Derivatives, piperidine derivatives, processes for their preparation and pharmaceutical drugs based on them

 

(57) Abstract:

The invention relates to a piperidine derivative of General formula (I) where Z represents the group -(CH2)m-CH(OR3) or a carbonyl group, R1is hydrogen or (C1- C3)alkyl, R2- (C1- C3)alkyl, or R1and R2together form a chain -(CH2)n, where n is the number of 3 - 5, or -(CH2)2-O-(CH2)2-, m = 0 - 1, n = 1 - 2, R3- hydrogen or-COCH3and R4- hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, h = 2, or their pharmaceutically acceptable salts. The compounds of formula (I) possess analgesic and local anesthetic effects, and can find application in medicine. 8 C. and 27 C.p. f-crystals, 6 PL.

The present invention relates to new compounds that have local anaesthetic and analgesic effect, method of their production and their use in the manufacture of pharmaceuticals.

Often used analgetikom is pethidine, but its local anaesthetic effect is weak. Anastrozole and analgesic effect of pethidine after spinal injection is often insufficient in both relations is the quiet serious flaws for example, the development of tolerance, addiction, the risk of respiratory depression. There is thus a need for tools that provide local anesthesia and residual analgesic effect with fewer side effects than the currently used combination. Such funds must be used during the operation of local anesthetics after spinal and epidural injection. In the connection well would be the weakening of postoperative pain.

Known (J. Med. Chem. 8, pages 847 - 851 (1965) Hardy D. G. et al) the dependence of activity on the structure of some analogues of pethidine, exhibiting analgesic activity. In the patent Sweden N 96 980 described 1-methyl-4-phenylpiperidine-4-carboxylic acid and its two amide, but also that these compounds can be used in the production of new medicines that are not revealed any specific pharmaceutical effect.

In WO SE 90/00 818 describes some substituted 4-phenylpiperidine-4-carboxamide effecting local anesthetic and analgesic actions.

The new compounds of the present invention, having the following formula (A):

< / BR>
where Z represents a group

< / BR>
vzaad or unbranched or branched alkyl group with 1-3 carbon atoms, and

R2represents an unbranched or branched alkyl group with 1-3 carbon atoms or

b) R1and R2together form a chain -(CH2)n-, where n represents 3, 4 or 5, or -(CH2)2O(CH2)2-;

m represents 0 to 1;

p represents 1 or 2;

R3represents hydrogen or-COCH3;

R4represents hydrogen, -CH3, -OH or-OCH3provided that when Z represents a carbonyl group, then p = 2, and pharmaceutically acceptable salts of compounds of formula (A).

R4may be in position 2, 3 or 4.

Preferred compounds of the present invention are those in which R4(in the benzene ring, associated with the group Z) is in position 2 and in which:

R4represents hydrogen, m = 0, R3represents hydrogen, p = 2 and R1and R2the same and are ethyl group; or

R4represents hydrogen, m = 0, R3represents hydrogen, p = 2, R1represents a methyl group and R2represents ethyl group; or

R4represents hydrogen, m = 0, R3represents hydrogen, p = 2 and R1and R2together form a chain(Chastellet methyl group and R2is ISO-propyl group; or

R4represents a methoxy group, m = 0, R3represents hydrogen, p = 2, R1represents a methyl group and R2represents ethyl group; or

R4represents a methyl group, m = 0, R3represents hydrogen, p = 2, R1represents a methyl group and R2represents ethyl group; or

R4represents hydrogen, m = 0, R3represents hydrogen, p = 1 and R1and R2the same and are ethyl group.

Preferred salts of the present invention are pharmaceutically acceptable salts. Especially preferred hydrochloride.

Other examples of salts that can be used are citrate, methanesulfonate and maleate.

Compounds of the present invention is more suitable for the treatment of pain, because they are less toxic and more effective as a local anesthetic agents and analgesics. The compounds of formula A and their pharmaceutically acceptable salts can give surprisingly good effect as spinal and epidural anesthetics, but additional analgesic effect, which lasts for a long time after discontinued in order to avoid risks, associated with the use of such combinations. Connections also give unexpectedly higher effect than known compounds of this combined procedure.

