Source: https://russianpatents.com/patent/210/2108332.html
Timestamp: 2020-01-20 20:22:07
Document Index: 736041160

Matched Legal Cases: ['art 74', 'arts 4', 'arts 4', 'art 1', 'art 1', 'art 2', 'art 1', 'art 2', 'arts 35', 'art 2', 'arts 41']

Derivatives of n-(3-hydroxy-4-piperidinyl)-(dihydrobenzofuran, dihydro-2h-benzopyran or dihydrobenzoic)- carboxamide and pharmaceutical composition
C07D319/04 - 1,3-Dioxanes; Hydrogenated 1,3-dioxanes
C07D317/08 - having the hetero atoms in positions 1 and 3
C07D307/78 - Benzo [b] furans; Hydrogenated benzo [b] furans
Derivatives of N-(3-hydroxy-4-piperidinyl) (dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic) carboxamide and pharmaceutical composition. The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal motility. The proposed pharmaceutical composition based on them. Compounds according to the invention are low toxic. 2 C. p. F.-ly, 4 PL.
The invention relates to the field of new chemical substances that have valuable pharmaceutical properties, and relates to derivatives of N-(3-hydroski-4-piperidinyl)-(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic)-carboxamide, having the activity to stimulate gastrointestinal peristalsis, and pharmaceutical compositions containing these compounds.
Known derivatives (3-hydroxy-4-piperidinyl)-benzamide having the stimulating activity of the gastrointestinal peristalsis (EP-A-0076530 and the patent of the USSR N 1593569 and EP-A-0299566 and compliance is h, dihydro-2H-benzopyran or dihydrobenzoic)-carboxamide according to the invention is superior to these known compounds for the pharmaceutical activity of the specified type.
Compounds according to the invention have the formula:
where A is the radical of formula (a-1), -CH2-CH2-, formula (a-2), -CH2-CH2-CH2or of the formula (a-3), -CH2-CH2-O, where one or two hydrogen atoms in the radical (a-1) can be substituted C1-C6- alkyl radical,
R1- halogen,
R2- amino group,
R3is hydrogen or C1-C4-alkyl.
L - C3-C6-cycloalkyl, C3-C6alkenyl or formula (b-1) - Alk-R5formula (b-2), - Alk-X-R6formula (b-3), -Alk-Y-C(=0)-R8or of the formula (b-4), Alk-Y-C(=0)-NR10R11,
where each Alk - C1-C6-alcander; R5is hydrogen, cyano, C3-C6-cycloalkyl, phenyl, optionally substituted by halogen or Het; R6is hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl, haloethanol, optionally substituted C1-C4-alkylcarboxylic, 3-cyano-2-pyridinyl, 2-methyl-5-pyridyl, 4-hydroxy-2-pyrimidinyl, 2-methyl-3-pyrazinyl or 3,4-dihydro-4-oxo-2-hintline; X is oxygen or NH; RSUB>6-alkoxy; Y is - NR9or a simple link, where R9is hydrogen, C1-C4-alkyl or phenyl; R10and R11each independently - C1-C6-alkyl or taken together with the nitrogen atom to which they are attached, may form pyrrolidinyl ring; Het systems simple cyclic ether selected from the group consisting of
where R12is hydrogen or C1-C4-alkyl;
or Het is a heterocyclic system is selected from the group consisting of pyridinyl or benzimidazolyl, substituted C1-C6-alkyl, or Het is a monocyclic amide system selected from the group consisting of:
R14is hydrogen or C1- C6-alkyl,
R15- halogen, C1-C6-alkyl or phenyl,
G1- -CH2-CH2- CH=CH - or-C(=0)=CH2-
or Het is a bicyclic amide system selected from the group consisting of
where R16- C1-C6-alkyl or phenylmethyl;
R17- C1-C6-alkyl;
R18is hydrogen or halogen;
G3- -S-(CH2)2- or-S-CH=CH-;
G4- -CH=CH-CH=CH-, -CH=CCl-CH=CH-, -CH=N-CH=CH - or-N=CH-N=CH-.
In the scope of the invention vorovaniya piperidine derivatives of the formula
where R1, R2, R3and A have the meanings indicated in the formula (I), an intermediate product of the formula L-W (III), where L is the value specified in the formula (I), and W is halogen or sulfonyloxy, or aldehyde of formula L'= 0 (VI)
L' = 0 connection formula L-H in which two adjacent hydrogen atom in C1-C6-alcantera or C3-C6-cycloalkenyl replaced =0; or alkene of the formula NC-CH=CH2(XV), in a reaction inert solvent, optionally in the presence of a base, iodide salt or reducing agent; and optionally, if desired, restore the connection formulas
where R1, R2, R3A and Alk are defined in formula (I), in a reaction inert solvent in the presence of a catalyst and in an atmosphere of hydrogen, the result is a compound of the formula
and then enter the specified compound of the formula (1-d) reaction with a reagent of the formula R-W R - R6, -C(=0)-R8or-C(=0)R10R11and W is halogen or methylthiourea, optionally in a reaction inert solvent, optionally in the presence of base, you get a compound of the formula:
where R1, R2, R3, R9, Alk and A defined in formula (I); or when W is defined in formula (I), in a reaction inert solvent in the presence of acid, you get a compound of the formula:
or if desired, turn the compound of the formula:
where R1, R2, R3, R6, Alk and A defined in formula (I), in a reaction inert solvent in the presence of acid, you get a compound of the formula:
and when desire turns compound of formula (I) in its therapeutically active non-toxic salt accession when treatment with acid; or, conversely, to convert the acid salt to the free base by treatment with alkali, and/or receive a stereochemical isomeric form. Your definitions of "halogen" is shared by fluorine, chlorine, bromine and iodine; alkyl (C1-C6" defines saturated hydrocarbon radicals with a straight or branched chain having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 2-methylpropyl and similar; "cycloalkyl C3-C6" is the generic definition for cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; "cycloalkane C5-C6" is generic for Cyclopentanone and cyclohexanone; "alkenyl C3-C6" defines hydrocarbon radicals with Parker, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and similar; and when alkenyl C3-C6substituted at a heteroatom, then the carbon atom indicated alkenyl C3-C6associated with the specified heteroatom is preferably saturated; "alcander C1-C6" defines the divalent hydrocarbon radicals with a straight or branched chain containing 1 to 6 carbon atoms, such as, for example, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol, 1,5-pentandiol, 1,6-hexandiol and their branched isomers.
