Arylalkylamine

 

(57) Abstract:

The invention relates to arylalkylamines formula I, where B - A, OA, NH2, CF3, aromatic heterocycle selected from pyridine, pyrazine and pyrimidine; Q is absent or denotes alkylene with 1-6 carbon atoms; R1and R2independently from each other represent OR5where R5- Or cycloalkyl with 3-7 carbon atoms; And the alkyl with 1-10 carbon atoms, and their physiologically acceptable salts. The compounds of formula I and their physiologically acceptable salts are inhibitors of phosphodiesterase IV and can be used to obtain medicines with the specified action, preferably for the treatment of asthmatic diseases. In addition, the invention relates to a method for producing compounds of formula I, process for the preparation of pharmaceutical compositions suitable for inhibiting phosphodiesterase IV and pharmaceutical compositions. 4 C. and 4 h.p. f-crystals.

The invention relates to a derivative of arylalkenes-pyridazine formula I

< / BR>
where In the means A, OA, NH2, NHA, NAA' or unsaturated heterocycle with 1 to 4 atoms of N, O and/or S, which may be unsubstituted or substituted one-, two -, or the/SUP> independently from each other represent-HE, OR5, -S-R5, -SO-R5, -SO2-R5Hal, -NO2-, -NH2-THE OTHER5or-NR5R6,

R1and R2together denote also-O-CH2-O-,

R5and R6independently of one another denote a, cycloalkyl with 3-7 carbon atoms, methylenecycloartanol with 4-8 carbon atoms or alkenyl with 2-8 carbon atoms,

A and a' independently of one another denote alkyl with 1-10 carbon atoms which may be substituted by 1-5 atoms F and/or CL, and

Hal denotes F, Cl, Br or I, and their physiologically acceptable salts.

1-benzoyl-tetrahydropyridine as ligands of the progesterone receptor are described, for example, in J. Med. Chem. 38, 4878 (1995).

The task of the invention are new compounds with valuable properties, especially those that can be used as medicines.

It was shown that the compounds of formula I and their salts possess very valuable pharmacological properties with good endurance.

In particular, they inhibit phosphodiesterase IV and can be used for the treatment of asthmatic diseases. Asthma action can be defined, n is the influence on the formation of tumor necrosis factor (TNF) and therefore suitable for the treatment of allergic and inflammatory diseases, autoimmune diseases and reactions of transplants. In addition, they can be used for the treatment of memory disorders.

The compounds of formula I can be used as active substances of medicines in medicine and veterinary medicine. In addition, they can be used as intermediate products for other active substances of medicines.

In accordance with the objects of the invention are the compounds of formula I, as well as the method of obtaining compounds of the formula I according to paragraph 1 of the claims, as well as their salts, characterized there that the compound of formula II

< / BR>
where R1and R2have the above meanings, is subjected to the interaction with the compound of the formula III

< / BR>
where and Q have the abovementioned meanings and L denotes CL, Br, HE or reactive esterified Oh group,

or the compound of formula IV

IV

where R1, R2and Q have the above meanings, is subjected to the interaction with the compound of the formula V

IN-CO-L, V

where has the specified value, and L denotes CL, Br, HE or reactive esterified Oh group,

and/or the base of the compounds of formula I by printing handling the , R2In, Q and L have the meanings stated for formula I, II, III, IV and V, unless otherwise noted.

A and a' denote preferably alkyl, and preferably alkyl, substituted 1-5 fluorine atoms and/or chlorine.

In the above formulas, the alkyl is preferably unbranched and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, preferably 1, 2, 3, 4 or 5 carbon atoms and preferably denotes methyl, ethyl, trifluoromethyl, pentafluoroethyl or propyl, further preferred are isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, neo-pentyl or isopentyl.

Cycloalkyl preferably has 3-7 carbon atoms and preferably denotes cyclopropyl or cyclobutyl, further preferred cyclopentyl or cyclohexyl, and cycloheptyl.

Methylenecycloartanol is preferably 4-8 carbon atoms and preferably denotes methylenecyclopropane and methylenecyclobutane, further preferred methylenecycloartanol and methylenechloride, in addition, also methylenechloride.

Alkenyl means preferably vinyl, 1 - or 2-propenyl, 1-butenyl, Isobutanol, second-butenyl, also preferred are 1-pentenyl of the equipment methylene or ethylene, additionally, the preferred propylene or butylene.

