FI60863B - FOERFARANDE FOER FRAMSTAELLNING AV NYA BENTSHYDRYLOXIALKYLAMINDERIVAT MED FOERLAENGD ANTIHISTAMINEFFEKT - Google Patents

Description

ΓΒ1 «« ANNOUNCEMENT / 7

Jgfijft LBJ UTLÄGGNINGSSKRIFT ÖU OÖ ύ C Patent granted 13 04 1932

Patent raeddelat '* ^ (51) Ky.ik.Va.3 C 07 D 295/08, 217/04

FINLAND-FINLAND (21) Patunttlhakumui - Patentantöknlnf 7 518 H S

(22) Hikemitpilvt— Aroöknlnpdtj 19.06.75 (23) AlkupUvt— Glltl | hetsd> f 19.06.75 (41) Tullut julkltakil - Bllvlt offentllj 25. 12.75

Patent and Registration Office .... ........... . ,. .....

'. (44) Date of shipment and issue. -

Patent- oeh registerstyrelsen Arnekan utlagd och utl.tkriftan pubhcerad 31.12.8l (32) (33) (31) Pyydetty etuolkeu * - Bagird prloritct 2li.O6.7lt Hungary-Hungary (HU) EE-22 U8 (71) E GY T Gyogyszervegyeszeti Gyär, 30, Kereszturi ut, Budapest X,

Hungary-Hungary (HU) (72) Ivan Beck, Budapest, Jozsef Rakoczi, Budapest, Kalman Bolla, Budapest, Katalin Porszasz, Pecs, Hungary-Hungary (HU) (7! +) Oy Kolster Ab (5I +) Method for new, extended for the preparation of benzhydryloxyalkylamine derivatives having antihistaminic activity - For the preparation of benzhydryloxyalkylamines having an antihistamine effect

This invention relates to novel general formula I.

- the preparation of benzhydryloxyalkylamine derivatives according to the formula X - / y - (! - o - (OH 2) n - ΐΓΛ (I) o, in which X is a halogen atom, a methyl or methoxy group, A is together with the nitrogen atom to which it is attached, A 6-9 membered, partially or fully saturated heterocycle which may be fused to another ring and which may have one or two methoxy groups as a substituent, and n is an integer of 2, 3 or 4 »and the preparation of pharmaceutically acceptable acid addition salts of these compounds.

60863

The new compounds of the general formula I have a prolonged antihistamine effect *

It is known from the literature that some benzhydryloxyalkylamines have antihistamine activity (British Patent No. 942,152; C.A. 60, 9250h).

It has also been found that if benzhydryloxyalkylamine is associated with a bulky, partially or fully saturated heterocyclic imine, then the obtained compounds have an enhanced antihistamine effect with a considerably longer duration, so that the compounds have a higher therapeutic value. These compounds have a selective antihistamine effect in both in vivo and in vitro experiments. When administered orally and subcutaneously to guinea pigs, the compounds inhibit histamine-induced alveolar convulsions more strongly and for a longer time than meclastine [1-methyl-2- (2- [α-methyl-p-chlorodiphenylmethoxy] ethyl) pyrrolidine hydrogen fumarate]. The therapeutic scope of the compounds is preferably affected by their low toxicity values.

The prevention of histamine-induced alveolar convulsions in guinea pigs was tested in vivo as follows:

The animals were placed in a glass vessel sprayed with a constant pressure of 0.2 histamine solution. Prior to administration of the test compounds, the control time required for the onset of alveolar spasms was measured in each animal, and the contraceptive efficacy of the compounds was compared with this control; otherwise, a compound commonly used in clinical medicine is used as a control compound.

Time contraception was considered 100 if typical "asphyxia" did not occur during the 3x control time.

Table I summarizes some typical results for both toxicity value and.

3 60863

Table I

Compound Toxicity Dose Prevention of alveolar convulsions induced in guinea pigs by histamine, e.g. LD-q me / ^ S mg / kg, in mice over $ no. 2 55Ο 0-2 85 90 20 1 100 100 90 10 100 100 - 90 5 300 10 100 - 20 7> 1600 .10 80 75 - 50 · 8 1230, 10 60 70 - 80 40

0.5 · 90 45 O

Meclastin 280 2 ^ 00 60 O

10 100 - O

Benzhydrylalkylamines of general formula I are prepared according to the invention of general formula II