Have in mind that the salts referred to above include therapeutically active non-toxic salt additive form, which is able to form compounds of formula (I).
The latter can be obtained by processing forms the Foundation of such appropriate acids as inorganic acids, for example kaleidotrope acid, for example hydrochloric, Hydrobromic and similar, sulfuric acid, nitric acid, phosphoric acid and similar; or organic acids such as acetic, propanoic, hydroxyestra, 2-hydroxypropanoate, 2-oxopropanal, tanginoa, proportionaly, batandjieva, (Z) -2-butandione what I methansulfonate, ethanesulfonate, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.
On the contrary, the salt form can be processed by alkali developing in the form of a free base.
The compounds of formula (I) containing acidic protons may also be converted to their therapeutically active non-toxic forms salts with metals or amines by treatment with appropriate organic or inorganic bases.
The compounds of formula (I) have at least two asymmetric carbon atom in its structure, namely the atoms located at the 3 - and 4-position piperidino kernel. Stereochemical isomeric forms of the compounds of formula (I) fall under the scope of the invention.
In addition, the compounds of the invention can form CIS/TRANS, more specifically, the substituents in these 3 - and 4-positions piperidino kernel mo"ptx2">
The reaction of N-alkylation of compound (II) compound (III) is conveniently carried out in a reaction inert solvent such as, for example, water, an aromatic hydrocarbon, for example benzene, methylbenzol, xylene, chlorobenzene, methoxybenzo and similar, alkanol, for example methanol, ethanol, 1-butanol, and similar halogenated hydrocarbons such as dichloromethane, trichloromethane and similar, ester, such as ethyl acetate, butyrolactone and similar ketones, such as 2-propanone, 4-methyl-2-pentanone and similar; a simple ester, for example, 1,4-dioxane-1,1'-oxybis-ethane, tetrahydrofuran and similar, in a polar aprotic solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, hexamethylphosphoramide, 1,3-dimethyl-3, 4, 5, 6-tetrahydro-2-(IH)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1, 1, 3, 3-tetramethylrhodamine, nitrobenzene, 1-methyl-2-pyrrolidinone and similar, or in mixtures of such solvents.
For trapping of acid released during the reaction can be used, the addition of an appropriate base, such as, for example, carbonate, bicarbonate, carboxylate, amide, oxide, hydroxide or alcoholate of an alkaline or alkaline-earth metal, e.g. the sodium, the sodium methylate and similar or organic bases, such as, for example, amine, e.g. N,N-dimethyl-4-pyridylamine, N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 1,4-diazabicyclo-(2,2,2)octane, 4-ethylmorpholine and similar.
In some cases it may be appropriate to add iodide salt, preferably the alkali metal iodide, or a crown ether, such as 1,4,7,10,13,16-hexaoxacyclooctadecane and similar.
Mixing and slightly rising temperatures may increase the reaction rate. Additionally can be beneficial holding this N-alkylation in an inert atmosphere, such as, for example, free from kislorod argon or nitrogen gas.
Alternative specified N-alkylation may be carried out while applying known in the art conditions of the reactions catalyzed phase transfer.
Such conditions include mixing of reagents with a suitable base and optionally in an inert atmosphere, as described above, in the presence of a suitable catalyst phase transfer, such as, for example, a halide, hydroxide, acid sulphate dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane, tetraurelia elevated temperature.
The compounds of formula (I) containing a hydroxy function, can About-to alkylaromatic in accordance with well-known in the art techniques O-alkylation, for example by mixing with an appropriate alkylating agent, if necessary, in the presence of sodium hydride.
The compounds of formula (I) containing a cyano-Deputy, can turn into with the, tereasa hydrogen, in the presence of an appropriate catalyst, such as, for example, platinum on charcoal, Raney Nickel and the like, catalysts, and optionally in the presence of a base, such as, for example, amine, e.g. N,N-diethylethanamine and similar, or hydroxide, for example sodium hydroxide, and similar.
Suitable solvents are, for example, alkanols, such as methanol, ethanol and similar; ethers such as tetrahydrofuran and similar, or a mixture of such solvents.
Pure stereochemical isomeric forms of the compounds of formula (I) and the intermediates of formula (II) can be obtained using known in the art techniques.
Diastereoisomer can be separated by physical separation methods such as selective crystallization and chromatography techniques, such as distribution in a counter, and enantiomers may be separated from each other by selective crystallization of their diastereomeric salts with optically active acids and optically active derivatives.
CIS - and transvestitemovie the racemates can be further split into their optical isomers, CIS (+), CIS (-), TRANS (+) and TRANS the forms can also be obtained from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the reaction is stereospecific manner.
The compounds of formula (I) containing Allenby fragment may be present in the "E" or "Z" shape, and the specified E - and Z - symbols have the meanings described in J.Org. Chem., 2849-2868 (1970).
The compounds of formula (I), their pharmaceutically acceptable salts and the possible stereoisomeric forms possess favorable properties promote gastrointestinal peristalsis. In particular, these compounds show considerable activity increased peristalsis in the colon (the large) intestine.
About the last property is proved by the results obtained in the following test on "reductions caused by the ascent of the colon".
The stimulating effect of the compounds of formula (I) motility (motor activity) gastrointestinal system may additionally be confirmed, for example, various tests described in The Journal Pharmacology and Experimental Thevapeutics, 234, 775 - 783 (1985) and in Drug Development Research, 8. 243 - 250 (1986).
The test of "emptying from the stomach liquid food in rats", described in the last article, and the test of "emptying from the stomach calorie food in dogs after the appointment of lidamycin advanced LASS="ptx2">
In addition, the compounds of formula (I) and their pharmaceutically acceptable acid additive salts and the possible stereoisomeric forms have special receptor - binding profile.
Some groups of compounds of the invention, particularly compounds in which the radical A is not substituted by alkyl (C1-C6have bad 5HT3antagonistic activity induced by high doses of serotonin in the ileum of the Guinea pig.