Hal preferably denotes F, Cl or Br, but also I.

The remains of R1and R2may be the same or different and are 3 - and 4-position of the phenyl ring. They indicate, for example, independently from each other hydroxy, -S-CH3, -SO-CH3, -SO2CH3, F, Cl, Br or I or together denote methylenedioxy. Especially preferably, they represent each methoxy, ethoxy, propoxy, cyclopentyloxy or fluorine, debtor, triptoreline, 1-fluoro-, 2-fluoro-, 1,2-debtor-, 2,2-debtor-, 1,2,2-Cryptor - or 2,2,2-triptoreline.

The balance represents preferably 2 - or 3-furyl, 2 - or 3-thienyl, 1-, 2 - or 3-pyrrolyl, 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-isothiazole, 2-, 3 - or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl also preferred 1,2,3-triazole-1-, -4 - or-5-yl, 1,2,4-triazole-1-, -3 - or-5-yl, 1 - or 5-tetrazolyl, 1,2,3-oxadiazol-4 - or-5-yl, 1,2,4-oxadiazol-3 - or-5-yl, 1,3,4-thiadiazole-2 - or-5-yl, 1,2,4-thiadiazole-3 - or-5-yl, 1,2,3-thiadiazole-4 - or-5-yl, 3 - or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-,5-,6- or 7-benzofuran, 2-, 3-,4-,5-,6- or 7-benzothiazyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-,Lil, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazole, 4-,5-,6 - or 7-benzo-2,1,3-oxadiazole, 2-, 3-, 4-, 5-, 6-, 7- or 8-chinolin, 1-, 3-, 4-, 5-, 6-, 7- or 8-ethanolic, 3-, 4-, 5-, 6-, 7- or 8-indolinyl, 2-, 4-, 5-, 6-, 7- or 8-hintline.

Balance means further preferably methyl, ethyl, propyl, n-butyl, methoxy, ethoxy, propoxy, N-methylamino, N, N-dimethylamino, N-ethylamino or N,N-diethylamino.

For the entire scope of the invention, the radicals that are present multiple times, may be the same or different, i.e. are independent of each other.

In accordance with the objects of the invention are, in particular, such compounds of the formula I, in which at least one of these residues have the above preferred values. Some preferred groups of compounds can be expressed by the following partial formulae Ia-Id, which correspond to the formula I and which is not designated in more detail radicals are indicated for the formula I values, which, however,

in Ia R1and R2independently of one another denote OA,

Q is absent and the

In denotes a pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl or isoxazolyl;

in Ib R1and R2
in Ic R1and R2together represent-O-CH2-O-,

Q is absent,

In denotes a pyridinyl, pyrazinyl, pyrimidinyl, thiazolyl, imidazolyl or isoxazolyl;

in Id R1and R2independently of one another denote OA,

Q is absent,

In denotes a or OA.

The compounds of formula I, as well as source materials for their production however get itself known methods, as are described in the literature (for example, Houben Weyl, Methods der organischen Chemie, Georg Thieme Verlag, Stuttgart), namely under the conditions of the reactions, which are known for these interactions and are suitable. You can use known here in more detail is not described variants.

In the compounds of formulas II and IV remains R1, R2and Q have the above significance, in particular, these preferred values.

In the compounds of formulas III and IV the remainder of the Q denotes preferably methylene or ethylene, also preferred propylene or butylene.

In the compounds of formulas III and IV balance has indicated, the preferred values, while L denotes CL, Br, HE or reactive esterified Oh group.

The source of the substance, if desired, can be obtained in situ, so they are not isolated from the reaction mixture, and immediately subjected to further interaction to obtain the compounds of formula I.

On the other hand, it is possible to conduct the reaction Paladino.

The compounds of formula I can preferably be obtained by reaction of compounds of the formula II with compounds of formula III.

Source materials of formulas II and III are partially known. If they are not known, they can be obtained using known methods.

The interaction of compounds of the formula II with compounds of formula III in the presence or absence of an inert solvent at temperatures between about -20 and about 150oC, preferably between 20 and 100oC.

