CS215053B2 - Method of making the 1,1-biphenyl-2-ylalkylaminoderivatives - Google Patents

Description

The present invention relates to a process for the production of a novel class of 1,1'-biphenyl-2-ylalkylamino derivatives which are useful in the chemotherapy of cardiovascular disorders.

Cardiovascular disorders are responsible for thousands of deaths each year. Cardiac arrhythmias are one of these disorders contributing to these deaths. Although the true causes of arrhythmias are unknown, they are believed to be caused by some abnormalities in the rate, regularity or site of cardiac pulses, or disorders affecting the order of atrial and ventricular activation.

Several drugs are currently used to treat arrhythmias, including quinidine, procainamide, lidocaine, and digitalis. Recently, great interest has been directed to the novel antiarrhythmic drug, aprindine (a 2-aminoindan derivative - see U.S. Patent No. 3,923,313). Several diphenylakylamines have also recently been reported to have useful antiarrhythmic activity (see U.S. Pat. Nos. 4,001,328,

034 011 and 3 987 201).

Unfortunately, however, most, if not all existing drugs, have undesirable side effects and there is a continuing need for new drugs to be used in the treatment of arrhythmias and to be accompanied by a reduced incidence of adverse side effects.

Accordingly, the invention provides a process for the preparation of compounds of formula I

in which

X represents a hydrogen atom or a halogen substituent at any position of the phenyl ring,

5 6

R represents a hydrogen atom, a hydroxyl group, a C = K group, a CONR R group, where R * 'and R' are each independently hydrogen or an alkyl group

O 0 with 1 to 6 carbon atoms, or a COgR residue where R is hydrogen or C 1 to C 4 alkyl,

R represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,

Z represents a group "(C &j)" where R is ^an integer of 2 to 4, or a group

OH

-CHgCHCHg- a

R ^ and R ^ are each independently hydrogen, C až-C alky alkyl, C--alkenyl wherein Cenyl-C alk alkenyl contains C až-Ceny phenylalkyl, or both of these symbols, taken together with the adjacent nitrogen atom, form a heterocyclic radical containing 5 to 7 ring atoms, and pharmaceutically acceptable salts thereof.

Preferred are compounds of formula I wherein:

X represents a hydrogen atom or a fluorine, chlorine or bromine atom, not attached at the 5-position of the biphenylyl ring, r 'represents a hydrogen atom, a hydroxyl group, a CONHg group or a COOH group,

R ^ represents a hydrogen atom or a methyl group,

Z represents a group ® ^ ^{o <3nol for} 2 or 3, or a group -CHgCHťOHJCHg- in the case where R ¹ is hydrogen, and

R ^ and R ^ are each independently hydrogen, C až-C 1 alky alkyl, CHg-alkenyl wherein C alk-C alk-alkenyl contains C až-C f-phenylalkyl having 1 to 3 carbon atoms in the alkyl moiety, or both of these symbols, together with the adjacent nitrogen atom, form a heterocyclic radical selected from the group consisting of pyrrolidine and piperidine, and their pharmaceutically acceptable acid addition salts or quaternary ammonium salts.

Other preferred compounds of formula I meet one or more of the following requirements:

1) X is hydrogen or fluorine;

2) r 'is hydroxy,

3) R ¹ is C = N,

4) R ¹ represents a CONH 8 group,

5) R 6 represents a hydrogen atom,

6) R 6 is other than hydrogen,

7) R 1 represents a C 1 -C 4 alkyl group, in particular an isopropyl group,

8) R 6 represents a hydrogen atom or a C 1 -C 4 alkyl group,

9) Z is -CHgCHgCl2-,

10) Z is -CH 2 -CHCH 8 -,

OH

(11) they are pharmaceutically acceptable acid addition salts;

12) it is a pharmaceutically acceptable quaternary ammonium salt.

