Substituted dihydropyrimidine, the retrieval method, intermediate compounds, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes the new substituted dihydropyrimidine General formula I, where the values of R1, R2, R3AIR1AIR2Q indicated in the first paragraph of the claims. Also describes the method of production thereof, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, in particular migraine. 5 s and 5 C.p. f-crystals, 2 tab.

The invention relates to new substituted dihydropyrimidines, methods for their preparation, pharmaceutical compositions containing them and their use as pharmaceuticals, in particular for the prevention or treatment of disorders characterized by excessive expansion of vessels, such as migraine.

Migraine - non-fatal disease that affects one in ten people. The main symptom is pain; other symptoms include vomiting and photophobia. For many years the most widely used treatment of migraine included the appointment of ergoalkaloidov, which gave some unpleasant side effects. Recently as novog the new substituted hydropyridine show 5-HT1-like agonistic activity, and therefore can be used in the treatment of disorders characterized by excessive expansion of vessels, such as migraine.

The present invention relates to compounds of the formula

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to their pharmaceutical acceptable salts of the acid accession, their N-oxides and their stereochemical isomeric forms, in which =a1-a2=a3-a4= - bivalent radical of the formula:

=N-CH=CH-CH= (a),

=CH-N=CH-CH= (b)

=CH-CH=N-CH= c),

=CH-CH=CH-N= (d)

in which in said bivalent radicals one or two hydrogen atoms may be replaced by halogen, hydroxy, C1-6the alkyl or C1-6alkyloxy;

R1is hydrogen or C1-6alkyl;

R2is hydrogen or C1-6alkyl;

R3is hydrogen or C1-6alkyl;

Alk1- C1-5alcander;

Alk2- C1-15alcander;

Q is a radical of the formula:

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in which R4is hydrogen, cyano,

R5is hydrogen,

R6is hydrogen or C1-6alkyl; or R7and R8each independently hydrogen,

R9, R10, R11, R12, R13R14, R15, R22each independently is hydrogen, C1-6alkyl,

q = 1 or 2, r = 1 or 2.

Some of the compounds of formula (1) may also exist in their tautomeric forms. Such forms are also included in the scope of the present invention, although it is not specifically indicated in the above formula.

In the preceding definitions, halogen denotes fluorine, chlorine, bromine and iodine;

C1-6alkyl defines saturated hydrocarbon radicals with straight and branched chain with 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and other;

C3-6alkenyl determine the hydrocarbon radicals with straight and branched chain, containing one double bond and having from 3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3 pentenyl, 3-methyl-2-butenyl and others; and the carbon atom mentioned C3-6alkenyl associated with the nitrogen atom preferably is saturated, C3-6- quinil determines the hydrocarbon radicals with straight and branched chain, containing one triple bond and having from 3 to 6 carbon atoms, such as, for example, 2-PROPYNYL, 3-butynyl, 2-butynyl, 2-pentenyl, 3-pentenyl, 3-hexenyl and others; and the carbon atom in okasankaar is a General concept for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; C1-5alcander determine divalent saturated hydrocarbon radicals with 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol and their branched isomers; C2-15alcander defines bivalent saturated hydrocarbon radicals with straight and branched chain with 2 to 15 carbon atoms, such as, for example, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol, 1,7-heptanediol, 1,8-octanediol, 1,9-nonanediol, 1,10-decanediol, 1,11-undecanedioic, 1,12-dodecanediol, 1,13-tridecanol, 1,14-tetradecane, 1,15-pentadecanedioic, and their branched isomers. The term "C(O)" refers to a carbonyl group.

Pharmaceutically acceptable salts of the acid accession above include therapeutically active non-toxic form acid salts of adhesion, which is able to form compounds of formula (1). The latter can easily get treatment forms the Foundation of such appropriate acids as inorganic acids, for example kaleidotrope acids, for example hydrochloric, Hydrobromic and others; sulfuric acid, nitric, phosphoric acid, and others; or organical, perpendicularly, butanedioate, (Z)-2-botanically, (E)-2-botanically, 2-malic acid, 2,3-diablocody acid, 2-hydroxy-1,2,3-propanetricarboxylic, methansulfonate, econsultation, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oksibenzoynoy, 4-amino-2-oksibenzoynoy and other acids. And the salt form can be converted by treatment with alkali in the form of a free base. The term "salt accession also includes hydrates and forms of accession of the solvent, which is able to form compounds of formula (1). Examples of such forms are, for example, hydrates, alcoholate, and others.