Most of the compounds of the invention do not show any obvious visible affinity receptor binding serotonergically 5HT1and serotonergically 5HT2receptors and have little or no dopaminergic antagonistic activity.
Because of the useful properties enhance gastrointestinal peristalsis on the basis of these compounds can be prepared in various forms for admission.
To prepare the pharmaceutical compositions of the invention an effective amount of a specific compound in the form of base to acid additive salts as the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier, which may have rassooli preferably presented in the form of a unit dose, it is preferable to assign orally, rectally or via parenteral injection.
For example, upon receipt of the compositions in the form of oral dosages may apply any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, and similar, in the case of oral liquid preparations such as suspensions, syrups, elexir and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, agents, dezintegriruetsja agents and similar in the case of powders, pills, capsules and tablets.
Due to the simplicity of their reception of tablets and capsules represent the most advantageous oral dosage form units, and in this case, obviously, apply solid pharmaceutical carriers.
For parenteral compositions, the carrier typically includes sterile water, at least a large part, although can include other ingredients, for example, in order to facilitate solubility. Can be prepared for example, injectable solutions, in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
Can also be prepared injectable sue.
In the compositions suitable for appointment through the skin, the carrier optionally comprises an agent that enhances the penetration and/or a suitable wetting agent, optionally in combination with small amounts of suitable additives of any nature, which does not have a significant adverse impact on the skin.
These supplements can facilitate the application to the skin and/or may be useful to obtain the desired compositions. These compositions can be administered in various ways, for example, by transdermal, locally, in the form of ointment.
Acid additive salts of compounds (I) because of their increased solubility in water as compared with the corresponding forms the Foundation are clearly more suitable for the preparation of aqueous compositions.
Particularly beneficial to produce the aforementioned pharmaceutical compositions in the form of dosage units for ease of their purpose and uniformity of dosage. The form of dosage units refers to physically discrete units suitable as unit doses, each unit contains a defined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required FA is either tablet in the form of a nucleus or coated), capsules, pills, powders, wafers, injectable solutions or suspensions, the number of constituting a full teaspoon, tablespoon, and similar and segregated multiple combinations of them.
Because of their ability to stimulate peristalsis of the gastrointestinal system, and in particular their ability to enhance motor activity of the colon, the described compounds are useful to bring in norm or to improve emptying of the stomach and intestines in subjects suffering from upset peristalsis, such as reduced motility of the stomach and/or thin and/or thick guts.
Because of the usefulness of the compounds of the invention are offered for the treatment of warm-blooded animals suffering from disorders of motor activity of the gastrointestinal system, such as, for example, gastroparesis, dyspepsia, accompanied by flatulence, bezyatiny dyspepsia, pseudoprobability and especially violated the passage of contents through the colon.
This will include General purpose effective to stimulate motor activity of the gastrointestinal tract number of the compounds of formula (I), N-oxide, pharmaceutically acceptable acid-adit is subramania also have therapeutic value in the treatment of motor activity of the upper digestive tract and disorders gastroesophageal reflux.
In General it is considered that the effective dose is 0.001 - 10 mg/kg body weight and more preferably 0.01 to 1 mg/kg body weight.
A. Obtaining an intermediate product
Example 1. a) To a solution of 8.1 parts of 4-amino-5-chloro-2,3-dihydro - 2,2-dimethyl-7-benzofuranol acid in 218 parts of trichloromethane and 3.43 parts of N, N-diethylethanamine dropwise added 3.63 parts of ethylchloride maintaining the temperature below 10oC.
After stirring for 1/2 h at 10oC all added to a solution of 6.26 parts of ethyl-4-amino-3-methoxy-1-piperidinecarboxylate in 145 parts of trichloromethane at 10oC. Stirring is continued for 1/2 h at room temperature.
The reaction mixture was washed with water, 5% sodium hydroxide and water and then dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 12,3 part (93,2%) ethyl-CIS-4-[(4-amino-5-chloro - 2,3-dihydro-2,2-dimethyl-7-be the part of the intermediate product 1, 15, 9 parts of potassium hydroxide and 156 parts of 2-propanol were mixed for 12h at the temperature of the return stream.
The reaction mixture was evaporated and to the residue was added water. All was evaporated again and the residue was diluted with water. The product was extracted with dichloromethane (2 times) and the combined extracts were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2(CH3OH) NH3) 90:10). Eluent of the desired fraction was evaporated, and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 7,24 part (71,0%) of CIS-4-amino-5-chloro-2,3-dihydro-N-(3-methoxy-4-piperidinyl)- 2,2-dimethyl-7-benzoperoxide; so pl. 179,3oC (intermediate 5).
In a similar manner were also obtained intermediate products listed in the table. I.
Example 2. a) a Solution of 9.1 parts of 5-chloro-2,3-dihydro-4-benzo-furanken [described in J. Het. Chem., 17 (6) 1333 (1980)], 9,6 part N-bromosuccinimide and 130,5 parts of benzene were mixed for 1 h at the temperature of the return stream. The solvent was evaporated, and the residue was dissolved in 387,4 part of trichlormethane.
The solution was washed with water (2200 parts). The organic layer sushi>4/CH2Cl250:50).
Eluent of the desired fraction was evaporated to obtain 11.8 in part (87,9%) of 7-bromo-5-chloro-2,3-dihydro-4-benzoguanamine (intermediate 8).
b) To a cooled (-70oC) and stir the mixture of 15.6 parts of a solution N. utility in hexane 2.5 polyarnosti and 44.5 parts of tetrahydrofuran was added dropwise a solution of 4 parts of the intermediate product 8 26.7 parts of tetrahydrofuran in a stream of nitrogen.
The reaction mixture is stirred for 1 hours at approximately -60oC and poured into saturated suspension of carbon dioxide (ice) of 44.5 parts of tetrahydrofuran. The mass was given the opportunity to warm to room temperature while stirring, and added 80 parts of water. The aqueous layer was kind of balanced out and dried in vacuum at 60oC, with the receipt of 1.1 parts (32,2%) 4-amino-5-chloro-2,3-dihydro-7-benzofuranol acid:
So pl. 258,4oC (intermediate 9).