- <-cn2> m of the cyclic imino compounds of formula (Y) (II) in which A is as defined above, Y is a halogen atom or a hydroxyl group, where m is an integer of 2, 3 or 4, or Y is a hydrogen atom, in which m is zero, by the following methods: a) a compound of general formula II wherein Y is a halogen atom, 4 60863

m is 2, 3 or 4, and A is as defined above, is reacted with general formula III

CH3.

x σ - oh (ui)

"O

or b) a compound of general formula II wherein Y is a hydroxyl group, m is 2, 3 or 4, and A is as defined above, is reacted with a benzhydrol derivative of the general formula 17 «OHj x - 0 - Bal (IT) ~ <0 with a benzhydryl derivative represented by the formula wherein X is as defined above and Hal is a halogen atom, or

u) a compound of general formula II wherein Y is a hydrogen atom, m is zero and A is as defined above is reacted with a compound of general formula V

CH 2 .- 0-4-0 (^ -, (T) '0 in which X and n are as defined above and Z is a halogen atom or a tosyloxy group.

5 60863

In all three embodiments of the present invention, a compound of general formula II is reacted with a compound of general formula III, IV or V most preferably in the presence of a base, and the resulting compound of general formula I may be converted to an acid addition salt by reaction with a pharmaceutically acceptable inorganic or organic acid. The acid addition salt can be preferably prepared without isolating the compound.

The resulting compounds of general formula I and their acid addition salts can be converted into pharmaceutical compositions by forming them, alone or in combination with other pharmaceutically active compounds, using carriers and / or excipients used in the pharmaceutical industry, pills, coated pills, capsules, suspensions, emulsions , dilutions and other pharmaceutical products.

The method according to the invention is described in more detail by means of the following examples.

Example 1

To a mixture of 4 * 2 g of sodium amide and 80 ml of dry benzene is added 27.9 g (0.12 mol) of α-methyl-p-chlorohenzhydrol and then 17 * 6 g (0.1 mol) of N- (8- chloroethyl) -heptametyleeni-imine. The mixture is stirred at reflux for 20 hours. After cooling, the mixture is washed with 2 x 20 ml of water and then with 4 x 50 ml of 2N hydrochloric acid. The acidic extracts are combined and the pH of the combined extracts is adjusted to 9 with concentrated aqueous sodium hydroxide solution. The separated organic phase is extracted with 3 x 30 ml of hentene. The solvent is distilled off, and the residue is purified by distillation. The N- [2- (p-chloro-α-methyl-phenylbenzyloxy) -ethyl] -heptamethyleneimine thus obtained boils at 158-162 ° C / 2Ω 0.005 mm Hg. Yield: $ 55 ·: 1 * 5574 · The hydrogen fumarate salt of this compound can be crystallized from ethanol, m.p. 144-145 ° C.

Analysis for C 8 H 18 N 2 O 2 NO 2 requires: C 66.51 H 7.05 Cl 7 * 26 N 2.86 Found: C 66.56 H 7 * 18 Cl 7 * 35 N 2.78.

Example 2

To a mixture of 4 * 2 g of sodium amide and 80 ml of dry benzene is added 27.9 g (0.12 mol) of α-methyl-p-chlorobenzhydrol and then 16.2 g (0.1 mol) of N- (8- chloroethyl) -heksametyleeni-imine. The mixture is stirred at reflux for 20 hours and, after cooling, the mixture is washed with 2 x 20 ml of water. The benzene solution is dried over magnesium sulfate, e 60863 until anhydrous, then clarified with activated carbon. Dry hydrogen chloride gas is then introduced into the solution. The separated crystalline product is filtered through a glass filter and then recrystallized from acetone.

In this way, N- [2- (α-methyl-p-chloro-α-phenylbenzyloxy) -ethyl] -hexamethyleneimine hydrochloride is obtained in a yield of $ 65, m.p.

170-171 ° C.

Analysis for C 22 H 29 Cl 2 NO calculated: C 67.12 H 7.41 Cl 18.07 N 4.06 Found: C 67.03 H 7.47 Cl 17.95 N 4.12 Example 3

To a solution of 27.9 g (0.12 moles) of α-methyl-p-chlorobenzhydrol in 100 ml of petroleum ether is added 20 g of anhydrous ground calcium chloride. Dry hydrogen chloride gas is bubbled through the solution for 2 hours at 0-5 ° C. The mixture is filtered and the filtrate is evaporated. To the resulting α-methyl-p-chlorobenzhydryl chloride are added 16.2 g (0.1 mol) of N- (P-hydroxyethyl) -hexamethyleneimine and 10.6 g (0.1 mol) of sodium carbonate. The mixture is heated to 125 ° C and maintained at this temperature for 6 hours. After cooling, 100 ml of benzene are added to the mixture. After filtration and clarification, dry hydrogen chloride gas is passed through the solution. The crystalline product thus formed is filtered through a glass filter and recrystallized from acetone. The N- [p-chloro-α-methyl-α-phenylbenzyloxyethyl] -hexamethyleneimine hydrochloride thus obtained melts at 170-171 ° C; yield: $ 35 (this product is identical to the product of Example 2).