As inert solvents are suitable, for example, hydrocarbons as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons like trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers like diethyl ether, and monotropy esters (methylglycol or ethylglycol), etilenglikolevye esters (diglyme); ketones such as acetone or butanone; amides as ndimethylacetamide, dimethylacetamide or dimethylformamide (D); NITRILES like acetonitrile; sulfoxidov as dimethylsulfoxide (DMCO); carbon disulfide; carboxylic acids as formic acid or acetic acid; nitro compounds, as nitromethane or nitrobenzene; esters like ethyl acetate, or mixtures of these solvents.

In addition, the compounds of formula I can be obtained by reacting compounds of the formula IV with compounds of the formula V. the Initial compounds of formulas IV and V are typically known. If they are not known, they can get itself known methods. For example, in J. Med.Chem. 38, 4878 (1995) describes the obtaining of 1-benzoyl-tetrahydropyridine.

In the compounds of formula V, the radical-CO-L denotes pre-activated carboxylic acid, preferably a halide by carbonate acid.

The interaction of compounds of the formula IV with compounds of formula V takes place under the same conditions with regard to reaction time, temperature and solvent, as described for the interaction of the compounds of the formula II with compounds of formula III.

The basis of a formula I can use acid richest base and acid in an inert solvent as ethanol and subsequent evaporation. For this interaction can be used, in particular acids, which form physiologically acceptable salts. For example, it is possible to use inorganic acids, such as sulphuric, nitric acid, halogen acids as hydrochloric or Hydrobromic acid, phosphoric acid as orthophosphoric acid, sulfamic acid, and also organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic one - or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic, acetic, propionic, pavlikova, diethyloxalate, malonic, succinic, Emelyanova, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinoyl acid, methane - or econsultation, ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, p-toluensulfonate, naphthalene-mono and disulfonate, louisanna acid. Salts with physiologically unacceptable acids, for example, picrate, can be used for isolation and/or purification of the compounds of formula I.

On the other hand, if you prefer, you can select free base form is, the subject of the invention is the use of compounds of the formula I and/or their physiologically acceptable salts for pharmaceutical compositions, in particular, non-chemical way. For this purpose, they can together with at least one solid, liquid and/or semi-liquid carrier or auxiliary substance, and optionally in combination with one or more other active substances translate into a suitable dosage form.

The subject invention are also drugs of formula I and their physiologically acceptable salts as inhibitors of phosphodiesterase IV.

In addition, the subject invention are pharmaceutical compositions containing at least one compound of the formula I and/or one of its physiologically acceptable salts.

These compositions can be used as drugs in medicine and in veterinary medicine. As carriers can be used organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohol, alkalophile, poliatilenglikola applications can be used, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, for rectal use - suppositories, for parenteral use, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, for topical application are ointments, creams or powders. New connections can be liofilizovane and received lyophilizate can be used, for example, to obtain drugs for injection. These preparations can be sterilized and/or contain auxiliary substances, such as, for example, lubricating, preservative, stabilizing and/or wetting means, emulsifiers, salts for influencing the osmotic pressure, buffer substances, dyes, giving taste and/or many other active substances, for example one or more vitamins.

The compounds of formula I and their physiologically acceptable salts can be used for the treatment of diseases in which increased (camp) levels (cyclo-adenosine-monophosphate) leads to slowing or inhibition of inflammation and muscle. Particularly compounds according to the invention can be used in the treatment of allergies, asthma, chronic bronchitis is the description of the temperature is indicated in degrees Celsius. In the following examples, "conventional treatment" includes: adding, if necessary, water, establishing, if necessary, depending on the structure of the final product pH is between 2 and 10, extraction with ethyl acetate or dichloromethane, separating, drying the organic phase over sodium sulfate, evaporation and purification by chromatography on silica gel and/or by crystallization.

Mass spectrometry (MS): EI (ionization by collision of electrons) M+FAB (fast atom bombardment) (M+N)+< / BR>
Example 1

In the suspension 4,70 g of 3-(3,4-acid)-1,4,5,6-tetrahydropyridine ("And") in 150 ml of tetrahydrofuran added 2.24 g of potassium tert-butylate and stirred for 30 minutes. Add to 7.3 g of 4-nicotinoyl-aminobenzoylamino and stirred for 10 hours at room temperature. Remove the solvent and processed as usual. Get 1-(4-nicotinoyl-amino-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 239oC (decomposition).