Similarly, there was obtained 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylic acid (intermediate 10).
Example 3. a) a Mixture of 40 parts of methyl 4-(acetylamino)-5-chloro-2-(2-propyloxy)-benzoate and 172 parts of phenoxybenzoyl stirred for 45 min at all, were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2CH2/CH3OH 97:3). Eluent of the desired fractions was evaporated and the residue crystallized from acetonitrile, with the receipt of 11.9 parts of methyl 5-(acetylamino)-6-chloro-2H-1-benzopyran-8-carboxylate (intermediate 11).
b) a Mixture of 31.3 parts of the intermediate product 11, 31 parts of N,N-diethylethanamine and 395 parts of methanol was gerasoulis under normal pressure at room temperature with 4 parts of 10% palladium catalyst on coal.
After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was suspenderbelt in the water, and the product was extracted with dichloromethane (2 times).
The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified twice by chromatography on a column (silica gel; CH2Cl2/CH3OH 97,5:2,5).
Eluent of the desired fractions was evaporated and the residue crystallized from acetonitrile. The product was filtered and dried, obtaining 19,1 part (69,7%) methyl-5-(acetylamino)-3,4-dihydro-2H-1-benzopyran-8-carboxylate.
So pl. 175,1oC (sub-the TEI of acetonitrile was mixed for one hour at the temperature of the return stream.
After cooling, the reaction mixture is poured into 300 parts of water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 17,8 part (81,5%) methyl-5-(acetylamino)-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylate.
So pl. 184,2oC (intermediate 13).
d) a Mixture of 1.34 parts of the intermediate product 13, 2,62 parts of potassium hydroxide and 20 parts of water were mixed for 3 hours at the temperature of the return stream.
After cooling, the reaction mixture was padillas to pH 4 with concentrated hydrochloric acid. The precipitate was filtered and dried to obtain 0.65 parts (60,7%) of 5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-carboxylic acid.
So pl. 225,9oC (intermediate 14).
Example 4. a) To a solution of 104,6 parts of methyl-2-hydroxide-4-(acetylamino)benzoate in 470 parts of N,N-dimethylformamide portions were added 24 parts of a dispersion of sodium hydride in mineral oil (50%) in nitrogen atmosphere.
After stirring for 1 h at room temperature, to the mixture was added a solution of 55.2 parts of 3-chloro-2-Menna the mixture was evaporated, and the residue was dissolved in dichloromethane.
This solution was washed with water, 10% sodium hydroxide and water and then dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybisethane. The product was filtered and dried to obtain 65,8 part (50%) of methyl-4-(acetylamino)-2-//2-methyl-2-propanyl/hydroxy/benzoate (intermediate 15).
b) a Mixture of 72 parts of the intermediate product 15 and 226 parts of 1-methyl-2-pyrrolidinone stirred for 1.5 hours at the temperature of the return stream.
After cooling, the reaction mixture is poured into ice water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybisethane.
The product was filtered and dried to obtain 35,4 part (49,8%) of methyl-4-(acetylamino-2-hydroxy-3-)2-methyl-2-propenyl/benzoate. The mother liquid was evaporated, and the residue was consistently suspendible in water and precrystallization of 2,2'-oxybisethane with obtaining advanced to 17.6 parts (24,6%) of methyl-4-(acetylamino-2-hydroxy-3-)2-methyl-2-propenyl/benzoate.
Total yield: 53,0 part 74,6% (intermediate 16).
c) the Mixture is round reverse flow.
After cooling, the reaction mixture was poured into a mixture of ice-water, and was extracted with dichloromethane (2 times).
The combined extracts were washed with 10% sodium hydroxide and water and then dried, filtered and evaporated.
The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 105,5 part (83,3%) of methyl-4-(acetylamino)2,3-dihydro-2,2-dimethyl-7-benzofuran-carboxylate (intermediate 17).
d) a Mixture of 10.5 parts of the intermediate product 17, 5, 87 parts of N-chlorosuccinimide and 158 parts of acetonitrile is stirred for 1 h at the temperature of the return stream.
After cooling, the reaction mixture is poured into ice water. The product was extracted with dichloromethane (2 times) and the combined extracts were dried, filtered and evaporated. The residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 11,9 part (99,9%) of methyl-4-(acetylamino)-5-chloro - 2,3-dihydro-2,2-dimethyl-7-benzophenoneoxymate (intermediate 18).
e) a Mixture of 11.9 parts of the intermediate product 18, 22, 4 parts of potassium hydroxide and 200 parts of water were mixed for 3 h at the temperature of the return stream. After cooling, the pop-2,3-dihydro-2,2-dimethyl-7-benzofuranol acid (intermediate 19).
Example 5. A mixture of 3.9 parts of intermediate 2, of 2.54 parts of sodium carbonate, 1 crystal of potassium iodide and 144 parts of 4-methyl-2-pentanone stirred for 1 h at a temperature of return flow using water separator.
After the addition of 3.2 parts of 1-(2-chloroethyl)-3-ethyl-2,3-dihydro-1H-benzimidazole-2-it is the stirring was continued overnight while the temperature of the return stream. The reaction mixture was rinsed with water. The organic layer was dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 96:4).
Eluent of the desired fraction was evaporated and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 70oC obtaining 2,30 part (37.3%) of CIS-4-amino-5-chloro-N-/1-/2-/3-ethyl - 2,3-dihydro-2-oxo-1H-benzimidazole-1-yl/ethyl/-3-methoxy-4-piperidinyl/- 2,3-dihydro-7-benzoperoxide.
So pl. 173,7oC (compound 1).
Example 6. A mixture of 4.2 parts of monobrominated 3-/2-bromacil/-2 - methyl-4H-hinzelin-4-it, 3.3 parts of the intermediate product 2, 4,24 parts of sodium carbonate and 160 parts 4-methyl-2-pentanone and a few crystals of potassium iodide peremeci delalla between trichloroethanol and water. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified twice by chromatography on a column (silica gel; CHCl3/CH3OH 97: 3; HPLC; silica gel; C6H5-CH3) ISO-C3H7OH 80: 20). Eluent of the desired fraction was evaporated, and the residue crystallized from acetonitrile.