The invention also provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

The biphenylylalkylamines produced by the process of the invention are basic substances which readily react with organic or inorganic acids to form salts. Those acid addition salts that are substantially as non-toxic as the free amines from which they are derived are referred to as pharmaceutically acceptable acid addition salts and are also within the scope of the invention. Such salts are prepared using conventional inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or perchloric acid. Pharmaceutically acceptable acid addition salts may also be prepared by reacting amines with organic acids such as formic acid, acetic acid, succinic acid, maleic acid, p-toluenesulfonic acid or methanesulfonic acid, and citric acid.

Pharmaceutically acceptable salts also include the quaternary ammonium salts of the amine bases of formula (I). Such salts may be prepared by reacting a tertiary biphenylylalkylamine of the invention with an alkylating agent such as a C 1 -C 6 alkyl halide, C 1 -C 6 alkyl sulphate or alkyl benzene sulphate. alkyl moieties of 1 to 6 carbon atoms. Typical alkylating agents commonly used to prepare useful quaternary ammonium salts include methyl bromide, n-butyl iodide, isopentyl chloride, dimethyl sulfate, ethylbenzene sulfate, and diisopropylsulfate.

The compounds of the above formula (I) of the epoxide of formula (XX) according to the invention are prepared by the preparation of:

CH,

-CH

-CH, (II) wherein 2

X and R are as defined above and f 'is as defined above or represents a protected hydroxyl group, condenses with an amine of the formula

HHR ³ R ⁴ in which

R @ 1 and R @ ⁴ are as defined above, and the resulting product is optionally deprotected, whereupon the optionally obtained base of formula (I) is converted into a pharmaceutically acceptable salt.

2-hydroxy-4-biphenylylbutylamines according to the invention, i.e. a compound of formula I, in which Z

OH is -C 1 CH 2 Cl 2 -, may be prepared by reaction of an amine of the formula

HNR? R ⁴ with 4-biphenylyl-1,2-epoxybutane. Epoxybutane can be obtained by oxidation of 4-biphenylyl-1-butene with a peracid. The desired 4-biphenylyl-1-butene can be prepared by reacting an allyl halide with a biphenylyl methyl halide. The overall course of the reaction is shown in the reaction scheme:

In the formulas shown in this scheme, X, and R ^ are as defined above, and Hal is chlorine, bromine, or iodine.

The starting materials of formula IX can be prepared from a compound of formula III

X OH

Λ = CH-CH ₂ -CH = CH ₂ (III)

Compounds of formula III are prepared by reacting an aldehyde of formula

with a Grignard reagent of the formula Cl 2 CH-CHg-MgBr (see Org. Syn. J, 121).

The hydroxy compound of formula (III) can be converted to the corresponding nitrile, amide or carboxylic acid in a conventional manner, for example by phosphorous bromide bromination followed by reaction with sodium cyanide to form the corresponding nitrile, followed by optional hydrolysis to give the corresponding amide or carboxylic acid. These compounds can be converted to the corresponding epoxides by treatment with m-chloroperbenzoic acid. When converting a compound of formula III to an epoxide, it may be necessary to first protect the hydroxyl group, for example by forming a silyl ether (see Syn. Comm. £ 277 (1976)), which corresponds to the general formula _in OSi ^{x 1} q-ch ₂ - ch = ch ₂

H

The epoxidized silyl ether formed can be reacted directly with an amine of the formula HNR ³ R 6 to give the corresponding compound (r '= hydroxyl) or deprotected. ^r

The condensation of the amine with 4-biphenylyl-1,2-epoxybutane is generally carried out by mixing the epoxide with about a two to three molar excess of the amine in an inert organic solvent such as ethanol. The reaction may be carried out in a pressure vessel at a temperature of from 100 to 200 ° C, at which temperature the reaction is substantially complete in 8 to 16 hours. Less drastic reaction conditions can be used for the reaction. The product can be isolated by evaporation of the reaction solvent and further purification can be carried out by distillation, salt formation and the like.

