The method of obtaining derivatives benzhydrylpiperazine

 

(57) Abstract:

The inventive product is derived benzhydrylpiperazine f-ly 1, where R1-H, Hal, lower alkyl, lower alkoxy, trifluoromethyl; R2-H, Hal; R3-H, Hal, CF3; n is an integer from 2 to 6, R4and R5- one N other benzoyl, substituted NO2or CH3O or R4and R5together with the nitrogen atom to which they are attached, heterocyclic group, such as Succinimidyl, 4-phenylsuccinic, 2 - oxopentanenitrile, 3 - benzyl-2 - oxopentanenitrile,1,2,3,4 - tetrahydro-2,4 - diorskin - Azzolini,3,4-dihydro-4 - oxothiazolidine,3,4 - dihydro-4-oxo-2-metilfentanil, 3,7-dihydro-1,3-dimethyl - 2,6-dioxo-1H-purinol, 3,7-dihydro-3,7-dimethyl-2,6-dioxo-1H-purinol. Reagent 1: Amin f-crystals X-(CH2)n-NR4R5where x-Ha1, tosyl. Reagent 2: benzhydrylpiperazine. Reaction conditions: excess reagent specified amine, aprotic solvent. The compounds possess anti-histamine activity without side sedative action. Connection structure of f-crystals 1 2 tab.

The invention concerns a method of obtaining new derived benzhydrylamine-piperazine, which can find application in medicine.

Known production, lcil, alkoxy or halogen, Rllrepresents hydrogen or alkyl, the group NRll" Rll' means substituted group dialkylamino, alkylamino, pyrrolidino, piperidino, morpholino or piperazine derivatives. These compounds act on the Central nervous system and, in particular, have a sedative effect. [Cm. the following documents: -BURGER, MEDICINAL CHMISTRY 4th edition, volume III, Manfred WOLFF, pages 559-564 WIL EYN.Y. Eds I. M. MELON and A. BuZAS Fr 74.23.262 and Fr 76.13.592-GOOTIES I. and E. Coll R. 0.099.148]

The purpose of the invention to develop new compounds that have anti-histamine activity, identical to or exceeding antihistaminics activity called derivatives, but do not have a sedative action.

This goal is achieved by the proposed method of obtaining derivatives benzhydrylamine-piperazine of General formula I

< / BR>
where R1hydrogen, halogen, lower alkyl, lower alkoxy or cryptomaterial;

R2hydrogen or halogen;

R3hydrogen, halogen or cryptomaterial;

n is an integer between 2 and 6 inclusive;

R4and R5represent one of a hydrogen atom and the other group of benzoyl, substituted nitro or methoxy, or R4and R5form together with the nitrogen atom to which they are Holy the sludge, 3-benzyl-2-oxopentanenitrile, 1,2,3,4-tetrahydro-2,4-dioxopiperazinyl, 3,4-dihydro-4-oxothiazolidine, 3,4-dihydro-4-oxo-2-metilfentanil, 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purinol, 3,7-dihydro-3,7-dimethyl-2,6-dioxo-1H-PU - rinil, characterized in that the compound of General formula II

X-(CH2)n-N where n, R4and R5have certain values and X represents the group of halogen or Totila, is subjected to the interaction with the excess benzhydrylamine-piperazine of General formula III

-(CH2)2-NNH where R1-R3have the values given in inert aprotic solvent, such as toluene, and, if necessary, the obtained target product is converted into the acid additive salt.

Acid additive salts of the compounds according to the invention receive a classical way by interacting with pharmaceutically acceptable acids, such as, for example, acetic acid, hydrochloric acid, corporationa acid, methansulfonate.

Compounds according to the invention have valuable pharmacological properties, in particular, antihistaminics and antispasmodic properties and can be used in particular for the treatment of spasmodic States and al the magnetic resonance and infrared spectrum, as well as their elemental analysis.

P R I m e R 1. 1-[2-(Benzhydryl)ethyl]-4-[2-(phthalimido)ethyl]piperazinediones-lifenet (formula I, R1=R2=R3=H;

NR4R5= - n=2;)

Charged to the reactor and 15.3 g of bromoethylamine, 36 g benzhydrylamine-piperazine, 500 mg of potassium iodide in 250 ml of anhydrous toluene. The reaction mixture is heated for 6 h to 120aboutC. Absorb the residue 100 ml of water, extracted with 100 ml of toluene. Dried and evaporated solvents. This way obtain 27 g of oil which crystallized from ethanol. Solid dehydrate and get to 25.5 g of crystals (So pl. 101aboutC).

To those of 25.5 g of the obtained solid substance dissolved in 100 ml of acetone, added to 10.5 g methansulfonate. Dehydrate and get that through 34 g dimethanesulfonate (So pl. 124aboutC) empirical formula:

WITH29H31N3ABOUT3, 2(CH4ABOUT3S)

Calculated With 59,26; N 5,94; N 6.35mm; S RS 9.69.

Found, 59,24; N. Of 5.99; N 6,36; S 9,79.

