Derivatives chromane or thiochroman and methods for their production (options)

 

(57) Abstract:

Usage: in medical practice to suppress the pain and the regulation of the cardiovascular system. Product: 3-(dipropylamino)-5-proportionalintegral, so pl. 150-151 oC, 66 %: 3-(methyl-3-phenylpropyl)amino-5-N-methylcarbamoyl, so pl. 150-151oC (oxalate). 5 C. and 38 C.p. f-crystals.

The invention relates to new substituted 3-aminopropanal and thiochroman, their enantiomers and salts; processes for their preparation, pharmaceutical compositions containing such therapeutically active compounds and to new intermediates used in obtaining these therapeutically active compounds and to the use of said active compounds in therapy.

The purpose of this invention is to provide compounds for therapeutic use, especially compounds having therapeutic activity through the Central nervous system (CNS). An additional objective is the provision of compounds having a selective action on 5-hydroxy-tryptamine receptors in mammals, including humans.

Therapeutically useful 3-amino-dihydro(1)-benzopyran and benzothiophen with afti compounds defined by the formula:

< / BR>
in which Z is an oxygen atom or sulfur;

R is a hydrogen atom, or lower alkyl;

R1a hydrogen atom, lower alkyl or aryl-lower alkyl;

R2a hydrogen atom, lower alkyl or aryl lower alkyl;

or R1and R2together form a ring of 4 to 6 carbon atoms;

R3a hydrogen atom, hydroxy, lower alkoxy, aryl-lower alkoxy, acyloxy or aryloxy-group, when Z is a sulfur atom, and R3is hydroxy, lower alkoxy, arlinski alkoxy; acyloxy or aryloxy-when Z is an oxygen atom, and R3is in position 5 or 8, when Z is an oxygen atom;

R4and R5independently are a hydrogen atom, lower alkyl or halogen, and their mono - or di-S-oxides, when Z is a sulfur atom, and their pharmaceutically acceptable salts.

Hydrochloride 3-chromanin with two alkyl groups in the aromatic ring, having a Central stimulant activity, described in the journal J. Med. Chem. 1972, volume 15, S. 863-865.

The aim of the present invention is to provide new compounds that have high affinity for 5-hydroxytryptamine receptors in the Central nervous system and at the same time, they de>Thus, the group of new compounds of the formula I of the present invention, as well as their enantiomers and salts are used in therapeutic treatment of conditions that are treated with 5-hydroxytryptamine, and disorders, such as depression, anxiety, loss of appetite, senile dementia, migraine, disease of Alzheimer, hypertension, disorders of thermoregulation and sexual disorders. Additional aspects of this invention involve the use of these substances, their enantiomers and salts to suppress pain and the regulation of the cardiovascular system.

Thus, the invention provides a substance of the formula

< / BR>
in which X is an oxygen atom or a group S=(O)p;

p integer: 0, 1 or 2; R is a hydrogen atom is fluorine or alkyl (C1-C6; R1is a hydrogen atom, an alkyl, C1-C6or alkenyl C2-C6; R2is a hydrogen atom, an alkyl, C1-C6, alkenyl C2-C6; alkyl (C1-C4)aryl, in which aryl may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur, and optionally substituted by halogen atom, cyano-, triptorelin, C1-C6-alkyl, C2-to transform the five - or six-membered cycle, which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur;

R3is a halogen atom, cyano-, triptorelin, a group of SO3CF3N3, NO2C1-C6alkyl, C2-C6alkenylphenol, amino group, NR5R6, COR7five - or a six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and which is: (a) optionally substituted by one or more substituents which are independently selected from halogen, cyano, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group, or b) condensed via two adjacent carbon atoms with an aryl ring, and the above-mentioned aryl optionally substituted by one or more substituents which are independently selected from halogen, cyano, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group;

R4is a hydrogen atom, halogen or alkyl group of C1-C6;

R5is a hydrogen atom, an alkyl, C1-C6, alkenyl C2-C6; R6is alkalo or six-membered cycle, which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur;

R7is hydrogen atom, chlorine, bromine, a hydroxyl group, a C1-C6alkyl, C2-C6alkenylphenol, C1-C4CNS, NR8R9or five, or a six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted by one or more halogen atoms, cyano-, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group;

R8and R9each independently is a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol group five - or a six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur and which is optionally substituted by halogen atom, cyano-, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group, or may together form a five - or six-membered ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur; or the enantiomers or salts.

An additional aspect of the formula I,

< / BR>
in which X is an oxygen atom or a group S=(O)p;

p integer: 0, 1 or 2; R is a hydrogen atom, fluorine or alkyl (C1-C6; R1is a hydrogen atom, an alkyl, C1-C6or alkenyl C2-C6; R2is a hydrogen atom, an alkyl, C1-C6alkenyl C2-C6; alkyl (C1-C4) aryl, in which aryl may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur, and optionally substituted by halogen atom, cyano-, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group; or

R1and R2together may form a five - or six-membered cycle which may contain 1 or 2 heteroatoms;

R3is a halogen atom, triptorelin group C1-C6alkyl, C2-C6alkenylphenol, -NR5R6, COR7five - or a six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and which is: (a) optionally substituted by one or more substituents which are independently selected from halogen, cyano, triptorelin, C1-C6alkyl, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group;

R4is a hydrogen atom or halogen;

R5is a hydrogen atom, an alkyl, C1-C6alkenyl C2-C6;

R6is alkyl (C1-C6or alkenyl C2-C6or

R5and R6together may form a five - or six-membered cycle which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur;

R7is a hydrogen atom, a C1-C6alkyl, C2-C6alkenylphenol, C1-C4CNS group NR8R9or five, or a six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and optionally substituted by one or more halogen atoms, cyano-, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group;

R8and R9each independently is a hydrogen atom, a C1-C6as the heteroatoms, selected from nitrogen, oxygen or sulphur and which is optionally substituted by halogen atom, cyano-, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group, or may together form a five - or six-membered ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur; or the enantiomers or salts.

A preferred group of therapeutically active compounds of the formula I are those in which R1and R2each independently is a hydrogen atom, n-propylene, isopropyl or cyclopropyl and R3is a carbonyl group COR7. Among these groups there are such definitions R7as alkyl, aminoalkyl, for example methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl and cyclobutyl or aryl, aminoaryl, for example, phenyl, thienyl, forfinal and furanyl. Another preferred group is such that when R3is aryl, such as phenyl, teinila, florfenicol or TuranAlem. Another preferred group is such that when R3is alkyl, for example n-propylene, isopropyl or alkenyl, such as Isopropenyl and allyl. Another preferred gruo enantiomers.

Substances of the formula I, in which R3is cyano-, carboxy-, COCl, COBr, NH2or SO3CF3group, are novel intermediate compounds for the preparation of therapeutically active compounds of formula I.

Alkyl, C1-C6in the formula I is a normal, branched and cyclic alkyl groups having from 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, methylcyclopropyl, ethylcyclopropane, methylcyclobutane. Preferred alkyl groups have from 1 to 4 carbon atoms.

Alkenyl C2-C6in the formula I represents a normal or branched alkeneamine group having from 2 to 6 carbon atoms and containing one or two double bonds, for example alkyl, propenyl, Isopropenyl, butenyl, Isobutanol, pentanol, isopentanol. Preferred alkeneamine groups have from 2 to 4 carbon atoms and one double bond.

Alkoxy, C1-C4in the formula I represents a normal CNS group having from 1 to 4 carbon atoms, for example methoxy, Rhyl can contain 1 or 2 heteroatoms, selected from nitrogen, oxygen or sulfur, in the definition of R2in the formula I represents an aryl residue having from 3 to 12 carbon atoms in the aromatic ring and optionally 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur in the aromatic ring associated normal or branched alkalinous chain, having from 1 to 4 carbon atoms in the aliphatic chain. The aromatic ring may be substituted by one or more groups: nitrile, triptorelin, halogen, such as fluorine, chlorine, bromine, iodine, alkyl (C1-C6such as methyl, ethyl, propyl, alkenyl C2-C6for example allyl, propenyl, or alkoxy, C1-C4preferably in the meta and/or para-position. Examples of suitable aryl groups in the alkyl, C1-C4the aryl are phenyl, naphthyl, diphenyl, thienyl, furyl, peril, pyrimidyl and pyridinyl. Preferred alkyl (C1-C4aryl groups are unsubstituted and substituted phenylaniline groups in which the alkyl group is a normal or branched alkyl having from 1 to 4 carbon atoms, and the aromatic ring may be substituted by one or more groups, such as fluorine, chlorine, bromine, iodine, nitrile, doctitle is phenylpropyl.

The halogen atom in the formula I represents a fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine and bromine.

Five - or six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and which is: (a) optionally substituted by one or more substituents which are independently selected from halogen, cyano, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group, or b) condensed via two adjacent carbon atoms with an aryl ring, and the above-mentioned aryl optionally substituted by one or more substituents which are independently selected from halogen, cyano, triptorelin, C1-C6alkyl, C2-C6alkenylphenol or C1-C4CNS group; in the definition of R3in formula I, is either a) substituted or unsubstituted phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinil or morpholinyl, or b) substituted or unsubstituted chenail, ethanolic, chinadoll, chanaxati or indolyl.

Five - or six-membered aryl, which 9in the formula I is a phenyl, thienyl, furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, piperazinil or morpholinyl.

Examples of suitable five - or six-membered cyclic structures that can be formed by the radicals R1and R2or R5and R6or R7and R8and which may contain an additional heteroatom selected from nitrogen, oxygen or sulfur, are piperazine, morpholine, pyrrolidine, pyrrole, pyrrolin, imidazole, imidazoline, imidazolidine, pyridine, pyrazole, pyrimidine, pyrazin, pyridazin.

Substances of this invention have one or two asymmetric carbon atom. When R is a hydrogen atom, substances have an asymmetric carbon atom adjacent to the nitrogen atom, that is, C3and when R is alkyl (C1-C6substances have an asymmetric carbon atom adjacent to the nitrogen atom, and the asymmetric carbon atom adjacent to the alkyl group, that is, C4. Thus, these substances exist in the form of two or four optical isomers, i.e. enantiomers. In the scope of protection of this invention includes both the pure enantiomers and racemates is or existing enantiomers.

For the formation of non-toxic, pharmaceutically acceptable acid additive salts of the compounds of this invention can be used both organic and inorganic acids. Examples of acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, Hydrobromic, citric, acetic, lactic, tartaric, Panova, ethicalfashion, sulfamic, amber, methylsulfonate, propionic, glycol, malic, gluconic acid, pyruvic acid, phenylacetic, 4-aminobenzoic, Anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, nicotine, methansulfonate, econsultancy, hydroxyethanesulfonic, benzosulfimide, a pair of toluensulfonate, Sultanova, naphthalenesulfonate, ascorbic, cyclohexylsulfamate, fumaric, maleic and benzoic acid. These salts are easily obtained by methods that are known in this field of chemistry.

The substances of formula I can be obtained using the following processes that make up an additional aspect of this invention.

A. The transformation of the substances of the formula II

< / BR>
in which Y is tsepliaeva group, such as triftorbyenzola (OSO2CF3), the halogen atom, uppy V carboxypropyl COZ, in which Z is chlorine, bromine, hydroxyl group ORpwhere Rpis alkyl (C1-C6, with the formation of the substances of the formula I, in which R3is a group of COZ (IA).

The compound of formula II can be converted into a substance of the formula IA in the next catalytic cycle. The metal M0must be nonvalent transition metal (M), such as palladium or Nickel, which can undergo oxidative connection relations aryl-Y, for example, relations aryl-SO3CF3. This metal can be generated in place of the divalent metal M" Aryl-CO-M-Y is formed by processing carbon monoxide (CO).

Additional reagents are alcohol, such as methanol, ethanol; amine base, such as trialkylamine, such as triethylamine; in an inert organic solvent, preferably a polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, acetonitrile, etc. Usually the reaction is carried out at a temperature between +40 and +120oC and a pressure of between 100 and 500 kPa. Then optionally followed by hydrolysis and treatment with thionylchloride, such as thionyl chloride, in order that the SUB> is a group of COZ (IA) can also be obtained using the reverse process. Interaction in the form of a catalytic cycle using nonvalence transition metal M0such as palladium or Nickel, which can undergo oxidative connection for the connection of the Z-Y, where Z is a chlorine atom, bromine, OH group, ORpand ORpis alkyl (C1-C6and Y tsepliaeva group, such as OSO2CF3, a halogen atom, treatment with carbon monoxide followed by the addition of compounds of formula III in which X, R, R1, R2and R4such as defined in formula I.

The connection of the Z-CO-M-Y may also be formed directly from the Z-CO-Cl. Reaction conditions and reagents are the same as described above in method a). A suitable hydrolysis of ester carboxylic acid gives the free acid which can be converted into a derivative of the acid halide.

c. The transformation of compounds of formula II

< / BR>
in which X, R, R1, R2and R4such as defined above, and Y is tsepliaeva group, such as SO3CF3, chlorine or bromine, by treatment cyanide reagent, such as copper cyanide, education is given in an inert organic solvent, such as dimethylformamide, hexamethylendiamine phosphoric acid, etc. at a temperature between +20 and +200oC, preferably between 50 and 150oC and normal pressure.

d. Amination of the compounds of formula IA

< / BR>
in which X, R, R1, R2and R4such as defined above, and Z is a chlorine atom, bromine, OH group or orpand ORpis alkyl (C1-C6.

If the compound of formula IA is a complex ether carboxylic acids, it must first be subjected to hydrolysis to the free acid. Then the free acid is transferred to the amide of formula IC through a derivative of the acid chloride by reaction with the corresponding amine with other8R9where R8and R9such as defined in the formula I, in a nonpolar aprotic solvent, for example toluene, benzene under reflux at a temperature between 0 and 100 oC.

e. According to the Wittig reaction with the formation of the compounds of formula I in which R3is alkenylphenol group C2-C6(IE)

< / BR>
5-carboxy-chroman/thiochroman-derivative, in which X, R, R1, R2and R4such as defined in formula I, and R7is alkyl, determine the tion, with the formation of the corresponding alkenylphenol group (IE).

f. Catalytic hydrogenation of 5-alkene-chroman/thiochroman-derivative of the formula I, in which R3is alkenylphenol, group C2-C6using hydrogen and palladium, hydrogen and platinum or hydrogen and Raney Nickel to obtain the corresponding derivative of the formula I, in which R3is an alkyl group of C1-C6(IF).

g. Substitution of 5-brahaman/thiochroman is derived by processing trialkylaluminium reagent in the presence of nonvalence metal, preferably palladium, with the formation of the substances of the formula I, in which R3is alkyl (C1-C6alkenyl C1-C4or aryl, in the presence of carbon monoxide gives compound of formula I, in which R3is a group COR7in which R7defined as alkyl, C1-C6alkylen C2-C6or aryl.

The substitution can be carried out in one of the following ways:

h. The conversion of 5-carboxy-chroman/thiochroman-derivative of the formula I

< / BR>
in which X, R, R1, R2and R4such as defined above, and Z is chlorine or bromine, using R7oC.

i. The hydrolysis of compounds of formula I in which R3is a cyano group (IB)

< / BR>
in which X, R, R1, R2and R4such as defined above, optionally followed by treatment with thionylchloride, such as thionyl chloride, tierbroker, in order to obtain the compound of formula (I) in which R3is a group COZ, where Z is hydroxyl, chlorine or bromine.

j. Substitution of substances of the formula I, in which R3is a cyano group (IB)

< / BR>
in which X, R, R1, R2and R4such as defined above, by treatment with a suitable ORGANOMETALLIC reagent, preferably organolithium such as R7Zi or a Grignard reagent, such as R7Mg-halide, in an inert organic solvent, preferably a non-polar aprotic solvent, such as is the complex to obtain the compound of formula I, in which R3is a group COR7where R7is alkyl (C1-C6, alkenyl C2-C6or aryl.

k. Hydrogenation of 5-alkene-thiochroman/Romanovo derivative of the formula I, in which R3is alkenylphenol group C2-C6using hydrogen and palladium, hydrogen and platinum or hydrogen and Raney Nickel or azodicarboxylate potassium, with formation of the corresponding thiochroman/Romanovo derivative of the formula I, in which R3is alkyl (C1-C6.

l. The transformation of compounds of formula II

< / BR>
in which Y is tsepliaeva group, such as triftorbyenzola, phosphonate, halogen, such as bromine or iodine, and R, R1, R2such as defined above, by replacing the group Y to R3that is alkenylphenol group C2-C6(IE).

The compound (II) can be transformed into (IE) by reacting with a transition metal such as palladium or Nickel, which may form a ligand complex and subject to oxidative connection. Suitable alkanniny Deputy can be entered in the result of processing trialkyl is, what, for example, lithium chloride. The interaction is preferably carried out in a polar aprotic solvent such as dimethylformamide, dioxane, acetonitrile or dimethylsulfoxide at a temperature between +40 and 120oC.

m. The transformation of compounds of formula II

< / BR>
in which Y is tsepliaeva group, such as triftorbyenzola, phosphonate, halogen, such as bromine or iodine, and R, R1, R2such as significantly higher, by replacing the group Y on five - or six-membered aryl which may contain 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur and which is, or substituted or condensed via two adjacent carbon atoms with an aryl ring, which is defined above, with the formation of the substances of formula IF.

The compound (II) can be transformed into (IF) by interaction with transition metal such as palladium or Nickel, which are capable of forming ligand complex and subject to oxidative connection. Suitable aryl Deputy can be entered in the result of processing trialkylsilanes or airborne acid.

Additional reagents are amine, such as triethylamine, and a lithium salt, for example PI is informed, dioxane, acetonitrile or dimethylsulfoxide at a temperature between +40 and 120oC.

The following method describes one of the ways to obtain the intermediate compounds of formula IB, in which R1, R2and R4such as defined in formula I.

In accordance with the invention the compounds of formula I are usually given orally, rectally or by injection in the form of pharmaceutical preparations comprising the active ingredient or in the form of free base or pharmaceutically acceptable non-toxic acid additive salts, such as hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulpham, citrate, tartrate, oxalate and the like in a pharmaceutically acceptable dosage forms. Dosage form may be a solid or liquid preparation. Usually the active substance may comprise from 0.1 to 99 wt. the weight of the preparation, more specifically between 0.5 and 20 by weight of the drug intended for injection and between 0.2 and 50 by weight of the preparation suitable for oral destination.