The term "stereochemical isomeric form" here defines all the possible isomeric forms, which may be of the compounds of formula (1). If not mentioned or stated otherwise, the chemical designation of compounds denotes the mixture of all possible stereochemical isomeric forms, said mixtures containing all diastereomers and enantiomers of basic molecular structure. Moreover, stereogenic centers may have the R - or S-configuration; and (C3-6alkenilovyh radicals can have the E - or Z-configuration. Stereochemical isomeric forms of the compounds formno radical of formula (a) and (c);

R1accordingly methyl or hydrogen, preferably hydrogen;

R2accordingly methyl or hydrogen, preferably hydrogen;

R3accordingly methyl or hydrogen, preferably hydrogen;

Alk1- C1-3alcander, preferably methylene;

Alk2- C2-6alcander, preferably 1,3-propanediyl or 1,4-butanediyl;

Q is preferably a radical of the formula (aa), (bb), (dd), (gg) or (ii);

R4respectively hydrogen, cyano, aminocarbonyl or methyl, preferably R4is hydrogen or cyano;

R5respectively hydrogen or C1-6alkyl, preferably R5is hydrogen, methyl, ethyl or propyl;

R6respectively hydrogen or C1-6alkyl, better R6is hydrogen or methyl;

R7and R8each independently hydrogen, hydroxy, halogen or methyl, preferably both R7and R8is hydrogen, or R7is hydrogen and R8is hydroxy;

R9respectively hydrogen, hydroxy, preferably R9is hydrogen;

R10respectively hydrogen or phenylmethyl, preferably hydrogen;

r is preferably 2;

R11and R12both site is responsible hydrogen, halogen or methyl, preferably hydrogen or chlorine;

R15and R16- each usually independently hydrogen, halogen or methyl, preferably hydrogen or chlorine;

R17and R18each independently hydrogen, hydroxy, chlorine or methyl, preferably R17and R18are both hydrogen, or R17is hydrogen and R18hydroxy;

R19and R20each independently hydrogen, hydroxy, halogen or methyl, preferably both hydrogen, or R19is hydrogen and R18- chlorine;

R21and R22each independently hydrogen, halogen, C1-6alkoxy, C1-6alkylthio, amino, mono - or di(C1-6alkyl)amino, preferably R21is hydrogen, chlorine, methylthio or amino, and R22is hydrogen;

R23and R24usually each independently hydrogen, halogen or C1-6alkyl, preferably R23and R24hydrogen or chlorine; r is preferably 2;

R25and R26- preferably both hydrogen;

R27- usually hydrogen or methyl, better hydrogen; and

aryl is preferably phenyl.

Interesting compounds are those compounds of formula (1) in which R1and R2both hydrogen;

Also of interest are those compounds of formula (1), in the group of interesting compounds the compounds of formula (1) in which a =a1-a2=a3-a4= - bivalent radical of formula (c).

Particularly interesting compounds are the compounds of formula (1) in which Q is a radical of the formula (aa), (bb), (dd), (gg) or (ii), in particular (bb), (dd), (gg) or (ii).

The most interesting compounds where Q is the radical of the formula (bb), R7and R8both hydrogen.

Another group of particularly interesting compounds are those in which Q is a radical of the formula (dd), R11, R12and R13is hydrogen and q - 2.

Another group of the most interesting compounds are those in which Q is a radical of the formula (gg), R17and R18- hydrogen.

And another group of interesting compounds where Q is the radical of the formula (ii), R21- methylthio and R22- hydrogen.