Bifenylylalkylaminy corresponding to the above formula I wherein R ¹ is hydrogen and Z is - _(CH2) n- may be prepared from the corresponding bifenylylalkanolaminů in which R ¹ is hydroxy by dehydration to the corresponding bifenylylalkenylaminy and subsequent reduction of the olefinic double bonds. For example -alkanolamines biphenylyl, such as N-methyl-N- (2-phenethyl) -3-hydroxy-3- (5-bromo-1,1 ^# -biphenyl-2-yl) propylemin can be dehydrated by reaction with sulfuric acid to give N-ethyl-N- (2-phenethyl) -3- (5-bromo-1,1'-biphenyl-2-yl) -2-propenylamine. Hydrogenation of the latter with a suitable catalyst such as palladium on carbon gives the corresponding biphenylylalkylamine, namely N-methyl-K- (2-phenethyl) -3- (5-bromo-1,1'-biphenyl-2-yl) propylamine.

A řÝ

Compounds of general formula I wherein R ¹ represents a group R ³ -C0NR in which one or both R ^ and R ^ are each alkyl having 1 to 6 carbon atoms, may be prepared by reaction of the appropriate acid chlorides or esters, i.e. A compound of formula I wherein r 'is an ester or acid chloride moiety with an excess of a primary or secondary amine of formula HNRNRR.

Biphenylylalkylamines are within the scope of the invention which carry readily cleavable groups on the amine nitrogen (i.e., where R ³ or R * represents an easily cleavable group) are useful as antiarrhythmic agents as well as intermediates. Typical easily removable substituents on nitrogen include methyl and benzyl. For example, N-benzylamine can be debenzylated by hydrogenation in the presence of a catalyst such as palladium on carbon. N-methylamines can be demethylated by reaction with haloformate followed by basic hydrolysis.

Any of the above processes for the preparation of the compounds of the invention may be carried out to give the corresponding N-methyl- or N-benzyl-biphenylylalkylamine. These compounds may be demethylated or debenzylated to give compounds of the above formula wherein R 1 and R 2 are both hydrogen. Such compounds can then be realkylated as desired to yield any of a variety of other compounds of the invention. For example, N-benzyl-N-isopropyl-4-cyano-4- (5-chloro-1,1'-biphenyl-2-yl) butylamine can be debenzylated by hydrogenation to give the corresponding secondary amine, N-isopropyl-4- cyano-4- (5-chloro-1,1'-biphenyl-2-yl) butylamine. The secondary amine may then be subjected to realkylation, for example by reaction with an alkyl halide such as n-pentyl bromide or n-propyl iodide, an alkenyl halide such as allyl bromide, 3-pentenyl iodide or 2-methyl-2-butenylbromide, or a phenylalkyl halide such as 2-phenethyl bromide or 3 -phenylpropyl iodide. This alkylation process is a preferred method for preparing a wide variety of biphenylylalkylamines from conventional starting materials.

As mentioned above, the biphenylylalkylamines produced by the process of the invention are basic in nature and can therefore be reacted with acids to form pharmaceutically acceptable acid addition salts. These salts are prepared by simply mixing biphenylylalkylamines with the appropriate acids in suitable organic solvents, such as diethyl ether. The acid addition salts normally crystallize out of solution and can be filtered and optionally recrystallized.

When the biphenylylalkylamines falling within the scope of the invention are tertiary amines, i.e., when R and R in formula I above have different meanings from hydrogen, they are readily prepared from quaternary ammonium salts by reaction with alkylating agents containing a lower alkyl group. Thus, for example, by the reaction of a tertiary amine such as N, N-dimethyl-3-aminocarbonyl-3- (1,1 ^of biphenyl-2-yl) propylamine with an alkylating agent such as allyl bromide in a suitable solvent such as dichloromethane effects quaternization to to give N-allyl-N, N-dimethyl-3-ominokarbonyl-3- (1,1 ^{-biphenyl-on-2-yl)} propylaminium bromide. These quaternary salts are generally highly crystalline solids and are also within the scope of the invention as antiarrhythmic agents.