Similarly obtained by interaction of a with 4-isonicotinoyl-benzoyl chloride:

1-(4-isonicotinoyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 247o(Razin, the yield point of 197o[Obtained by catalytic hydrogenation of 1-(4-nitrobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, the yield point of 203oWith in 150 ml of tetrahydrofuran in the presence of 3.5 g of Raney Nickel at room temperature] and 1.6 ml of pyridine in 150 ml of acetonitrile, add 1.2 g of nicotinergic-hydrochloride and stirred for 2 hours. Remove the solvent and processed as usual. After recrystallization get 1-(4-nicotianamine-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydropyrimidin, hydrochloride, the yield point of 239oC (decomposition).

Similarly, by following interaction "derivatives":

1-(3-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, the yield point of 168oC;

1-(2-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, the yield point of 154oC;

1-(3-aminobenzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, the yield point of 168oC;

1-(3-aminobenzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

sulfanilyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

with nicotinanilide receive the following connections:

1-(3-nicotianamine-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 159oC (decomposition);

1-(2-nicotianamine-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin;

1-(4-nicotianamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(3-nicotianamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 235oC;

1-(4-nicotianamine-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 224oC (decomposition);

1-(3-nicotianamine-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyridine;

1-(4-nicotianamine-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-nicotianamine-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-nicotianamine-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with isonicotinoyl is in, the yield point of 247oC (decomposition);

1-(3-isonicotinoyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 175oC (decomposition);

1-(2-isonicotinoyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin;

1-(4-isonicotinoyl-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 266oC;

1-(3-isonicotinoyl-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-isonicotinoyl-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 244oC (decomposition);

1-(3-isonicotinoyl-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-isonicotinoyl-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-isonicotinoyl-benzoyl)-3-(3-methoxy-4-methyl-sulfanilyl)-1,4,5,6-tetrahydro-pyridazin;

1-(4-isonicotinoyl-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)- 1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride pikolinos acid the following compounds:

1-(4-picolylamine-benzoyl)-3-(the hydro-pyridazin,

1-(2-picolylamine-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-picolylamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-picolylamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-picolylamine-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-picolylamine-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine,1-(4-picolylamine-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-picolylamine-benzoyl)-3-(3-methoxy-4-methyl-sulfanilyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-picolylamine-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride furan-2-carboxylic acid the following compounds:

1-(4-(furan-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(furan-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(furan-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(furan-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-Tetra>/BR>1-(4-(furan-2-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(furan-2-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(furan-2-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(furan-2-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(furan-2-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride thiophene-2-carboxylic acid the following compounds:

1-(4-(thiophene-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(thiophene-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(thiophene-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(thiophene-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(thiophene-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(thiophene-2-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,
1-(4-(thiophene-2-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(thiophene-2-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride pyrazin-2-carboxylic acid the following compounds:

1-(4-(pyrazin-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 213oC;

1-(3-(pyrazin-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 204oC;

1-(2-(pyrazin-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrazin-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin, the yield point of 186oC;

1-(3-(pyrazin-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrazin-2-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(pyrazin-2-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrazin-2-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

Similarly produced by the interaction of the above "amino" with chloride imidazole-4-carboxylic acid the following compounds:

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(imidazol-4-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(imidazol-4-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(imidazol-4-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(imidazol-4-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(imidazol-4-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "aminophenylamino)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(2,4-dimethyl-thiazole-5-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride isoxazol-5-carboxylic acid the following compounds:

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(socmin)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(isoxazol-5-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(isoxazol-5-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(isoxazol-5-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride pyrimidine-2-carboxylic acid the following compounds:

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(pyrimidine-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(pyrimidine-2-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3-ethoxy-4-methods the 6-tetrahydro-pyridazin,

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(pyrimidine-2-carbylamine)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-2-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" with chloride pyrimidine-4-carboxylic acid the following compounds:

1-(4-(pyrimidine-4-carbylamine)-benzoyl)-3- (3, 4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 196oC;

1-(3-(pyrimidine-4-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-(pyrimidine-4-carbylamine)-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-4-carbylamine)-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-(pyrimidine-4-carbylamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-4-carbonilla)-benzoyl)-3-(3-cyclo-pentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-4-carbylamine)-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-4-carbylamine)-benzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-(pyrimidine-4-carbylamine)-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly, by interaction

1-(4-aminobenzylidene)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine,

1-(3-aminobenzylidene)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine,

1-(2-aminobenzylidene)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzylidene)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine,

1-(3-aminobenzylidene)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzylidene)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine,