An NMR spectrum (base in solution in CDCL3, ethanol TM):

of 7.6 ppm (m) 4H, (phthalimido); and 7.1 ppm (m, 10H, (f2C);

at 5.3 ppm (S, 1H, (CH-0); and 3.8 ppm (t), 2H (CH2-N-C=0);

the 3.5 ppm (t, 2H, (CH2-0); 2,5 ppm (m), N, (CH(SO2); 1070 cm-1(SO2).

P R I m m e R 2. 1-[2-(Benzhydryl)ethyl]-4-[2-(hydroxy-benzamido)ethyl]-piperazine-dimethanol ONAT (formula 1, R1=R2=R3=H; n=2;

NR4R5= -NH

The reactor is placed to 8.4 g of N-(2-bromo-ethyl)-3,4-dihydro-2,4-dioxo-2H-1,3-benzo - Kazyna (0,0311 mol), 18,4 benzhydrylpiperazine In (0,0622 mol) and 250 mg of potassium iodide in 150 ml of toluene. The reaction mixture is heated for 6 h at 120aboutAnd hydrolyzing the residue 100 ml of water, decanted and again the aqueous phase is extracted with 50 ml of toluene. Dried toluene fractions are combined and the solvent is evaporated. Thereby obtaining 16 g of crude oil, which is purified by chromatography on a column of silica gel. The pure product is isolated and receive of 6.65 g of the target product. To those of 6.65 g of oil dissolved in acetone (50 ml) was added 2,3 equivalent methansulfonate. The crystals are sucked off and thus receive 7,8 g dimethanesulfonate gross formula

WITH28H33N3O32CH3SO3H.

An NMR spectrum (solvent Dl3; ethanol TMS)

2,2 2,9 (m), N, CH2N; 3,4 (t), 2H,O-CH2; 3.6(t), 2H, CH2-N-SN; 5,2(S), 1H, CH 0; 6,5 8,1(m), 14N, arene. 7,6 (m), 1H, NH; and 9.2 (m, 1H, HE.

Acting on enaleni below.

5 2.1 2.7 (m), N, CH2-N; 3.4 (t, 2H, CH2-ON;

3.5 (s, 3H, CH3-O; 3.6 (t, 2H, CH2-N - C=O;

5.1 (s, 1H, CH-O; 6.7 (m, 4H, arom;

7.0 (s), 5H, arene; 7.1-7.8 (m, 4H, arene.

8 2.3-2.7 (m, 12H, CH2-N; 3.5 (t, 2H, O-CH2;

3.7 (t, 2H, CH2-N-C=0; 5.2 (s, 1H, CH-O;

7.0-7.4 (m, 4H, arene; 3.0-7.6 (m, 4H, CH2-N-C=0.

14 2.2-2.7 (m, 12H, CH2-N; 3.5 (t, 2H, O-CH2;

3.7 (t, 2H, CH2-N-C=O; 5.3 (s, 1H, CH-O;

6.9-7.8 (m, 12H, arene.

16 1.4-1.9 (m, 4H, C-CH2-CH2-C;

2.1-2.7 (m, 12H, CH2-N; 3.5 (t, 2H, CH2-O.

3.6 (t) 2H, CH2-N-C=O; 5.2 (s, 1H, CH-O;

7.1 (m, 10H, arene. 7.3-7.6 (m, 4H, arene.

17 1.0-1.9 (m, 6H, C(CH2)3-C; 2.0-2.8 (m, 12H, CH2N;

3.4 (t, 2H, CH2-O; 3.5 (t, 2H, CH2-N - C=O;

5.1 (s, 1H, CH-O; 7.0 (s), 10H, arene;

7.2 and 7.6 (m) 4H, arene.

18 1.1-1.8 (m, 8H, C-(CH2)4 C; 1.9-2.7 (m, 12H, CH2-N

3.4(t); 2H, CH2-O; 3.5 (t, 2H, CH2-N - C=O;

5.1 (s, 1H, CH-O; 7.0 (s) 10H, arene;

7.2-7.6 (m, 4H, arene.

24 2.2-2.8 (m, 12H, CH2-N; 3.4 (t, 2H, CH2-O

3.9(t), CH2-N-C; 5.2 (s, 1H, CH-O; 6.9 (s), 10H, arene;

6.8-8.0 (m, 5H, arene.

25 2.2-2.6 (m, 12H, CH2-N; 2.4 (s, 3H, CH3;

3.4 (t, 2H, O-CH2;

3.9 (t, 2H, CH2-N-C;

5.1 (s, 1H, CH-O; 7.0 (s), 10H, arene;

6.8-8.0 (m, 4H, arene.

27 2.1-2.7(m, 12H, CH2-N; 3.4(t, 2H, CH2-O2.7(m), 12H, CH2N;

3.4(t, 2H, CH2-O; 3.8(t, 2H, CH2-N-C;

5.1(s, 1H, CH-O;

6.6-7.2(m, 15H, arene, NH.