In order to obtain pharmaceutical preparations containing a substance of the formula I in unit dosage form for oral use, selected the target substance, such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then the mixture is pressed into tablets. If you require coated tablets, the base, prepared as described above, may be coated with a concentrated sugar solution which may contain gum Arabic, gelatin, talc, titanium dioxide, etc., Alternative tablet may be coated with polymer, which is known to the specialists in the field of chemistry, dissolved in a volatile organic solution or mixture of organic solvents. These coatings can be added colouring matter, in order to easily distinguish between tablets containing different active substances or different number of active substances.

For the preparation of soft gelatin capsules, the active substance can be mixed, for example, with vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substance using either of the above environments for tablets, for example lactose, with whom llulose or gelatin. In addition, hard gelatin capsules can be filled with liquid or semi-solid drugs.

Single dose for rectal application can be solutions or suspensions, or may be prepared in the form of suppositories comprising the active substance in a mixture with a neutral liquid Foundation, or gelatin rectal capsules comprising the active substance in a mixture with vegetable or paraffin oil.

Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from about 0.2 to 20 by weight of the active substances described here, the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Such liquid preparations may not necessarily contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other environment for medications that are known to the expert in this field.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5 to 10 wt. Rasstavleny in different vials single dose.

Suitable daily doses of the substances of this invention in therapeutic treatment of humans are about from 0.01 to 100 mg/kg body weight by oral appointment and from 0.001 to 100 mg/kg body weight at parenteral appointment.

Example 1. 3 dipropylamino-5-triftormetilfullerenov.

3 dipropylamino-5-hydroxychromone (Torberg and neg. Acta Phasm. Suec. 1987, 24) 1.4 g (4.0 mmol) and 0.1 g (0.75 mmol) N,N-dimethylaminopyridine dissolved in 50 ml of methylene chloride and cooled to -30oC. Add 0.75 ml (5.7 mmol) of 2,4,6-collidine and then 1.0 ml (6.0 mmol) of anhydride of triftoratsetata. The solution is stirred for 3 h at -20oC and then allowed to warm to room temperature. This solution was washed with aqueous solution of acid sodium carbonate, dried over sodium sulfate and evaporated to dryness. Light yellow oil finally purified by the method of flash chromatography (silica gel) by elution with a mixture of ethyl acetate/hexane 1:9. The output is 55 So pl. 125-127oC (oxalate).

Example 2. 3 dipropylamino-5-methoxycarbonylamino.

3 dipropylamino-5-triftormetilfullerenov (example 1: 4,43 g, 11.6 mmol) was dissolved in 80 ml of a mixture of dimethylformamide/methanol 6:2 and the solution Tegaserod 15 min at 20Oropesa and 3.5 ml (25 mmol) of triethylamine. The mixture is heated to 70oC in an atmosphere of CO and stirred for 5 hours the Solution is cooled, diluted with 200 ml of toluene, washed with aqueous solution of sodium bicarbonate, dried with sodium sulfate and evaporated to dryness, the oil cleanse method flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1:8. The output is 76 So pl. 150-152oC (hydrochloride).

Example 3.

3 dipropylamino-5-carbamothioyl. 3 dipropylamino-5-methyloxirane (example 2: 400 mg, 1.37 mmol) dissolved in 10 ml of methanol and add 60 ml (1.5 mmol of sodium hydroxide in 2 ml of water. The mixture is refluxed 5 h, cooled, filtered through Celite and evaporated to dryness. The residue is boiled with chloride sulfuricum SOCl2(5 ml, 68 mmol) within 30 min the Excess of chloride sulfured then removed in vacuum to obtain the hydrochloride of 3-dipropylamino-5-chloroformiate resin. This light brown resin is dissolved in 50 ml of methylene chloride and passed through a solution of a stream of gaseous ammonia for 2 minutes the Solution is washed with aqueous sodium hydrogen carbonate solution, dried with sodium sulfate and evaporated to dryness. The oil cleanse method flash chromatography (on silica gel) by elution with a mixture of etilefrine 4. 3 dipropylamino-5-N,N-dimethylcarbamoyl.

Specified in the title substance was prepared according to the method similar to the one used in example 3, from 3-dipropylamino-5-methoxycarbonylamino and using instead of ammonia, gaseous dimethylamine. An NMR spectrum 13With: 189,3; 170,3; 149,9; 137,4; 126,7; 126,1; 124,9; 65,8; 64,7; 48,2; 47,7; 30,7; 26,0; 15,1; 10,9.

Example 5. 3 Dipropylamino-5-N,N-diisopropylcarbodiimide.

Specified in the title substance was prepared according to the method similar to the one used in example 3, from 3-dipropylamino-5-methyloxirane. So pl. 228-230oC (hydrochloride).

Example 6. 3 dipropylamino-5-N-methylcarbamoyl.

Specified in the title substance was prepared similarly to the method used in example 3, from 3-dipropylamino-5-methoxycarbonylamino and instead of using ammonia gaseous methylamine. So pl. 95-97 oC (oxalate).

Example 7. 3 dipropylamino-5-azithromy.

Hydrochloride 3-dipropylamino-5-chloroformiate (4.42 g, a 13.4 mmol), prepared from 3-dipropylamino-5-methoxycarbonylamino (example 2) according to the method similar to the one used in example 3 in 20 ml of dry tetrahydrofuran add the l of tetrahydrofuran at -78oC. This solution is stirred for 15 min at -78 oC and then allowed to warm to room temperature for 10 minutes Then slowly add 30 ml of water. The organic phase is decanted, dried with sodium sulfate and evaporated to dryness. The residue is purified by the method of flash chromatography (on silica gel) by elution with a mixture of ethyl acetate/hexane 1:8. Specified in the title compound crystallizes in the form of a salt of ethyl acetate. So pl. 106-108oC (oxalate).

Example 8. 3 dipropylamino-5-cyclopropanecarbonitrile.

Specified in the title compound was prepared according to the method similar to the one used in example 7, instead of using dimethylsulfate lithium dicyclopropyl lithium (J. Org. Chem. volume 41, S. 22, 1976), So pl. 100 - 102oC (oxalate).

Example 9. 3 dipropylamino-5-tert-butylcarbamoyl.

Specified in the title compound was prepared according to the method similar to the one used in example 7, instead of using dimethylsulfate lithium di-tert-mutilmedia lithium (tert-utility and complex copper bromide dimethyl sulfide). So pl. 118-120oC (oxalate).

Example 10. 3 dipropylamino-5-tert-butylcarbamoyl.

Specified in the header of soedineniya lithium Diisopropylamine magnesium (from propylene chloride and CuBr complex*dimethyl sulphide). So pl. 60-62oC (oxalate).

Example 11. 3 dipropylamino-5-(4-tortenelmebol)chroman.

Specified in the title compound was prepared according to the method similar to the one used in example 7, using instead dimethylcarbamate lithium di-(4-forfinal) cuprate magnesium (from 4-performane bromide and iodide of copper). So pl. 98,3-98,4oC (oxalate).

Example 12. 3 dipropylamino-5-(thienylboronic)chroman.

Specified in the title compound was prepared according to the method similar to example 7, using instead dimethylcarbamate lithium di-(2-thienyl)cuprate lithium (2-titillate and modestou copper). So pl. 87-88,5oC (oxalate).

Example 13. 3 dipropylamino-5-isopropylcarbonate.

A solution of 0.62 g (1,74 mmol) methyltriphenylphosphonium in dried diethyl ether (20 ml) under nitrogen atmosphere at room temperature, type of 1.74 mmol n-utility (0.7 ml of a 2.5 molar solution) and the solution stirred for 4 hours, Dissolve 0.4 g (1,45 mmol) 3-dipropylamino-5-acetylcholine (example 7) in 2.0 ml of dried diethyl ether and this solution is added to the previously prepared by Wittig reagent. The mixture is stirred at room temperature and evaporating it to dryness gives a solid substance, which was finally purified by the method of flash chromatography with elution with a mixture of ethyl acetate/hexane 1:4. The collected fractions were evaporated and gave specified in the title compound as a colourless oil. An NMR spectrum13C: 11,82, 21,94 24,28 26,69 52,79 53,64 67,70 115,03 118,73 120,07 126,83, 144,88 145,27 154,03.

Example 14. 3 dipropylamino-5-aminochrome.

Dissolve 1.0 g (3.4 mmol) of 3-dipropylamino-5-methoxycarbonylamino (example 2) in methanol (20 ml). Added 0.16 g (4.1 mmol) of sodium hydroxide in 1.0 ml of water and the solution is refluxed in nitrogen during the night. The solution is evaporated to dryness, add 20 ml of toluene and again evaporated to dryness. The residue is dissolved in 20 ml of toluene, add to 1.87 g (6.8 mmol) diphenylphosphinite and the solution is refluxed for 2 hours Add 2 ml of methanol and boiling continued for another 4 hours the Solution is cooled, washed with water and extracted with diluted hydrochloric acid. An acidic aqueous phase is neutralized with an aqueous solution of sodium hydroxide and extracted with toluene. Dried toluene phase with sodium sulfate and evaporated with toluene. Dried toluene phase with sodium sulfate and evaporated it to dryness. The residue is dissolved in ethanol containing 10 hydrated hydroxide by nilwala. Washing with water, drying the organic phase and evaporating it to dryness gives specified in the header of the substance in the form of oil, which turns into dichloroisoproterenol salt. So pl. 173-174oC.

Example 15. 3 dipropylamino-5-nitropropan.

3 dipropylamino-5-aminochrome (example 14, 0.05 g, 0.2 mmol) dissolved in a mixture of 0.08 ml (1 mmol) triperoxonane acid and 5 ml of water. A clear solution is cooled to 0-4oC. With good stirring, added dropwise sodium nitrite (0,017 g, 2.5 mmol) in 1 ml of water. The solution is stirred for 15 min and neutralized with calcium carbonate. Add a solution of sodium nitrite (0.5 g, 7.2 mmol) in 1 ml of water and then a mixture of copper sulfate (0.01 g, of 0.62 mmol) and cuprous oxide in 1 ml of water. The solution was stirred at 0oC for 20 min and then at room temperature for 2 hours the Solution is extracted with diethyl ether. The organic phase is dried with sodium sulfate and evaporated to dryness. The residue is purified by the method of flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1:9. Get the specified header connection so pl. 150-151oC (hydrochloride).

Example 16. 3 dipropylamino-5-azithromy.

3 dipropylamino-5-aminochrome (example 14, 0.05 g, 0.2 mmol) diasterous on metamediary at the 5oC during the night the solution treated and purified by the method of example 15, receiving specified in the header of the connection so pl. 167-168oC (oxalate).

Example 17. 3 dipropylamino-5-(pyrrol-1-yl)chroman.

3 dipropylamino-5-aminochrome (example 14, 0.6 g, 2,42 mmol) dissolved in 10 ml of acetic acid and add 0.4 g (3 mmol) of 2,5-dimethoxytetrahydrofuran. The solution is refluxed for 1 h, This solution is neutralized aqueous sodium hydroxide and extracted with toluene. The organic phase is dried with sodium sulfate and evaporated to dryness. The residue is purified by the method of flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1:9 and receive specified in the header connection. An NMR spectrum13C: 11,75 21,89 24,81 52,69, 53,15 67,94 108,93 115,67 118,22 118,44 121,87 127,22 141,47 155,27.

Example 18. 3-methyl-3-phenylpropyl)amino-5-hydroxychromone.

3-amino-5-methoxypropan (Torberg al. Acta Phasm. Snec. 1987, p.24) (2 g, 9.28 are mmol) is dissolved in 50 ml of methanol and acidified with acetic acid to a pH of 6.0. The solution is cooled to 0 oC and added 0.87 g (to 13.8 mmol) cyanoborohydride sodium together with 3-phenylpropanal (1,22 ml, 9.28 are mmol). Remove the cooling and the solution stirred at room temperature for 4 hours Add a night at room temperature. The solution was diluted with toluene and washed with water. Drying with sodium sulfate and evaporation to dryness gives the oil. This oil is purified by the method of flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1: 4. The selected fraction is evaporated and get the oil, which is treated with an aqueous hydrogen bromide (47) at 120oC 1 h the Solution is cooled and neutralized with sodium hydroxide and extracted with toluene. The organic phase is dried with sodium sulfate and evaporated, receiving specified in the procurement of the compound in the form of oil. An NMR spectrum13C: 22,502 29,09 33,47 38,19 53,66 67,76 102,004 109,2 110,46 125,78 127,05 128,36 142,2 155,29 158,28.

Example 19. 3-(methyl-3-phenylpropyl)amino-5-methoxycarbonylamino.

3-(methyl-3-phenylpropyl)amino-5-hydroxychromone (example 18, 1 g, 3,37 mmol) was dissolved in 20 ml of methylene chloride at 20oC. Type of 0.32 ml (4 mmol) of pyridine, with 0.65 ml (5.9 mmol) of anhydride of triftoratsetata and 0,041 g (0.59 mmol) of dimethylaminopyridine (DMAP) at 20oC and under nitrogen atmosphere. The solution is stirred for 3 h at -20oC. Remove the cooling and the solution was diluted with toluene, washed with aqueous sodium bicarbonate solution, dried with sodium sulfate, filtered through silica gel and evaporated to dryness. The remaining oil RA,103 g (0.25 mmol) of 1,3-bis (diphenylphosphino) propane and from 0.76 ml (5 mmol) of triethylamine and the solution is rinsed with gaseous carbon dioxide under vigorous stirring. The pressure in the reaction vessel increases to 20.2 kPa using a balloon with carbon dioxide, is supplied with a regulator. Stirring is continued overnight at 75oC. the Pressure and the temperature is brought to normal values and the solution was diluted with toluene and washed with water. Dried organic phase is evaporated to dryness. The remaining oil purified by the method of flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1:4. The selected fraction is evaporated and receive specified in the procurement compound as a colourless oil. An NMR spectrum13C: 26,88 29,0 33,2 37,85 51,64 53,37 55,44 67,24 120,6 123,06 123,4 125,59 126,47 128,17 128,17 128,24 130,36 142,01 154,93 167,29.

Example 20. 3-(methyl-3-phenylpropyl)amino-5-N-methylcarbamoyl.

3-(methyl-3-phenylpropyl)amino-5-methoxycarbonylamino (example 19, 0.32 g, were 0.94 mmol) dissolved in 10 ml of methanol. Added 0.08 g of sodium hydroxide (2 mmol) in 1 ml of water and the solution is boiled overnight in nitrogen atmosphere. The solution is evaporated to dryness and again evaporated to dryness in conjunction with toluene (10 ml). The remaining solid is refluxed in chloride Sulfuryl for 30 min and evaporated to dryness. Light brown resin was dissolved in 20 ml of tetrahydrofuran, treated gas is tworoom sodium bicarbonate. Drying and evaporation gives the resin, which is finally purified by the method of flash chromatography on silica gel with elution with a mixture of ethyl acetate/hexane 1:2. The selected fraction is evaporated and get listed in the title compound as a colourless resin. Crystallization from ethyl acetate mavelikara salt forms white needles. So pl. 150-151oC (oxalate).

Example 21. 3 dipropylamino-5-triftormetilfullerenov.

3 dipropylamino-5-hydroxybenzamide (European patent 0222 996; 420 mg, was 1.58 mmol) and 0.27 g (0,29 ml) collidine dissolved in 15 ml of methylene chloride and cooled to -30oC. are added dropwise 0,54 g (0,32 ml) anhydride of triftoratsetata and allow the mixture to warm to room temperature. After 20 min, diluted with a mixture of methylene chloride. The solution was washed with saturated sodium bicarbonate solution, dried with sodium sulfate and evaporated in vacuum. Chromatography on silica gel by elution with chloroform gives 0,62 g specified in the connection header in the form of a Foundation. The output is 98 So pl. 37-38oC. an NMR Spectrum133C (200 MHz, CDCl3), M. D. 148,3 136,7 128,4 127,2 126,3 122,0 117,1 115,2 55,6 52,5 28,0 26,6-22,6 11,8.

Example 22. 3 dipropylamino-5-methoxycarbonylamino (6:2) dimethylformamide/methanol and the solution Tegaserod when tori 10 at 22oC 15 min. the reaction mixture was added 11 mg of palladium acetate, 19 mg of 1,3-bis-diphenylthiophene and of 0.48 ml (0.35 g) of triethylamine. The mixture is heated to 70oC in an atmosphere of carbon monoxide and stirred for 5 hours. The solution is cooled, diluted with 30 ml of toluene, washed with saturated sodium bicarbonate solution, dried with sodium sulfate and evaporated in vacuum. The chromatography was carried out on silica gel by elution with a gradient of chloroform from 10 ethyl acetate in chloroform gives 310 mg specified in the title compound (base) as a light yellow oil. Output 64 is an NMR Spectrum13C (200 MHz, CDCl3), M. D. 168,2 136,6 134,8 131,6 130,1 126,5 125,7 56,7 52,5, 52,1, 30,4, 28,022,3 11,9.

Example 23. 3 dipropylamino-5-acetylthiazole.

3 dipropylamino-5-methoxycarbonylamino (for example 22, 310 mg, 1.01 mmol) was dissolved in 8 ml of methanol and add 60 ml of sodium hydroxide in 2 ml of water. After boiling for 5 h the mixture is cooled and evaporated in vacuum. The residue is dissolved in thionyl chloride (5 ml) and then boiled for 1 h, the Excess thionyl chloride is evaporated in vacuum, obtaining a resin. The residual resin is dissolved in a minimum amount of tetrahydrofuran and added dropwise to a cooled to -78oC Rast is UP>C, then she is allowed to warm to room temperature and after 10 min the reaction is interrupted by adding 0.9 ml of water. The reaction mixture was filtered through Celite and evaporated to dryness. The residue is dissolved in ether, washed with a saturated solution of sodium bicarbonate, treated with brine, dried with sodium sulfate and evaporated in vacuum, obtaining the crude base in the form of oil. The crude residue is subjected to chromatographicaliy on silica gel by elution with a gradient from chloroform to 5 ethyl acetate in chloroform. Hydrochloric salt was obtained by dissolving the pure base in ether and the addition of an excess of ethereal HCl solution. Recrystallization in a mixture of trichloromethane/diethyl ether to give 92 mg specified in the title compounds as white solids. The outlet 27 so pl. 141-142oC. an NMR Spectrum13C (200 MHz, CDCl3), M. D. 201,9 138,4 135,9 131,7 131,2 127,2 127,0 59,9 54,1 51,8 29,9 27,9 26,1, 18,6 18,2, 11,6.

Example 24. 5-allyl-3-(dipropylamino) thiochroman.