1-(3-aminobenzylidene)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzylidene)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzylidene)-3-(3-methoxy-4-methylsulphonyl-phenyl)-1,4,5,6-tetrahydro-pyridazine;

1-(4-aminobenzylidene)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyrid toxigenic)-1,4,5,6-tetrahydro-pyridazin, hydrochloride, the yield point of 225oC;

1-(3-nicotianamine-benzylcarbamoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-nicotianamine-benzylcarbamoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-nicotianamine-benzylcarbamoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-nicotianamine-benzylcarbamoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-nicotianamine-benzylcarbamoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-nicotianamine-benzylcarbamoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-nicotianamine-benzylcarbamoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-nicotianamine-benzylcarbamoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-nicotianamine-benzylcarbamoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly obtained by interaction

1-(4-aminobenzylidene)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, isonicotinohydrazide

1-(4-isonicotinoyl-benzylcarbamoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, hydrochloride, the yield point of 209ooC.

Example 3

Into a solution of 2.0 g of 1-(4-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, the yield point of 197oWith and 0.8 ml of pyridine in 160 ml of dichloromethane added 0.6 ml of ethyl ether of Harborview acid (V) and stirred for 2 hours. Remove the solvent and processed as usual. After recrystallization from a mixture of isopropanol/petroleum ether to obtain 2.2 g of 1-(4-ethoxycarbonyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine, the yield point of 165oC.

Similarly, by interaction, "In" the following "derivatives":

1-(3-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine,

1-(2-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine,

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

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

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

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

1-(4-aminobenzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazine,

1-(4-aminobenzoyl)-3-(3-methoxy-4-methylsulfinylphenyl)-1,4,5,6-tetrat:

1-(3-ethoxycarbonyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 181oC;

1-(2-ethoxycarbonylethyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-ethoxycarbonyl-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin, the yield point of 147oC;

1-(3-ethoxycarbonyl-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-ethoxycarbonyl-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin, the yield point of 166oC;

1-(3-ethoxycarbonyl-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-ethoxycarbonyl-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-ethoxycarbonyl-benzoyl)-3-(3-methoxy-4-methyl-sulfanilyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-ethoxycarbonyl-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino derivatives with methyl ether of Harborview acid the following compounds:

1-(4-methoxycarbonylamino-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 226oC;

1-(the-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-methoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-methoxycarbonylamino-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-methoxycarbonylamino-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-methoxycarbonylamino-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-methoxycarbonylamino-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-methoxycarbonylamino-benzoyl)-3-(3-methoxy-4-methyl-sulfanilyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-methoxycarbonylamino-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Similarly produced by the interaction of the above "amino" acetylchloride the following connections:

1-(4-acetamido-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin, the yield point of 230oC;

1-(3-acetamido-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(2-acetamido-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin,

1-(4-acetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(3-acetamido-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-Tetra is BR>1-(3-acetamido-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-acetamido-benzoyl)-3-(3,4-methylenedioxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-acetamido-beitel)-3-(3-methoxy-4-methylsulphonyl-phenyl)-1,4,5,6-tetrahydro-pyridazin,

1-(4-acetamido-benzoyl)-3-(3-triptoreline-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin.

Example 4

A solution of 2.0 g of 1-(4-aminobenzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine and 0.8 ml of N-utilizationof in 160 ml of dichloromethane is stirred for 2 hours at room temperature. Remove the solvent and processed as usual. After recrystallization from a mixture of isopropanol/petroleum ether to obtain 2.1 g of 1-(4-amiloride-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazine.

Similarly, by reaction with potassium cyanate get 1-(4-oregonensis)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin, So pl. 251oC.

Example 5

Analogously to examples 2 and 3 receive the following connections:

1-(4-nicotinamidase)-3-(3-propoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin, So pl. 239oC.

1-(4-triftoratsetatov)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin, So pl. 211oC.

1-(4-ethoxycarbonyl xterminator)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin, So pl. 147oC.

1-(4-propoxycarbonylphenoxide)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin, So pl. 113oC.