Example 4

To a solution of 22.6 g (0.2 moles) of heptamethyleneimine in 100 ml of acetone is added 43.1 g (0.1 moles) of P- (p-chloro-o-methyl-α-phenylbenzyloxy) - ethyl (p-toluene) sulfonate. The mixture is boiled for 16 hours, then the solvent is evaporated. The residue is dissolved in 80 ml of water, and the pH of the solution is adjusted to 9 by adding aqueous sodium hydroxide solution. The organic phase is extracted with 3 x 30 ml of benzene. The benzene solution is dried and evaporated to dryness, and the product obtained is distilled under reduced pressure; bp 138-162 ° C / 0.003 mm Hg. Yield: $ 42.

(the product is identical to the product of Example 1).

Examples 5-13

Correspondingly, by modifying the methods described in Examples 1-4, the following compounds shown in Table 2 are prepared: 7 60863

Table 2

Example X XX -if "* A. .Salt Melting point ° C

no: _v_ 5 Cl 2 HCl 170-171 6 Cl 3 Ό HCl 165-167 7 Br 2 - "~ fumarate 149-150 • 8 F 2 -" - SCI 117-120 9 CHy-O-2 - "- HCl 111 -113 10 -CH- * 2 - "- HCl 139-141> | 1 Cl 4 -" - HCl 147-149 12 Cl 2 "CO HCl 148-150" 00H3 13 Cl 2 II »J HCl 104-108 ^^ ^ OCE, p

Claims (1)

A process for the preparation of new benzhydryloxyalkylamine derivatives of the general formula I having a prolonged antihistamine effect, of the general formula I, wherein X is a halogen atom, a methyl or methoxy group, A is together with the nitrogen atom to which it is attached a 6-9 membered, partially or fully saturated heterocyclic ring which may be fused to another ring and which may have one or two methoxy groups as a substituent, and n is an integer of 2, 3 or 4, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that the cyclic imino compound of the general formula II "n - (CHO) -Y II yy 2 m in which A is as defined above, Y is a halogen atom, or a hydroxyl group in which m is an integer 2 , 3 or U, or Y is a hydrogen atom, where m is zero, is reacted in the presence of a base, a) if Y is a halogen atom and m is 2, 3 or 4, the general formula n III-CH, I with a benzhydrol derivative of the formula III in which X has the same meaning as above, or b) if Y is a hydroxyl group and m is 2, 3 or 4, CCH \ i> - C - Hai / With a benzhydryl derivative according to the formula 60 wherein X is the same as above and Hal is a halogen atom, or c) if Y is a hydrogen atom and m is zero, the general formula V is CH-. // 3 X -VX) with a benzhydryl ether of the formula C - O - (CH 2) - 2 \ __ / JL nv, in which X and n are as defined above, and Z is a halogen atom or a tosyloxy group, and, if desired, a compound of general formula I the compound is preferably converted into an acid addition salt by reaction with a pharmaceutically acceptable acid without isolation. 10 60863 For use in the preparation of benzylhydryloxyalkylamines with a compound antihistamine effect having all of the formulas I CH-. / ΓΛ 1 ^ W 1 2n w color X is a halogen atom, not a methyl or methoxy group, A is used to reduce the number of molten atoms, in which case a mixture of 6-9 LEDs, is present or heterologously heterated, somewhat a condenser account and an annotating ring with a methoxy group, and a methane group of 2.3 or 4, and a pharmaceutical form of a compound solution, a solid state, having a cyclic imaging form in the form of a compound - (CH „) -Y II ____y im color A is an anhydrous atom, Y is a halogen atom or a hydroxyl group, colors are melt and heltal 2,3 or 4, if Y is a vateatom, colors are null, colors are en bas a) ifall Y är en halogenatom and m är 2,3 eller 4, med ett benshydrolivativat med den allmänna formuleln III ch3 ν = Λ ^ Χ i color X har ovan angivna betydelse, eller b) ifall Y är en hydroxylgrupp och m is 2,3 or 4, with benzhydryl derivatives having the formula IV CU ΧΛ 1 X- (\) - C - Hai W / IO