Preferred are the following compounds:

N-[(3,4-dihydro-2H-pyrano[2,3-b] -pyridine-2-yl)methyl] -N'-2 - pyrimidinyl-1,3-propandiamine;

N-[(3,4-dihydro-2H-pyrano[2,3-b] -pyridine-2-yl)methyl] -N'- (1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N-oxide-N-[(3,4-dihydro-2H-pyrano[2,3-b] -pyridine-2-)methyl] -N'- 2-pyrimidinyl-1,3-propandiamine;

N-[(3,4-dihydro-(2H)-pyrano[2,3-c]-pyridine-2-yl)methyl]-N'- 2-pyrimidinyl-1,3-propandiamine;

N-[(3,4-dihydro-2H-pain-2-yl)methyl] -N'- 2-pyridinyl-1,3-propandiamine; and

N"-cyano-N-[(3,4-dihydro-2H-pyrano[2,3-b] -pyridine-2-yl)- methyl]-amino] propyl]-N'-propylaniline;

their pharmaceutically acceptable salts are acid accession or stereochemical isomeric form.

The compound of formula (I) can generally be obtained by reaction of a diamine of the formula (II) with a reagent of formula (III). In formulas (II), (III) and all subsequent formulas, variables= a1-a2=a3-a4=" R1, R2, R3, Alk1, Alk2, Alk3and Q are the same as defined under formula (I). In the formula (III) W1- reactive leaving group such as, for example, halogen, i.e. chlorine, bromine; alkyloxy, i.e., methoxy, ethoxy etc.; aryloxy, i.e. phenoxy etc.; alkylthio, i.e., methylthio, ethylthio etc.; aaltio, i.e. sensatio and others.

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These reactions can be carried out by stirring the diamine of formula (II) with a reagent of formula (III), but you can with the addition of an appropriate solvent, such as, for example, alcohol, i.e., ethanol and others; halogenated hydrocarbons, i.e. trichlormethane and others; ether such as tetrahydrofuran, etc.; aromatic hydrocarbons, such as methylbenzol and others, or mixtures thereof. Acid, which can be formed during the reaction is neutralized by adding olocnoro metal, for example, sodium bicarbonate or potassium; a suitable organic base, such as N, N-diethylethanamine, pyridine and other grounds. Elevated temperatures can accelerate the reaction. Preferably the reaction is carried out at the boiling temperature of the reaction mixture.

The compounds of formula (I) can also be obtained reductive N-alkylation of amino derivatives of formula (VI) with the appropriate aldehyde of formula (V) in which Alk3is a direct bond or C1-4alcander.

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This reaction is conducted by stirring the reactants in a suitable solvent, such as, for example, alcohol, i.e., ethanol and others; ether, i.e., tetrahydrofuran, etc.; an aromatic solvent, i.e., methylbenzol, etc. or their mixtures. You can use a water separator to remove water formed during this reaction. Then the resulting Imin you can restore reagents reactive hydride, such as, for example, sodium borohydride, or by catalytic hydrogenation in an appropriate catalyst, such as, for example, palladium carbon, platinized charcoal, skeletal Nickel catalyst for hydrogenation and other in a suitable solvent, such as, for example, alcohol, i.e. methanol, Atanasova acid, for example, acetic acid, propanoic acid, and others. It is possible to conduct the reaction at elevated temperatures and pressures.

The intermediate aldehyde of formula (V) can be obtained by restoring derived acyl of the formula (IV), in which Alk3defined as above and Y is halogen. The acyl halide can be obtained by reaction of the acid of formula (IV), where Y is OH, with a halogenation reagent such as thionyl chloride, trichloride phosphorus, tribromide phosphorus, oxalicacid and others. The latter reaction can be carried out in excess of halogenation reagent or appropriate solvents, such as, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane and others; aromatic hydrocarbons, such as methylbenzol and others; ethers such as tetrahydrofuran, 1,4-dioxane, and others; or bipolar aprotic solvents such as N, N-dimethylformamide, N,N-dimethylacetamide, and others. To increase the speed of reaction can be used agitation and elevated temperatures. The above restore acylhomoserine formula (IV) can, for example, to carry out catalytic hydrogenation with a catalyst such as palladium carbon, palladium on barium sulphate, platinized charcoal and drugie with bipolar aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, and others. You can add a catalytic poison, such as thiophene, quinoline/sulfur and others.