To a solution of 3-(dipropylamino)-5-triftormetilfullerenov (example 21, 1.28 g, up 3.22 mmol), 76 mg (0.06 mmol) of tetrakis-(triphenylphosphine) palladium (O) and a few crystals of 2,6-di-tert-butyl-4-METHYLPHENOL in 10 ml of anhydrous toluene add 1,17 g is added 1 ml of pyridine to the cooled solution and then 2.1 ml of a complex of hydrogen fluoride pyridine (Steele and al. J. Org. Chem. 1987, 52 so, S. 422). After stirring 1 h at room temperature the reaction mixture was added 50 ml of diethyl ether and successively treated with 50 ml of 1-molar sodium hydroxide solution with water (2 times), washed with saturated sodium chloride solution and dried with sodium sulfate. After filtration and removal of solvent in vacuo get the crude substance in the form of a dark oil. The chromatography was carried out on silica gel by elution with a gradient from hexane to 5 ethyl acetate in hexane gives 0.85 grams specified in the header of the substance in the form of (base) of light yellow oil. The output 91 is an NMR Spectrum13C (200 MHz, CDCl3), M. D. 139,0 136,5 134,0 133,0 126,1 125,9 125,0 116,0 57,0 52,6 37,7 29,5 27,7 22,5. Part of the Foundation and transferred to the monohydrochloride salt by dissolving the numeric base in ether and the addition of an excess of ethereal HCl solution. The recrystallization their mixture of acetonitrile-ether-hexane gives a more solid with so pl. 164-165oC.

Example 25. 3-(dipropylamino)-5-propertyarray hydrochloride.

To a stirred suspension of azodicarboxylate potassium (0,76 g, 3.9 mmol) [freshly prepared from diethylazodicarboxylate and potassium hydroxide] and 5-allyl-3-(N, N-dipropylamino)thiochrome 4) as long until there is no longer yellow staining. After 30 min stirring at room temperature, add 200 mg of azodicarboxylate potassium and again decompose, as described above. This process continues until, while according to the analysis (gas chromatography) will not remain the source material in the mixture. Upon completion of the reaction (2 h and 4 add potassium salts) the solvent is removed in vacuum. To the residue add dvuhpolyarnyy solution of sodium hydroxide, which is twice extracted with diethyl ether, and the combined organic extracts are treated with a saturated solution of sodium chloride and dried with sodium sulfate. The crude base obtained as easily painted oil after removal of the solvent in vacuo. The chromatography was carried out on silica gel by elution with a gradient from hexane to 5 ethyl acetate in hexane gives specified in the title compound (base) as a clear oil. Hydrochloric salt is obtained by dissolving the pure base in ether and the addition of an excess of ethereal HCl solution. Recrystallization (chloroformmethanol ether) to give 0.3 g of a white solid, yield 66 So pl. 150-151 oC. an NMR Spectrum13(Base; 200 MHz, CDCl3), M. D. 141,6 133,/P> There is evidence that patients with depression may be a violation of the transmission in the Central nervous system. These violations, as it turned out, sign the neurotransmitter nor-adrenaline and 5-hydroxytryptamine (5-HT). It is believed that the drugs that are most commonly used to treat depression work by improving neurotransmission or one or both of these physiological agonists. Available data suggest that the increase in transmission 5-hydroxytryptamine can mainly improve depressive mood and anxiety, while increasing neurotransmission of norepinephrine rather improves symptoms of inhibition that occurs in patients with depression. In recent years there have been many efforts to develop new drugs with high selectivity to improve neurotransmission and 5-HT in the Central nervous system.

The mechanism of action for drugs that are commonly used today in the treatment of cerebral depression, is indirect, i.e. they act by blocking the re-uptake of neurotransmitters (norepinephrine and 5-hydroxytryptamine), widelyused is therow in synaptic branching and the result is restored, the corresponding neurotransmission.

A different way to enhance neurotransmission in the Central 5-HT-neurons would be to use a direct agonist 5-HT-receptor. Then, in order to minimize side effects, would be the preferred high selectivity for receptors of this type.

Antagonism inhibiting autoreceptors located on the cell bodies of 5-HT neurons, would be another fundamentally different way to improve neurotransmission 5-hydroxytryptamine.

Unexpectedly, we found that the group of compounds of the formula I has a selective, directly stimulating or inhibiting effect on the subgroup of Central 5-HT receptors. Another observation is that some of these substances are especially good oral bioavailability. In order to estimate the incentive effect and the selectivity of 5-HT receptors was measured affinity for different receptors in the rat brain (outside the body) using receptor test (Kinm).

Testing outside the body. Analysis of receptor binding.

The analysis of binding HTIA. The cerebral cortex hippocamp from each rat dissected and homogenized in 15 ml obladenno is ascorbic acid, pH 7.5 using Ultra-Turrax" (firm) and Kunkel, , Staufen, Germany) for 10 C. After centrifugation for 12,5 min at a speed of 17,000 rpm (39800 in Ekmanovskoe the centrifuge, refrigerated JA-17 rotor / firm Beckman, G. Palo Alto, USA) tablets re-suspended in the same buffer solution and repeat the homogenization and centrifugation. Each tablet add 5 ml of 0.32 molar sucrose solution, cooled to 0oC and homogenize for 5 C. These samples are stored frozen at -70oC. When they are diluted with buffer to a concentration of 8 mg tissue/ml and homogenizers within 10 sec. Homogenizate tissue incubated for 10 min at 37oC and then they add 10 µmol of pargyline followed by re-incubation for 10 min.

The analysis of binding were carried out as described Parwathi in J. Neurochem. 1986, T. 47, S. 529 - 540. The mixture after incubation (2 ml) contains 3H-8-OH-DPAT (0.25 to 8 nanomoles), 5 mg/ml tissue homogenizate in 50 mmol/l buffer solution of Tris-HCl containing 4 mmol/l of calcium chloride and 5.7 mmol/l ascorbic acid, pH 7.5. Six different concentrations of 3H-8-OH-DPAT were analyzed. Experiments on the binding began with and was filtered through glass filters Whatman Gee-EF/Bi with a device for harvesting cells Brandes (Gaithersburg, PCs Maryland, USA). These filters were twice washed in 5 ml of buffer 50 mmol/l Tris-HCl, cooled to 0oC with a pH of 7.5 and perform pulse counting in 5 ml of "Redi-SALW h-PI (firm Beckman) in ekmanovskoe acquired scintillation camera e-es 3801. Nonspecific binding was measured by adding 10 mmol/l 5-hydroxytryptamine to the reaction mixture. Data binding were processed by computer analysis using the least squares method (nonlinear) / Munson and Rodbard. Anal. Biochem. 1980, T. 107, S. 220 - 239).

The test results are expressed in the form Kiand are given in nanomoles/liter for Example, 3-dipropylamino-5-azithromy has a value of Ki1,0 (nanomoles/l), 3-dipropylamino-5-carbamothioyl has Ki3.1 nmol/l, 3-dipropylamino-5-N-methylcarbamoyl - Kinmol/l and 3 dipropylamino-5-(2-taylorreneethomas) has Ki1.7 nmol/L.

Example 26. 5-methoxy-3-cyclopropylamino-chroman-hydrochloride.

The target compound was obtained according to known methods reductive amination (Cdinton F. Lane, Synthesis 1975, volume 146, page 135) of methoxy-3-chromanone and cyclopropylamine. So pl. 188-189oC.

Example 27. 3-(N-Cyclopropylamino)-5-hydroxychromone.

3-(N-Cyclopropylamino)-5-metaxia is ane of a mixture of dry ice/ethanol at -20oC. To stir the mixture for half an hour was added BBr3with 4.1 ml, 44 mmole), dissolved in methylene chloride (60 ml). Yellow clear solution was slowly warmed up to 0oC and kept at this temperature until until GC is not indicated completion of the reaction (3-5 h). Then the solution was poured on crushed ice (200 g) and added enough conc. ammonia (aq.) to achieve a pH of 8-9. The mixture was extracted by a simple ether (3200 ml). The collected ether phases were dried (magnesium sulfate), filtered and concentrated in vacuo, giving a white solid. Crystallization from absolute ethanol gave 3-(N-cyclopropylamino)-5-hydroxychromone (3,9 g, 88 yield) as colorless needles. So pl. 147-148oC.

Example 28. 3-(N-Cyclopropylamino)-5-triftoratsetilatsetonom.

The target compound was obtained by analogy with the procedure used in example 1, on the basis of the product formed in example 27. The base was characterized as chlorhydrate salt. So pl. 207-209oC (decomposition).

Example 29. 3-(N-Cyclopropylamino)-5-(N-cyclopropyl)carbamylcholine.

3-(N-Cyclopropylamino)-5-triftoratsetilatsetonom (0.51 g, 1.5 mmole) and triethylamine (and 0.46 ml, 3, is nookie carbon (repeated three times). Added cyclopropylamine (2,9 ml, 42 mmole), 1,3-bis(diphenylphosphino)propane (0,023 g, 55 mcmole) and palladium (II) acetate (0.12 g, 55 mcmole), and then the mixture was shaken at 70oC for 3 h under a pressure of CO 2 to 2.5 bar. After cooling to room temperature the reaction mixture was distributed between saturated sodium bicarbonate and ether (530 ml). The collected ether phases were dried (magnesium sulfate), filtered and concentrated in vacuum. Instant chromatography of the crude product on silica using THF-ethyl acetate (8: 92) as eluent gave 0.32 g of a white solid. Recrystallization from a mixture of THF-ether gave 3 -(N-cyclopropylamino)-5-(N-cyclopropyl)carbamoylated 0.17 g, 42 output in the form of colorless needles. So pl. 126-127oC.

Example 30. Hydrochloride-3-cyclopropylamino-5-[N-(2,6-xylidine)carbarnoyl] -chromane.

Sodium salt of 3-(N-cyclopropyl-N-TRIFLUOROACETYL)aminopropan-5-carboxylic acid (2.1 mmole) obtained in example 28, after N-triftoratsetata, complex esterification (according to example 2) and the subsequent hydrolysis and thionyl chloride (10 ml) under nitrogen atmosphere was heated under reflux for 2 hours, the Excess thionyl chloride was evaporated together with dry is the very in methylene chloride (10 ml) and added dropwise to a stirred solution of 2,6-dimethylaniline (0.52 g, 4.3 mmole) and dry pyridine (6 ml) under nitrogen atmosphere at room temperature. When the reaction was completed within two hours, according to TLC and capillary GC), volatiles were evaporated on a rotary evaporator. The residue was re-dissolved in dry toluene and concentrated in vacuo again (four times). Cleaning with instant chromatography (flash chromatography) on silica using a mixture of THF-n-hexane (1:4) as eluent gave to 0.72 g of 3-(N-cyclopropyl-N-triptoreline)-5-[N-(2,6 - xylidine)carbarnoyl] -chromane (72 yield) as a colorless solid. So pl. 146-149oC (crystallized from a mixture of CHCl3-n-hexane). Part of this amide (0,44 g, 0.95 mmole) was added in small portions over 15 min to a stirred suspension of tetrahydroaluminate lithium (0,072 g, 1.9 mmole) in 20 ml of dry THF (distilled from benzophenone-Ketil-sodium) in nitrogen atmosphere. The mixture is stirred at 45oC up until TLC and capillary GC showed completion of the reaction (40 h), and then it was extinguished by careful addition of an aqueous sodium potassium tartrate (0.5 M). After adjusting the pH to 10 (concentrated ammonia solution was extracted by a simple ether (2 50 ml). Collected Tata oil was chromatographically on dvuhkilogrammovoy column, eluruumi a mixture of CHCl3EtOAc (1:1), giving 3-cyclopropylamino-5-[N-(2,6-xylidine)carbarnoyl]-chroman (0,071 g, 22 total yield) as oil. A slight excess of HCl (approximately 3 M in ether) was added dropwise to a stirred and chilled (+4oC) a solution of the base from above the stage and methanol (2 to 4 ml). The solvents then the rotor was evaporated, added ether and re-evaporation was carried out for the removal of traces of HCl. When the flask is filled with ether, was left in the refrigerator over night, oil hardened. Crystallization from absolute ethanol gave the hydrochloride of 3-cyclopropylamino-5-[N-(2,6-xylidine)carbarnoyl]-chromane in the form of colorless needles. So pl. 189-191oC (decomposition).

Example 31. 3-(N,N-diallylamine)-5-methoxypropan and 3-(N-allylamino)-5-methoxypropan.

Hydrochloride 3-amino-5-methoxypropane (Acta Pharm. Suec. 24 (1987)) (5.0 g, 23 mmole), allylbromide (3.4 ml, 39 mmole), anhydrous potassium carbonate (9.6 g, 69 mmol) and DMF (8.0 ml) were mixed under nitrogen atmosphere at room temperature for 72 h was Added ether (150 ml) salt was filtered off with suction and the clear filtrate was concentrated in vacuum. The residue was purified on a silica column, eluruumi 1000 ml-mi THF-n-hexane (1: 9) and 1000 is 56 output) in the form of oils. Diallylamine derived above, allocated as chlorhydrate salt by adding a small excess of HCl (approximately 3 M in ether) to the ethereal solution of the amine. The crude HCl salt crystallized upon standing, with the ether in the cold. So pl. 139-140oC.

Example 32. 3-(N-allyl-N-n-propylamino(-5-methoxypropan.

3-(N-Allylamino)-5-methoxypropan (1.3 g, 5.9 mmole), obtained as described in example 26, n-propyliodide (2.1 ml, 21 mmol), anhydrous potassium carbonate (3.0 g, 21 mmol) and acetonitrile (5.5 ml) were mixed in a nitrogen atmosphere at 47oC (oil bath temperature) for five days before until GC showed complete reaction. Was added ether (40 ml) salt was filtered off by suction and the clear filtrate was concentrated in vacuo, yielding 3-(N-allyl-N-n-propylamino)-5-methoxypropan (1.24 g, 81 output) in the form of oil. The base was precipitated from the ether solution by adding a slight excess of HCl (approximately 3 M in ether). Crystallization of the crude HCl salt gave colorless needles. So pl. 117-118oC.

Example 33. 3-(N-allyl-N-n-propylamino)-5-hydroxychromone.

The target compound was obtained by analogy with the procedure used in example 27, with use. the. pl. 78-80oC.

Example 34. 3-(N-Allyl-N-n-propylamino)-5-triftoratsetilatsetonom.

The target compound was obtained by analogy with the procedure of example 1 using the product from example 33 as a source material. MC/EI; 70 ev/m/z 379 (M+, 8), 350 (100), 246 (10).

Example 35. 5-acetyl-3-(N-allyl-N-n-propylamino)chroman.

3-(N-Allyl-N-n-propylamino)-5 - triftoratsetilatsetonom (0.28 g, of 0.74 mmole), lithium chloride (0,097 g, 2.3 mmole), PdCl2(dppf)=dichloro[1,1'-bis(diphenylphosphino)ferrocene] -palladium(O) (0,031 g, 0.04 mmole) t 2,6-di-tert.-butyl-4-methylindene (0.005 g) was dissolved in DMF (5.0 ml) in a three-neck round bottom flask (50 ml) with a magnetic stirrer. The flask was akoumianakis then entering CO (three times). Added tetramethylsilane (0,12 ml of 0.89 mmole), the mixture is then stirred in an atmosphere of CO (1 ATM.) if 120oC (temp. oil bath) for 4 h the Solvent was evaporated, the residue was distributed between aqueous ammonia (2 M) and methylene chloride (3 15 ml), and the organic phase was dried (sodium sulfate), filtered and concentrated in vacuum. Chromatography on a column of silica using THF-n-hexane (1: 9) as eluent gave 5-acetyl-3-(N-allyl-N-n propylamino)chroman listello 3 M in ether). The crude salt was collected and dried in vacuum at 40oC, giving a white amorphous powder. So pl. 125-127oC.

Example 36. Hydrochloride 3-isopropylamino-5-methoxypropane.

The target compound was obtained analogously to the procedure used in example 26, starting from 5-methoxy-3-chromane and Isopropylamine. So pl. 255oC.

Example 37. 3-(N, N-isopropyl-n-propyl)amino-5-methoxypropan.

A mixture of the product obtained in example 36 (14 g), and 0.6 mol, 1-iodopropane (15 g, of 0.08 mol), potassium carbonate and acetonitrile (250 ml) were mixed under conditions of reflux distilled for 4 days. After chromatography the desired product was separated in the form of a colorless oil. GC-MS (Cl-mode) M+1 264 (100).

Example 38. 3-(N, N-isopropyl-n-propyl)amino-5-hydroxychromone.

The product from example 37 (10 g, of 0.038 mol) was demetiliruetsa using trichromate boron in dichloromethane. GC-MS (Cl-mode) M+1 250 (100).

Example 39. 3-(N, N-isopropyl-n-propylamino)-5-triftormetilfullerenov.

The target compound was obtained analogously to the procedure used in example 1 using the product from example 38 as a source material. GC-MC (Cl-mode) M+1 382 (100).

Example 40. Hydrochloride 5-acetyl-3-(N-isopropy is obtained in example 39, and with the addition of CO in the Parr apparatus at 2 bar. So pl. 170oC.

Example 41. 3-(N-isopropyl-N-n-propylamino)-5-methoxycarbonylamino.

The target compound was obtained analogously to the procedure used in example 2, on the basis of the product obtained in example 39 (3 g, to 0.016 mol), Pd(OAc)2(75 mg), 1,3-bis(diphenylphosphino)-propane (150 mg), DMF (50 ml) and methanol (25 ml) in a Parr apparatus under pressure CO (2 bar) at 70oC for 6 h, GC-MS (Cl-mode) M+1 292 (100).

Example 42. Hydrochloride 3-(N-isopropyl-N-n-propylamino)-5-(N-methyl)-carbamylcholine.

The product obtained from example 41 (1 g, 0,0034 mol), NaCl (50 mg), methanol (30 ml) and saturated aqueous solution of CH3NH2(5 ml) was subjected to reaction in a steel vessel at 80oC during the night. After processing colorless oil was turned into chlorhydrate salt. So pl. 123oC.

Example 43. Hydrochloride 3-(N-isopropyl-N-n-propylamino)-5-(N-ethyl)carbamylcholine.

The target compound was obtained analogously to the procedure used in example 42, on the basis of the product obtained in example 41 (1 g, 0,0034 mol), KCN (50 mg), methanol (40 ml) and ethylamine (5 ml, 70 aqueous solution) in a steel vessel at 80oC for 4 days. Chromatographic obermoeller-N-n-propylamino)-5-(N-cyclopropylmethyl)-carbamoylated.