Example 6

Analogously to examples 2 and 3 by reacting 1-(4-aminobenzoyl)-3-(3,4-acid)-4-methyl-1,4,5,6-tetrahydropyridine with nicotinanilide get a connection:

1-(4-nicotinamidase)-3-(3,4-acid)-4-methyl-1,4,5,6-tetrahydropyrimidin, So pl. 190oWITH,

C get the connection:

1-(4-ethoxycarbonylmethyl)-3-(3,4-acid)-4-methyl-1,4,5,6-tetrahydropyrimidin, So pl. 141oWITH,

with acetylchloride get a connection:

1-(4-acetamidobenzoyl)-3-(3,4-acid)-4-methyl-1,4,5,6-tetrahydropyrimidin, So pl. 223oC.

The following examples relate to pharmaceutical compositions:

Example: Injection vials

A solution of 100 g of the active substance of the formula I and 5 g of disodium hydrogen phosphate in 3 l of double-distilled water using 2 N hydrochloric acid to establish a pH equal to 6.5, sterile filtered, filled into injection vials, lyophilized in sterile sterile conditions and closed. Each injection vial contains 5 mg of active substance.

Example: Suppositories

Example: Solution

Prepare a solution of 1 g of the active substance of the formula I, 9,38 g NaH2PO42H2O, 28,48 g PA2NRA4N2O and 0.1 g of benzylaniline in 940 ml of double-distilled water. Set the pH value of 6.8, add up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: Ointment

Mix 500 mg of active substance of the formula I with 99.5 g of vaseline under aseptic conditions.

Example E: Tablets

Of a mixture of 1 kg of active substance of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate in the usual way pressed tablets such that each tablet contains 10 mg of active substance.

Example F: Bean

Analogously to example E is pressed tablets, which are then the usual way is covered with a layer of sucrose, potato starch, talc, tragant and dye.

Example G: Capsules

2 kg of active substance of the formula I fill in the usual way in capsules of hard gelatin, so that each capsule contains 20 mg of active substance.

Example N: Ampoules

A solution of 1 kg of outdoor activities is t and sterile closed. Each ampoule contains 10 mg of active substance,

Example I: Inhalation aerosol

14 g of the active substance of the formula I are dissolved in 10 l of isotonic NaCl solution and fill with a solution of ordinary spray containers with a pump mechanism. The solution can be injected into the mouth or nose. One injection (about 0.1 ml) corresponds to a dose of approximately 0,14 mg

1. Arylalkylamine formula I

< / BR>
where - As, OA, NH2, CF3, aromatic heterocycle selected from pyridine, pyrazine and pyrimidine;

Q is absent or denotes alkylene with 1-6 carbon atoms;

R1and R2independently from each other represent OR5where R5- Or cycloalkyl with 3-7 carbon atoms and an alkyl with 1-10 carbon atoms,

and their physiologically acceptable salts.

2. The compounds of formula I on p. 1, representing

(a) 1-(4-nicotianamine-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydropyrimidin,

(b) 1-(4-ethoxycarbonyl-benzoyl)-3-(3-ethoxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

(C) 1-(4-nicotianamine-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

(g) 1-(4-ethoxycarbonyl-benzoyl)-3-(3-cyclopentyloxy-4-labels is ahydro-pyridazin,

(e) 1-(4-isonicotinoyl-benzoyl)-3-(3-cyclopentyloxy-4-methoxyphenyl)-1,4,5,6-tetrahydro-pyridazin,

(W) 1-(4-nicotianamine-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydropyrimidin,

(C) 1-(4-ethoxycarbonyl-benzoyl)-3-(3,4-acid)-1,4,5,6-tetrahydro-pyridazin.

3. The method of obtaining compounds of formula I on p. 1, and their salts, characterized in that the compound of formula II

< / BR>
where R1and R2have the above values,

subjected to interaction with the compound of the formula III

< / BR>
where and Q have the above meanings;

L is CL, Br, HE or reactive esterified Oh-group,

and/or a basic compound of formula I by treatment with acid is transferred into one of its salts.

4. The method of obtaining pharmaceutical compositions suitable for inhibiting phosphodiesterase IV, characterized in that the compound of formula I under item 1 and/or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid carrier or auxiliary substance is transferred in a suitable dosage form.

5. Pharmaceutical composition suitable for inhibiting phosphodiesterase IV, characterized those whom her.

6. The compounds of formula I on p. 1 and their physiologically acceptable salts for the treatment of asthmatic diseases.

7. The compounds of formula I on p. 1 and their physiologically acceptable salts as inhibitors of phosphodiesterase IV.

8. The compounds of formula I on p. 1 and their physiologically acceptable salts for obtaining medicines that are suitable for the inhibition of phosphodiesterase IV.