The sequence of reactions starting from an intermediate of formula (IV) to obtain compounds of formula (I) can be done in one reactor.

The compounds of formula (I) can also be obtained N-alkylation of an amine of formula (VI) an intermediate compound of formula (VII), in which W2- reactive leaving group such as, for example, halogen, for example chlorine, bromine or iodine; sulfonyloxy, for example, methanesulfonate, methylbenzenesulfonate and other appropriate solvents, such as ketones, such as 2-butanone and others ; ethers such as tetrahydrofuran and others; aromatic hydrocarbons, such as methylbenzol and others; bipolar aprotic solvents such as N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and others.

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Stirring and heating may accelerate the reaction. The acid formed during the reaction is neutralized by adding a suitable base such as a carbonate of an alkali metal, for example sodium carbonate or potassium, bicarbonate of an alkali metal, for example bicarbonate sodium or potassium, and others; cootey (I) can also be converted into each other by transformations of functional groups. For example, the compound of formula (I), where Q is half of pyrimidinyl, can be converted to tetrahydroindole well-known procedures catalytic hydrogenation.

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In addition, the compounds of formula (I) bearing C3-6Altenilpe or C3-6altergroup, can be converted into the corresponding compounds, C1-6accelgroup, following the well-known technology of hydrogenation. The compounds of formula (I) bearing a cyano can be converted into the corresponding compounds bearing Deputy aminomethyl, a well-known method of hydrogenation.

Compounds bearing the Deputy alkyloxy can be converted to compounds bearing a hydroxy-group, by treating compound of alkyloxy the corresponding acid with a reagent such as, for example, galoidvodorodnykh acid, such as Hydrobromic, or trichromacy boron and others.

Compounds bearing amino Deputy, can N-allievate or N-alkilirovanii well-known procedures, N-acylation or N-alkylation.

N-oxides of compounds of formula (I) can also be obtained following the techniques well known methods.

Intermediate compounds of formula (VII), where "=a

Intermediate compounds of formula (VII), where "=a1-a2=a3-a4=" - bivalent radical of formula (c), Alk1is methylene, and W2- reactive leaving group, especially halogen, for example, be obtained as described in example 2, the Experimental part. These intermediate compounds represented by formula (VII-c).

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Other intermediate compounds are new and you can get them by following well-known procedures.

Pure stereochemical isomeric forms of the compounds of this invention can be obtained using known procedures. Diastereoisomer get by means of physical separation, such as selective crystallization and chromatography such as liquid chromatography. Enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts of optically active acids. These pure stereochemical isomeric form can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction takes place stereospecific. Better, when receiving a specific stereoisomer is specified, the connection will be synthesized stereochemically isomeric forms of the compounds of formula (I) is included in the scope of the invention.

The compound of formula (I), their pharmaceutically acceptable salts are acid accession and stereochemical isomeric forms possess interesting pharmacological properties: they are 5HT1-like agonistic activity. Compounds of the present invention have significant sosudosuzhayushcheye activity. They are useful in the prevention and treatment of conditions characterized by or associated with a headache, for example, associated with vascular disorders, especially migraine. These compounds are also useful in the treatment of venous insufficiency and treatment of conditions associated with low blood pressure.

Vasoconstrictor activity of the compounds of formula (I) can be identified using in vitro test, as described in "Instantaneous changes of alpha-adrenoreceptor affinity caused bymoderate cooling in canine cutaneous veins" in the American Journal of discrimination 234(4), H330-H337, 1978; or according to the test described in pharmacological example, where serotoninto the reaction of the compounds of the present invention was tested on the basilar arteries of pigs.