The target compound was obtained from 3-(N-cyclopropylmethyl-N-n-propylamino)-5-triftoratsetilatsetonom (1.08 g, 0,0026 mole), obtained as described in examples 36-39, 1,3-bis(diphenylphosphino)propane (40 g), palladium acetate (II (22 mg) and cyclopropanemethylamine (2.3 g, 0,0264 mole) in 30 ml of DMF, which was placed in a glass vessel Parra. Added CO 2 Bor. and the mixture was shaken at 60oC for 4 h After treatment and chromatographic purification was obtained target compound in the form of crystals with so pl. 124oWith (basis) in the form of needles. So pl. 94-95oC.

Example 45. Hydrochloride 3-(N-cyclopropyl-N-n-propylamino)-5-phenylalanine.

The target compound was obtained from a mixture of 3-(N-cyclopropyl-N-n-propylamino)-5-triftormetilfullerenov obtained analogously to examples 36-39 (2 g, 5.1 mmole), trimethylpentane (1.8 g, 4.8 mmole), tetrakis(triphenylphosphine)-palladium (O) (280 mg, 0.24 mmole). The lithium chloride (600 mg, 14.4 mmole) and 2,6-di-tert.-butyl-4-METHYLPHENOL in 60 ml of dioxane and 6 ml of DMF was mixed with 105oC in a steel vessel for 3 days. The mixture was filtered and extracted. Chromatographic purification on axinellidae column gave the target compound with a yield of 55 Connection videosamerican

3-(N, N-Dipropylamino)-5-triftoratsetilatsetonom (0,70 g of 1.76 mmole), triethylamine (0.39 g, 0.54 ml, 3.9 mmole) and DMF (5 ml) were mixed together and the solution was deguileville (10 mm RT. senior room temp. 15 min) and then exposed to CO in the atmosphere (3). Then was added palladium (II) acetate (12 mg), 1,3-bis-diphenylphosphinoethyl (22 mg) and cyclopropylamine (3.0 g, and 3.7 ml, 52,8 mmole). The resulting mixture was again subjected to the action of atmospheric CO and heated to 70oC and stirring for 4 h the Solution was cooled, evaporated in vacuum (vacuum pump), then was diluted with ethyl acetate. The mixture was washed with a solution of bicarbonate (three times), were treated with saline, dried (sodium sulfate) and was evaporated in vacuo, yielding the crude product. Chromatography on silica (silica) (eluent:50 ethyl acetate/hexane) gave 0,38 g of substance in the form of a white solid crystals (64 output). So pl. 109-110oC. 13C NMR (200 MHz, CDCl3) minutes $ . 171,1, 137,8, 134,5, 133,2, 128,0, 126,0, 122,7, 56,5, 52,5, 29,9, 28,1, 23,0, 22,4, 11,9, 7,0.

Example 47. 3-(N, N-Dipropylamino)-5-methoxycarbonylamino.

3-(N, N-Dipropylamino)-5-triftormetilfullerenov (620 mg, 1.6 mmole) was dissolved in 11 ml of a mixture of DMF/methanol 6:2, and the solution was deguileville within 15 mi g). The mixture was heated to 70oC in an atmosphere of carbon monoxide and stirred for 5 hours the Solution was cooled, it was diluted with 30 ml of toluene were washed with saturated sodium bicarbonate, dried (sulfonate sodium) and evaporated in vacuo. Chromatography on silica (eluent: gradient CHCl3__ 10 EtOAc/CHCl3) gave 310 mg (64 output) of target compound (base) as a slightly yellow oil.13C NMR: (200 MHz, CDCl3) million dollars. The oil.3C NMR: (200 MHz, CDCl3) million dollars. 168,2, 136,6, 134,8, 131,6, 130,1, 126,5, 125,7, 56,7, 52,5, 52,1, 30,4, 28,0, 22,3, 11,9.

Example 48. 3-(N-Isopropyl-N-n-propylamino)-5-phenyl-1-axochiapan.

Hydrochloride 3(N-isopropyl-N-n-propylamino)-5-phenyldiamine (310 mg, 0,86 mmole) was dissolved in 6 ml of chloroform, and to the cooled solution (ice bath) was added m-chlormadinone acid (348 mg, 1,72 mmole) in one portion. The reaction mixture was allowed to mix at room temperature for 18 hours the Solvent was removed in vacuo, and the residues were extracted with a mixture of ether/2 M NaOH was treated with saline and dried (sodium). The solvent was evaporated in vacuo, giving crude mixture. Chromatography on silica (eluent: 25 ethyl acetate/methylene chloride) DVCAM white solid. So pl. 109-112oC.

Example 49. 5-(2-furanyl)-3-(N-isopropyl-N-n-propylamino)-1-axochiapan.

Hydrochloride 5-(2-furanyl)-3-(N-isopropyl-N-n-propylamino)-thiochroman (341 mg, 0.97 mmole) was dissolved in 7 ml of methylene chloride and cooled to -20oC. was Added m-chlormadinone acid (258 mg, of 1.27 mmole) in one portion and the reaction mixture was left to mix at room temperature for 18 hours the Solvent was removed in vacuo, and the residues were extracted with a mixture of ether/2 M sodium hydroxide was treated with saline and dried (sodium sulfate). The solvent was evaporated in vacuo, giving crude mixture. Chromatography on silica (eluent:25 ethyl acetate/methylene chloride) gave 35 mg of the nonpolar diastereoisomer of the target compounds 75 mg polar (main) diastereoisomer of target compound and 92 mg diastereomeric mixture (25: 75 GC), giving a combined output 63 Nonpolar (minor) isomer (not quite white solid): so pl. 63-65oC. Polar (main) isomer (not quite white solid): so pl. 83-85oC.

Example 50. 5-(2-furanyl)-3-(N-isopropyl-N-n-propylamino)-1,1-dictationgrammar.

5-(2-furanyl)-3-(N-isopropyl-N-n-propylamino)-1-axochiapan (VI is x then, until the solution became acidic. The solvent was removed in vacuum. The obtained white solid was dissolved in 3 ml of methylene chloride, and the solution was cooled to -15oC. was Added m-chlormadinone acid (1018 mg of 0.58 mmole) in one portion and the reaction mixture was left to mix at room temperature for 18 hours Reacted only minor diastereoisomer, giving the desired sulfon due to steric reasons. The solvent was removed under vacuum and the residues were extracted with a mixture of ether/2 M sodium hydroxide was treated with saline and dried (sodium sulfate). The solvent was evaporated in vacuo, giving crude mixture. Preparative TLC (eluent:20 ethyl acetate/methylene chloride) gave 5 mg (5 exit) of target compound. MS 347.13C NMR: (200 MHz, CDCl3) million dollars. 151,7, 143,0, 139,3, 132,3, 131,6, 127,5, 125,6, 123,5, 111,7, 110,5, 54,3, 51,3, 49,4, 47,4, 34,4, 23,3, 21,7, 20,0, 11,8.

Example 51. Hydrochloride 5-(5-furanyl)-3-N-isopropyl-N-n-propylamino)thiochroman.

To a solution of 3-(N-isopropyl-N-n-propylamino)-5-triftormetilfullerenov (0,92 g, 2,31 mmole), ethanol (10,2 ml), lithium chloride (0.20 g, 4.8 mmole), 2 A sodium carbonate (3.4 ml) and tetrakis(triphenylphosphine)palladium(O) (49,0 mg 0,042 mmole) dissolved in toluene (23 militate the solution was heated to 95oC for 2 h, then the reaction mixture was left to cool. The reaction mixture was filtered, and the solvent was evaporated in vacuum. The residue was taken into ether, washed with 2 M ammonia, processed salt solution and dried (sodium sulfate). Removal of solvent in vacuo gave the crude compound. Chromatography on silica (eluent:3 ethyl acetate/chloroform) gave 0.68 g (yield 93) of target compound (base) as a slightly yellow oil. Chlorhydrate salt was obtained by dissolving the pure base in ether and adding dropwise an excess of ethereal HCl solution, and then recrystallization (ethyl acetate/ether), giving colorless crystals. So pl. 145-147oC.

Example 52. 5-isopropylamino-3-(N-isopropyl-N-n-propylamino)thiochroman

3-(N-Isopropyl-N-n-propylamino)-5-triftormetilfullerenov (0,99 g, 2,49 mmole) was dissolved in dioxane (15 ml) and the solution was deguileville (10 mm RT.article room temp.), then subjected to the action of CO in the atmosphere (3). Was added Isopropylamine (1.1 ml, 12.5 mmol), palladium acetate (15 mg) and 1,3-bis-di-phenylphosphine (29 mg). The resulting mixture was again subjected to the action of atmospheric CO and heated to 80oC with stirring for 4 h the Solution cooling is (2), processed salt solution, dried (sodium sulfate) and was evaporated in vacuo, giving crude substance. Chromatography on silica (eluent:30 ethyl acetate/hexane) gave 0,76 g butter (exit 87), which crystallized and was precrystallization (from hexane), giving a white solid. So pl. 90 - 91oC.

Example 53. 3-(N-Isopropyl-N-n-propylamino)-5-triftormetilfullerenov.

5-Hydroxy-3-(N-isopropyl-N-n-propylamino)thiochroman (3.13 g, 11.9 mmole) and kallidin (2,02 g, 2.2 ml, 16.7 mmole) was dissolved in 100 ml of methylene chloride and cooled to -30oC. was added dropwise triftormetilfullerenov anhydride (a 4.03 g, 2.4 ml, 14.3 mmole) and the mixture was left to be heated up to ambient temperature and after 20 min, it was diluted with methylene chloride. The solution was washed with saturated sodium bicarbonate, dried (sodium sulfate) and was evaporated in vacuum. Chromatography on silica (eluent:3 ethyl acetate/hexane) gave 3.9 g (83 output) of target compound in the form of a slightly yellow oil. MS 397.13C NMR: (200 MHz, CDCl3) million dollars. 148,3, 136,7, 128,8, 127,2, 126,3, 121,9, 117,0, 115,5, 52,8, 48,8, 47,1, 30,2, 28,8, 23,7, 21,2, 20,9, 11,7.

Example 54. 3-(N-Isopropyl-N-n-propylamino)-5-methoxycarbonylamino.

3-(N-Isopropanol was deguileville within 15 minutes To the reaction mixture was added Pd(OAc)2(17 mg), 1,3-bis-diphenylphosphinoethyl (29 mg) and triethylamine (0.54 g, 0.75 ml, 5.4 mmole). The mixture was heated to 70oC in an atmosphere of carbon monoxide and stirred for 4 h the Solution was cooled, it was diluted with toluene, washed with saturated sodium bicarbonate, dried (sodium sulfate) and was evaporated in vacuum. Chromatography on silica (eluent:5 ethyl acetate/hexane) gave 0,69 g (yield 92%) of target compound (base) as a clear oil. MS 307.13With NMR: (200 MHz, CDCl3) million dollars. 168,3, 137,0, 134,8, 131,6, 130,1, 126,5, 125,7, 53,9, 52,2, 48,9, 47,3, 32,7, 30,1, 23,8, 21,1, 11,8.

Example 55. Hydrochloride 3-(N-isopropyl-N-n-propylamino)-5-phenyldiamine.

To a solution of 3-(N-isopropyl-N-n-propylamino)-5 - triftormetilfullerenov (0.95 g, 2,39 mmole), ethanol (10.5 ml), lithium chloride (0.20 g, 4.8 mmole), 2 M sodium carbonate (3.5 ml) and tetrax(triphenylphosphine)palladium(O) (50 g, 0,043 mmole) dissolved in toluene (23 ml), was added phenylboric acid (0.35 g, 2.9 mmole) in one portion under nitrogen atmosphere. The resulting solution was heated to 95oC for 5 h, then the reaction mixture was left to cool. The reaction mixture was filtered; the solvent was evaporated the m sodium). Removal of solvent in vacuo gave the crude compound. Chromatography on silica (eluent: methylene chloride) gave 0.73 g (yield 94) of target compound (base) as oil. Chlorhydrate salt was obtained by dissolving the pure base in ether and adding dropwise an excess of ethereal HCl solution, then precrystallization (ethyl acetate/ether), giving a slightly yellow solid. So pl. 110 - 112oC.

Example 56. (R)-3-(N-Isopropyl-N-n-propylamino)-5-(3-Typen)chroman.

(R)-3-(N-isopropyl-N-n-propylamino)-5 - triftoratsetilatsetonom (0.3 g, 0.8 mmole), 3-tithebarn acid (0.2 g, 1.6 mmole), lithium chloride (0.07 g, 1.6 mmole), sodium carbonate (2 M, 3 ml), ethanol (7 ml) and toluene (15 ml) were mixed in a three-neck round bottom flask under nitrogen atmosphere. Was added the catalyst, Pd(PPh3)4and the reaction mixture stirred at 90oC for 4 h the Solvent was removed in vacuum as long as there was about 15 ml, before it was diluted with diethyl ether, the mixture was filtered (NH3, 2 M) and dried (magnesium sulfate). The solvent was removed in vacuo, giving a brownish oily residue which was purified using flash chromatography (silica, meth). Chlorhydrate salt was precipitated from diethyl ether at 0oC. T. pl. 174-175oC.

Example 57. (R)-3-(N-Isopropyl-N-n-propylamino)-5 - triftoratsetilatsetonom (0.4 g, 1.1 mmole), 2-tithebarn acid (0.27 g, 2.1 mmole), lithium chloride (0.09 g, 2.1 mmole), sodium carbonate (2 M, 3 ml), ethanol (7 ml) and toluene were mixed in a nitrogen atmosphere, and then was added Pd(PPH3)4(0.03 g, catalytic amount). The mixture was then stirred for 8 h at 90 oC. the Solvent was removed in vacuum as long as there was 10 ml, the Residue was diluted in diethyl ether, was filtered ammonia (2 M) and dried by magnesium sulfate. The solvent was removed in vacuo, giving a brownish oily residue which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 10: 1), giving the target compound with a yield of 94 (0.3 g). a (base) -36oC (methanol, 0.1 M, 22oC). Chlorhydrate salt was precipitated from diethyl ether at 0oC. T. pl. 189-191oC.

Example 58. (R)-5-Isopropoxycarbonyl-3-(N-isopropyl-N-n-propylamino)chroman.

(R)-3-(N-isopropyl-N-n-propylamino)-5 - triftoratsetilatsetonom (0.4 g, 1.1 mmole), triethylamine (0.2 g, 2.2 mmole), DMF (6 ml) and isopropanol (2 ml) smelyalata, CO in the burette with water), then was added 1,3-bis(triphenylphosphine)propane (0.02 g, catalytic amount) and palladium acetate (P) (0.08 g, catalytic amount). The mixture was mixed at 80oC for 7 h, the Solvent was removed in vacuo, and the residue was dissolved in diethyl ether, was filtered ammonia (2m) and dried (magnesium sulfate). The solvent was removed in vacuo, giving a yellow oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 10:1), giving the target compound with a yield of 66 (0.2 g). a (base) -110,5oWith methanol, 0.1 M, 22oC). Chlorhydrate salt was precipitated from diethyl ether at 0oC and precrystallization from a mixture of ethyl acetate/diethyl ether. So pl. 153 to 155oC.

Example 59. (R)-3-(N-isopropyl-N-n-propylamino)-5-(2-N-thiazolidinedione)chroman.

(R)-5-Chlorocarbonyl-3-(N-isopropyl-N-n-propylamino)chroman (0.65 g, 2.3 mmole) and 2-aminothiazole (0.68 g, 6.8 mmole) dissolved in methylene chloride (50 ml), stirred at room temperature for 2 hours the solvent in vacuo gave a brown oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate; 10:1), d is then precrystallization from a mixture of ethyl acetate/diethyl ether. a (HCl-salt) -20,0oC. Sinters at less than 140oC.

Example 60. (R)-3-(N-Isopropyl-N-n-propylamino)-5-(3-pyridine)chroman.

(R)-3-(N-Isopropyl-N-n-propylamino)-5 - triftoratsetilatsetonom (of 0.37 g, 0.96 mmole) was dissolved in toluene in a nitrogen atmosphere. Was added ethanol (7 ml), 2 M sodium carbonate (3 ml), lithium chloride (0.08 g, 1.9 mmole), 3-pyridinone acid (0.7 g, 0.5 mmole) and finally Pd(PPH3)4(0.04 g) and the reaction mixture was heated under reflux for 6 hours the Solvent was removed in vacuum as long as there was 10 ml, the Residue was diluted in diethyl ether, was washed with 2 M ammonia and dried (magnesium sulfate). Removal of solvent gave a yellow oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate 5:1), giving the target compound with a yield of 94 (0.28 g) a (base ) -47,6oC (methanol, 0.1 M, 21oC). Dioxalate was precipitated by adding oxalic acid (2.2 equiv.) dissolved in diethyl ether to a solution of the base in diethyl ether. Then the salt was precrystallization from a mixture of ethanol/diethyl ether. Sinters at less than 135oC.

Example 61. (R)-3-(N-Isopropyl-N-n-propylamino)-5-finalgame is luola (25 ml) under nitrogen atmosphere. Was added ethanol (11.5 ml, lithium chloride (0,22 g, 5.2 mmole), sodium carbonate (2 M, 3.8 ml), Pd (PPh3)4(0,054 g 0,047 mmole) and phenylboric acid (0,38 g, 3.1 mmole) and the reaction mixture stirred at 90oC for 7 h, the Solvent was removed in vacuum as long as there was 15 ml, the Residue was diluted in diethyl ether, was filtered ammonia (2 M) twice and dried (magnesium sulfate). Removal of solvent in vacuo gave a yellow-brown oily residue, which was purified using flash chromatography (silica, methylene chloride), yielding the target compound with a yield of 86 (0.7 g). a 50,7o(MeOH, 0.1 M, 22oC). HCl - salt was precipitated from ether by slow addition of HCl in ether cooled with ice to a solution of the base. The crude salt was precrystallization from a mixture of ethyl acetate/diethyl ether, yielding 650 mg, needle-like crystals. So pl. 141-142oC.

Example 62. 5-aminocarbonyl-3-(N-isopropyl-N-n-propylamino)chroman.

A solution of (R)-5-chlorocarbonyl-3-(N-isopropyl-N-n-propylamino)chroman (0,37 g, 1.3 mmole) in methylene chloride (30 ml) was carefully flushed with ammonia for 30 s Immediately formed a white precipitate. The reaction mixture was then stirred for 30 min at room however the PoE oil, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 10: 1). The target compound was obtained in a yield of 58 (0.21 g) as colorless crystals from a mixture of diethyl ether/hexane. a 115, 8mmo(MeOH, 0.1 M, 21oC). So pl. 120,6 - 122 oC.

Example 63. (R)-3-(N-Isopropyl-N-n-propylamino)-5-N-phenylenecarbonyl.