The product was filtered off and dried in vacuum at 60oC obtaining 3,10 part (60,5%) of CIS-4-amino-5-chloro-2,3-dihydro-N-/3-methoxy-1-/2-/2-methyl-4-oxo - 3(4H)-chinadoll/ethyl/-4-piperidinyl/-7-benzoperoxide;
So pl. to 274.9oC (compound 30).
Example 7. The mixture 4,07 part of the intermediate product 7, 3,82 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone stirred at reflux (with water separator) within 1 h
Then was added 2.7 parts of 6-chloro-2-/3-chlorpropyl/- 2H-pyridazin-3-one, and stirring at a temperature of return flow continued throughout the night. The reaction mixture was evaporated, and the residue was taken in dichloromethane.
This solution was washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 95: 5). Eluent the obtaining of 3.9 parts (63,7%) of CIS-5-amino-6-chloro-N-/1-/3-/3-chloro-1,6 - dihydro-6-oxo-1-pyridazinyl/propyl/-3-methoxy-4-piperidinyl/- 3,4-dihydro-2H-benzopyran-8-carboxamide.
So pl. of 149.5oC (compound 136).
Example 8. A mixture of 3.4 parts of the intermediate product 7, 3.16 part tetrahydro-2-furnitureleather (ester), 80 parts 4-methyl-2-pentanone and 1.58 parts of sodium carbonate were mixed under heating with reflux condenser (with water separator) within 30 PM
The reaction mixture was evaporated, and the residue was diluted with water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated, the residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95:5)
Eluent of the desired fraction was evaporated, and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain 2,44 part (57.6%) of CIS-5-amino-6-chloro-3,4-dihydro-N-/3-methoxy-1-// tetrahydro-2-furanyl/methyl/-4-piperidinyl/-2H-1-benzopyran-8-carboxamide.
So pl. 158,1oC (compound 76).
Example 9. A mixture of 3.53 parts of the intermediate product 5, 2.1 part 1-/3-chlorpropyl/-3-ethyl-2-imidazolidinone, 94 parts of N,N-dimethylformamide and 1.58 parts of sodium carbonate were mixed for 20 h at 70oC.
The reaction mixture was evaporated, and the residue was diluted into what was literalis and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 96:4).
Eluent of the desired fraction was evaporated, and the residue was turned into salt candiate in 2-propanol. The product was filtered and dried to obtain 4,18 part (70,0%) acandidate CIS-4-amino-5-chloro-N-/1-/ 3-/3-ethyl-2-oxo-1-imida-tolidine/propyl/-3-methoxy-4-piperidinyl/- 2,3-dihydro-2,2-dimethyl-7-benzoperoxide (1:1).
So pl. 208,0oC (compound 121).
Example 10. A mixture of 2.6 parts of 2-iodomethyl-1,3-dioxolane, 3.3 parts of the intermediate product 2, 2,12 parts of sodium carbonate and 47 parts of N,N-dimethylformamide stirred for 3 days at 70oC.
After cooling, the reaction mixture was evaporated. The residue was distributed between dichloromethane and water. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95:5).
Eluent of the desired fraction was evaporated, and the residue crystallized from acetonitrile to which was added a few drops of water). The product was filtered off at 0oC and dried in vacuum at 40oC with the receipt of 2.3 parts (55,8%) of CIS-4-P> So pl. 149,1oC (compound 83).
Example 11. The mixture 2,78 part 1-/3-chlorpropyl/-2-methyl-1H - benzimidazole, 3.3 parts of intermediate 2, 2,04 parts of N,N - diethylethanamine and 94 parts of N,N-dimethylformamide stirred for 20 h at 70oC.
The reaction mixture was evaporated and to the residue was added water. The product was extracted with dichloromethane (2 times) and the combined extracts were washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile to which was added a few drops of water) to obtain 2,30 part (44,6%) monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-/3-methoxy-1-/3-/2-methyl-1H-benzimidazole-1-yl/propyl/-4-piperidinyl/-7-benzoperoxide.
So pl. 151,5oC (compound 27).
Example 12. A mixture of 3.3 parts of the intermediate product 2, and 4.4 parts of ethyl N-/2-oxoethyl/-N phenylcarbamate, 2 parts of a solution of thiophene (4% methanol was gerasoulis at normal pressure and at 50oC with 2 parts of 5% platinum catalyst on coal.
After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was diluted with water and the product was extracted with dichloromethane (2 times).
Oblonga (silica gel; CH2Cl2/CH3OH 95:5).
Eluent of the desired fraction was evaporated, and the residue was suspenderbelt 2,2'-oxybuprocaine. The product was filtered and dried to obtain is 3.08 parts (58,6%) hemihydrate ethyl CIS-N-[2-[4-[[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)-carbonyl]amino]-3 - methoxy-1-piperidinyl-]-N-phenyl-carbamate.
So pl. 116,4oC (compound 57).
Example 13. To a stirred mixture of 3.4 parts of the intermediate product 7, 2 parts of tetrahydrofuran, 2 parts of a solution of thiophene (4% methanol and 119 parts of methanol was added dropwise a mixture of 11 ml of a solution of acetaldehyde in 10% tetrahydrofuran and 8.9 parts of tetrahydrofuran in the course of the hydrogenation.
After completion of the hydrogenation the catalyst is filtered, and the filtrate was evaporated. The residue was dissolved in dichloromethane, and this solution was washed with water (2 times), dried, filtered and evaporated. The residue was precrystallization from acetonitrile.
The product was filtered and dried to obtain 2,66 part (72,3%) of CIS-5-amino-6-chloro-N-/1-ethyl-3-methoxy-4-piperidinyl/-3,4-dihydro-2H - 1-benzopyran-8-carboxamide.
So pl. 153,8oC (compound 81).
Example 14. A mixture of 3 parts of 1-hexanal, 3,7 part of the intermediate product at the 50oC with 2 parts of 5% platinum catalyst on coal.
After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was purified using chromatography on a column (silica gel; CH2CI2/ CH3OH/ NH3/ 98:2).
Eluent of the desired fraction was evaporated, and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 70oC obtaining a 3.2 part (68,5%) of CIS-4-amino-5-chloro-N-(1-hexyl-3-hydroxy-4-piperidinyl)-2,3-dihydro-7 - benzoperoxide.