Possessing useful pharmacological properties, the compounds can be used for the preparation of various pharmaceutical forms for the appointment. To prepare the pharmaceutical compositions is about joining as an active ingredient is mixed with a pharmaceutically acceptable carrier, which can be in any form depending on the assignment method. These pharmaceutical compositions are preferably prepared in a standardized dosage forms acceptable to assign orally, rectally, subcutaneously or parenterally. For example, in preparing the compositions in oral dosage form, you can use any of the usual pharmaceutical media, such as water, glycols, oils, alcohols and other in the case of liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricant, binder, agents that promote decomposition and others, in the form of powders, pills, capsules and tablets. Because of the ease of destination tablets and capsules represent the most acceptable form of oral unit dosage when using solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes sterile water, at least a large part, although can include other ingredients, for example to impart solubility. Can be prepared, for example, solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of both. Prepare another suspension for injection in to the compositions, acceptable for percutaneous destination, the carrier may contain an agent that enhances the penetration and/or a suitable wetting agent with a possible combination with suitable additives of any nature in small quantities, this Supplement should not negatively affect the skin. Such supplements can facilitate the appointment and/or to be useful in the preparation of the desired compositions. These compositions can be assigned in different ways, for example as an ointment on transdermal local overlay. Pharmaceutical compositions better to mould in the form of dosage units for ease of application. The form of dosage units in the description and the formula refers to physically discrete units that are acceptable as uniform doses, each unit dose contains a certain amount of active ingredient calculated to obtain the desired therapeutic action, together with the required pharmaceutical carrier. Examples of such forms of dosage units are tablets (including simple tablets or coated tablets), capsules, pills, powders, pills, solutions or suspensions for injection, the volume of a teaspoon, tablespoon, and others.

Compounds of the present invention may be used and low pressure, venous insufficiency and especially headaches and migraines. It is also proposed a method of treating warm-blooded animals suffering from conditions associated with vasodilation, such as low blood pressure, venous insufficiency and headaches, particularly migraine, the use of effective amounts of compounds of formula (I), its pharmaceutically acceptable acid salt of joining or stereoisomeric forms. Professionals can easily determine the effective amount from the test results presented below. In General, the effective amount is from 1 μg/kg to 1 mg/kg body weight and in particular from 2 μg/kg 200 μg/kg body weight. The desired dose may be administered in two, three, four or more doses at certain intervals during the day. Such fractional doses can be molded as a separate unit dosages, e.g., containing from 0.005 to 20 mg, specifically 0.1 to 10 mg of active ingredient per unit dosage.

The following examples are intended to illustrate the present invention but in no way do they limit it in any aspects.

The experimental part.

A) Obtaining intermediate compounds

Example 1.

3-Chlorobenz dichlormethane (100 ml) and the mixture stirred at room temperature for 2 hours. The mixture was washed with saturated sodium bicarbonate solution and extracted. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The residue is purified open column chromatography on silica gel (eluent: CH2Cl2/CH3OH 98/2, 96/4, 90/10 and 80/20). Pure fractions are collected and evaporated. The product is used without further purification to yield 2.16 g (70%) (8-oxide ()-2- (chloromethyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine (InterMedia. 1)).

Example 2.

a) a Mixture of aluminum (0,137 M) and HgCl2(0,012 g) in tetrahydrofuran (100 ml) is stirred and heated in nitrogen atmosphere at 40oC. was Carefully added 3-bromo-2-propenyl (0,2265 M) in tetrahydrofuran (100 ml) and the mixture was stirred at 60oC for 1 hour. The mixture is cooled to -60oC and added dropwise 4-methoxy-3-pyridinecarboxamide (0,0985 M) in tetrahydrofuran (100 ml). The mixture was stirred at 0oC for 1 hour and then 2 hours at 20oC. the Mixture is treated with an aqueous NH4Cl, stirred 30 minutes, filtered and the filtrate is evaporated to dryness. Water is added and the mixture extracted with EtOAc. The organic layer was poured. The aqueous layer was alkalinized, extracted with EtOAc, dried (Na2SO4), otfiltrovat and evaporated to dryness. The product uses the thionyl chloride are added dropwise (0,456 M) to a solution of intermediate compound 2 (0,0456 M) in dichloromethane (150 ml) and the mixture is stirred at room temperature overnight. The mixture is evaporated to dryness, the residue is washed with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The product is used without further purification to yield 10 g(89%) ()-3-(1-chloro-3-butenyl)-4-methoxypyridine (InterMedia. 3).