The most preferred compounds of the present invention, known at the present time, are compounds according to example 13 and example 6A, i.e. the compounds of formula XIII and the compounds of formula VI where:

R4represents H, R1and R2are both-C2H5;

R4represents H, R1represents-CH3and R2represents-C2H5;

R4is H and R1+R2represents -(CH2)4;

R4represents H, R1represents-CH3and R2is isopropyl;

R4is 2-OCH3, R1represents-CH3and R2represents-C2H5;

R4is 2-CH3, R1represents-CH3and R2represents-C2H5.

Getting

To obtain the substituted piperidine-4-carboxamido formula (A) according to the present invention compounds can be divided into six groups, which were obtained according to schemes 1 to 5.

Lane is the Rupp, 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamide (VI), obtained according to the following reaction scheme:

Circuit 1

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1and R2such as indicated above.

Aminoketone 1 was obtained by performing the reaction of manniche, i.e. the interaction of 4-phenylpiperidine-4-carbonitrile with formaldehyde and acetophenone. Carbonyl group of compound I was reduced by sodium borohydride to obtain a secondary alcohol II. Hydrolysis of ceanography in alkaline medium gave the amino acid III. Hydroxyl group azetilirovanie and carboxylic acid IV were converted into suitable amide V by carboxylic acid. Selective alkaline hydrolysis of the ester group of compounds V gave the corresponding secondary alcohols VI.

Enantiomerically pure forms of compounds VI, where R1represents-CH3and R2represents-C2H5or R1and R2the same and represent-C2H5received according to the following reaction scheme:

Scheme 2

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
4-Phenylpiperidine-4-carbonitrile was Basilashvili with getting aminonitriles VII, which is hydrolyzed in an alkaline medium in the amino acid VIII. Acid mainly palladium catalyst gave the secondary amine X, which alkilirovanie or (R) - or (S)-3-chloro-1-phenyl-1 - propanol with the receipt of two enantiomeric pairs VI, where R1represents-CH3and R2represents-C2H5or R1and R2the same and represent-C2H5.

Aromaticheski substituted piperidine-4-carboxamide, in which R1represents-CH3, R2represents-C2H5and R4represents - CH3, -OH or-OCH3constitute (together with compound XI, in which R1and R2the same and represent-C2H5and R4represents hydrogen) third (ketones XI) and fourth (alcohols (VI) the group of new compounds. They were received by the following reaction scheme:

Scheme 3

< / BR>
< / BR>
< / BR>
The reaction manniche between the secondary amine X, where R1represents-CH3and R2represents-C2H5or R1and R2the same and represent-C2H5, formaldehyde and a suitable benzophenone (R4represents hydrogen, -CH3or-OCH3) gave the ketone XI. Carbonyl group aromaticheski substituted ketones XI (R4represents-CH3, -OCH3or-OH) was reduced by sodium borohydride to obtain the alcohol VI. The connection is I tribromide boron.

Diethylamide (XIII) 1-(2-hydroxy-2-phenylethyl)-4-phenylpiperidine-4-carboxylic acid (fifth type of new compounds) was obtained according to the following reaction scheme:

Scheme 4

< / BR>
< / BR>
< / BR>
Secondary amine X, where R1and R2the same and represent-C2H5, alkilirovanie penacerrada obtaining ketone XII, which was reduced by sodium borohydride to the secondary alcohol XIII.

The sixth group of compounds, 1-(2-hydroxy-3-phenylpropyl)- 4-phenylpiperidine-4-carboxamide (XVIII) was obtained according to the following scheme:

Scheme 5

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where R1and R2such as indicated above.

4-Phenylpiperidine-4-carbonitrile alkilirovanie (2,3-epoxypropyl) benzene to obtain a secondary alcohol XIV. Compounds XV, XVI, XVII and XVIII were obtained as described for compounds III, IV, V and VI, respectively.

In the following examples detail the formation of compounds (indicated by the same Roman numerals) according to the present invention.

EXAMPLE 1

Obtain 1-(3-oxo-3-phenylpropyl)-4-phenylpiperidine-4 - carbonitrile

(Compound I)

A mixture of 4-phenylpiperidine-4-carbonitrided (41.6 g, 187 mmol), formaldehyde (8.4 g, 280 mmol), acetophenazine 48 PM After cooling was collected by filtration of precipitated in the sludge material, resulting in a received 40.0 g of the hydrochloride with so pl. 207 - 210oC.