(R)-5-chlorocarbonyl-3-(N-isopropyl-N-n-propylamino)chroman (0.65 g, 2.3 mmole) and aniline (0,86 g, 9.2 mmole) dissolved in methylene chloride (30 ml), stirred at room temperature for 1 h, the Reaction mixture was then washed with 2 M ammonia and dried (sodium sulfate). The solvent was removed in vacuo, giving a brownish oily residue which was purified using flash chromatography (silica, methylene chloride/ethyl acetate 5: 1), giving the pure target compound with a yield of 91 (0.75 g). a (base) -91,3 o(MeOH, 0.1 M, 21oC). Chlorhydrate salt was precipitated from diethyl ether at 0oC, and then precrystallization from a mixture of ethyl acetate/diethyl ether. Sinters at less than 120oC.

Example 64. (R)-5-(2-peril)-3-(N-Isopropyl-N-n-propylaminoethyl.

(R)-3-(N-isopropyl-N-n-propylamino)-5 - triftoratsetilatsetonom (0.4 g, 1 ) and toluene (15 ml) were mixed under nitrogen atmosphere in a three-neck 100 ml round bottom flask, equipped with a condenser. Finally was added Pd (PPh3)4(0.03 g, catalytic amount) and the reaction mixture was heated under reflux for 2 h, then it was diluted with diethyl ether, washed (2 M ammonia) and dried (sodium sulfate). The solvent was removed in vacuo, giving a brownish oily residue which was purified using flash chromatography (silica, metalachlor/ethyl acetate, 10:1), giving the pure target compound with a yield of 95 (0.3 g). a (base) - 57,4o(MeOH, 0.1 M, 21oC). Chlorhydrate salt was precipitated from diethyl ether at 0oC, and then precrystallization from a mixture of ethyl acetate/diethyl ether. So pl. 151-152oC.

Example 65. 5-formyl-3-(N-isopropyl-N-propylamino)chroman.

a) 5-Hydroxymethyl-3-(N-isopropyl-N-propylamino)chroman. 5-Methoxycarbonyl-3-(N-isopropyl-N-propylamino)chroman (0,69 g, a 2.36 mmole) was dissolved in 25 ml dry methylene chloride and cooled to -78oC. was added dropwise a 1 M solution of diisobutylaluminium in hexane (6.6 ml) and the reaction mixture was left to warmed to room temperature for 50 minutes was added dropwise a 1 M solution of KOH, and then the reaction mixture was placed in a refrigerator is ü was removed in vacuum, giving of 0.60 g (97 output) target compound as a clear oil.13C NMR: (200 MHz, CDCl3) million dollars. 154,6, 140,1, 127,0, 120,5, 119,8, 116,3, 69,0, 62,9, 50,9, 48,9, 47,8, 27,2, 24,3, 21,0, 20,1, 11,7.

b) 5-formyl-3-(N-isopropyl-N-propylamino)chroman (0,60 g of 2.27 mmole) was dissolved in 50 ml of methylene chloride and to the solution was added in a single portion of the manganese dioxide (1.98 g, an increase of 22.7 mmole) and the reaction mixture was left to mix at room temperature for 8 days. The reaction mixture was filtered through a layer of celite were washed with warm methylene chloride, and the solvent was removed in vacuum. Chromatography on silica (eluent:5 ethyl acetate/hexane) gave 0.33 g (56 output) of target compound (base) as a slightly yellow oil. 13C NMR: (200 MHz, CDCl3) million dollars. 193,0, 155,1, 135,0, 127,0, 126,8, 124,0, 69,2, 50,3, 48,9, 47,7, 28,1, 24,3, 21,1, 19,9, 11,6.

Example 66. (R)-3-(N-Isobutyl)amino-5-(N-methyl)-carbamoylated.

To a stirred solution of (R)-3-amino-5-(N-methyl)carbamylcholine in methanol (25 ml) was added somelady aldehyde (0.33 g, 4,60 mmole). The mixture was cooled to 0oC, and portions were added cyanoborohydride sodium (0.34 g, 5,44 mmole). The pH value was brought to approximately pH 5 with acetic acid. The mixture was mixed at room is incomplete reaction, and the mixture is stirred for a further 20 minutes the Solvent was evaporated, and the residue was distributed between ether (100 ml) and 1M ammonia solution (20 ml). The layers were separated, the aqueous phase was extracted with ether (650 ml). The combined organic layers were washed 1 M solution of ammonia (20 ml), dried (magnesium sulfate), filtered and evaporated. The residue was chromatographically on a short column of silica gel (eluent:ethyl acetate + 0.5 conc. ammonia). Pure fractions were merged and evaporated, giving 0,81 g (74 ) of target compound as white solids: I. pl. 111-112,8 oC ()21-33,1, (c 2,6, MeOH).

Example 67. Hydrochloride (R)-3-(N-isobutyl-N-propyl)amino-5-(N-methyl)-carbamylcholine.

Propionic aldehyde (0.11 g, 131 μl, is 1.82 mmole) was added to a stirred cooled with ice to a solution of (R)-3-(N-isobutyl)amino-5-(N-methyl)-carbamylcholine (0,43 g, 1.65 mmole) in methanol (10 ml). Added portions cyanoborohydride sodium (0.14 g, of 2.15 mmole), and the pH was brought to 5 with acetic acid. The reaction mixture was stirred at room temperature. To complete the reaction, it was necessary several times to add Propionaldehyde. To the reaction mixture were added 0.20 g, 248 μl, 3,44 mmole. The solvent UDA is odny layer was extracted with ether (50 ml). The combined organic layers were washed with saline (20 ml), dried (magnesium sulfate), filtered and evaporated. The crude product was filtered through a short column of silica gel (eluent: ethyl acetate/hexane 1:1 + 0.5 conc. ammonia). Eluent was removed under vacuum, giving a colourless oil, which was turned into a hydrochloride in a mixture of HCl/ether.

Example 68. (R)-3-(N-(2-pyridyl)methyl)amino-5-(N-methyl)-carbamoylated.

(R)-3-amino-5-(N-methyl)-carbamylcholine (1,02 g, 4,96 mmole) was dissolved in methanol (30 ml). The reaction vessel was covered with aluminum foil to prevent exposure to light. The solution was cooled to 0oC and added picolinamides (0,69 g, 617 μl, 6,45 mmole). Then added cyanoborohydride sodium (0,53 g, 8,44 mmole) in portions, and the pH was brought to 5.5 with acetic acid. The reaction mixture was stirred at room temperature for 2 hours was Added 50 μl, of 0.52 mmole of picolylamine in order to complete the reaction, and the mixture was mixed for 1 h the Solvent was removed in vacuo, and the residue was distributed between ether (100 ml) and 1 M solution of ammonia (25 ml). The layers were separated, and the aqueous layer was extracted with ether (250 ml). United es additional NaCl was extracted with ethyl acetate (4100 ml). The combined organic layers were dried (sodium sulfate), filtered and evaporated giving a yellow solid. Recrystallization from a mixture of ethyl acetate:hexane (35:65) gave a white solid, which was necessary to further purify by chromatography on a column (ethyl acetate:ethanol, 1:1 + 1 conc. ammonia) to give 0.64 g (43) of target compound as a white solid. So pl. 141,2-141,6oC; ()21-26,2 (c 3,0, MeOH).

Example 69. Hydrochloride (R)-3-(N-hexyl)amino-5-phenylpropane.

To a solution of (R)-3-amino-5-phenylpropane (1,00 g of 4.44 mmole) in methanol (25 ml) was added under stirring, hexanal (0,49 g of 0.60 ml, 4,91 mmole). The mixture was cooled to 0oC, and portions were added cyanoborohydride sodium (0.36 g, 5.78 mmole). The pH was brought to 5.5 with acetic acid. The reaction mixture was stirred at room temperature for 2.5 hours Due to incomplete conversion of starting material was added in portions 300 ál (2,46 mmole) hexanes. The solvent was removed under reduced pressure, and the residue was distributed between ether (100 ml) and 1 M solution of ammonia (25 ml). The layers were separated, and the ether extract was filtered 1 M solution of ammonia (25 ml). The aqueous phase was removed, and the ether phase in which the PMC and is filtered and washed with chilled ice hexane. After drying, was 0,86 g (56) of target compound as white crystals: I. pl. 171,6-174,2oC; ()21+82,8 (c 1, MeOH).

Example 70 Hydrochloride (R)-3-(N-methyl-N-propyl)amino-5-phenylpropane.

(R)-3-(N-propyl)amino-5-phenylpropan (0,46 g of 1.74 mmole) was dissolved in methanol (15 ml). Was added formaldehyde (0,70 g 8,70 mmole) and the reaction vessel was cooled in an ice bath. Portions were added cyanoborohydride sodium (0,58 g, 9,23 mmole), which is then brought to pH 6 with a few drops of concentrated acetic acid. The reaction mixture was stirred at room temperature for 3 hours the Solvent was evaporated, and the residue was distributed between ether (50 ml) and 1 M solution of ammonia (10 ml). The layers were separated, and the aqueous phase was extracted with ether (50 ml). The combined organic layers were washed 1 M solution of ammonia (10 ml), dried (magnesium sulfate), filtered and evaporated. The residue was purified using column chromatography (eluent:hexane: ethyl acetate 70:30 + 0.1 conc. NH3), giving 0.40 g (81) the corresponding base of the target compound in the form of unpainted oil which hardened after standing: ()21-35,9 (from 1.0, MeOH). Conversion into hydrochloride was carried out in a mixture of HCl/ether, who yl)ethyl]amino-5-phenylpropane.

To a solution of (R)-3-amino-5-phenylpropane (0,41 g and 1.83 mmole) in dry DMF (2.0 ml) was added potassium carbonate (0.28 g, 2,02 mmole) and 2-(2-thienyl)ethylbromide (0.36 g, of 1.80 mmole). The reaction mixture was stirred in nitrogen atmosphere at 65oC for 6 h, the Solvent was removed in vacuo, and the residue was distributed between ether (50 ml) and 1 M solution of ammonia (10 ml). The layers were separated, and the aqueous phase is saturated with NaCl and extracted with additional ether (25 ml). The organic layers were combined, dried (magnesium sulfate), filtered and concentrated. The residue was purified using chromatography on a column (eluent:ethyl acetate: hexane, 35:65 + 0.2 conc. NH3), giving 0,19 g (31) of the base (target compound) as a pale yellow oil: ()21+8,2 in a mixture of HCl/ether, yielding 0.20 g (total yield: 29) target connection: so to 191.6 square-193,2oC.

Example 72. 3 Dipropylamino-8-fluoro-5-triftoratsetilatsetonom.

a) 2-fluoro-5-methoxybenzoic acid. The target compound was prepared according to the method described by the authors Hay and Blanchard (Canad. J. Chem. 43, 1306 (1965)). In a three-neck round-bottom flask (1000 ml) equipped with magnetic stirrer, thermometer, reflux condenser and a tube for gas, dissolved the ü industrial 4-fluoro-3-methylanisole (35.4 g, 252 mmole) and 33 HBr in acetic acid (10.1 ml, 51 mmol), and then the mixture was heated on an oil bath up to 90-95oC. All the time through the solution was passed a stream of oxygen at a rate of approximately 660 ml/min After 3 h the reaction mixture was cooled to room temperature and then evaporated in a rotary dry conditions. Painted in the color purple solid, thus obtained, was transferred into the flask it-Meier, dissolved in boiling water (350 ml) containing concentrated hydrochloric acid (5-10 ml), and then was left to crystallize in a cold place over night. The crude acid was filtered off by suction, washed with small portions of ice-cold water up until the wash liquid became pale yellow, was dissolved in 2 M of hydrocity sodium (120 ml) and was washed with toluene (2100 ml). The organic extracts were discarded. The aqueous phase was filtered by suction, was cooled in a beaker in an ice bath and carefully padillas concentrated hydrochloric acid until then, until all the acid was not deposited. The contents of chemical beaker was heated to the boiling point, whereby the largest part of the acid was dissolved. The solution was cooled by komnatnaya water (350 ml), and then were dried in a vacuum oven at 40oC, giving to 31.5 g of target compound in the form of a gray-white solid. So pl. 146-148oC.

b) 2-Fluoro-5-methoxybenzamide. In a three-neck round bottom flask (500 ml), equipped with a magnetic stirrer and reflux condenser, was heated under conditions of reflux distilled in a nitrogen atmosphere for 2 h 2-fluoro-5-methoxybenzoic acid (33,8 g, 189 mmole) and thionyl chloride (200 ml). The excess thionyl chloride was evaporated, leaving an oily residue, which was dissolved in methylene chloride (100 ml) and was evaporated. This procedure was repeated 3 times. The crude acid chloride acid, thus obtained, was dissolved in methylene chloride (100 ml) and added dropwise over 10 min to a cold (-40.-50oC) and mechanically stirred solution of dry THF (300 ml) and liquid ammonia (100 ml) in a three-neck round-bottom flask (1000 ml) under nitrogen atmosphere. When the addition was completed, the cooling bath was removed and the mixture was slowly warmed to room temperature while stirring was continued. Water was added (50 ml) to dissolve the precipitated precipitated salts obtained two-phase solution was concentrated to dryness using rotary evaporation. The crude amide was filtered and were not colorless. Drying under reduced pressure over night gave 32,0 g of target compound in the form of light brown crystals. So pl. 122 - 124oC.

c) 2-Fluoro-5-methoxyaniline. In a round bottom flask (500 ml), equipped with a reflux condenser and a magnetic stirrer, bromine (11,4 ml, 223 mmole) was added dropwise to a cold (+4oC) and stirred solution of sodium hydroxide (35.5 g, 887 mmol) and water (322 ml). Then portions were added 2-fluoro-5-methoxybenzamide (31,9 g, 189 mmol). The mixture was heated on an oil bath was heated under reflux for 1 h, cooled to room temperature and was extracted by a simple ether (3300 ml). Drying the combined ether phases (potassium carbonate), filtered, evaporation of the solvent and vacuum distillation of the oily residue gave of 20.1 g of the target compound as a pale yellow oil (so Kip. 113-114oC) 14 mm RT.cent.), which hardened in the cold (so pl. 27-28oC).

d) 2-Fluoro-5-methoxyphenol. The method used for the production of phenol, is essentially the procedure described by the authors Claudi and other (Med. Chem, 33, 2408 2421 (1990) with modifications according to the method Lambooy (J. Amer. Chzem. Soc. 72, 5327 5328 (1950)). In a three-neck round-bottom flask (1000 ml) equipped with drip the slot (35 ml) and water (200 ml), and then was cooled to 3 to 5oC. To the stirred mixture is added dropwise at a temperature above 2-4oC was added a solution of sodium nitrite (6,07 g, 88 mmol) in water (20 ml). When the addition was completed, the solution was mixed for five minutes and then was added urea (0,48 g) followed by addition of water (100 ml). Meanwhile prepared the apparatus consisting of a three-neck round-bottom flask (1000 ml), thermometer, electric heating casing, a device for steam distillation and long (40 cm) water fridge, on top of which was attached dropping funnel (500 ml). Into the flask was placed CuSO45H2O (56 g), concentrated sulfuric acid (160 ml) and water (160 ml). The mixture was heated to 150oC, dropwise from a dropping funnel was added the diazonium salt solution is cooled all the time by adding to it small pieces of ice, and after the system was passed a stream of steam to remove phenol. The distillate was extracted with ether (3 400 ml) and the combined ethereal extracts were dried (magnesium sulfate), filtered and concentrated in vacuum. The crude phenol was purified on a column of silica, eluruumi a mixture of ether/n-hexane (15:85), giving a 4.03 g of target compound in the form of the crystallographic analysis in the connection header is based on the method, described by the authors Thorberg and others in Acta Chem. Scand. 24, 169-182 (1987). Trichloroacetic acid (approximately 0.04 g) was added to a stirred solution of 2-fluoro-5-methoxyphenol (6.8 g, 48 mmol) and etilenovogo ether (9.1 ml, 95 mmol) in a nitrogen atmosphere in a round bottom flask (50 ml) at +4oC. the Mixture is stirred at room temperature over night. The excess of etilenovogo ether was subjected to rotary evaporation, and the residue was dissolved in ether (100 ml). The ether solution was washed with saturated sodium carbonate (25 ml), dried (potassium carbonate), filtered and concentrated in vacuum. The oily residue was dissolved in dry toluene (100 ml) and the solution was first concentrated using a rotary evaporator, and then the vacuum pump (0.1 mm, RT.cent.), giving 10.0 g of the protected phenol as a yellow oil. In a dry three-neck round bottom flask (100 ml), equipped with a magnetic stirrer and a rubber tube, 8.8 g (41 mmol) of the protected phenol obtained above was dissolved in dry THF (30 ml) under nitrogen atmosphere. The solution was cooled to -25oC in a bath of dry ice, and then for 15 minutes to mix the solution with a syringe was added dropwise a 1.6 M n-utility in hexane (32 ml, 51 mmol). When adding the head 60 mmol) was added dropwise over 5 minutes while maintaining the temperature at -25.-20oC (exothermic reaction). When the addition was completed, the solution was warmed up to -5oC for 2 h, and then poured into ice 2 M hydrochloric acid (200 ml). After stirring for 40 min, the hydrolysis was completed, as you can see according to TLC. The resulting mixture was washed with ether (3250 ml). The combined ether phases were dried (magnesium sulfate), filtered and concentrated in vacuum. The yellow solid residue was dissolved in ether (50 ml) and concentrated, giving 7,12 g of the crude 3-fluoro-2-hydroxy-6-methoxy benzaldehyde as a yellow crystalline solid. The crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) obtained above, Acrylonitrile (13 ml, 193 mmole) and 1,4-diazabicyclo(2,2,2)octane (0.66 g, 5.9 mmole) was heated under reflux in a three-neck round bottom flask (50 ml) under nitrogen atmosphere for 4 hours Rotary evaporation of volatiles left a thick red oil, which was subjected to flash chromatography on a column of silica, eluruumi mixture of methylene chloride and n-hexane (4: 5). Concentration of the appropriate fractions gave the crude product (91 GC), which crystallized from ethyl acetate, giving 1,31 g of target compound in videor-5-methoxy-2-H-chromen (1.23 g, 6.0 mmol) and 2 M sodium hydroxide solution (25 ml) was heated under reflux in an atmosphere of nitrogen for 7.5 hours, and then stirred at room temperature over night. To the solution was added an excess of concentrated hydrochloric acid with stirring. After cooling the suspension in an ice bath, the precipitated carboxylic acid was usacialis dry, transferred into a 250 ml flask for hydrogenation (Parr) was dissolved in glacial acetic acid (110 ml). Was added palladium (5) on charcoal (0.104 g g). Hydrogenation in a Parr apparatus at 1 ATM. the pressure of hydrogen and 40 - 50oC (IR lamp) for 10 h was completed the reaction. The suspension was filtered through celite, and the filtrate was concentrated in vacuum. The residue was dissolved in toluene (25 ml) and the solution was concentrated by rotary evaporation. This procedure was repeated once. Evaporation using a vacuum pump (0.05 mm RT.CT.) gave 1.12 g of target compound in the form of a gray-white solid. So pl. 140-145oC (Razlog.)