 

Same patents:

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to acylaminocinnamic derivative of the formula (I), where R denotes phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R1is hydrogen, alkyl, R2is hydrogen, alkyl or phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, R3is phenyl which is not substituted or may be substituted with halogen, alkyl, trifluoromethyl, hydroxy and alkoxygroup, or represents naphthyl, lH-indol-3-yl or 1-alcheringa-3-yl, R4' and R4"is hydrogen, alkyl, and one of the radicals R4' and R4"is hydrogen, and R5- cycloalkyl, D-azacycloheptan-2-he-3-yl or L-azacycloheptan-2-he-3-yl, or its salt

The invention relates to an improved process for the preparation of 8-methyl-8-azabicyclo[3,2,1]Oct-3-silt ester of indole-3-carboxylic acid hydrochloride which is a substance tropisetrona and is used as an antiemetic, effective for vomiting caused by anticancer chemotherapy drugs

The invention relates to N-(N'-substituted glycyl)-2-cyanopyrrolidine formula I, where R denotes: a)1R1aN (CH2)m-, where R1means pyridinoline or pyrimidinyl fragment, optional one - or disubstituted independently of one another by halogen, trifluoromethyl, cyano - or nitro-group; R1adenotes hydrogen or C1-C8alkyl, m is equal to 2,3, b)3-C12cycloalkyl, optional one-deputizing in position 1 WITH1-C3hydroxyalkyl,) R2(CH2)n- where either R2denotes phenyl, optional one-, two - or tizamidine selected independently of each1-C4alkoxygroup, halogen or phenylthiourea, optional one-deputizing in the phenyl ring with hydroxymethyl; or denotes a C1-C8alkyl, [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8the alkyl, pyridinoline or nattily fragment, or cyclohexenyl, or substituted and n is 1-3, or R2denotes fenoxaprop; and n is 2; d) (R3)2CH(CH2)2-, where each R3independently represents phenyl; d) R4(CH2)p-, where R4ebony in position 1 WITH1-C3hydroxyalkyl, W) R5that means indanyl piperidinyl fragment, optionally substituted benzyl, and [2.2.1] or [3.1.1] bicyclic carbocyclic fragment, optional single or mnogozalny1-C8by alkyl, substituted or1-C8alkyl, optionally one or mnogozalny independently from each other hydroxy-group, hydroxymethyl or phenyl, optional one - or disubstituted independently selected from each other WITH1-C4the alkyl, C1-C4alkoxygroup or halogen, in free form or in the form of an acid additive salt

The invention relates to a new method of obtaining derivatives of 3-pyrrolin-2-carboxylic acid of the formula I, where1- C1-C6-allyloxycarbonyl; R2is hydroxyl, WITH1-C4-alkoxy or their ammonium salts, the removal of base sulfoxylate residue from the compounds of formula II, where R1and R2as above; R3- C1-C6-alkyl, benzyl, trifluoromethyl, naphthyl, phenyl which may be substituted by a residue comprising SN3, NO2, halogen

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to the derivatives of propanolamine formula (I) and their pharmaceutically acceptable salts, where R1and R2means phenyl, naphthyl, pyridyl, thienyl, pyrimidyl, thiazolyl, hinely, piperazinil, oxazolyl, which may be substituted with halogen, HE, NO2, NH2, COOH, etc., R3-R8mean hydrogen, hydroxyl, (C1-C8-alkoxy, NH2-THE OTHER9, -N(R9R10, R9-R10mean hydrogen or (C1-C8)alkyl, X is CH or N, Y represents CH or N, provided that the residues R1, R2X and Y are not simultaneously mean R1- phenyl, R2is phenyl, X is CH, Y is CH

The invention relates to new derivatives of azetidine and pyrrolidine General formula

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where a represents an optionally unsaturated 5 - or 6-membered ring which may contain heteroatom selected from N and S, and which may be substituted by oxo or (1-6C) alkyl; R1, R2and R3independently of one another represent H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, and halogen atom; X is an atom of O or S and n = 1 or 2, or its pharmaceutically acceptable salt, except 3-(naphthas-1-yl-oxy)-pyrrolidine and 3-(5,6,7,8-tetrahydro-naphthas-1-yl-oxy)-pyrrolidin