EXAMPLE 2

Obtain 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carbonitrile

(Compound II)

Ketone 1 (48.2 r, 136 mmol) and sodium borohydride (20.0 g, 526 mmol), suspended in methanol (500 ml) was heated at 50oC for 15 hours the solvent evaporated and was slowly added 2 N. chlorodrol acid (150 ml). Then the solution was podslushivaet 5 N. sodium hydroxide and was extracted with three portions of chloroform (3 x 100 ml). The combined extracts were dried over potassium carbonate, filtered and the solvent evaporated. Yield 41.0 g so pl. 109 - 112oC.

EXAMPLE 3

Obtain 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxylic acid

(Compound III)

A solution of the nitrile II (20.3 g, 63 mmol) and potassium hydroxide (17.5 g, 313 mmol) in ethanol (50 ml) and water (80 ml) was heated in an autoclave at 140oC for 6 hours After cooling, the solution was evaporated to one-third of its original volume and then acidified chlorotalonil acid to pH 2. The precipitate was filtered. Got 22.0 g of the hydrochloride with so pl. 280oC.

EXAMPLE 4

Render III (11.3 g, 30 mmol), acetic anhydride (200 ml) and 4-dimethylaminopyridine (0.3 g) was heated at 50oC for 15 hours the solvent evaporated and the residue was thoroughly dried at 80oC in a vacuum Cabinet and then recrystallized from dioxane. Received 10.2 g of the hydrochloride with so pl. 189 - 193oC.

EXAMPLE 5

Obtain 1-(3-acetoxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamido

(Compound V)

To a suspension piperidinecarboxylic acid IV (5.0 g, 12 mmol) in dichloromethane (100 ml) was added dropwise with stirring oxalicacid (6 ml). The reaction mixture was stirred at 50oC for 2 h the solvent evaporated, add a few milliliters of toluene and again evaporated solvent. The residue was dissolved in dichloromethane (50 ml) and the resulting solution was added dropwise with stirring to a solution of the appropriate amine (36 ml) in dichloromethane (20 ml), cooled in ice water. The reaction mixture was stirred at room temperature for 4 hours the solvent evaporated and the residue was which between dilute sodium hydroxide (20 ml) and dichloromethane (3 x 20 ml). The organic extract was dried over potassium carbonate, filtered and evaporated to dryness. Adding florodora in diethyl ether to the air is storytale (table 1).

EXAMPLE 6A

Obtain 1-(3-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamido

(Compound VI)

A suspension of ester V (12 mmol) in 2 BC, the sodium hydroxide (60 ml) and ethanol (40 ml) was heated at 70oC for 3 hours the Solution was evaporated to half of its original volume and then was extracted with three portions of diethyl ether (3 x 50 ml). The ether extract is dried over potassium carbonate, filtered and obtained the hydrochloride as described in example 5. The obtained compound was purified by recrystallization from a specified solvent (table 1).

EXAMPLE 7

Obtain 1-benzyl-4-phenylpiperidine-4-carbonitrile

(Compound VII)

A mixture of 4-phenylpiperidine-4-carbonitrile (41.4 g, 223 mmol), benzylbromide (41.9 g, 245 mmol) and sodium carbonate (29.7 g, 281 mmol) in 1-butanol (300 ml) was stirred at room temperature for 12 h the solvent evaporated and added 1 n sodium hydroxide (100 ml). The aqueous phase was extracted three times with dichloromethane (3 x 150 ml). The combined extracts were dried over potassium carbonate, filtered and evaporated to dryness. The output amounted to 59.0 g connection so pl. 76 - 79oC.

EXAMPLE 8

Obtain 1-benzyl-4-phenylpiperidine-4-carboxylic acid

(Seegenerally one-third of its original volume and neutralized chlorotalonil acid. Precipitated precipitated material was collected by filtration, resulting in 18.6 g of amino acids so pl. 288 - 290oC.

EXAMPLE 9

Obtain 1-benzyl-4-phenylpiperidine-4-carboxamido

(Compound IX)

Carboxylic acid VIII transformed into a suitable amide as described for compounds V. Amide with R1that represents-CH3and R2representing-C2H5was allocated in the form of a free base and recrystallized from ethyl acetate, receiving the output 62%, so pl. 108 - 112oC. Amide, in which R1and R2the same and represent-C2H5was allocated in the form of the hydrochloride and recrystallized from a mixture of acetonitrile and ethyl acetate. The output is 54%, so pl. 204 - 206oC.