The biphenylylalkylamines of the invention are useful as antiarrhythmic agents. The fact that the compounds of the invention are effective antiarrhythmic agents has been demonstrated in dogs suffering from cardiac arrhythmia induced by uabain. A typical experiment is to anesthetize one or more non-blooded dogs of any sex with natriumpentobarbital. A radial vein of each dog is then inserted with a No. 23 wing infusion needle to which the dog is administered uabein to induce an arrhythmia, and the test compound. Each experimental dog is continuously monitored on the electrocardiograph during the experiment. Once the cardiac arrhythmia induced by uabain persists for 30 minutes, the compound of the invention is administered at a rate of 200 µg / kg body weight of the dog per minute using a wing infusion needle.

If the arrhythmia does not return to normal sinus rhythm (as measured by electrocardiography) within 10 minutes of the start of test compound administration, the test compound infusion rate will increase to 500 µg / kg per minute. If the arrhythmia reverses, the infusion of the test compound is generally continued until the dog receives twice the amount of active ingredient that caused the arrhythmia reversal to normal sinus rhythm. After termination of the test compound, the dog's heart is monitored by electrocardiography until arithmetic occurs again, or at most 2 hours, when the experiment is terminated.

The results of several such experiments are shown in the following table. The first part of the table lists the test compounds, which are identified by capital letters, which are then in the second part of the table in the first column labeled Compound. Most of the compounds were tested more than once as indicated by the data in the number of dogs column. The amount of uabsine required to induce arrhythmia is given in [mu] g / kg dog body weight. The arrhythmia reversal dose and total dose of test compound are given in mg / kg body weight of the test animal. The duration of reversal of arrhythmia is given in minutes.

compound X R ¹ R ² OF R ³ R ⁴ number dogs AND F H H CHgCHgCHg ch ₃ ch ₃ 2 (B) F OH H CHgCl2 CHg ^C 2 ^h 5 ^C 2 ^H 5 3 C F OH H CHgCHgCl2, H ϊ-ο _Λ 4 D Cl OH H C ^ CHHgCHg ch ₃ CH ₃ 3 E H OH H ch ₃ CH ₃ 2 F H OH H CHgCHgCHg □ 2 G H COOH H C ^CHgClC CH ₃ CH 3 2 H H GN H C 1 H 6 CHpCH? CH ₃ GH ₃ 1 AND H H H ch ₂ ch ch ₂ 1 ^ 3¾ i- ^c 3iy 4 OH J H conh ₂ H CH 2 Cl 2 CH ₃ CH ₃ 2

compound uabain , A2 g / kg Reversal dose (mg / kg) total dose (mg / kg) Reversal Duration (minutes) AND 80 4.0 8.0 12 . 85 3.4 - - (B) 85 2.5 5.0 32 75 5.8 11.5 120+ 75 3.5 7.0 18 C 60 2.8 5.5 120+ 70 8.0 9.5 85+ 80 3.0 6.0 65 70 3.0 6.0 105+ D '70 2.5 5.0 5 60 0.9 1,8 120+ 70 6.0 10.0 43+ E 70 8.5 8.7 3 60 1,8 3.6 51

compound uabain Ug / kg Reversal dose (mg / kg) total dose (mg / kg) Reversal Duration (minutes) F 60 2.5 5.0 93 70 3.0 6.0 42 G 60 4.8 9.5 45 75 10.0 10.0 - H 70 6.3 10.5 13 AND 60 1.9 3.8 83 55 2,0 4.0 48 70 1 .5 3.0 26 65 1.6 3.2 23 J 70 2.6 5.2 53 60 1.9 3.8 120+

The pharmaceutical compositions normally contain about 1 to 50% by weight of the compound of the invention. The compounds of the invention may be administered parenterally, for example in the form of liquid injectable solutions or suspensions, or orally in the form of solid mixtures from which they can be compressed or filled into gelatin capsules. Pharmaceutical carriers, diluents or excipients commonly used in the preparation of solid compositions include starch, glucose, lactose, gelatin, malt, rice flour, silica gel, hydroxyethylcellulose, magnesium carbonate, sodium benzoate, and the like.