The invention relates to the field of organic chemistry, and in particular to an improved process for the preparation of omeprazole, which is the first drug from the group of drugs to regulate the secretion of gastric acid

The invention relates to the derivatives of hintline formula I in which Z denotes-O-, -NH - or-S-; m = 1-5, integer, provided that when Z represents-NH-, m = 3 - 5; R1is hydrogen, C1-3alkoxy; R2is hydrogen; R3hydroxy, halogen, C1-3alkyl, C1-3-alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; X1denotes-O-, -NR7, -NR8CO-, where R7and R8each is hydrogen, C1-3alkyl; R4choose one of the listed in paragraph 1 of the claims of the seven groups, except 4-(3,4,5-trimethoxyphenyl)-6,7-dimethoxyquinazoline, 4-(3-methoxybenzylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenylthio)-6,7-dimethoxyquinazoline, 4-(3-chlorophenoxy)-6,7-dimethoxyquinazolin and 4-(3,4,5-trimethoxyaniline)-6,7-dimethoxyquinazolin, or their salts

The invention relates to substituted 1-phenylpyrazol-3-carboxamide formula (Ia) in which R1xis in position 4 or 5 and denotes the group-T-CONRaRbin which T represents a direct bond or (C1-C7-alkylen; NRaRbdenotes a group selected from (a), (b), (C); R5and R6denote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8)-alkenyl or R5and R6together with the nitrogen atom to which they are linked, represent a heterocycle selected from pyrrolidine, piperidine, research, piperazine, substituted in position 4 by Deputy R9; R7denotes hydrogen, (C1-C4)-alkyl or benzyl; R8denotes hydrogen, (C1-C4)-alkyl, or R7and R8together with the carbon atom to which they are attached, form a (C3-C5-cycloalkyl; R9denotes hydrogen, (C1-C4)-alkyl, benzyl or a group-X-NR'5R'6in which R'5and R'6represent, independently from each other, (C1-C6)-alkyl; R10denotes hydrogen, (C1-C4)-alkyl; s= 0-3; t=0-3, provided that (s+t) in the same group greater than or equal to 1; the divalent radicals a and E together with the atom is which in addition, may be substituted by one or more (C1-C4-alkilani; R2xand R3xdenote, independently of one another, hydrogen, (C1-C6)-alkyl, (C3-C8-cycloalkyl, (C3-C8-cyclooctylmethyl provided that R2xand R3xdo not simultaneously denote hydrogen or R2xand R3xtogether form tetramethylene group; and their pharmaceutically acceptable salts

The invention relates to the derivatives of hintline formula (I), where Y1represents-O-, -S-, -NR5CO-, where R5is hydrogen; R1represents hydrogen or C1-3alkoxy; R2represents hydrogen; m is an integer from 1 to 5; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl or cyano; R4is one of five groups, which is optionally substituted by Spiridonova, phenyl or aromatic heterocyclic group with 1-3 heteroatoms selected from O, N and S, or contains such a group; and their salts, to processes for their preparation and to pharmaceutical compositions containing a compound of the formula (I) or its pharmaceutically acceptable salt as an active ingredient

The invention relates to new derivatives of pyrrolidine or piperidine F.-ly (I), their enantiomers and pharmaceutically acceptable salts

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where R10- H or C(O)N(R1)YZ, R1- N, Y - (CH2)p, (CH2)qCH(R3) or CH(R3)(CH2)q, R3- aryl, aralkyl or heteroaryl, q = 1-3, p = 2 or 3, Z - CO2H, CO2-alkyl or 5-tetrazol, X-S(O) M-(CH2)nor piperidine-1-yl, m = 2, n = 2, R5Mr. And selected from piperidine-2-yl, piperidine-3-yl, piperidine-4-yl or N-substituted piperidine

The invention relates to arylalkylamines formula I, where R1and R2each, independently of one another, denote H or A; R3and R4each, independently of one another, denote OR10R5is phenyl residue substituted R6Q - alkylene with 1-6 C-atoms, R6denotes - NH2, -NR8R9, -NO2; R8is hydrogen, R9- alkanoyl with 2-8 C-atoms which may be substituted by 1 to 5 fluorine atoms, -cooa or-SO2A; And - alkyl with 1-6 C-atoms, R10- Or cycloalkyl with 3-7 C-atoms, and their physiologically acceptable salts, methods for their production and pharmaceutical compositions based on them
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