EXAMPLE 10

Getting 4-phenylpiperidine-4-carboxamido

(Compound X)

A solution of a suitable tertiary amine IX (13 mmol, obtained from the hydrochloride in the usual way) in methanol (200 ml) was first made at atmospheric pressure in the presence of 5% palladium on charcoal (100 mg) until spent the calculated amount of hydrogen. The catalyst was filtered and the solvent evaporated. Received as described in example 5, hydrochloride and recrystallized their SUB> with the release of 94%, so pl. 214 - 217oC, and amide, in which R1and R2the same and represent-C2H5with the release of 91%, so pl. 238 - 240oC.

EXAMPLE 6B

Obtaining optically active 1-(3-hydroxy-3-phenylpropyl)-4 - phenylpiperidine-4-carboxamido

(Compound VI, where R1represents-CH3and R2represents-C2H5or R1and R2the same and represent-C2H5)

A mixture of the appropriate amine X (4.0 mmol, obtained from the hydrochloride in the usual way), (R)-3-chloro-1-phenyl-1-propanol (0.70 g, 4.12 mmol; obtained by H. C. Brown et al in J. Org. Chem. 53 p. 2916 - 2920 (1988)) or (S)-enantiomer (industrial production), sodium carbonate (0.46 g, 4.3 mmol) and potassium iodide (50 mg) in 1-butanol (20 ml) was heated under reflux for 30 hours the solvent evaporated and added 0.5 n sodium hydroxide (10 ml). The aqueous phase was extracted three times with diethyl ether (3 x 20 ml). The combined extracts were dried over potassium carbonate and filtered. Besieged hydrochloride as described in example 5. The salt was recrystallized from this solvent (table 1). The following are the values of specific rotation of [ []2D0(=mg/ml)], obtained in absolute ethanol:

RSUB>; +20.4 (2.8); -21.8 (2.8).

EXAMPLE 11A

Obtain 1-(3-oxo-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamido

(Compound XI)

The reaction of manniche carried out as described in example 1, between the amine X with R1that represents-CH3and R2representing-C2H5or R1and R2the same and represent-C2H5, formaldehyde and the appropriate acetophenone with R4that represents hydrogen, 2-OCH3, 3-OCH3, 4-OCH3or 2-CH3gave the corresponding ketones XI. Compounds XI, where R1and R2the same and represent - C2H5and R4represents hydrogen, recrystallized from acetonitrile. Yield 70%, so pl. 189 - 192oC. Aromaticheski substituted ketones XI recrystallized from this solvent and had a melting temperature, are shown in table 2.

EXAMPLE 11B

Getting ethylmethylamine 1-[3-(2-hydroxyphenyl)-3-oxopropyl] - 4-phenylpiperidine-4-carboxylic acid

(Compound XI, where R1represents-CH3, R2represents-C2H5and R4is 2-OH)

It chilled in ice water to a solution of compound XI, where R4is 2-OCH3, (1.3 g, 2.9 mmol is whether at room temperature for 24 hours The dichloromethane solution which was diluted with ammonia and the organic phase was separated and dried over sodium sulfate. The solvent evaporated and the residual base was converted into the hydrochloride as described in example 5 (table 2). The yield was 1.0 g

EXAMPLE 6C

Getting aromaticheski substituted ethylmethylamino 1-(3 - hydroxy-3-phenylpropyl)-4-phenylpiperidine-4-carboxylic acid

(Compound VI)

Ketones XI (1 mmol) in which R4is 2-OCH3, 3-OCH3, 4-OCH3, 2-CH3or 2-OH, and sodium borohydride (6 mmol) suspended in tetrahydrofuran and stirred at room temperature for 48 hours the Product was isolated as described in example 2 and obtained the hydrochloride as described in example 5. Solvents for recrystallization and melting point are shown in table 2.

EXAMPLE 12

Getting diethylamide 1-(2-oxo-2-phenylethyl)-4-phenylpiperidine - 4-carboxylic acid

(Compound XII)

The mixture of secondary amine X (1.0 g, 3.8 mmol) in which R1and R2the same and represent-C2H5, pencilvania (0.81 g, 4.1 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in 1-butanol was stirred at room temperature for 5 days. The product was isolated is lonitrile and dioxane gave 0.8 g of the product with so pl. 209 - 212oC.