c) a Mixture of intermediate compound 3 (0,0405 M) and Zn (0,1591 M) in acetic acid (400 ml) was stirred at room temperature for 1 hour. The mixture is filtered and the filtrate is evaporated to dryness. The residue was washed with 10% NaOH and extracted with CH2Cl2. The organic layer is dried (Na2SO4), filtered and evaporated to dryness. The residue is purified (7 g) short open columnar chromatography on silica gel (eluent: CH2Cl2/CH3OH 97/3). Pure fractions are collected and eluant is evaporated. The product is used without further purification to yield 4 g (60%) of 3-(3-butenyl)-4-methoxypyridine (InterMedia. 4).

d) a Mixture of bis(trimethylsilyl)sulfate (0,0318 M) and sodium methoxide (0,0278 M) in 1,3-dimethyl-2-imidazolidinone (50 ml) is stirred under nitrogen for 1 hour. Add intermediate compound 4 (0,0184 M) in 1,3-dimethyl-2-imidazolidinone (10 ml) and the mixture was stirred at 150oC 4 hours. The mixture was washed with saturated R is throwaway and evaporated to dryness. The product is used without further purification to yield 1.4 g (51%) of 3-(3-butenyl)-4-pyridinol (InterMedia. 5).

A mixture of intermediate compound 5 (0.01 M) in trichloromethane (100 ml) cooled in an ice bath. Added dropwise bromine (0.01 M) in trichloromethane (50 ml) and the mixture stirred at room temperature for 1 hour. Add N, N-diethylethanamine (40 ml) and the mixture was stirred at 100oC 3 hours. The mixture is evaporated to dryness and the residue purified short open column chromatography on silica gel (eluent: CH2Cl2/CH3OH 97/3). Pure fractions are collected and evaporated to yield 1.2 g (52%) ()-2-methyl bromide-3,4-dihydro (2H)pyrano[3,2-c]pyridine (InterMedia. 6).

B) obtain the final compounds

Example 3.

2-(methyl bromide)-3,4-dihydro-(2H)-pyrano[2,3-b]pyridine (0,0156 M) and (N-2-pyrimidinyl-1,3-propandiamine (0,0312 M) was stirred at 100oC for 1.5 hours. First, a mixture of clear open column chromatography on silica gel (eluent: CH2Cl2/CH3OH 90/1) and then on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). Pure fractions are collected and evaporated. The oily residue was transferred to salt hydrochloric acid (1:3) in 1,1'-oxybisethane/2-propanol, to yield 1.8 g (25%) ()-N'-(3,4-dihydro-2H-pyrano[2,3-b] /SUP>C (Conn. 1).

Example 4.

A mixture of compound (1) (0,0047 M) and hydrochloric acid in 2-propanol (0,0205 M) in methanol (45 ml) hydronaut at room temperature under normal pressure in a Parr apparatus at the palladium on charcoal (0,43 g) as a catalyst. After uptake of hydrogen (2 EQ.) the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is purified open column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 9/1). Pure fractions are collected and evaporated. The residue was transferred to salt hydrochloric acid (2:5) in 2-propanol and evaporated to dryness. The residue is dried over P2O5and KOH with the release of 0.93 g (43%) of N'-[(3,4-dihydro-2H-pyrano[2,3-b] pyridine-2-yl) methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine dihydrochloride. 2-propanoate (2:1). monohydrate; So pl. br143.3oC (Conn. 2).

Example 5.

A mixture of 0.01 M intermediate compounds 1 and 0,315 M N'-2-pyrimidinyl-1,3-propandiamine stirred at 100oC for 90 minutes. First, the mixture is purified by two flash chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 9/1) and then GHUR (eluent: CH2Cl2/(CH3OH/NH3) 9/1). Pure fractions are collected, ihydro-2H-pyrano[2,3-b]pyridone-2-yl) methyl] -N'-2-pyrimidinyl-1,3-propandiamine, N-oxide of candiota (2:1). monohydrate; So pl. 108,0oC (Conn. 3).

Example 6.