Carrier flights used in liquid formulations include ethanol, sodium chloride solution, sterile water, glucose syrup, acacia, ground oil, essential oil, wheat germ oil, sorbitan trioleate, ethyl oleate, lecithin, and the like. , subcutaneously or, preferably, by the intravenous route.

The effective amount of anti-arrhythmic drug administered may vary depending upon the route of administration, the patient being treated for arrhythmia at the time of administration, the severity of the disease, the patient being treated, and similar factors. A patient suffering from arrhythmia and in need of treatment is normally given the dose of antiarrhythmia needed to reverse the arrhythmia to normal sinus rhythm. The compounds of the invention are generally formulated for parenteral administration and administered by intravenous infusion at a dose capable of reversing the arrhythmia. The compounds are then administered at a maintenance dose, either parenterally or orally.

The dose of active ingredient commonly used to induce a reversal of arrhythmia ranges from about 0.1 to 50 mg / kg body weight. A typical effective dose for intravenous administration is from about 0.5 to 20 mg / kg. Maintenance treatment is carried out by administering the active compound of the invention at a dose of about 0.1 to 35 mg / kg body weight. A tablet suitable for oral administration for the maintenance treatment or prophylactic treatment of a human patient may contain, for example, from about 7 to 750 mg of the biphenylylalkylamine of the invention in combination with a suitable carrier. Such a tablet may be administered to a patient to effectively manage cardiac arrhythmia about one to three times a day.

The invention is illustrated by the following non-limiting examples.

Example 1

N, N-diisopropyl-2-hydroxy-4- (1,1'-biphenyl-2-yl) butylamine

A solution of 4.0 g of 1,2-epoxy-4- (1,1'-biphenyl-2-yl) butane in 50 ml of ethanol containing 6.0 g of diisopropylamine was heated to 160 ° C in a pressure reaction vessel at this temperature. is stirred for 16 hours. The reaction mixture was cooled to room temperature and concentrated to an oily residue by evaporation of the solvent under reduced pressure. The oily material was dissolved in 200 ml of diethyl ether, washed with water and extracted with 6 N hydrochloric acid. The acid layer was separated, washed with fresh diethyl ether and basified by addition of 10% sodium hydroxide. The alkaline solution is extracted several times with diethyl ether, the ether extracts are combined and washed with water and dried. Evaporation of the solvent gave an oily product which, by distillation, yielded 1.8 g of N, N-diisopropyl-2-hydroxy-4- (1,1'-biphenyl-2-yl) butylamine, b.p. .

For C ₂₂ H _3] NO calculated: 81.18% G, 9.60% H 4.30% N i Found: 81.42% C, 9.82% H, 4.26% N.

Example 2

Using an analogous procedure to that of Example 1, 1,2-epoxy-4- (1,1'-biphenyl-2-yl) butane is reacted with isopropylamine to give N-isopropyl-2-hydroxy-4- (1,1 1-Biphenyl-2-yl) butylamine. The basic amine thus formed gives a reaction with hydrogen chloride N-isopropyl-2-hydroxy-4- (1,1'-biphenyl-2-yl) butylammonium chloride, m.p. 153-154 ° C.

For C ₁₉ H ₂₅ C1NO calculated: 71.34% C, 8.19% H, 4.38% N;

Found: C, 71.21; H, 7.95; 4.36 »

Example 3

N-tert-butyl-4-hydroxy-4 - [(5-fluoro-1,1'-biphenyl) -2-yl] butylammonium chloride

To a solution of 5.0 g of N-tert-butyl-4-hydroxy-4 - [(5-fluoro-1,1'-biphenyl) -2-yl] butylamine in 200 ml of diethyl ether was added excess hydrogen chloride with stirring. The precipitate formed is filtered off and recrystallized from ethanol and diethyl ether. 3.2 g of N-tert-butyl-4-hydroxy-4- C (5-fluoro-1,1'-biphenyl) -2-yl] butylammonium chloride are obtained, m.p. 143-145 ° C.