EXAMPLE 13

Getting diethylamide 1-(2-hydroxy-2-phenylethyl)-4-phenylpiperidine - 4-carboxylic acid

(Compound XIII)

A mixture of the ketone XII (0.5 g, 1.2 mmol, converted into the free amine as usual) and sodium borohydride (0.3 g, 7.9 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature for 4 days. The product was isolated as in example 2. Hydrochloride besieged as described in example 5 and the product was recrystallized twice from a mixture of acetonitrile and ethyl acetate. Yield 0.2 g, so pl. 203 - 205oC.

EXAMPLE 14

Obtain 1-(2-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carbonitrile

(Compound XIV)

A mixture of 4-phenylpiperidine-4-carbonitrile (6.3 g, 34 mmol) and 2,3-epoxypropyl) benzene (5.0 g, 37 mmol) in dioxane was heated under reflux for seven days. The solvent evaporated and the residue was which between dilute sodium hydroxide and diethyl ether. The ether extract is dried over potassium carbonate, filtered and the product was converted into the hydrochloride as described in example 5. Recrystallization from a mixture of ethanol and acetonitrile gave 10.0 g of the product with so pl. 246 - 249oC.

EXAMPLE 15

Obtain 1-(2-hydroxy-3-phenylpropyl)-4-fave so, as described in example 8. Got 9.5 g of amino acids so pl. 288 - 290oC.

EXAMPLE 16

Obtain 1-(2-acetoxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxylic acid

(Compound XVI)

Secondary alcohol XV (2.0 g, 5.9 mmol) was azetilirovanie as described in example 4. Recrystallization from dioxane gave 2.0 g of amino acids so pl. 179 - 182oC.

EXAMPLE 17

Obtain 1-(2-acetoxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamido

(Compound XVII)

Carboxylic acid XVI was transformed into suitable amides as described for compounds V. Hydrochloride recrystallized from ethyl acetate. Got amide, in which R1represents-CH3and R2represents-C2H5with the release of 83%, so pl. 185 - 187oC, and amide, in which R1and R2the same and represent - C2H5with a yield of 75%, so pl. 164 - 167oC.

EXAMPLE 18

Obtain 1-(2-hydroxy-3-phenylpropyl)-4-phenylpiperidine-4 - carboxamido

(Compound XVIII)

Esters XVII hydrolyzed as described in example 6A. Hydrochloride recrystallized from a mixture of acetonitrile and ethyl acetate. Received connection XVIII, where R1represents-CH3and R2predstavi and represent-C2H5with the release of 55%, so pl. 166 - 169oC.

PHARMACEUTICAL

For the manufacture of pharmaceutical products is one of the new compounds dissolved in a liquid carrier suitable for injection, for example, in physiological solution. Drugs used are aqueous solutions containing 0.1 - 100 mg/ml, preferably 3 to 20 mg/ml of active compound per hydrochloric salt.

BIOLOGICAL STUDIES

Spinal anesthesia

Compounds of the present invention was tested for spinal anesthesia mouse. Each group contained six animals. As connections were used for comparison pethidine.

Measured average duration (minutes) of motor blockade and complete analgesia (twitching tail) in mice after vnutriobolochechnoe (spinal, spinal) injection of 5 Ál of the test solution. The duration of action considered from the moment of injection.

Conclusion

Because local anesthetic effect usually observed in combination with an analgesic effect, the compounds of the present invention can be more useful than pethidine. There is also the option to replace the of Avani presented in tables 1 - 6.

1. Derivatives of piperidine of the formula AND

< / BR>
where Z represents a group

< / BR>
taken in a direction from left to right in the formula A,

or carbonyl group,

where (a) R1represents hydrogen or an unbranched or branched alkyl group with 1 to 3 carbon atoms,

R2represents an unbranched or branched alkyl group with 1 to 3 carbon atoms; or

b) R1and R2together form a chain - (CH2)n-, where n represents 3, 4 or 5, or -(CH2)2O(CH2)2-;

m represents 0 to 1;

p represents 1 or 2;

R3represents hydrogen or-PINES3;

R4represents hydrogen, -CH2HE or-och3provided that when Z represents a carbonyl group, R = 2, and their pharmaceutically acceptable salts.

2. Connection on p. 1, where Z is

< / BR>
where R3is

< / BR>
R4represents hydrogen;

m = 0, p = 2,

R1and R2such as specified in paragraph 1.

3. Connection on p. 1, where Z is

< / BR>
R3represents hydrogen,

R4represents hydrogen;

m = 0, p = 2;

R1and R2such as the UB>4
such as specified in paragraph 1.