(g) Benzyl ether of 8-fluoro-5-methoxypropan-3-yl-carbamino acid. 8-Fluoro-5-methoxypropanol-3-carboxylic acid (1.12 g, 85 mmol), diphenylphosphoryl (1.3 ml, 5.9 mmole) and toluene (10 ml) was mixed treor was peredevalsya under 100oC for 2 hours was Added benzyl alcohol (and 0.61 ml, 5.9 mmole) in one portion, and stirring was continued at 90oC for 17 hours Volatiles were evaporated, and the residue was taken in toluene (25 ml). After washing the 10th acetic acid (130 ml) and 2M ammonia (1 30 ml) the solution was dried (magnesium sulfate), filtered and concentrated in vacuo giving a brown oil. Flash chromatography of the crude product on a column of silica, eluruumi a mixture of ethyl acetate and toluene (3:97) gave the compound as oil (contaminated 2 unreacted isocyanate according to GC).

h) 3-Amino-8-fluoro-5-methoxypropan. Benzyl ether of 8-fluoro-5-methoxypropan-3-yl-carbamino acid (1,37 g, 4.0 mmole) in absolute ethanol (90 ml), glacial acetic acid (10 ml) and the 5th palladium on charcoal (0,090 g) were mixed in a 250 ml flask hydrogenation (Parr). Hydrogenation in a Parr apparatus under hydrogen pressure of 1 ATM and 45oC (IR lamp) during the night was completed the reaction (consumption of hydrogen 80 ml at 20oC). The suspension was filtered through celite, and the filtrate was concentrated using rotary evaporation. The residue was dissolved in toluene (25 ml) and again concentrated. This procedure was repeated Adina mainly (93 GC) of the named header connection (as acetate).

i) 3-Dipropylamino-8-fluoro-5-methoxypropan. In a round bottom flask, equipped with a magnetic stirrer, were placed the crude acetate 3-amino-8-fluoro-5-methoxypropane (1.18 g, approximately 3.9 mmole) obtained in the previous phase, dry methanol (10 ml), propanal (2.8 ml, 39 mmol), glacial acetic acid (pH 3-4) and bergeret sodium (0.25 g, 3.9 mmole), but without molecular sieves. The reaction mixture was stirred in nitrogen atmosphere at room temperature for 1 h the Solution was filtered through Celite, and the solvent was evaporated, leaving a liquid residue, which was diluted with water (25 ml) and was extracted with ether (2100 ml), after adjusting the pH to 10-11 using 5 M sodium hydroxide. The collected ether phases were dried (C2CO3), filtered and concentrated in vacuum. Flash chromatography of the crude substances by Dookie-silicon column, eluruumi with ethyl acetate (2-m and 10-m) in n-hexane gave 0,235 g of target compound as a colourless oil.

j) of the Hydrochloride of 3-dipropylamino-8-fluoro-5-hydroxychromone. Chlorhydrate salt of 3-dipropylamino-8-fluoro-5-methoxypropane was obtained by adding an excess of the hydrochloride in ether to a stirred and chilled (+4oC) the solution of the base (0,235 g, from 0.84 mmole) in ether be (25 ml), equipped with a magnetic stirrer and a rubber stopper, salt obtained above was dissolved in methylene chloride (7 ml) under nitrogen atmosphere. The solution was cooled in a bath of dry ice to -40oC, then slowly add trichromacy boron (0,158 g, 1.7 mmole) in methylene chloride (1 ml) to stir the solution with a syringe. When the addition was complete (2 min), the solution temperature was slowly raised to +4oC and maintained at this level by using an ice bath. After a total reaction period (7 hours) the solution was poured into saturated sodium bicarbonate (20 ml). The mixture was extracted with ether (330 ml) and the collected ether phases were washed with saline, dried (sodium sulfate), filtered and concentrated in vacuum. Flash chromatography of the crude product on a column of silica, eluruumi a mixture of ethyl acetate and n-hexane (15:85) gave of € 0.195 g of 3-dipropylamino-8-fluoro-5-hydroxychromone in the form of oil. The target compound was obtained by using a deposition base excess hydrochloride in ether and drying the thus obtained salt in a vacuum oven at 50oC for 5 h Output 0,220 g (99 from the base), white amorphous solid. So pl. 190-192oC.

k) 3-Dipropylamino-8-fluoro-Alcoy and rubber stopper, 3 dipropylamino-8-fluoro-5-hydroxychromone-hydrochloride (0,211 g 0,70 mmole), 2,4,6-kallidin (0,110 ml, from 0.84 mmole) and methylene chloride (7.3 ml) were mixed under nitrogen atmosphere. Bright solution was deposited to -40oC in a dry ice bath, then slowly (5 min) to stir the mixture with a syringe was added triftormetilfullerenov anhydride (0,230 ml of 1.37 mmole) in methylene chloride (0.3 ml). When the addition had ended, the solution was mixed for 1 h (temperature was increased to 0oC), then poured into a cold (+4oC) saturated sodium bicarbonate (20 ml) and was extracted with ether (240 ml). The collected ether phases were washed with water (1 30 ml), dried (sodium sulfate), filtrowanie and concentrated in vacuum. The crude product was subjected to instant chromatography on a column of silica, eluruumi a mixture of ethyl acetate/n-hexane (1:19), giving 0,213 g named in the title compound in the form of butter.

Example 73. Hydrochloride 3-dipropylamino-8-fluoro-5-(2-furyl)chromane.

In a three-neck round bottom flask with a capacity of 25 ml, equipped with a magnetic stirrer and reflux condenser, under nitrogen atmosphere were mixed with the following reagents: 3-dipropylamino-8-fluoro-5-triftormetilfullerenov (0.104 g g, 0.25 mmole), the absolute is at sodium (0.7 ml) and tetrakis(triphenylphosphine)palladium (0) (0,0073 g). The mixture was heated on an oil bath to a temperature of reflux distilled (75-80oC). After 3 h, GC analysis showed a partial response (20 product and 66 of the source material). So I added another 2-foilborne acid (0,031 g to 0.28 mmole) in absolute ethanol (0.2 ml) and tetrakis (triphenylphosphine)palladium(0) (0,009 g). The mixture is stirred at 75-80oC overnight, then poured into 2M ammonia (40 ml) and was extracted with ether (240 ml). The collected ether phases were dried with sodium sulfate, filtered and concentrated in vacuum. The crude product was purified using flash chromatography on a column dioxide aluminum, eluruumi a mixture of ethyl acetate and n-hexane (2: 98). The appropriate fractions were merged and concentrated, giving an oil, consisting of impure product (72 GC). This material was purified using another loop flash chromatography on a column of silica, eluruumi a mixture of ethyl acetate and methylene chloride (1:99), giving 0,042 g (51 output) 3-dipropylamino-8-fluoro-5-(2-furyl)chromane in the form of oil. The target compound was obtained from the base, as described for the hydrochloride of 3-dipropylamino-8-fluoro-5-hydroxychromone above. White crystalline solid. So pl. 162-164 oC.

Example 74. Hydrochloride 3-d the th magnetic stirrer and input for the carbon monoxide from the burette to hydrogenation, mixed dioxane (1.3 ml), 3-dipropylamino-8 - fluoro-5-triftormetilfullerenov (example 63k) (0,110 g of 0.20 mmole) and Isopropylamine (amount of 0.118 ml, 1.4 mmole). The flask was akoumianakis and was filled with carbon monoxide. This procedure was repeated twice. Was added 1,3-bis(diphenylphosphino)propane (0,0032 g) and palladium (II) acetate (0,0016 g) and the mixture is then stirred at 75oC in an atmosphere of carbon monoxide at 1 ATM. GC analysis showed that the reaction was unexpectedly slow. Mixing during the night did not improve the yield of the desired product (59 GC), and still had a lot of triflate (27 GC). Respectively, was added 1,3-bis(diphenylphosphino)propane (0,0065 g) and palladium acetate (0,0032 g). Unfortunately, the stirring during the night did not improve the yield, and has resulted in some decomposition of the product, as evidenced by GC. At this time, the reaction mixture was treated by adding saturated sodium bicarbonate (5 ml) and extracting the mixture with ethyl acetate (210 ml). The combined organic phases were dried (sodium sulfate), filtered and concentrated in vacuum. The crude product was subjected to flash chromatography on a column of silica, eluruumi with ethyl acetate (15 and 33) in n-hexane, Yes the-8-fluoro-5-N-isopropylcarbamate in the form of oil. The target compound was obtained from the base, as described for 3-dipropylamino-8-fluoro-5-hydroxychromone-hydrochloride above. White solid. So pl. (70 eV); m/z (Rel. int. ), 337 (4,4, M + 1), 336 (17, M), 308 (21), 307 (100), 236 (36), 194 (6), 177 (6), 43 (19).

Example 75. (R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5 - triftormetilfullerenov.

(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5 - hydroxychromone (0.71 g, of 2.66 mmole) and kallidin (0,49 ml, and 3.72 mmole) was dissolved in 25 ml of methylene chloride and cooled to -40 oC. was added dropwise triftormetilfullerenov anhydride (0.54 ml, 3.2 mmole) and the mixture was left to be heated up to ambient temperature, and after reaching the 0oC reaction took place. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, dried (sodium sulfate), filtered and evaporated in vacuo, giving crude substance. Chromatography on silica (eluent: methylene chloride) gave 0,82 g (77 exit) of target compound in the form of a light oil. ()2181,5oC (C=0,1, CHCl3).

Example 76. Hydrochloride (R)-5-acetyl-8-fluoro-3-(N-isopropyl-N-propylamino)-chromane.

(R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5 - triftormetilfullerenov (403 mg, 1,01 mmole) was dissolved in 3 the(7 mg) and 1,3-bis-diphenylphosphinoethyl (14 mg). The resulting mixture was heated up to 80 - 90 oC under stirring for 3.5 hours, the Solution was cooled and was added 5 ml of 2 M HCl solution, and the reaction mixture stirred at room temperature for 1 h the Mixture was diluted with ether, and washed with 2 M ammonia solution. The aqueous phase was re-extracted with ether and the combined ether phases were treated with saline, dried (magnesium sulfate), filtered and evaporated in vacuo giving a brown-orange oil as raw material. Chromatography on silica (eluent:15 ethyl acetate/hexane) gave 201 mg) as a yellow oil (68 exit). ()21165,1o(C=0,1, CHCl3). The HCl salt was precipitated from ether and precrystallization from a mixture of ethyl acetate/ether, giving a white solid. So pl. 148oC.

Example 77, Hydrochloride (R)-5-phenyl-8-fluoro-3-(N-isopropyl-N-propylamino)-chromane.

To a solution of (R)-8-fluoro-3-(N-isopropyl-N-propylamino)-5-triftormetilfullerenov (0,58 g of 1.45 mmole), ethanol (7 ml), lithium chloride (124 mg, 2.9 mmole), 2M sodium carbonate (2.2 ml) and tetrakis(triphenylphosphine) palladium (0) (31 mg, 0.026 mmole) dissolved in toluene (15 ml) was added phenylboric acid (0,22 g, of 1.74 mmole) in one portion and the camping was left to cool. The reaction mixture was filtered, and the solvent was evaporated in vacuum. The remains were taken in ether, washed with 2 M ammonia, processed salt solution and dried (magnesium sulfate). Removal of solvent in vacuo gave the crude compound. Chromatography on silica (eluent: methylene chloride + methylene chloride + ammonia) gave 0.42 g (89 exit) of target compound (base) as oil. ()2145,0o(C=0,1, CHCl3). Chlorhydrate salt was obtained by dissolving the pure base in ether and adding dropwise an excess of ethereal HCl solution, giving a white solid. So pl. 202-203oC.

Example 78. Hydrochloride (R)-5-[carbonyl(2,6-dimetilfenil)]-8-fluoro-3-(N, N-dipropylamino)chromane.

2-Bromo-m-xylene(0.5 ml, 3.6 mmole) was dissolved in 4 ml of anhydrous THF under nitrogen atmosphere and cooled to -78oC. was Added dropwise n-utility (a 1.6 M in hexane, 2.0 ml, 3.2 mmole) and the reaction mixture was left to mix at -78 oC for 1 h (R)-8-fluoro-5-formyl-3-(N,N-dipropylamino)chroman (0,30 g of 1.07 mmole) was dissolved in 5 ml anhydrous THF and added dropwise to the reaction mixture, and then she was left mixed at -78oC for 1 h, the Reaction mixture was slaked to relax and took a 2 M solution of ammonia, and then was extracted three times with ether. The combined ether portions were treated with saline, dried (magnesium sulfate), filtered, and the solvent was removed in vacuo, yielding the crude alcohol as a white solid. The crude solid throughout the night were subjected to mild blowing a stream of nitrogen to remove excess 2-bromo-m-xylene. The crude alcohol was oxidized directly in the next reaction stage without further purification. Oxalicacid (122 μl, 1.4 mmole) was dissolved in 5 ml of anhydrous methylene chloride under nitrogen atmosphere and cooled to -78oC. For 5 min was added DMSO (of 0.24 ml, 3.4 mmole), then the reaction mixture was left to mix at -78oC for 5 minutes the Crude alcohol (from previous stage) was dissolved in 10 ml of anhydrous methylene chloride was added over 10 min to the reaction mixture. After stirring at -78oC for 25 min was added triethylamine (0.75 ml, 5.4 mmole), and after 5 min the reaction mixture was left to warmed to room temperature. To the reaction mixture was added 2 M solution of ammonia in water, and the mixture was extracted three times with methylene chloride. United methylenchloride phases were dried (alwaysi silica (eluent:8,7 ethyl acetate/hexane) to give 345 mg (84 exit) of target compound in the form of a slightly yellow oil. ()2157,0o(C= 0,1, CHCl3). Mass spectrum (70 eV) m/z (relative intensity) 383 (56M+), 354 (100), 283 (26), 355 (36). Chlorhydrate salt was prepared by dissolving the pure base in ether and adding dropwise an excess of ethereal HCl. Sol was dried in a vacuum oven at 50oC, giving a white solid in the form of a hemihydrate, which is sintered at 80oC.

Example 79. Hydrochloride (R)-8-fluoro-3-(N-isopropyl-N-n-propylamino)-5-(5-oxazolyl)chromane.

(R)-8-fluoro-5-formyl-3-(N-isopropyl-N-n-propylamino)chroman (of 0.48 g, 1.7 mmole), dosimetrician (of 0.37 g, 1.9 mmole) and potassium carbonate (0.28 g, 2.0 mmole) was suspendibility in methanol (50 ml, dried 3 angstroms) in nitrogen atmosphere. The reaction mixture was heated under reflux for 1 h was Added diethyl ether and 2 M ammonia. The layers were separated, and the aqueous phase was extracted twice with diethyl ether. The organic layers were combined and dried (sodium sulfate). The solvent was removed in vacuo, giving a colorless oily residue, which was purified using instant chromatography (silica, methylene chloride/ethyl acetate, 10: 1), giving the target compound with a yield of 60 (320 mg). ()2D255o(c 5 mg/ml, MeOH). Mass spectrum (78), 30 (11). The HCl salt was precipitated from diethyl ether, and it is sintered at a temperature of from 80oC.

Example 80. (R)-8-fluoro-5-methoxycarbonyl-3-(N,N-di-n-propylamino)chroman.

(R)-8-fluoro-3-(N, N-di-n-propylamino)-5-triftormetilfullerenov (0.95 g, 2.4 mmole), triethylamine (0,53 g, 5.2 mmole), 1,3-bis(diphenylphosphino)propane (100 mg, catalytic amount), palladium (II) acetate (50 mg, catalytic amount) and DMF/MeOH (18 ml, 6:2) were mixed in a 50 ml three-neck round-bottom flask. The flask was akoumianakis then entering CO (repeated three times). The reaction mixture was stirred at 70oC for 7 h, the Solvent was removed in vacuo, and the residue was dissolved in diethyl ether/2M ammonia. The layers were separated, and the aqueous phase was extracted once with ether. The combined ether layers were dried (magnesium sulfate) and the solvent was removed in vacuo, yielding a brown oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 20: 1) to give 650 mg of the target compound in the form of a light oil (87 exit). ()2D192 (c 10 mg/ml, MeOH). Mass spectrum (70 eV) m/z (relative intensity) 309 (20, M+), 281 (18), 280 (100), 56(10), 43(22), 42 (12), 41 (16).

Example 81. (R)-8-fluoro-5-formyl-actuarials in THF (30 ml, dried sodium) in nitrogen atmosphere. The solution was cooled to -78oC, then for 10 min was added diisobutylaluminum (DIBAL-H, 1,0 M, and 8.4 ml, 8.4 mmole). The cooling bath was removed, and the temperature of the reaction mixture gave the opportunity to rise slowly to room (20 oC). The reaction mixture was stirred for 3 h before the reaction mixture was slaked by adding 2 M sodium hydroxide (2 ml). Was added a saturated sodium tartrate and diethyl ether, and the mixture was mixed until then, until the gel did not dissolve. The layers were separated, and the aqueous phase was extracted twice with ether. The combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo, giving the alcohol. Oxalicacid (0,30 g, 2.3 mmole) was dissolved in methylene chloride under nitrogen atmosphere. The solution was cooled to -78oC, then thereto is added dropwise over 5 min was added DMSO (0.4 g, 5.0 mmol). After stirring for 5 min was added the alcohol, dissolved in methylene chloride over a 30 minute period. The reaction mixture was stirred for 30 min, then during the 5-minute period was added triethylamine (1.1 g, 10.5 mmol). After 30 min the cooling bath was removed and the reaction mixture on the, how were added sodium bicarbonate. The layers were separated, and the aqueous phase was extracted twice with ether. The combined organic layers were dried (magnesium sulfate) and the solvent was removed in vacuo, yielding oily residue which was purified using flash chromatography (silica, methylene chloride silica, methylene chloride/ethyl acetate, 20:1) to give 350 mg of target compound (60 output). ()2D1-86 (c 10 mg/ml, MeOH). Mass spectrum (70 eV) m/z (relative intensity) 279 (5, M+), 250 (56), 179 (48), 151 (13), 149 (10), 123 (31), 103 (28), 98 (24), 77 (11), 72 (26), 70 (40), 57 (15), 56 (54), 55 (18), 54 (16), 44 (11), 43 (100), 42 (64), 41 (79).