For C ₂₀ H ₂₇ C1KNO calculated: 68.26% C, 7.73% H, 3.98% N;

Found:% C, 68.03;% H, 7.98;% N, 3.92.

Examples 4 to 9

The following acid addition salts of the corresponding amines are prepared as described in Example 3:

N, N-diisopropyl-4-hydroxy-4 - [(5-fluoro-1,1'-biphenyl) -2-yl] butylammonium chloride, m.p. 153-155 ° C;

For C ₂₂ H ₃₂ ClNO 3 Calculated: C 69.65%, H 8.22%, Ni 3.69%. Found: C 69.34%, H 8.18%, N 3.61%.

185 DEG-186 DEG C. N-isopropyl-4-hydroxy-4-methyl-4- (1,1'-biphenyl-2-yl) butylammonium chloride,

For C ₂₀ H ₂₈ C1NO calculated: 71.94% C, 8.45% H, 4.19 »Nj Found: 71.84% C, 8.48% H, 4.02% N.

N-isopropyl-4-methyl-4- ^{(1,1'-biphenyl-2-yl)} butylamonlumchlorid mp 182-183 ° C. For C ₂₀ H ₂₈ C1NO

calculated: 75.56% C, 8.88% H, 4.41% Nj found: 75.83% C, 8.57% H, 4/20% N. N, N-diisopropyl-4-hydroxy-4- (1,1 ') (biphenyl-2-yl) butylammonium chloride, m.p. 172-174 ° C, For C ₂₂ H ₃₂ C1NO calculated: 73.00% C, 8.91% H, 3.87% N; found: 72.80% C, 8.61% H, 3.93% N.

N-isopropyl-N-methyl-4-hydroxy-4- ^{(1,1'-biphenyl-2-yl)} -butylanoniumchlorid mp 130-133 ° C,

For C ₂₀ H ₂₈ ClNO calculated; % C, 71.94;% H, 8.45;% N, 4.19;

Found:% C, 72.08;% H, 8.22;% N, 3.92.

Example 10

N, N-dimethyl-4- ^{(1,1'-biphenyl-2-yl)} butylamine

A solution of 4.6 g of N, N-dimethyl-4-hydroxy-4- ^{(1,1'-biphenyl-2-yl)} butylammonium chloride in 100 ml of 4N sulfuric acid was heated to 100 ° C and stirred for 1 hour. The reaction mixture was cooled to 5 ° C and basified by addition of 10% sodium hydroxide. The alkaline solution was extracted with diethyl ether, the ether extracts were combined and washed with water and dried. Evaporation of the solvent under reduced pressure gave 3.3 g of N, N-dimethyl-4- (1,1'-biphenyl-2-yl) -3-butenylamine.

A solution of 3.0 g of N, N-dimethyl-4- (1,1'-biphenyl-2-yl) -3-butenylamine in 200 ml of ethyl acetate containing 2.0 g of 5% palladium on carbon is stirred for 1 hour at 25 ° C in a hydrogen atmosphere at a pressure of 0.28 MPa. The reaction mixture was filtered and the solvent was evaporated. The oily residue was dissolved in diethyl ether (100 mL) and excess hydrogen chloride was added with stirring. The precipitate formed is filtered off and recrystallized from ethanol and diethyl ether. N-N-dimethyl-4- (1,1'-biphenyl-2-yl) butylammonium chloride (2.1 g), m.p. 114 DEG-116 DEG C., is obtained.

For C ₁₈ H ₂₄ ClNO: calculated: 74.59 * G, 8.35% H, 4.83% N;

Found:% C, 74.48;% H, 8.30;% N, 4.71.