30 2.3-3.0(m, 12H, N-CH2; 3.2(s, 3H, N-CH3;

3.3(t, 2H, CH2-O; 3.4(s, 3H, N-CH3;

4.2(t, 2H, CH2-N; 5.2(s, 1H, CH-O;

7.0(s), 10H, arene; 7.3(s, 1H, CH=n

31 1.2-1.9(m, 4H, C-(CH2)2-C; 2.0-2.4(t, 2H, CH2N;

3.2(s, 3H, CH3-N; 3.3(t, 2H, CH2-O;

5.1(s, 1H, CH-O; 7.1(s), 10H, arene; 7.9(s, CH=n

38 1.2-2(m), 4H, C-CH2-CH2-C; 2.1(s, 3H, CH3(arom);

2.3-2.7(m, 12H, CH2-N; 3.3(s, 3H, CH3N;

3.4(t, 2H, CH2-O; 4.2(t, 2H, CH2N;

5.1(s, 1H, CH-O; 7.0(m, 9H arene;

7.2(s, 1H, CH=N

39 1.2-1.9(m, 4H, C-CH2-CH2-C;

2.3-2.8(m, 12H, CH2-N; 3.3(s, 3H, CH3N;

3.4(t, 2H, CH2-O; 3.5(s, 3H, CH3N;

4.2(t, 2H, CH2-N; 5.3(s, 1H, CH-O;

6.9(m), 4H, arene; 7.1(s), 5H, arene;

7.4(s, 1H, CH=N

42 1.3-2(m), 4H, C-CH2-CH2-C; 2.3-2.6(m, 12H, CH2N;

3.3(s, 3H, CH2-N; 3.4(t, 2H, CH2-O;

3.5(s, 3H, CH3-N; 4.2(t), CH2-N; 5.2(s, 1H, CH-O;

7.1(m, 8H, arene; 7.4(s, 1H, CH=n

43 1.2-2.0(m, 4H, C-CH2-CH2-C

2.3-2.8(m, 12H, CH2-N; 3.2(s, 3H, CH3N;

3.3(t, 2H, CH2-O; 3.4(s, 3H, CH3N;

3.6(s, 3H, CH3-O; 4.1(t, 2H, CH2N;

5.1(s, 1H, CH-O; 6.7(m), 4H, arene; 7.0(s, 9H, arene.

44 2.3-2.7(m, 12H, CH2-N, 3.3(s, 3H, CHP CLASS="ptx2">

Description of the pharmacological tests

1) Actimetry

Locomotor activity of mice was determined using the PV actimetry Boisse and Simon.

Put five mice in a box, closed the lid, passing through it in two perpendicular beams of light that mouse was crossed when moving.

These movements were calculated by the computer in thirty minutes and one hour.

Strap with holes.

After 30 min after intraperitoneal administration of the derivatives corresponding to the invention, each mouse was placed for 5 min on an automated bar with holes, and noted in the minutes number of surveyed holes.

Effective dose 50 is calculated as a function of the obtained results.

Phenylbenzophenone (FBH).

Pain in the peritoneum of mice is called intraperitoneal injection phenylbenzophenone (FBH). The decrease of pain syndrome characterized by crooked position of the animal examined by injection of the test product for 30 min prior to the introduction of FBH.

Effective dose 50 is calculated as a function of the percentage of attenuation of pain syndrome to control animals.

The test substance is introduced party of Guinea pigs for 30 minutes until the new placing them in the chamber for controlling the resistance to histamine. The Guinea pig is considered protected if it can withstand ten minutes remaining in the aerosol of histamine, without signs of asphyxia.

The average effective dose is calculated as a function of the obtained results.

Anti-histamine activity.

Determined the dose that protects 50% of the Guinea pigs regarding lethal dose of histamine.

The product is introduced for 30 minutes before intravenous injection of hydrochloric acid histamine. Effective dose 50 is calculated as a function of the obtained results.

The results are shown in table. 2.

The METHOD of OBTAINING DERIVATIVES BENZHYDRYLPIPERAZINE General formula

< / BR>
where: R1hydrogen, halogen, lower alkyl, lower alkoxy or cryptomaterial;

R2hydrogen or halogen;

R3hydrogen, halogen or cryptomaterial;

n-2-6 integer;

R4and R5one hydrogen, the other group of the benzoyl is clichesque group, selected from the group: Succinimidyl, 4-phenylsuccinic, 2-oxopentanenitrile, 3-benzyl-2-oxopentanenitrile, 1,2,3,4-tetrahydro-2,4-dioxoimidazolidin, 3,4-dihydro-4-oxothiazolidine, 3,4-dihydro-4-oxo-2-metilfentanil, 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purinol, 3,7-dihydro-2,7-dimethyl-2,6-dioxo-1H-purinol,

characterized in that the compound of General formula

< / BR>
where n, R4and R5have the specified values;

X group is a halogen or Totila,

subjected to interaction with excess benzhydrylamine-piperazine of General formula

< / BR>
where R1R3have the specified values,

in inert aprotic solvent, such as toluene, and, if necessary, the obtained target product is converted into the acid additive salt.

 

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