5. Connection on p. 1, where Z is

< / BR>
where R3represents hydrogen;

m = 0, p = 2;

R1, R2and R4such as specified in paragraph 1.

6. Connection on p. 1, where Z is

< / BR>
where R3represents hydrogen;

R4represents hydrogen;

m = 1, p = 1;

R1and R2such as specified in paragraph 1.

7. Connection on p. 1, where R4is in position 2.

8. Connection on p. 3, where R1and R2are each ethyl group.

9. Connection on p. 3, where R1represents a methyl group and R2represents ethyl group.

10. Connection on p. 3, where R1and R2together form a chain -(CH2)4-.

11. Connection on p. 3, where R1represents a methyl group and R2represents the isopropyl group.

12. Connection PP. 1 and 7, where R1represents a methyl group, R2represents ethyl group, R3is hydrogen, R4represents a methoxy group, m = 0 and p = 2.

13. Connection PP. 1 and 7, where R1represents a methyl group, R2represents ethyl group is on p. 1, where R1and R2are each ethyl group, R3is hydrogen, R4represents hydrogen, m = 0 and R = 1.

15. Connection on p. 3, which represents the (R)-form, where R1represents a methyl group and R2represents ethyl group.

16. Connection on p. 3 represents (R)-form, where R1and R2are each ethyl group.

17. Connection on p. 3 represents (S)-form, where R1represents a methyl group and R2represents ethyl group.

18. Connection on p. 3 represents (S)-form, where R1and R2are each ethyl group.

19. Connection on p. 1 where the pharmaceutically acceptable salt is a hydrochloride.

20. Connection on p. 2, where it is in the form of its hydrochloride.

21. Connection on p. 3 is in the form of its hydrochloride.

22. Connection on p. 1 used in therapy to regulate nerve blockade.

23. Pharmaceutical drug with analgesic and local Anastasiya activity containing compound under item 1 or its pharmaceutically acceptable salt as an active component is on the number of active component is in the range of 0.1 to 100 mg/ml, preferably 3 to 20 mg/ml

25. Pharmaceutical drug for p. 23 used to block nerve by injection epidurally or intrathecally (inside membranes of the spinal cord).

26. Pharmaceutical drug for p. 23 with analgesic and local anesthetic effect.

27. Pharmaceutical drug for p. 23 with analgesic effect.

28. Derivatives of piperidine of General formula 1, used to produce a pharmaceutical composition with analgesic and local anesthetic effects.

29. Derivatives of piperidine under item 28 is used to produce a pharmaceutical composition with analgesic effect.

30. The method of treatment of a subject suffering from pain, characterized in that the specified subject is administered an effective amount of the compounds under item 1.

31. The method of obtaining the compounds of formula (A) under item 1 and its pharmaceutically acceptable salts, characterized in that conduct the interaction of 4-phenylpiperidine-4-carbonitrile with formaldehyde and acetophenone with getting aminoketone formula I

< / BR>
(reaction manniche), after which the carbonyl group of compound I may be restored with sodium borohydride to obtain voiceprofile group of compound III will acetimidoyl with the receipt of ester IV

< / BR>
and carboxyl group of compound IV is converted into suitable amide V

< / BR>
the acid chloride of the acid, after which selective alkaline hydrolysis of the ester group of compounds V get a connection VI,

< / BR>
the corresponding compound of formula (A), where R4is hydrogen, Z is R = 2 and R1and R2such as indicated in n.1, and the compound obtained is converted into its pharmaceutically acceptable salt.

32. The method of obtaining the compounds of formula (A) under item 1 and its pharmaceutically acceptable salts, characterized in that benzylium 4-phenylpiperidine-4-carbonitrile with getting aminonitriles VII

< / BR>
which is hydrolized in an alkaline medium in the amino acid VIII

< / BR>
after which the compound VIII is converted into suitable amide IX

< / BR>
by carboxylic acid and carry out the hydrogenolysis of benzylamine in the presence of palladium catalyst to obtain secondary amines X

< / BR>
which alkylate (R)- or (S)-3-chloro-1-phenyl-1-propanol with the receipt of two enantiomeric pairs of compounds VI and the compound obtained is converted into its pharmaceutically acceptable salt.

