solution of 197 ° C. and 1.6 mL of pyridine is mixed with 1.2 g nicotinoyl chloride hydrochloride and the mixture is stirred for 2 hours. The solvent is removed and the residue is finished with the usual reaction. Recrystallization gave 1- (4-nicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 239 ° C. (decomposition) is obtained.

Similarly "amine derivatives":

1- (3-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 168 ° C .;

1- (2-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 154 ° C .;

1- (3-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 168 ° C .;

1- (3-aminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine

Reaction with nicotinoyl chloride causes the following compounds:

1- (3-nicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, 159 ° C. (decomposition);

1- (2-nicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-nicotinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, 235 ° C .;

1- (4-nicotinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 224 ° C. (decomposition);

1- (3-nicotinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly the "amine derivative" is reacted with isicotinoyl chloride to give the following compounds:

1- (4-isonicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 247 ° C. (decomposition);

1- (3-isonicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, 175 ° C. (decomposition);

1- (2-isonicotinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-isonicotinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 266 ° C .;

1- (3-isonicotinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-isonicotinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 244 ° C. (decomposition);

1- (3-isonicotinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-isonicotinoylaminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-isonicotinoylaminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-isonicotinoylaminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" is reacted with picolinoyl chloride to yield the following compounds:

1- (4-picolinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-picolinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-picolinoylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-picolinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-picolinoylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-picolinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-picolinoylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-picolinoylaminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-picolinoylaminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

Obtain 1- (4-picolinoylaminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine.

Similarly, the "amine derivative" is reacted with furan-2-carbonyl chloride to yield the following compounds:

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (furan-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (furan-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (furan-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (furan-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (furan-2-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" is reacted with thiophene-2-carbonyl chloride to yield the following compounds:

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-thiophene-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-thiophene-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-thiophene-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-thiophene-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-thiophene-2-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" is reacted with pyrazine-2-carbonyl chloride to yield the following compounds:

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 213 ° C .;

1- (3- (pyrazine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 204 ° C .;

1- (2- (pyrazine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 186 ° C .;

1- (3- (pyrazine-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 225 ° C .;

1- (3- (pyrazine-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrazine-2-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" is reacted with imidazole-4-carbonyl chloride to yield the following compounds:

1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (imidazole-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (imidazole-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (imidazole-4-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (imidazole-4-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

Obtain 1- (4- (imidazole-4-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine.

Similarly, the "amine derivative" is reacted with 2,4-dimethylthiazole-5-carbonyl chloride to yield the following compounds:

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyripy chop,

1- (3- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyripy chop,

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydro Pyridazine,

1- (3- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydro Pyridazine,

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydro Pyridazine,

1- (4- (2,4-dimethylthiazole-5-carbonylamino) -benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetra Obtain hydropyridazine.

Similarly, the "amine derivative" is reacted with isoxazole-5-carbonyl chloride to yield the following compounds:

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (isoxazole-5-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (isoxazole-5-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (isoxazole-5-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (isoxazole-5-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (isoxazole-5-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" is reacted with pyrimidine-2-carbonyl chloride to yield the following compounds:

1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (pyrimidine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (pyrimidine-2-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

Obtain 1- (4- (pyrimidine-2-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine.

Similarly, the "amine derivative" is reacted with pyrimidine-4-carbonyl chloride to yield the following compounds:

1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 196 ° C .;

1- (3- (pyrimidine-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2- (pyrimidine-4-carbonylamino) benzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

Obtain 1- (4- (pyrimidine-4-carbonylamino) benzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine.

Similarly,

1- (4-aminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-aminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-aminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzylcarbonyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-aminobenzylcarbonyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzylcarbonyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-aminobenzylcarbonyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzylcarbonyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzylcarbonyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzylcarbonyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine was reacted with nicotinoyl chloride to :

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. 225 ° C .;

1- (3-nicotinoylaminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-nicotinoylaminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-nicotinoylaminobenzylcarbonyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-nicotinoylaminobenzylcarbonyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-nicotinoylaminobenzylcarbonyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, 1- (4-aminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine is reacted with isicotinoyl chloride

1- (4-isonicotinoylaminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, hydrochloride, m.p. Get 209 ° C,

By reacting with ethyl chloroformate

1- (4-ethoxycarbonylaminobenzylcarbonyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. Obtain 143 ° C.

Example 3

2.0 g of 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, 160 g of dichloromethane, m.p. A solution of 197 ° C. and 0.8 ml pyridine is mixed with 0.6 ml ethyl chloroformate (“B”) and the mixture is stirred for 2 hours. The solvent is removed and the residue is finished with the usual reaction. Recrystallized from isopropanol / petroleum ether, 2.2 g of 1- (4-ethoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. Obtain 165 ° C.

Similarly, the "amine derivative"

1- (3-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-aminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-aminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-aminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is reacted with "B"

1- (3-ethoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 181 ° C .;

1- (2-ethoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-ethoxycarbonylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 147 ° C .;

1- (3-ethoxycarbonylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-ethoxycarbonylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 166 ° C .;

1- (3-ethoxycarbonylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-ethoxycarbonylaminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-ethoxycarbonylaminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-ethoxycarbonylaminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" and methyl chloroformate are reacted with the following compounds:

1- (4-methoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 226 ° C .;

1- (3-methoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-methoxycarbonylaminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-methoxycarbonylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-methoxycarbonylaminobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-methoxycarbonylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-methoxycarbonylaminobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-methoxycarbonylaminobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-methoxycarbonylaminobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-methoxycarbonylaminobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine is obtained.