Example 11

N-Isopropyl-3-aminocarbonyl-3- (1,1'-biphenyl-2-yl) -propylamine

A solution of 2.1 g of N-benzyl-N-isopropyl-3-aminocarbonyl-3- (1,1'-biphenyl-2-yl) propylamine in 200 ml of ethanol containing 2.0 g of 5% palladium on carbon The mixture was heated to 40 ° C under a hydrogen atmosphere at 40 psi for 45 minutes. The reaction mixture is filtered and the filtrate is concentrated by evaporation of the solvent. The residue was dissolved in diethyl ether, washed with water, evaporated and the residue crystallized from n-hexane. 150 mg of N-isopropyl-3-aminocarbonyl-3- (1,1'-biphenyl-2-yl) propylamine, m.p. 92-95 ° C, are obtained.

For Ο _{19 24} Ν Η ₂ Ο calculated: 76.99% C, 8.16% H, 9.45% N;

Found:% C, 76.78;% H, 8.14;% N - 9.57.

Example 12

Using an analogous procedure, the appropriate N-benzylamine is hydrogenated to give N-isopropyl-4-aminocarbonyl-4- (1,1'-biphenyl-2-yl) butylamine, m.p. 121-122 ° C. For C, QH _{2 2} g N ₂ O Calculated: 77.38% C 8.44% H 9.02% N i Found: 77.19% C, 8.16% H, 8.91% N.

Example 13 1-Methyl-1- [4-hydroxy-4- (1,1'-biphenyl-2-yl) butyl] -pyrrolidinium iodide

To a solution of 3.0 g of 1- [4-hydroxy-4- (1,1'-biphenyl-2-yl) butyl] pyrrolidine in 10 ml of ethanol, was added in a single portion 1.3 g of methyl iodide. The reaction mixture was stirred at room temperature for 16 hours, then the solvent was evaporated under reduced pressure. Crystallization of the oily residue from petroleum ether gave 4.2 g of 1-methyl-1- [4-hydroxy-4- (1,1'-biphenyl-2-yl) butyl] pyrrolidinium iodide, m.p. 157-159 ° C.

For C ₂₁ H _28! NO calculated: 57.67% C, 6.45% H, 3.20% N;

Found: C 57.75, H 6.19, N 3.22.

Example 14

Using the procedure described in Example 13, reaction of the appropriate tertiary amine with an alkylating agent gave the quaternary ammonium salt, N, N-dimethyl-11-isopropyl-4-hydroxy-4- (1,1'-biphenyl-2-yl) butylammonium iodide, m.p. 93-95 ° C.

For Ο ₂₎ Η _3θ ΙΝΟ calculated: 57.41% C, 6.88% H, 3.19% N;

Found: C 56.93, H 6.69, 3.19 N.

Example 15

N, N-Dimethyl-4-hydroxy-4 - [(5-chloro-1,1'-biphenyl) -2-yl] butylammonium chloride

To a three-necked 3 L flask equipped with a stirrer and thermometer was charged with 5.0 g (0.21 mol) of magnesium, added enough ether to just cover the magnesium and activate the magnesium by slowly adding a small amount of ethylene dibromide. An ethereal solution of 31.6 g (0.2 mol) of N, N-dimethyl-3-chloropropylamine was added to the resulting mixture, and the reaction mixture was stirred at room temperature to dissolve virtually all of the magnesium.

After the dropwise addition of an ethereal solution of 48.7 g (0.23 mol) of 2-phenyl-4-chlorobenzaldehyde, the reaction mixture is stirred overnight. into diethyl ether.

The mixture is extracted with 6 N hydrochloric acid, the extract is basified with 10% sodium hydroxide, the alkaline phase is extracted with diethyl ether, the organic extract is washed with water and dried over sodium sulfate. Upon concentration of the solution, a solid crystallized out, which was dissolved in diethyl ether and converted to the title compound by treatment with hydrogen chloride. / *

The product resulting in a yield of 13.7 g melts at 119-121 ° C.

Example 16

N, N-dimethyl-4 - [(5-chloro-1,1'-biphenyl) -2-yl] -3-butenylammonium chloride

In a 250 ml flask, 3.0 g (0.1 mol) of the product of Example 15 was stirred and refluxed in 80 ml of 4 N sulfuric acid for 6 hours. The reaction mixture was cooled, poured into ice water, basified with 10% sodium hydroxide, extracted with diethyl ether, washed with water, dried over sodium sulfate and concentrated. The base thus obtained is converted to the hydrochloride (the title compound) and then recrystallized from ethanol and diethyl ether. 1.6 g of the expected product are obtained, m.p. 149.5-150 ° C.