So pl. 130,4oC (compound 8).
Example 15. A mixture of 4.5 parts of (1,1-dimethylethyl//2-oxoethyl/methylcarbamate, and 5.5 parts of intermediate 2, 1 part of a solution of thiophene (4% methanol, 198 parts of methanol and 2 parts of potassium acetate was gerasoulis at normal pressure and at room temperature with 2 parts of 10% palladium catalyst on coal.
After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was distributed between trichloromethane and water. The organic layer was separated, washed with water, dried, filtered and evaporated.
The residue was utverjdala 2,2'-Arcebispo the e at 40oC with the receipt of 6.3 parts (76,6%) of (1,1-dimethylethyl)-CIS-[2-[4-[(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl) carbylamine [-3-methoxy-1-piperidinyl]ethyl]methylcarbamate (compound 41).
Example 16. To heated under reflux to a solution of 17.4 parts of intermediate 2 in 195 parts of 2-propanol was added 4,03 part 2-propenenitrile. Stirring at the temperature of reflux distilled continued for 18 h
The reaction mixture was evaporated, and the residue was crystallized from 2-propanol. The product was filtered off and dried in vacuum at 60oC with the receipt of 14.8 parts (73,7%) of CIS-4-amino - 5-chloro-N-[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2,3-dihydro-7-benzoperoxide.
So pl. 190,7oC (compound 97).
Example 17. A solution of 15.7 parts of CIS-4-amino-5-chloro-N-[1-(cyanomethyl)-3-methoxy-4-piperidinyl] -2,3-dihydro-7 - benzoperoxide in 178 parts of tetrahydrofuran and 158 parts of methanol was gidrirovaniya at normal pressure and at room temperature with 6 parts of Nickel Raney.
After the calculated amount of hydrogen was absorbed, the catalyst was filtered off and the filtrate was evaporated. The residue was purified using chromatography on a column (silica gel; CH2CI2/ CHoC and dried in vacuum at 40oC with the receipt of 8.5 parts (53,6%) of CIS-4-amino-N-[1-(2-amino-ethyl)-3-methoxy-4-piperidinyl] -5-chloro-2,3-dihydro-7 - benzoperoxide (compound 35).
Example 18. To a cooled (ice bath) mixture of 3.8 parts of monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-/3-methoxy-1-/2-/methylamine/ ethyl/-4-piperidinyl/-7-benzoperoxide in 104,3 part of trichloromethane was added 1,3 part 1-pyrrolidinecarbonyl chloride.
After stirring for 15 min at 0oC was added dropwise 1,31 parts of N,N-diethylethanamine, maintaining a temperature of up to 10oC. Stirring was continued for 20 h at room temperature.
The reaction mixture was washed with water, dried, filtered and evaporated. The residue is crystallized from acetonitrile to which was added a little water). The product was filtered off at 0oC and dried in vacuum at 40oC obtaining 3.3 parts (73,6%) monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-[methyl (1-pyrrolidinylcarbonyl)amino]ethyl]-4-piperidinyl]-7-benzoperoxide.
So pl. 112,0oC (compound 43).
Example 19. A mixture of 1.4 parts of 2-chloro-3-pyridylcarbonyl, 3,2 Castellamare and 1.3 parts of sodium carbonate were mixed for 20 h at 70oC. the Solvent was evaporated, and the residue was dissolved in trichloromethane.
The organic layer was washed with water, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CHCl3/CH3OH(NH3) 98 : 2).
Eluent of the desired fraction was evaporated, and the residue is crystallized from 2,2'-oxybisethane. The product was dried in vacuum at 60oC obtaining 1,44 part (35.4%) of hemihydrate CIS-4-amino-5-chloro-N-[1- [4-[(3-cyano-2-pyridinyl)amino] butyl] -3-methoxy-4-piperidinyl]- 2,3-dihydro-7-benzoperoxide.
So pl. 129,7oC (compound 6).
Example 20. A mixture of 1.18 part 2-chloro-4(3H)-hintlian, 2,40 connection parts 35 and the minimum amount of N,N-dimethylformamide were mixed for 3 h at 120oC.
After cooling, the reaction mixture was distributed between dichloromethane and methanol. The organic layer was separated, dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/Ch3OH 90 : 10).
Eluent of the desired fraction was evaporated, and the residue crystallized from acetonitrile to which was added a little water). The product was filtered off at 0oSinusoidal)amino]ethyl]-3-methoxy-4 - piperidinyl]-7-benzoperoxide.
So pl. 191,8oC (compound 88).
Example 21. The mixture 4,69 part dihydrochloride CIS-4-amino-N-[1- (2-amino-ethyl)-3-methoxy-4-piperidinyl] -5-chloro-2,3-dihydro-2,2 - dimethyl-7-benzoperoxide, 1,54 part 2-chloro-3-methylpyridazine and 1,68 parts of calcium oxide were mixed for 20 h at 120oC.
After cooling, the reaction mixture was diluted with water and the product was extracted with dichloromethane (3 times). The combined extracts were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 95 : 5).
Eluent of the desired fraction was evaporated, and the residue was converted into the salt of candiate in 2-propanol. The product was filtered and dried to obtain 1,38 part (23.1 per cent) of the monohydrate of candiota (1 : 1) of CIS-4-amino-5-chloro-2,3-dihydro-N-/3-methoxy-1-/2//3-methyl-2 - pyrazinyl/amino/ethyl-4-piperidinyl/-2,2-dimethyl-7-benzoperoxide.
So pl. 117,1oC (compound 170).
Example 22. A mixture of 5 parts of CIS-5-amino-N-[1-(3-aminopropyl)-3 - methoxy-4-piperidinyl]-6-chloro-3,4-dihydro-2H-1-benzopyran-8 - carboxamide, and 3.2 parts of 2-methylthio-4-pyrimidinone and 79 parts of acetonitrile is stirred for 2 days (the weekend) when temperature is eacom (water). The aqueous layer was separated and was extragonadal dichloromethane (2 times). The combined dichloromethane layers were dried, filtered and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH/NH3/ 95 : 5).