The mixture 0,0053 M intermediate compounds 6 and 0,0105 M N'-2-pyrimidinyl-1,3-propandiamine stirred at 100oC for 2 hours. The mixture was purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5) and high performance liquid chromatography on silica gel (eluent: hexane/CH2Cl2/(CH3OH/NH3) 5/4,5/0,5). Pure fractions are collected and evaporated. The residue is purified column chromatography NH2KROMASIC I. D.: 2.5 cm JOUR (15 μm) (eluent: CH2Cl2/CH3OH 96,5/3,5), 9 injections of 0.1 g dissolved in 10 ml of eluent. Pure fractions are collected and evaporated. The residue is dissolved in methanol (30 ml) and transferred to salt ethicality (2:5). The residue is filtered off and dried in vacuum, to yield 0.4 g (14%) (R 104542); So pl. 185,2oC ()-N'-[(3,4-dihydro-(2H)-pyrano[2,3-c]pyridine-2-yl) methyl]-N'-2-pyrimidinyl-1,3-propandiamine of candiota (5:2) (Conn. 4).

In table 1 (see end of description) are data of the obtained compounds.

C) Pharmacological example

Example 7.

The segments of the basilar arteries from pigs (anastasiosandy pentobarbital sodium) were fixed in trays the solution supported the 37oC, and the solution was flushed with a mixture of 95% O2- 5% CO2. The drugs were stretched to a stable basal tension of 2 grams.

Drugs narrowed serotonin (310-7M). Was measured response to the addition of serotonin and then serotonin was washed out. This procedure was repeated to achieve a stable response. In subsequent in the tub was introduced testwave connection and measured the narrowing of the drug. This is the response of contraction was expressed as a percentage of the response to serotonin in the previous measurements.

Table 2 presents the IC50concentration of compounds of formula (I).

D) Examples of compositions

"Active ingredient" (A. I.) here refers to the compound of formula (I), its pharmaceutically acceptable salt, acid or accession stereochemical isomeric form.

Example 8. Drops for oral administration

500 g of A. I. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60 - 80oC. After cooling to 30 - 40oC there was added 35 l of polyethylene glycol and the mixture is mixed well. Then was added a solution of 1750 g of saccharin sodium 2.5 l of purified water and while stirring EXT is achene, containing 10 mg/ml A. I. the resulting solution is filled in the correct containers.

Example 9. The solution is for oral purpose

9 g of methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 g of 2,3-diablocody acid and then 20 g of A. I. the Latter solution was combined with the rest of the first solution and thereto was added 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 g of saccharin sodium were dissolved in 0.5 l of water and added 2 ml strawberry and 2 ml essences gooseberry. The latter solution was combined with the first, was added much needed water to a volume of 20 l with obtaining a solution for oral purposes, containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution was filled into suitable containers.

Example 10. Capsules

20 g of the active ingredient, 6 g of acrylourethane, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate was vigorously mixed together. The resulting mixture was filled into 1000 hard gelatin capsules containing each 20 mg of the active ingredient.

Example 11. Tablets, film-coated

Cooking basics of what tworoom 5 g nitrilotriacetate and 10 g polyvinylpyrrolidone approximately 200 g of water. Wet powder mixture is sifted, dried and again sifted. Then to the mixture was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All were thoroughly mixed and merged into tablets obtain 10,000 tablets containing each 10 mg of the active ingredient.

Floor.

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then was added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melted 10 g of polyethylene glycol was dissolved in 75 ml of dichloromethane. The latter solution was added to the first and thereto was added 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated ink suspension and the mixture was gomogenizirovannykh. Fundamentals of tablets covered with this mixture in device for a covering.

Example 12. Injection

1.8 g methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate was dissolved in approximately 0.5 l of boiling water for injection. After cooling to about 50oC there with stirring was added 4 grams lactic acid, 0.05 g of polyethylene glycol and 4 g of A. I. the Solution was cooled to room temperature and populatiei (USP XVII p. 811) and filled into sterile ampoules.

Example 13. Suppositories

3 g A. I. was dissolved in a solution of 3 g of 2,3-diablocody acid in 25 ml of polyethylene glycol 400. Together melted 12 g of surfactant (SPAN and triglycerides) Witersol 555q.s. to 300 G. of the Latter mixture was thoroughly mixed with the first solution. Thus obtained mixture was poured into moulds at a temperature of 37 - 38oC with 100 suppositories containing each 30 mg/ml A. I.