Example 82. Hydrochloride (R)-5-[Carbonyl-(3,5-dimethylisoxazol)] -8-fluoro-3-(N,N-Li-n-propylamino)chroman.

4-Bromo-3,5-dimethylisoxazole (1,9 g, 10.7 mmol) was dissolved in THF (20 ml), dried with sodium) in nitrogen atmosphere. The solution was cooled to -90oC before for 10 min was added n-utility (a 1.6 M in hexane, 9.7 ml, 9.7 mmole). The reaction mixture is stirred for 15 minutes, then for 10 min was added (R)-8-fluoro-5 - formyl-3-(N,N-di-n-propylamino)chroman (0.6 g, 2.2 mmole), dissolved in THF (10 ml). The reaction mixture was stirred at -90oC for an additional 20 min, and then at -78oC for 15 min p who were, and the aqueous phase was extracted once with ether. The combined organic layers were dried (sodium sulfate). The solvent was removed in vacuo, giving a yellow oily residue, which was flushed through the night by a stream of nitrogen. Oxalicacid (0.28 g, 2.2 mmole) was dissolved in methylene chloride under nitrogen atmosphere. The solution was cooled to -78oC. dropwise over a 5 minute period was added DMSO (0,38 g, 4.8 mmole). The reaction mixture is stirred for 20 minutes, then for 15 min was added to the crude alcohol, dissolved in methylene chloride. The reaction mixture is stirred for 30 minutes was Added triethylamine (1.01 g, 10 mmol). Stirring is continued for 1 h, the cooling bath was removed and the reaction mixture was left to warmed to room temperature (21oC). Was added diethyl ether and sodium bicarbonate. The layers were separated, and the aqueous phase was extracted once with ether. The combined organic layers were dried (sodium sulfate) and the solvent was removed in vacuo, giving a yellow oily residue, which was purified using instant chromatography (silica, methylene chloride/hexane/ethyl acetate, 10:10:1) to give 340 mg of target compound (exit 42). Mass. SPECT is ri 0oC, and then precrystallization from a mixture of methylene chloride/diethyl ether. So pl. 202-205 areoC.

Example 83. Hydrochloride (R)-5-N-Morpholinyl-3- (N-isopropyl-N-n-propylamino)-chromane.

Digitalia acid (0.15 g, 1.1 mmole) and N,N-carbonyldiimidazole (CDI, 0.28 g, 1.8 mmole) was dissolved in THF (dried over sodium) in nitrogen atmosphere. The mixture was heated under reflux for 15 min and was added (R)-5-amino-3- (N-isopropyl-N-n-propylamino)chroman (NAE 277) (0.2 g, 0.8 mmole). The reflux was continued for 18 hours, the Reaction mixture was then merged with a similar reaction mixture from the identical response (outbound from 0.1 g of aniline). Was added diethyl ether and 2 M ammonia. The layers were separated, and the aqueous phase was extracted once with ether. The combined organic layers were dried (sodium sulfate) and the solvent was removed in vacuo, yielding oily residue. The residue was dissolved in diethyl ether under nitrogen atmosphere. Added sociallyengaged (0,23 g, 6 mmol) and the mixture was heated under reflux for 18 hours With vigorous stirring, water was added (0.3 ml) followed by addition of 0.3 ml of 15-th of sodium hydroxide and finally 1 ml of water. The solution decanters Italy was removed in vacuum, giving the crude residue, which was purified using instant chromatography (silica, methylene chloride/ethyl acetate, 5:1, containing 0.5 ammonia) to give 180 mg of target compound (47 out). ()2D1-39 (5 mg/ml, MeOH). Mass spectrum (70 eV) m/z (relative intensity) 318 (8, M+), 133 (14), 130 (13), 117 (10), 114 (32), 112 (45), 85 (28), 43 (100), 42 (27), 41 (44), 39 (23). The HCl salt was precipitated from diethyl ether and was precrystallization from a mixture of ethyl acetate/diethyl ether. The crystals are sintered at 70oC.

Example 84. (R)-5-Carbarnoyl-2-aminopropan.

a) (R)-5-Carbarnoyl-2-N-triptoreline. (R)-2-N-Triptorelin-5-triftoratsetilatsetonom (2.0 g, 5.0 mmol) was dissolved in DMF (20 ml) in a three-neck round-bottom flask. The flask was akoumianakis, followed by the CO-gas (repeated three times). Was added 1,3-bis(diphenylphosphino)-propane (0.2 g, catalytic amount), palladium (II) acetate (0.1 g, catalytic amount) and dioxane saturated with ammonia (20 ml), and then the reaction mixture was stirred at 70oC for 8 h, the Solvent was removed in vacuum. The residue was dissolved in a mixture of diethyl ether/ammonia (2M). The layers were separated, and the aqueous phase was extracted two times. The solvent of dalals mnia, methylene chloride: ethyl acetate, 4:1(+0.5 ammonia)), giving the target compound with exit 21 (0,30 g). So pl. 178-180oC. Mass spectrum (70 eV) m/z (relative intensity) 288 (5, M+), 176 (11), 175 (100), 174 (22), 158 (13), 131 (25), 130 (42), 51 (19), 44 (16).

b) (R)-5-Carbarnoyl-2-aminopropan. (R)-5-Carbarnoyl-2-N-triptoreline (0,30 g, the 1.04 mmole) was dissolved in methylene chloride (50 ml). Was added sodium hydroxide (5 ml 15-th solution in water), and the mixture is stirred for 4 hours, the Layers were separated, and the aqueous phase was extracted with methylene chloride four times. The organic layers were combined, and the solvent was removed in vacuo, giving a solid residue, which was suspenderbelt in diethyl ether (300 ml) and filtered. The ether was removed in vacuo, giving the target compound with a yield of 90 (180 mg). So pl. 194-196oC. ()2D1-36 (MeOH, 10 mg/ml). Mass spectrum (70 eV) m/z ( relative intensity) 192 (1, M+), 176 (26), 175 (100), 160 (13), 130 (14), 51 (22), 44 (13), 43 (83), 42 (15).

Example 85. (R)-2-N,N-Dibenzylamino-5-methoxycarbonylamino.

a) (R)-2-N,N-Dibenzylamino-5-methoxy-chroman (R)-5-Methoxy-2-aminopropane (2,6 n, 14 mmol), potassium carbonate (7.0 g, 51 mmol), benzylbromide (6.0 g, 35 mmol) and a catalytic amount iodotope potassium were mixed in acetonitrile (100 ml) in the atmosphere estatutos was dissolved in a mixture of diethyl ether and ammonia (2 M). The layers were separated, and the aqueous phase was extracted twice with diethyl ether. The ether layers were combined and dried (magnesium sulfate). The solvent was removed in vacuo, giving a yellow oily residue, which was purified using flash chromatography (silica, methylene chloride), yielding the target compound with a yield of 64 (3.2 g). The HCl salt was precipitated from diethyl ether at 0oC, and then precrystallization from a mixture of ethanol/diethyl ether. The crystals are hygroscopic and begin to melt very slowly, starting with the 100oC and finally melt between 118 and 120oC. ()2D1-20 (33 mg/ml, HCl salt in MeOH). Mass spectrum (70 eV) m/z (relative intensity) 360 (19), 359 (91, M+), 268 (16), 223 (11), 210 (15), 132 (72), 91 (100).

b) (R)-2-N,N-Dibenzylamino-5-hirokichi-chroman. Hydrochloride (R)-2-N,N-dibenzylamino-5-methoxypropane (1.6 g, 4.0 mmole) was dissolved in methylene chloride (40 ml) under nitrogen atmosphere. The solution is then cooled to -70oC. was Added dropwise over a 5 minute period trichromacy boron, dissolved in methylene chloride (25 ml). The reaction mixture is then heated slowly to 0 oC and stirred at this temperature over night. The reaction mixture is slowly poured in re what methylene chloride. The organic layers were combined and dried (magnesium sulfate). The solvent was removed in vacuo, giving a brownish oily residue which was purified using flash chromatography (silica, methylene chloride), yielding the target compound with a yield of 98 (135) mg ()2D1-94 (10 mg/ml, MeOH). Macc spectrum (70 eV) m/z (relative intensity) 346 (269, 345 (100), 132 (13), 91 (11).

c) (R)-2-N, N-Dibenzyl-5-triftoratsetilatsetonom. (R)-2-N,N-Dibenzylamino-5-hydroxychromone (1.5 g, 4.3 mmole) and kallidin (0.6 g, 5.2 mmole) was dissolved in methylene chloride (30 ml) under nitrogen atmosphere. The solution was cooled to -70oC, and within a 10-minute period was added dropwise triftormetilfullerenov anhydride (1.3 g, 4.7 mmole), dissolved in methylene chloride (20 ml). The cooling bath was removed and the reaction mixture was slowly warmed up to room temperature (21oC). The reaction mixture was filtered ammonia (2M) with m were dried (magnesium sulfate). The solvent was removed in vacuo, giving an orange solid residue, which was purified using flash chromatography (silica, methylene chloride), yielding the target compound with a yield of 90 (1.85 g). ()2D1-83 (20 mg/ml, MeOH). Macc spectrum (70 eV) m/z (relative intensity) 477 is salamino-5-triftoratsetilatsetonom (1.8 g, 3.8 mmole) and triethylamine (0.8 g, 8.3 mmole) was dissolved in a solution of DMF/MeOH (20 ml, 6: 2) in a three-neck round-bottom flask. The flask was pumped with subsequent input gas CO (repeated three times). Was added palladium (II) acetate (28 mg, catalytic amount) and 1,3-bis(diphenylphosphino)-propane (60 mg, catalytic amount) and the reaction mixture is stirred at 75oC for 6 h, the Solvent was removed in vacuo, giving a brownish oily residue. The oil was dissolved in a mixture of diethyl ether/ammonia (2 M). The layers were separated, and the aqueous phase was extracted once with diethyl ether. The combined ether layers were dried (magnesium sulfate). The solvent was removed in vacuo, yielding a brown oily residue, which was purified using instant chromatography (silica, methylene chloride/hexane, 1:1), giving the target compound with a yield of 95 (1.4 g). ()2D1is 147 (5 mg/ml, MeOH). Macc spectrum (70 eV) m/z( relative intensity) 388 (25), 387 (100, M+), 297 (10), 296 (62), 264 (27), 132 (40), 91 (79).

Example 86. (R)-5-Carbarnoyl-2-N,N-benzylamine.

(R)-2-N, N-Dibenzylamino-5-methoxycarbonylamino (1.4 g, 3.6 mmole) was dissolved in methanol (20 ml). Was added a solution of sodium hydroxide (0.16 g, 4.0 mmole) in water (6 ml), and the reactions which took place toluene, and the solvent was removed again (repeated twice in order to remove the water). The residue was dissolved in SOCl2(6 ml) and was heated under reflux for 1 h the Solvent was removed in vacuum. The residue was dissolved in methylene chloride (20 ml) and the solution was flushed ammonia gas for 2 minutes, the Reaction mixture was stirred at room temperature for 1 h before washing (2 M ammonia) and dried (magnesium sulfate). The solvent was removed in vacuo, giving crude brownish oily residue which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 5: 1 (+ 0.5 ammonia)), giving the target compound with exit 41 (0.55 g). ()2D1-129 (10 mg/ml, MeOH). Mass spectrum (70 eV) m/z (relative intensity) 372 (2, M+), 281 (43), 264 (27), 132 (19), 106 (12), 105 (18), 91 (100), 77 (12), 65 (25), 32 (22).

Example 87. (R)-5-[1-Methyl(-imidazolyl)] -3-(N-isopropyl-N-n-propylamino)-chroman.

(R)-5-Formyl-3-(N-isopropyl-N-n-propylamino)chroman (0.4 g, 1.5 mmole) was dissolved in methanol (15 ml), saturated with methylamine. Added a number of molecular sieves (3 angstroms). The solvent was removed in vacuum. The residue was dissolved in methanol (30 ml) under nitrogen atmosphere. Added by dosimetrical within 1 hour Added additional dosimetrician (0.36 g, 1.8 mmole) and potassium carbonate (0.25 g, 1.8 mmole), and the reflux continued for 3 hours was Added again dosimetrician (0.1 g, 5.2 mmole), and the reflux was continued for 12 hours, the Solvent was removed in vacuum. The residue was dissolved in a mixture of diethyl ether/2 M ammonia. The layers were separated, and the aqueous phase was extracted again with ether. The organic layers were combined and dried (sodium sulfate). The solvent was removed in vacuo, yielding a brown oily residue, which was purified using flash chromatography (silica, first methylene chloride/acetate, 5: 1, containing 0.5 ammonia, and then ethyl acetate/ethanol 50:1 + 0.5 ammonia) to give 200 mg of target compound (42 out). ()2D1-37 (30 mg/ml, MeOH). The HCl salt was precipitated from diethyl ether at 0oC and precrystallization from a mixture of ethanol/diethyl ether. So pl. 159-161oC (Razlog).

Example 88. a) (R)-3-(N-Isopropyl-N-n-propylamino)-5-methoxycarbonylamino.

(R)-3-(N-Isopropyl-N-n-propylamino)- 5-triftormetilfullerenov (4.0 g, 10.5 mmol), triethylamine (2.3 g, 23.1 mmole) and the mixture of DMF/methanol (18 ml, 6:2) mixed VC was added 1,3-bis(diphenylphosphino) propane (0.11 g, a catalytic amount) and palladium (II) acetate (0.07 g, catalytic amount), and the mixture is stirred at 70 oC for 17 h, the Reaction mixture was diluted with diethyl ether, washed with 2 M ammonia and dried (magnesium sulfate). Removal of solvent in vacuo gave a brown oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate, 10:1), giving the target compound with a yield of 82 (2.5 g). () -131,6o(MeOH, 0.1 M, 21oC).

Analysis of C17H25O3N:

Calculated: C 70,1; H 8,6; N 4,8.

Found: C To 70.2; H 8,6; N 5,1.

13C NMR (CDCl3) 300 MHz, 167,6, 155,0, 130,5, 126,5, 124,2, 123,0, 120,6, 69,1, 51,8, 50,6, 48,8, 47,6, 29,3, 24,3, 21,0, 19,9, 11,5

Mass. spectrum (70 eV) (relative intensity) 291 (48, M+), 276 (34), 262 (100), 191 (18), 18 (27), 70 (15), 56 (23), 43 (24).

HCl-salt was precipitated from diethyl ether at 0oC, and then precrystallization from a mixture of ethanol/diethyl ether. So pl. output reached 125.5-127,4oC.

Analysis for C17H26O3N1Cl1:

Calculated: C Of 62.3; H 8,0; N 4,3.

Found: C 62,5; H 7,9; N 4,4.

b) (R)-3-(N-Isopropyl-N-n-propylamino)-5-(N-isopropyl)-carbamoylated. (R)-3-(N-Isopropyl-N-n-propylamino)-5-methoxycarbonylamino (3 ml). The reaction mixture then was heated under reflux for 3.5 h and then the solvent was removed in vacuum. The residue was dissolved in toluene. The toluene was removed in vacuo (repeated twice) in order to form an azeotrope to remove water. The carboxylic acid was then dissolved in sulphonylchloride (5 ml) and was heated under reflux for 1 h, the Excess SOCl2was removed in vacuum. The acid chloride of the acid was then dissolved in methylene chloride (20 ml, dried by molecular sieves 3 angstroms), and then were added 4 ml of Isopropylamine. The reaction mixture was stirred for 1 h at room temperature (21oC), was diluted in diethyl ether, was filtered (2 M ammonia) and dried (magnesium sulfate). Removal of solvent in vacuo gave a yellow oily residue, which was purified using flash chromatography (silica, methylene chloride/ethyl acetate 5: 2), giving the pure target compound with a yield of 88 (0,46 g). a -90,4o(MeOH, 0.1 M, 21 oC). So pl. of 92.5-94oC.

1. Derivatives chromane or thiochroman General formula I

< / BR>
where X is oxygen or

wherep0, 1 or 2;

R is hydrogen;

R1hydrogen, C1WITH6- alkyl or C2- C6alkenyl;
1
- C6-alkyl or C1WITH4- alkoxygroup;

R3group NR5R6, COR7a 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and may have one or more substituents selected from halogen, C1WITH6-alkyl or C1WITH4-alkoxygroup;

R4hydrogen or halogen;

R5hydrogen, C1WITH6-alkyl or C2- C6alkenyl;

R6-C1C6-alkyl or C2C6alkenyl or R5and R6may together form a 5 - or 6-membered ring which may contain 1 or 2 heteroatoms selected from N, O or S;

R7WITH1WITH6-alkyl, C1- C4-alkoxygroup, NR8R9or 5 - or 6 - membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and possibly mono - or polygamist halogen, CN, CF3WITH1- C6-alkyl or C1WITH4-alkoxygroup;

R8or R9independently hydrogen, C1- C6-alkyl, C2WITH6alkenyl, 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and may samoobrazovanie 5 - or 6-membered nucleus, containing 1 or 2 heteroatoms selected from N, O or S,

enantiomer or salt of this compound.

2. Connection on p. 1, wherein X is oxygen.

3. Connection on p. 1, characterized in that X and p is 0, 1 or 2.

4. Connection PP. 1 to 3, characterized in that R3group NR5R6, COR7a 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and possibly substituted by one or more substituents, independently selected from halogen, C1WITH6-alkyl, C1WITH4-alkoxygroup, R7- C1WITH6-alkyl, C1WITH4-alkoxygroup, NR8R9- 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and possibly mono - or polygamist halogen, SP, CF3WITH1WITH6-alkyl or C1- C4-alkoxygroup, X, p, R, R1, R2, R4, R5, R6, R8, R9matter under item 1, enantiomer or pharmaceutically suitable salt.

5. The compound according to any one of paragraphs. 1 to 4, characterized in that R1and R2the same or different, hydrogen, n-propyl, isopropyl and cyclopropyl.

6. The compound according to any one of paragraphs. 1 5, the UB> - C4-alkyl, phenyl, furanyl or thienyl, possibly substituted with halogen, NR8R9where R8and R9hydrogen or C1- C4-alkyl or C1WITH4-alkoxygroup.

8. Connection on p. 6, wherein R4hydrogen, R1and R2n-propyl and R7methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, thienyl, furanyl, phenyl, N-methylaminomethyl or forfinal.

9. The compound according to any one of paragraphs. 1 to 5, characterized in that R3- phenyl, furanyl, thienyl or forfinal.