Eluent two desired fractions was evaporated and the residues separately crystallized from acetonitrile. The product was filtered off and dried in vacuum at 70oC with the first fraction from 2,22 part (35,2%) hemihydrate CIS-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4- hydroxy-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl]-2H-1 - benzopyran-8-carboxamide.
So pl. 142,6oC
The second fraction of 1.00 part (15,9%) hemihydrate CIS-5-amino-6-chloro-3,4-dihydro-N-[1-[3-[(4-hydroxy-2-pyrimidinyl) amino] propyl] -3-methoxy-4-piperidinyl]-2H-1-benzopyran-8 - carboxamide.
So pl. 143,5oC.
Total yield: 3,22 part (51,1%) of the product (compound 128).
Example 23. A mixture of 5.4 parts of CIS-4-amino-5-chloro-2,3-dihydro-N-[3 - methoxy-1-[3-(2-methyl-1,3-dioxolane-2-yl)propyl] -4-piperidinyl]-2,2 - dimethyl-7-benzoperoxide and 85 ml of aqueous 1% sulfuric acid solution was mixed for 2 h at the temperature of reflux distilled.
After cooling, the reaction mixture p is Alice and evaporated. The residue was purified using chromatography on a column (silica gel; CH2Cl2/CH3OH 95 : 5).
Eluent of the desired fraction was evaporated, and the residue was suspenderbelt 2,2'-oxybisethane. The product was filtered and dried to obtain a 2.4 part (51,6%) hemihydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3 - methoxy-1-(4-oxobutyl)-4-piperidinyl]-2,2-dimethyl-7-benzofuran - carboxamide.
So pl. 137,7oC (compound 112).
Example 24. A mixture of 6.3 connection parts 41 and 23.4 parts of 2-propanol, saturated with hydrochloric acid, and 198 parts of methanol were mixed for 15 min at the temperature of the return stream.
After cooling, the reaction mixture was evaporated. The residue was absorbed water, and all was podslushivaet ammonia. The product was extracted with trichloromethane, and the extract was dried, filtered and evaporated. The residue is crystallized from acetonitrile to which was added a few drops of water).
The product was filtered off at 0oC and dried in vacuum at 40oC with the receipt of 3.8 parts (72,9%) monohydrate CIS-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-1-[2-(methylamino)ethyl] - 4-piperidinyl] -7-benzoperoxide (compound 42).
Example 25. It chilled in an ice bath Rast is part of trichlormethane add 0,86 parts of N,N-diethylethanamine, and then added dropwise a solution of 0.77 part of ethylchloride in 29,8 part of trichlormethane.
After 0.5 h stirring at room temperature, add water. Separate the organic layer, dried, filtered and evaporated. The residue is purified through column chromatography (silica gel; CH2Cl2/Ch3OH/NH3/ 98 : 2).
Eluent target fraction is evaporated, and the residue is crystallized from acetonitrile (to which are added a few drops of water). The product is filtered at 0oC and dried in vacuum at 40oC, get 0,95 part (32,5%) hemihydrate ethyl-CIS-[2-[4[/4-amino-5-chloro-2,3 - dihydro-7-benzofuranyl/carbylamine]-3-methoxy-1-piperidinyl]ethyl] carbamate (compound 36).
So pl. 145, 2mmoC.
Compounds shown in table. 2, were prepared according to analogous methods described in any of examples 5 to 25.
Example 26. Compounds shown in table.3, were prepared according to analogous methods described in any of the examples.
Useful properties of the compounds of the invention to stimulate gastrointestinal peristalsis, and in particular their ability to increase contractility of the I, caused by the ascent of the colon (colon) cancer.
The experiment was conducted according to the following method. Segments of the colon length 4.5 cm vertically was suspendibility with preload of 2 g in 100 ml De Jolon (KCl 5.6 mmol; CaCl22H2O 0.54 mmol; NaHCO35.9 mmol; NaCl 154,1 mmol; glucose 2.8 mmol) at a temperature of 37.5oC and saturated with a gas mixture of 95% O2and 5% CO2. Reduction was measured as a result of isotopically using a control installation of the displacement sensor 7 HP DCDT-100, ISID.
After a stabilization period of about 20 minutes was given 3,410-6mol of methacholine with the time interval in 15 minutes if he was reproducible reduction in wash solution was administered the test compound. The effect of the compounds were investigated for 10 min and was expressed relative to the maximum concentration, caused by methacholine in the number of 3,410-6M effect for a representative number of compounds of the formula (I) shown in table. 4.
Compounds A, B, C, E and F described in EP-0076530 (corresponding to patent USSR N 1593569). Compound D is described in EP-A-0299566 (corresponding to the application for a patent of the USSR N 4356073/04).
D. Examples of songs
Example 28. Drops for oral administration.
After cooling to 30 - 40oC was added 35 l of polyethylene glycol and the mixture is mixed well. Then was added a solution of 1750 parts saccharin-sodium 2.5 l of purified water, and with stirring was added 2.5 liters of flavouring substances cocoa and the required amount of polyethylene glycol to a volume of 50 l, giving a solution of oral drops containing 10 mg/ml of active ingredient.
The resulting solution was filled into suitable containers.
Example 29. Solution for oral administration.
9 parts of methyl 4-hydroxybenzoate and 1 part of propyl 4-hydroxybenzoate was dissolved in 4 l of boiling purified water. In 3 l of this solution were dissolved first 10 parts of 2,3-dihydroxybutanedioate acid, and then 20 parts of the active ingredient.
This solution was combined with the remaining part of the first solution and was added to 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 40 parts saccharin-sodium was dissolved in 0.5 l of water, and was added 2 ml of raspberry and 2 ml of gooseberry family essences.
The latter solution was combined with the first, water was added in a necessary amount to a volume of 20 liters, giving oral solution containing 5 mg of active ingredient on a full teaspoon (5 ml).
20 parts of active ingredient, 6 parts of sodium lauryl, 56 parts of starch, 56 parts of lactose, 0.8 part of colloidal silicon dioxide and 1.2 parts of magnesium stearate was vigorously mixed together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules containing 20 mg of active ingredient each.
Example 31. Tablets, film-coated.