33. The method of obtaining the compounds of formula (A) under item 1 and it is idigicon and appropriate benzophenone with getting

< / BR>
then the carbonyl group of compound XI may be restored with sodium borohydride to obtain the compounds of formula VI and the compound obtained is converted into its pharmaceutically acceptable salt.

34. The method of obtaining the compounds of formula (A) under item 1 and its pharmaceutically acceptable salts, characterized in that the secondary amine X alkylate penacerrada obtaining ketone XII,

< / BR>
then restore with sodium borohydride to obtain a secondary alcohol XIII

which is a compound corresponding to the formula (A), where R4represents hydrogen, p = 1, and Z represents R1and R2represent each2H5and the compound obtained is converted into its pharmaceutically acceptable salt.

35. The method of obtaining the compounds of formula (A) under item 1 and its pharmaceutically acceptable salts, characterized in that 4-phenylpiperidine-4-carbonitrile alkylate (2,3-epoxypropyl)benzene to obtain a secondary alcohol XIV

< / BR>
then compound XIV is converted into the compound XVIII

< / BR>
which is a compound corresponding to the formula (A), where R4represents hydrogen, Z represents R = 1 and R1and R2such as decree

 

Same patents:

The invention relates to new biologically active compound from the series of heterocyclic compound of the formula I, showing the property activator germination of wheat seeds

The invention relates to new heterocyclic compounds having therapeutic activity, to processes for their preparation and intermediate compounds used for their production, to pharmaceutical preparations containing these compounds and to the use of these compounds in medicine

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of N-substituted azabicycloalkanes

The invention relates to 4-aryloxy - or 4-aaltio-piperidinyl derivative of the formula (I):

< / BR>
where

R1and R2each, independently of one another, signify unsubstituted or one - or twofold substituted with A, OH, OA, aryloxy with 6-10 C atoms, aralkylated with 7-11 C atoms, -O-(CH2)n-O-, Gal, CF3, NO2, NH2, NHA, NA2, NHAc, NAAc, NHSO2A and/or NASO2A phenyl residues;

X denotes O, S, SO or SO2;

"m" denotes 1, 2 or 3;

"n" represents 1 or 2;

A stands for an alkyl residue with 1-6 C-atoms;

Gal denotes F, Cl, Br or iodine;

and Ac denotes alkanoyl with 1-8 C-atoms, arkanoid with 1-10 C-atoms or aroyl with 7-11 C atoms, and their physiologically acceptable salts

The invention relates to new aryl-substituted derivatives of piperidine, which has antagonistic activity to the receptor NK3person, to a method for their production and to their use in pharmaceutical compositions

The invention relates to a new series of 4-phenylpiperazine, 4-phenylpiperidines and 4-phenyl-1,2,3,6-tetrahydropyridine

The invention relates to 4-amino-1-piperidinecarbonitrile formula (I):

< / BR>
where R1and R2each independently of one another denote H, A, Ph, Ph-ALK, CO-A, CO-Het, or known of the chemistry of protective peptides for amino group;

R1and R2together also denote alkylene with 4-5 C atoms, and one or two CH2- groups may be replaced by-O-, -S-, -CO-, -NH-, -NA - and/or N-CH2-Ph and, if necessary, the benzene ring may be precondensation so that the formed dihydroindole, tetrahydropyrimidines, tetrahydroisoquinolinium or dehydrobenzperidol the rest;

R3and R4each independently of one another denote H, A, Gal, -X-R5, CN, NO2, CF3CH2-CF3, SOn-R7or SO2-NR5R6;

R5denotes H, A, CF3CH2-CF3Ph, Ph-alk, C5-C7- cycloalkyl or C5-C7-cycloalkyl-alk;

R6denotes H or A, or

R5and R6together also denote alkylene with 4-5 C atoms, and one CH2group can be replaced by-O-, -S-, -NH-or-N-CH2-Ph;

R7denotes A or Romani;

Gal denotes F, Cl, Br or I;

Ph denotes unsubstituted or one-or two-, or three times substituted by A, OA, Gal, CF3, NH2, NHA or NA2phenyl;

Het denotes a saturated or unsaturated five - or six-membered heterocyclic residue with 1 to 4 atoms of nitrogen, oxygen and/or sulfur; and

"n" represents 1 or 2;

and their physiologically acceptable salts

The invention relates to applicable in medicine new derived aminotriazole or its hydrate and its pharmaceutically acceptable salts
Up!