10. The compound according to any one of paragraphs. 1 to 7 and 9, characterized in that R4halogen in position 8.

11. Connection on p. 1, representing a 3 dipropylamino-5 - azithromy, its enantiomer or salt.

12. Connection on p. 1, representing a 3 dipropylamino-5-carbamoylated, its enantiomer or salt.

13. Connection on p. 1, representing a 3 dipropylamino-5-N-methylcarbamoyl, its enantiomer or salt.

14. Connection on p. 1, representing a 3 dipropylamino-5-(2-thienylboronic)chroman, its enantiomer or salt.

15. Derivatives chromane or thiochroman General formula I

< / BR>- C6alkenyl;

R2hydrogen, C1WITH6-alkyl or C2- C6alkenyl,1WITH4- alkylaryl, where aryl may contain 1 or 2 heteroatoms selected from N or S, and possibly replaced WITH1WITH6-alkyl or C1WITH4-alkoxygroup;

R3COOH, COCl, COBr, N3or SO3CF3;

R4hydrogen or halogen;

R5hydrogen, C1WITH6-alkyl or C2- C6alkenyl;

R6C1C6-alkyl or C2C6alkenyl or

R5and R6may together form a 5 - or 6-membered nucleus which may contain 1 or 2 heteroatoms selected from N, O or S enantiomer or salt.

16. Connection on p. 15, wherein R1and R2- same or different, hydrogen, n-propyl, isopropyl and cyclopropyl.

17. Connection on p. 15, characterized in that R and R4hydrogen, R1and R2n-propyl and R3SO3CF3.

18. The compound according to any one of paragraphs. 1 14 with 5-HT-receptor activity.

19. The method of obtaining compounds of General formula

< / BR>
where X is oxygen or

p is 0, 1 or 2;

R is hydrogen;

R1hydrogen, C1WITH THE6alkenyl,1WITH4- alkylaryl, where aryl may contain 1 or 2 heteroatoms selected from N or S, and possibly replaced WITH1WITH6-alkyl or C1WITH4-alkoxygroup;

R4hydrogen or halogen;

R8and R9hydrogen, C1WITH6-alkyl, C2- C6alkenyl, 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and possibly substituted with halogen, SP, CF3WITH1WITH6-alkyl, C1- C4-alkoxygroup, or may together form a 5 - or 6-membered nucleus, containing 1 or 2 heteroatoms selected from N, O or S,

characterized in that miniroot compound of General formula IA

< / BR>
where X, R, R1, R2and R4have the values listed in paragraph 1;

Z is CL, OH or orpwhere RpWITH1WITH6-alkyl,

with the compound of the formula

OTHER8R9,

for the formation of amide of formula I, followed by the possible transformation of the obtained free base in salt, acid, or by conversion of the salts in the base or another salt with an acid, or a possible separation of the mixture of isomers to obtain pure enantiomers.

20. The method according to p. 19, characterized t the th of PP. 19 to 21, their enantiomers or pharmaceutically acceptable salts, in which X, p, R, R1, R2, R8, R9have the values listed in paragraph 19.

23. The method according to any of paragraphs. 19 to 22, characterized in that R1and R2the same or different, hydrogen, n-propyl, isopropyl or cyclopropyl.

24. The method according to any of paragraphs. 19 to 22, characterized in that R8and R9independently hydrogen or C1WITH4-alkyl.

25. The method according to any of paragraphs. 19 to 24, characterized in that R4halogen in position 8.

26. The method according to p. 19, characterized in that the compound which is 3-dipropylamino-5-carbamylcholine, 3 dipropylamino-5-N-methylcarbamoylmethyl.

27. The method according to p. 19, characterized in that when receiving 3 dipropylamino-5-carbamylcholine use 3-dipropylamino-5-chloroformiate, obtained by treating 3-dipropylamino-5 - methyloxirane sulphonylchloride.

28. The method of obtaining compounds of General formula

< / BR>
where X is oxygen or

p is 0,1 or 2

R is hydrogen;

R1hydrogen, C2WITH6-alkyl or C2- C6alkenyl;

R2hydrogen, C2WITH6-alkyl or C2- C6alkenyl,11WITH6-alkyl or C1WITH4-alkoxygroup;

R4hydrogen or halogen;

R7WITH1WITH6-alkyl, C1WITH4-alkoxygroup, 5 - or 6-membered aryl which may contain 1 or 2 heteroatoms selected from N, O or S, and possibly mono - or polygamist halogen, SP, CF3WITH1WITH6-alkyl or C1- C4-alkoxygroup,

enantiomer or salt it, characterized in that the derivative of 5-carboxysome-thiochroman General formula IA

< / BR>
where X, R, R1, R2and R4have the values listed in paragraph 1;

Z is chlorine, bromine,

process

R7Li,

where R7alkyl, alkenyl or aryl,

in the presence of copper compounds, followed by the possible transformation of the received base salt with an acid or a transformation of the salts in the base or another salt with acid or possible separation of the mixture of isomers to obtain pure enantiomers.

29. The method according to p. 28, wherein X is oxygen.

30. The method according to p. 28, characterized in that X and p is 0, 1 or 2.

31. The method according to any of paragraphs. 28 to 30, characterized in that X, p, R, R1, R2, R4and R7have the values listed in paragraph 28, the I, what R1and R2the same or different, hydrogen, n-propyl, isopropyl or cyclopropyl.

33. The method according to any of paragraphs. 28 to 32, characterized in that R7- C1WITH4-alkyl, phenyl, furanyl or thienyl, substituted with halogen.

34. The method according to p. 33, characterized in that R and R4hydrogen, R1and R2n-propyl and R7methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, thienyl, furanyl, phenyl or forfinal.

35. The method according to any of paragraphs. 28 to 34, wherein R4halogen in position 8.

36. The method according to p. 28, wherein the compound is 3-dipropylamino-5-acetylamino or 3-dipropylamino-5-(2-thienylboronic)chromanol.

37. The method of obtaining compounds of General formula I

< / BR>
where X is oxygen or

p is 0, 1 or 2;

R is hydrogen;

R1hydrogen, C1WITH6-alkyl or C2- C6alkenyl;

R2hydrogen, C1WITH6-alkyl or C2- C6alkenyl,1WITH4- alkylaryl, where aryl may contain 1 or 2 heteroatoms selected from N or S, and possibly replaced WITH1WITH6-alkyl or C1WITH4-alkoxygroup;

R35 - or 6-h which are substituents, selected from halogen, C1WITH6-alkyl and C1WITH4-alkoxygroup;

R4hydrogen or halogen,

its enantiomer, or salt, characterized in that make the compound of General formula II

< / BR>
where Y trimethylsulfonium, phosphonate, or halogen;

X, R, R1, R2and R4have the specified values,

the reaction with the transition metal to form a complex of the ligand, which is subjected to oxidative connection by processing trialkylsilanes or airborne acid for the formation of compounds of formula I, followed by the possible transformation of the received base salt with the acid, or the conversion of the salts in the base or another salt with an acid, or a possible separation of the mixture of isomers to obtain pure enantiomer.

38. The method according to p. 37, wherein X is oxygen.

39. The method according to p. 37, characterized in that X and p is 0, 1 or 2.

40. The method according to any of paragraphs. 37 to 39, characterized in that X, p, R, R1, R2, R3and R4have the values listed in paragraph 37, its enantiomers or its pharmaceutically suitable salts.

41. The method according to any of paragraphs. 37 to 40, characterized in that R1from PP. 37 to 41, characterized in that R3- phenyl, furanyl, thienyl or forfinal.

43. The method according to any of paragraphs. 37 to 42, wherein R4halogen in position 8.

 

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The invention relates to new derivatives of pianolasociety, pharmaceutical compositions containing these derivatives, their use for the treatment of hypertension or asthma in mammals, including humans, and method for producing the above compounds and compositions

The invention relates to a method for producing new derivatives benzocycloheptene acids

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention concerns to applying RARγ agonist for preparing a medicinal agent comprising one or some such agonists and designated for treatment of emphysema wherein RARγ agonist is taken among compounds of the formula (I):

wherein R1 means residue of the formula:

or , or , or ; R2 means (C2-C8)-alkanoyl, (C2-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or group -OCH2R3 wherein R3 means hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl; each among R4-R9 means independently of one another hydrogen atom or (C1-C6)-alkyl; or R8 and R9 mean in common (CRaRb)n wherein Ra and Rb mean independently of one another hydrogen atom or (C1-C6)-alkyl; n = 1, 2 or 3; R4-R7 have above given values; R10 means carboxyl, (C1-C6)-alkoxycarbonyl or mono- or di-(C1-C6)-alkylcarbamoyl; and their pharmaceutically acceptable salts; or among compounds of the formula (VI):

wherein R1 means C(O)R6 or CH2OH (wherein R6 means hydroxy-group or (C1-C6)-alkoxy-group); R2 means hydrogen atom, (C1-C15)-alkyl, (C1-C6)-alkoxy-group or cycloaliphatic group; R3 means hydrogen atom, hydroxy-group, (C1-C6)-alkyl, dihydroxy-(C1-C6)-alkyl, (C1-C10)-alkoxy-group or cycloaliphatic group; R4 and R5 mean independently of one another hydrogen atom, hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group; or among compound of the formula (VIII):

. Invention provides applying agonists eliciting the selective effect with respect to RARγ, for preparing a medicinal agent comprising one or some such agonists designated for emphysema treatment.

EFFECT: valuable medicinal properties of compounds.

4 cl, 5 tbl, 3 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of derivative of aminobenzopyrane of the formula (2): Method involves reduction of nitro-group in derivative of 2,2-dimethyl-2H-1-benzopyrane of the formula (1): with hydrazine in the presence of a metallic catalyst. Invention provides high selectivity of the process with respect to olefin bonds and simple treatment that results to small waste and doesn't effect on reactor.

EFFECT: improved method of synthesis.

2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel aminoalkyl-and amodialkylbenzopyran derivatives of the general formula (I): (a), where (a) group is a substitute in 6 or 7 position, where R is mono- or bicyclic (C6-C10)-aryl radical optionally substituted with one or two substitutes selected out of linear or ramified (C1-C5)-alkyls, linear or ramified (C1-C5)-alkoxy, hydroxy, halogen and trifluoromethyl; m is zero or integer 1-3; n, p, R1 and R2 are as indicated in the description, and both R3 and R4 are hydrogen or both are oxygen: and to pharmaceutically acceptable salts thereof.

EFFECT: selective reversible MAO-B inhibitors in vitro and in vivo, applicable as medicines for prevention and treatment of degenerative central nervous system disorders.

13 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel chromane derivatives of formula I: or their pharmaceutically acceptable salts, where: m equals 0 or 1; p equals 2; q equals 2; Ar is phenyl which is possibly substituted with a halogen atom; each R1 is independently a halogen; R2 is ; n equals 1 or 2; each of R3 and R4 is independently hydrogen or C1-12-alkyl; each of R5 and R6 is independently hydrogen or C1-12-alkyl; and each of R7 and R8 is independently hydrogen or C1-12-alkyl; or one of R7 and R8 is hydrogen and the other is a 5- or 6-member heterocyclyl containing one nitrogen atom, or R7 and R8 together with the nitrogen atom with which they are bonded can form an amidinyl group, a urea group, a guanidinyl group or a pyrrolidine ring which is possibly substituted with an amine group.

EFFECT: obtaining novel chromane derivatives and pharmaceutical compositions having 5-HT6 and/or 5-HT2a receptor modulator activity.

22 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: in the given invention, there is offered a method for preparing a compound of formula , where Y is specified of CH3, CH2OH, CH2CH2OH, CH2Br and Br; involving the stages: (1) reaction of the compound of formula where OX represents hydroxy or O-M+ where M+ represents cation chosen of Li+, Na+ and K+ and Y is such as specified above; with trans-cynnamaldehyde , with a secondary amine compound added; then (2) acid treatment of a product from the previous stage to prepare a compound of formula (I). The aforesaid method can be used for preparing tolterodine and fezoterodine which are effective in treating the hyperactive urinary bladder. There are also declared compounds of formulae V, VI and VII.

EFFECT: development of the effective method for preparing the compound.

25 cl, 19 ex

FIELD: medicine.

SUBSTANCE: invention relates to condensed bicyclic compounds, having affinity with mineralocorticoid receptor (VR) of formula [I] and formula [ii], as well as to pharmaceutical compositions on their basis. In general formula [I[ and [ii] ring A represents benzene ring, which has substituent R1, condensed with adjacent 6-membered heterocyclic ring, and said benzene ring additionally optionally is substituted with one or two substituent(s), selected from halogen atom and C1-8-alkyl group, R1 represents C1-8-alkylsulfonyl amino group or C1-8-alkyl aminosulfonyl group, R2 and R3 (a) are similar or different and represent group, selected from hydrogen atom, C1-8-alkyl group, and from 6- to 10-membered monocyclic or bicyclic aryl group (said aryl group is optionally substituted with halogen atom), (b) are combined with each other with formation of oxogroup or (c) are combined with each other on their ends together with adjacent carbon atom with formation of C3-10-cycloalkyl group, X represents the following group =N-, =C(R4)- or -CH(R4)-, R4 represents hydrogen atom, cyanogroup, halogen atom, C1-6-alkyl group, C2-6-alkenyl group, C3-10-dicloalkyl group, C1-7-alkanoyl group, carbamoyl group or C3-8cycloalkenyl group, Ar represents from 6- to 10-membered monocyclic or bicyclic aryl group, optionally containing one or several heteroatom(s), selected from sulphur atom, oxygen atom and nitrogen atom (said aryl group is optionally substituted with similar or different, one or two substituent(s), selected from halogen atom, cyanogroup, C1-8-alkyl group, trihalogen- C1-8-alkyl group and C1-8alkoxygroup), and dotted line represents presence or absence of double bond, Xa represents the following group =N- or =C(CN)-, RZ represents hydrogen atom or halogen atom, R25 and R35 represent alkyl group, and Ar3 represents phenyl group, optionally substituted with one or two group(s), which is(are) selected from halogen atom and trihalogenalkyl group.

EFFECT: compounds can be applied as antihypertensive medication.

15 cl, 18 tbl, 8 dwg, 71 ex

Bicyclic compound // 2640416

FIELD: pharmacology.

SUBSTANCE: in the general formula (1)

(1),

A is an unbranched C1-C3 alkylene group, wherein one methylene group is optionally substituted with O or S; n is an integer from 3 to 5; each of X1 and X2 is independently CH or N; each of W1 and W2 is independently a carboxyl group or W1 is a carboxyl group and W2 is a tetrazolyl group; V is a linear or branched C1-C8 alkylene group in which one methylene group is optionally substituted by O or S; R is a group selected from the following

,

,

where R1, R2, R3, R4 and R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may have a substituent group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a halogen C1-C4 alkyl group, a halogen C1-C4 vinyl group which may have a substituent group, an ethynyl group which may have a substituent group, a phenyl group which may have a substituent group on the aromatic ring, a phenoxy group which may have a substituent group on the aromatic ring, a benzyl group, which may have a substituent group on the benzene ring, a phenethyl group which may have a substituent group on the benzene ring, a benzyloxy group which may have a substituent group on the benzene ring, a benzylsulfanyl group which may have a substituent group on the benzene ring, a benzylamino group which may have a substituent group on the benzene ring, a phenyloxymethyl group which may have a substituent group on the benzene ring, a phenylsulfanylmethyl group which may contain a substituent group on the benzene ring, or a phenylaminomethyl group which may have a substituent group on the benzene ring, wherein the substituent group is indicated in the claims, m is an integer of 1 or 2 and each of Y1 and Y2 independently represents methylene, O or S, provided that they both do not represent S.

EFFECT: compounds can be used to prevent or treat disorders associated with soluble guanylate cyclase, such as hypertension, pulmonary hypertension, heart failure, endothelial dysfunction, atherosclerosis, peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction or impaired renal function.

9 cl, 41 tbl, 213 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel inhibitors of S-nitrosoglutathione reductase (GSNOR) of formula I, wherein X is selected from a group consisting of O and S; Y is selected from a group consisting of O and S; Z is selected from a group consisting of Z1, Z2, Z3 and Z4, wherein Z1 denotes , Z2 denotes , Z3 denotes and Z4 denotes , with the proviso that Z is only Z4, when at least one of X or Y is S; R1 is selected from a group consisting of hydrogen, (C1-C6) alkyl, (C1-C6) haloalkyl; R2 is selected from a group consisting of hydrogen, halogen; R3 is selected from a group consisting of hydrogen, halogen; R4 is selected from a group consisting of tetrazole, oxadiazolone, thiadiazolone, methylsulphonylcarbamoyl and N-hydroxycarbamoyl; and R5 is selected from a group consisting of carboxy, tetrazole or a pharmaceutically acceptable salt thereof, and to pharmaceutical compositions containing such inhibitors of GSNOR, and their use.

EFFECT: providing pharmaceutical compositions.

16 cl, 24 ex

Bicyclic compound // 2640416

FIELD: pharmacology.

SUBSTANCE: in the general formula (1)

(1),

A is an unbranched C1-C3 alkylene group, wherein one methylene group is optionally substituted with O or S; n is an integer from 3 to 5; each of X1 and X2 is independently CH or N; each of W1 and W2 is independently a carboxyl group or W1 is a carboxyl group and W2 is a tetrazolyl group; V is a linear or branched C1-C8 alkylene group in which one methylene group is optionally substituted by O or S; R is a group selected from the following

,

,

where R1, R2, R3, R4 and R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may have a substituent group, a C1-C6 alkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a halogen C1-C4 alkyl group, a halogen C1-C4 vinyl group which may have a substituent group, an ethynyl group which may have a substituent group, a phenyl group which may have a substituent group on the aromatic ring, a phenoxy group which may have a substituent group on the aromatic ring, a benzyl group, which may have a substituent group on the benzene ring, a phenethyl group which may have a substituent group on the benzene ring, a benzyloxy group which may have a substituent group on the benzene ring, a benzylsulfanyl group which may have a substituent group on the benzene ring, a benzylamino group which may have a substituent group on the benzene ring, a phenyloxymethyl group which may have a substituent group on the benzene ring, a phenylsulfanylmethyl group which may contain a substituent group on the benzene ring, or a phenylaminomethyl group which may have a substituent group on the benzene ring, wherein the substituent group is indicated in the claims, m is an integer of 1 or 2 and each of Y1 and Y2 independently represents methylene, O or S, provided that they both do not represent S.

EFFECT: compounds can be used to prevent or treat disorders associated with soluble guanylate cyclase, such as hypertension, pulmonary hypertension, heart failure, endothelial dysfunction, atherosclerosis, peripheral vascular disease, angina pectoris, thrombosis, myocardial infarction, erectile dysfunction or impaired renal function.

9 cl, 41 tbl, 213 ex

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