Obtain core tablets. A mixture of 100 parts of active ingredient, 570 parts of lactose and 200 parts of starch is mixed well and then moistened with a solution of 5 parts of sodium dodecyl sulfate and 10 parts of polyvinylpyrrolidone (Kollidon-K 90Rin about 200 ml of water.
A mixture of wet powder sifted, dried and sifted again. Then thereto was added 100 parts of microcrystalline cellulose (Avicel) and 15 parts hydrogenated vegetable oil (Stevotex). All well mingled and merged into tablets, giving 10,000 tablets containing 10 mg of active ingredient each.
The coating. To a solution of 10 parts of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol was added a solution of 5 parts of ethyl cellulose (Ethocel 22 eps) in 150 ml of dichloromethane. Then thereto was added 75 ml tx2">
The latter solution was added to the first, and then added 2.5 parts of octadecanoate magnesium, 5 parts of polyvinyl - pyrrolidone and 30 ml of concentrated suspensions (Opospray K-I-2109), and all were gomogenizirovannogo.
Core tablets were covered with the mixture in covering the device.
Example 32. Injectable solution.
of 1.8 parts of methyl 4-hydroxybenzoate and 0.2 parts of propyl 4-hydroxybenzoate was dissolved in about 0.5 l of boiling water for injection.
After cooling to about 50oC under stirring was added 4 parts of lactic acid, 0.05 parts of propylene glycol and 4 parts of active ingredient. The solution was cooled to room temperature and added water for injection in the required amount to 1 l, giving a solution containing 4 mg/ml of active ingredient.
The solution was sterilized by filtration (U. S. P XVII, page 811) and filled in sterile containers.
Example 33. Medical candles or suppositories.
3 parts of active ingredient was dissolved in a solution of 3 parts of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400. 12 parts of surfactant (SPAN) and triglycerides (Witepsol 555) required up to 300 parts of alicea so the mixture was poured into moulds at a temperature of 37 - 38oC for the formation of 100 suppositories containing 30 mg/ml of active ingredient each.
Example 34. Injectable solution.
60 parts of active ingredient and 12 parts of benzyl alcohol is mixed well, and added sesame oil in an amount necessary to bring the mixture up to 1 l, giving a solution containing 60 mg/ml of active ingredient.
The solution was sterilized and filled in sterile containers.
1. Derivatives of N-(3-hydroxy-4 - piperidinyl)-(dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic)-carboxamide of General formula I
in which a is a radical of formula (a - 1) -CH2-CH2-, formula (a - 2) -CH2-CH2-CH2or of the formula (a - 3) -CH2-CH2-O-, where one or two hydrogen atoms in the radical (a - 1) can be substituted C1- C4-alkyl radical,
R1- halogen;
R2- amino group;
R3is hydrogen or C1- C4-alkyl;
L - C3- C6-cycloalkyl, C3- C6alkenyl or a radical of formula (b - 1) -Alk-R5formula (b - 2) -Alk-X-R6formula (b - 3) -Alk-Y-C(=O)-R8or of the formula (b - 4) -Alk-Y-C(=O)-NR10R11where each Alk - C1- Chouse or Het, R6is hydrogen, C1- C6-alkyl, C3- C6-cycloalkyl, haloethanol, optionally substituted C1- C4-alkylcarboxylic, 3-cyano-2-pyridinyl, 2-methyl-5-pyridyl, 4-hydroxy-2-pyrimidinyl, 2-methyl-3-pyrazinyl or 3,4-dihydro-4-oxo-2-hintline, X is oxygen or NH, R8is hydrogen, C1- C6- alkyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethoxyphenyl, 2,6-dichlorophenyl or C1- C6-alkoxy -, Y -, - NR9or a simple link, where R9is hydrogen, C1- C4-alkyl or phenyl, R10and R11each independently - C1- C6-alkyl or taken together with the nitrogen atom to which they are attached, may form pyrrolidinyl ring, Het - the system is simple cyclic ether selected from the group consisting of
where R12is hydrogen or C1- C4-alkyl,
or Het is a heterocyclic system is selected from the group consisting of pyridinyl or benzimidazolyl, substituted C1- C6-alkyl, or Het is a monocyclic amide system selected from the group consisting of
where R14is hydrogen or C1- C6-alkyl;
R15- halogen, C1- CIDNA system, selected from the group consisting of
G3- -S-(CH2)2or-S-CH=CH-;
G4- -CH=CH-CH=CH-, -CH=CCl-CH=CH-, -CH=N-CH=CH - or-N=CH-N=CH-,
its salt or a stereochemical isomeric form.
2. Pharmaceutical composition for stimulating the activity of the gastro-intestinal motility, comprising the active principle and an inert carrier, characterized in that the active agent it contains derivatives of N-(3-hydroxy-4-piperidinyl)- (dihydrobenzofuran, dihydro-2H-benzopyran, dihydroergotoxine)-carboxamide of the formula I on p. 1 in an effective amount.
Amido - or urea - derivatives, or their pharmaceutical salts and the composition having inhibitory activity against acyl-coa:cholesterol acyltransferase // 2106340
Tuamarina b and method thereof (options) // 2101353
Esters cyclohexanehexol and herbicide tool // 2092484
The composition of the plasticizer for polyvinyl chloride compositions and method thereof // 2100356
The invention relates to compositions of plasticizers for polyvinyl chloride compositions that are used for the manufacture of penoplena, linoleum, footwear and sheet PVC, artificial leather, table cloths, etc
The method of obtaining 2-(furyl-2)-1,3-dioxolane (paralana) // 2076866
The invention relates to the field of chemistry of heterocyclic compounds and relates, in particular, to obtain 2-(furyl-2)-1,3-dioxolane, which is known as an intermediate reagent in thin organic synthesis and as a substance having biological activity
N-[((3,4-dichlorophenyl)-amino)-carbonyl]-2,3 - dihydrobenzofuran-5-sulfonamide or pharmaceutically acceptable salt, its production method and a composition having antitumor activity // 2072996
The invention relates to a new sulfobetaine intended for the treatment of cancer
Polycyclic biocidal compounds and pharmaceutical composition based on them // 2060249
The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents
Dihydrobenzofuran carboxamide or its pharmaceutically acceptable salts and method of production thereof // 2043991