Example 14. The solution for injection.

60 g A. I. and 12 g of benzyl alcohol were thoroughly mixed and added sesame oil q.s. up to 1 l with obtaining a solution containing 60 mg/ml A. I. the Solution was sterilized and filled into sterile ampoules.

1. Substituted dihydropyrimidine General formula I

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its pharmaceutically acceptable acid salt of accession, its N-oxide or its stereochemical isomeric form in which =a1-a2=a3-a4= bivalent radical of the formula: =N-CH=CH-CH= (a) =CH-N=CH-CH= (b) =CH-CH=N-CH= (c) =CH-CH=CH-N= (d)

in which one or two hydrogen atoms may be replaced by halogen, hydroxy, C1-6the alkyl or C1-6alkoxy;

R1is hydrogen or C1-6alkyl;

R2is hydrogen or C1-6the 2-15alcander;

Q is a radical of the formula

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< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
in which R4is hydrogen, cyano;

R5is hydrogen;

R6is hydrogen or C1-6alkyl or

R7and R8is hydrogen;

R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R24, R23, R25and R26is hydrogen;

R21and R22each independently is hydrogen, C1-6alkylthio;

q = 1 or 2;

r = 1 or 2.

2. Connection on p. 1, in which R1and R2both hydrogen and Alk2- 1,3-propandiol.

3. Connection on p. 1, where a1-a2=a3-a4is a bivalent radical of formula (a) or (c) .

4. Connection on p. 1, in which Q is a radical of the formula (aa), (BB), (dd), (gg) or (ii).

5. Connection on p. 1, in which the compound is a N-(3,4-dihydro-2H-pyrano/2,3-b/-pyridin-2-yl)methyl-N'-2-pyrimidinyl-1,3-propandiamine;

N-(3,4-dihydro-2H-pyrano/2,3-b/-pyridin-2-yl)methyl-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propandiamine;

N-(3,4-dihydro-2H-pyrano/2,3-b/-pyridin-2-yl)methyl-N'-2-pyrimidinyl-1,3-propandiamine, N-oxide;

N-(3,4-dihydro-2H-pyrano/3,2-c/pier is 4-pyrimidinyl-1,3-propandiamine;

N-(3,4-dihydro-2H-pyrano/2,3-b/-pyridin-2-yl)methyl-N'-2-pyridinyl-1,3-propandiamine; and

N"-cyano-N-[3-[[(3,4-dihydro-2H-pyrano/2,3-b/-pyridin-2-yl)methyl]amino] propyl]-N'-propylaniline,

their pharmaceutically acceptable salt, acid or accession their stereochemical isomeric form.

6. Pharmaceutical composition having vasoconstrictive action containing a pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient is used therapeutically effective amount of the compounds under item 1.

7. The method of obtaining the composition of p. 6, characterized in that a therapeutically effective amount of the compounds under item 1 is thoroughly mixed with a pharmaceutically acceptable carrier.

8. Connection on p. 1 with vasoconstrictive action.

9. Intermediate compounds of formula VII with

in which R3is hydrogen or C1-6alkyl and W2- chlorine, bromine, iodine, methanesulfonate or methylbenzenesulfonamide, its acid salt of accession or its stereochemical isomeric form.

10. A method of obtaining a connection on p. 1, characterized in that conduct intermediate interaction , is defined in paragraph 1;

W2- chlorine, bromine, iodine, methanesulfonate or methylbenzenesulfonamide,

with an intermediate compound of formula VI

in which R1, R2, Alk2and Q have the meanings specified in paragraph 1,

and if necessary, the compound of formula I is subjected to hydrogenation or dialkoxybenzene, or N-acylation, N-alkylation, and further, if desired, the compounds of formula I is transferred in the form of a salt processing pharmaceutically acceptable acid or base, or conversely, the salt form is converted into the free base or free acid by treatment with alkali, or acid, and/or you can get a stereochemical isomeric forms of the compounds of formula I.

 

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A< / BR>
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