Example 17

N, N-dimethyl-4 - [(5-chloro-1,1'-biphenyl) -2-yl] butylammonium chloride

8.4 g (0.011 mol) of N, N-dimethyl-4 - [(5-chloro-1,1'-biphenyl) -2-yl] -3-butenylammonium chloride are hydrogenated in 200 ml of ethanol in the presence of 1.0. g of 5% palladium-on-carbon as described in Example 10. The yield of 1.8 g is: melting point 131-133 ° C.

Example 18

This example describes the composition and preparation of a composition suitable for oral administration: a component

N-isopropyl-4-hydroxy-4- (1,1'-biphenyl-2-yl) butylammonium chloride 25 starch sucrose

200

275

500

The above ingredients are thoroughly mixed together with a suitable glidant and compressed into a tablet.

Example 19

This example describes the composition and preparation of a composition suitable for intravenous administration of a component

N, N-diethyl-4-aminocarbonyl-4- (5-fluoro-1,1'-biphenyl-2-yl) butylammonium chloride 250 mg isotonic sodium chloride solution 500 ml

10% aqueous glucose 500 ml

The infusion solution is prepared by mixing the above ingredients.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of 1,1-biphenyl-2-ylalkylamino derivatives of the general formula I d 1 t> 3 (I) in which: X represents a hydrogen atom or a halogen substituent at any position of the phenyl ring, 5 6 represents a hydrogen atom, a hydroxyl group, a G = N group, a GONRR group, Wherein R and R are each independently hydrogen or alkyl QQ 1 to 6 carbon atoms or a radical COGr, wherein R is hydrogen or alkyl having 1 to 4 carbon atoms, is hydrogen or alkyl having 1 to 3 carbon atoms, is - _{{CH2) n} - wherein fl is a number of 2 to 4, or OH R ³ and R ' -ch _{2 and} ch ₂ are each independently hydrogen, C 1 -C 6 alkyl, GH ₂ -alkenyl wherein C 2 -C 5 alkenyl or C 1 -C 3 phenylalkyl is present in the alkyl moiety, or both of these symbols, together with the adjacent nitrogen atom, form a heterocyclic radical containing from 5 to 7 ring atoms, and pharmaceutically acceptable salts thereof, characterized in that the epoxide of formula II (II) 215053 in which □ X and R are as defined above, and r is as defined above or represents a protected hydroxyl group, condenses with an amine of formula HNR ³ r ⁴ , where r 3 and R ⁴ are as defined above, and optionally the cleavage group is cleaved from the resulting product, whereupon the optionally obtained base of formula 1 is converted into a pharmaceutically acceptable salt. 2. The process of item 1 for the preparation of compounds of the above general formula I, wherein: X represents a hydrogen atom or a fluorine, chlorine or bromine atom, attached at the 5-position of the biphenylyl ring, r 'represents a hydrogen atom, a hydroxyl group, a C = N, COHH or COOH group; R represents a hydrogen atom or a methyl group, Z represents a group wherein a is 2 or 3, or represents -CHgCHCOlUGHg- when r 'is hydrogen, and R ^ and R ^ are each independently hydrogen, C až-C alky alkyl, CHg-alkenyl, where Cenyl-C alk alkenyl contains C až-Ceny phenylalkyl, or both these symbols, together with the adjacent nitrogen atom, form a heterocyclic radical selected from the group of pyrrolidine and piperidine, and their pharmaceutically acceptable acid addition or quaternary ammonium salts, characterized in that compounds of the above formula II and amines of the formula HNR are used as starting materials R ⁴ wherein X, R 4, + and R ⁴ are as defined herein and ar 'is as defined herein or is a protected hydroxyl group.