Similarly, the "amine derivative" and acetyl chloride are reacted to yield the following compounds:

1- (4-acetamidobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine, m.p. 230 ° C .;

1- (3-acetamidobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (2-acetamidobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-acetamidobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-acetamidobenzoyl) -3- (3-ethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-acetamidobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (3-acetamidobenzoyl) -3- (3-cyclopentyloxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-acetamidobenzoyl) -3- (3,4-methylenedioxyphenyl) -1,4,5,6-tetrahydropyridazine,

1- (4-acetamidobenzoyl) -3- (3-methoxy-4-methylsulfonylphenyl) -1,4,5,6-tetrahydropyridazine,

Obtain 1- (4-acetamidobenzoyl) -3- (3-trifluoromethoxy-4-methoxyphenyl) -1,4,5,6-tetrahydropyridazine.

Example 4

2.0 g 1- (4-aminobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine and 0.8 ml N-ethyl isocyanate in 160 ml dichloromethane The solution of is stirred at room temperature for 2 hours. The solvent is removed and the residue is finished with the usual reaction. Recrystallization from isopropanol / petroleum ether yields 2.1 g of 1- (4-ethylureidobenzoyl) -3- (3,4-dimethoxyphenyl) -1,4,5,6-tetrahydropyridazine.

The following examples relate to pharmaceutical formulations:

Example A: Vials for Injection

A solution of 100 g of the active compound of Formula 1 and 5 g of dibasic sodium phosphate dissolved in 3 l of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, filled into an injection vial, lyophilized under sterile conditions, , Seal by sterile method. Injectable vials containing 5 mg of the active compound are obtained.

Example B: Suppositories

A mixture of 20 g of the active compound of Formula 1 and 100 g of soy lecithin and 1400 g of cocoa butter is poured into a mold and cooled. Suppositories containing 20 mg of the active compound are obtained.

Example C: Liquid

A solution was prepared by dissolving 1 g of the active compound of Formula 1, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ 0, and 0.1 g of benzalkonium chloride in 940 ml of secondary distilled water. The solution is adjusted to pH 6.8, filled to 1 l, sterilized by irradiation. This solution can be used, for example, in the form of eye drops.

Example D: Ointment

500 mg of the active compound of Formula 1 is mixed with 99.5 g of waseline under aseptic conditions to prepare an ointment.

Example E: Tablets

A tablet is prepared by pressing a mixture of 1 kg of the active compound of Formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate in a conventional manner so that each tablet contains 10 mg of the active compound.

Example F: Tablets

Similar to Example E, tablets are compressed and then coated by conventional methods using a coating consisting of sucrose, potato starch, talc, tragacanth and a colorant to prepare a tablet.

Example G: Capsule

A hard gelatine capsule is filled with 2 kg of the active compound of formula 1 to prepare a capsule by a conventional method such that each capsule contains 20 mg of the active compound.

Example H: Ampoules

A solution of 1 kg of the active compound of formula 1 dissolved in 60 ml of secondary distilled water is sterilized by filtration, filled into ampoules, lyophilized under sterile conditions, and sealed by sterilization. An ampoule containing 10 mg of the active compound is obtained.

Example I: Inhalation Spray

14 g of the active compound of formula 1 are dissolved in 10 L of an isotonic NaCl solution and the solution is filled into a commercial spray vessel having a pump mechanism. The solution can be sprayed into the mouth or nose. One injection (about 0.1 mL) corresponds to a dose of about 0.14 mg.

Claims (1)

Compound of Formula 1 for the manufacture of a medicament for the treatment of osteoporosis, tumors, arteriosclerosis, rheumatoid arthritis, multiple sclerosis, diabetes, ulcerative colitis and AIDS: [Formula 1] (Wherein B is A, OA, NH ₂ , NHA, NAA 'or 1-4 N, O and / or S atoms which may be unsubstituted or mono-, di- or trisubstituted by Hal, A and / or OA Branch is an aromatic heterocycle, Q is absent or is alkylene having 1 to 6 carbon atoms, R ¹ , R ² are each independently of each other -OH, OR ⁵ , -SR ⁵ , -SO-R ⁵ , -SO ₂ -R ⁵ , Hal, -NO ₂ , -NH ₂ , -NHR ⁵ or -NR ⁵ R ⁶ , R ¹ and R ² together are —O—CH ₂ —O—, R ⁵ and R ⁶ are each independently of each other A, cycloalkyl having 3 to 7 carbon atoms, methylenecycloalkyl having 4 to 8 carbon atoms, or alkenyl having 2 to 8 carbon atoms, A and A 'are each independently alkyl having 1 to 10 carbon atoms which may be substituted by 1 to 5 F and / or Cl atoms, Hal is F, Cl, Br or I) And / or use of physiologically acceptable salts thereof.