HU182667B - Process for preparing diphenyl-alkane ethers - Google Patents

Abstract

NEW MATERIAL:Compound of formula I [R<1> and R<2> are H, halogne, lower alkyl, nitrile, etc.; A is a group of formula II (R<3> and R<4> are H, lower alkyl, aralkyl, or may form a ring of pyrrolidino, piperidino, etc.; together with adjacent N to b1 and b2 are lower alkylene chain] and its salts. EXAMPLE:1-[ 3-( N, N-dimethylamino )propoxy ]-1-( p-fluorophenyl )-4-phenylbutane. USE:Remedies for troubles of the brain and the coronary vessels, which have vasodilating action, spasmolytic action, activating action of brain metabolism and suppressing action of coagulation of blood platelets. PROCESS:The compound of formula I is obtained by reacting a compound of formula III (R<5> and R<6> are H, halogen, etc.; X' is halogen) and a compound of formula IV, and, if necessary, reducing the nitor group, or removing the benzyl or methyl group from the benzyloxy of benzylamino group.

Description

The present invention relates to a process for the preparation of compounds of the formula I and their salts

R ¹ is phenyl, furyl, thienyl, pyridyl or optionally substituted with one or two substituents; 25

R ² is phenyl optionally substituted with one or two substituents;

A ¹ and A ² are alkylene and

Z ¹ is a group -NR ³ R ⁴ wherein

R ³ and R ⁴ are each independently hydrogen, alkyl or phenylalkyl, or -NR ³ R ⁴ represents a heterocyclic group) by reaction of the corresponding hydroxy compound with haloalkylamine.

The novel compounds of formula I are useful as active ingredients in vasodilator compositions.

r'-ch-a'-r * R-CH-AR ⁷ d'-A ^ Z * ·

OH (i) (II) (III) rc-a'-r ⁷

0-Α * -0 * ι s a t

H-z D-X-D (arc) (V) (VII)

-1182667

The present invention relates to a process for the preparation of new diphenylalkane ethers. The novel compounds of the present invention have valuable biological effects, in particular cerebral vasodilators and antioxidant effects.

The process of the present invention provides compounds of formula I and pharmaceutically acceptable acid addition salts thereof, wherein R ¹ is furyl, thienyl or pyridyl, or optionally substituted with one or two halogen atoms, C 1-4 alkyl, C 4 -C 4 alkoxy, amino, nitro, di (C 1-4 alkyl) amino, benzyloxy, hydroxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, 1-4 phenyl substituted with C 1-4 alkanoylamino, C 1-4 alkylamino and / or N- (C 1-4 alkyl) -N- (C 1-4 alkanoyl) amino;

R ² is phenyl optionally substituted with one or two halogen atoms, C 1 -C 4 alkyl and / or C 1 -C 4 alkoxy; Z ¹ is -NR ³ R ⁴ , wherein

R ³ and R ⁴ are independently hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or

R ³ and R ⁴ together with the adjacent nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic group optionally containing oxygen or other nitrogen atoms, wherein the additional nitrogen atom is optionally hydrogen, C 1-4 alkyl, phenyl- C1-C4 alkyl) or phenyl;

A ¹ is C 2 -C 6 alkylene and A ² is C 2 -C 4 alkylene).

In the definition of compounds of formula I, "halogen" means fluorine, chlorine, bromine and iodine, while "phenyl (C1-C4) alkyl" means benzyl, phenylethyl, phenylisopropyl and we mean similar groups. C 1-4 -alkyl and C 1-4 -alkoxy may contain straight or branched chain alkyl; examples of which are methyl, ethyl, η-propyl, isopropyl, η-butyl, methoxy, ethoxy, η-propoxy, isopropoxy and n-butoxy. The term "C2-C6 alkylene" and "C2-C4 alkylene" refer to straight or branched alkylene groups such as ethylene, trinethylene, tetramethylene, pentamethylene, hexamethylene, methyl ethylene, methyl propylene and the like. we mean groups. Examples of "heterocyclic group" include pyrrolidino, piperidino, homopiperidino, morpholino, piperazino, N- (C 1-4 alkyl) piperazino, N- [phenyl (C 1-4) alkyl] piperazino or an N-phenylpiperazino group.

AJ. Pharmaeol. Exp't'l. Therap. 112, 318-325 (1954) discloses diphenylalkane ether derivatives of formula (A) wherein R is inter alia hydrogen, halogen or alkyl. These compounds have anti-histamine activity.

Surprisingly, it has been found that the novel diphenylalkane ether derivatives of formula (I) possess several valuable biological activities other than anti-histamine activity. These compounds primarily have cerebral and coronary vasodilating effects, improve organ oxygenation, have antispasmodic activity, and inhibit platelet aggregation. The ethers of the formula I have a very strong effect; for example, the brain vasodilator activity of the compounds of formula I in rats is, for example, many times higher than that of the compounds of formula A. The ethers of the formula (I) and their pharmaceutically acceptable salts may accordingly be used in medicine for the prevention and treatment of cerebral or coronary artery calcification, senility, and cerebral circulation disorders. Preferred compounds for pharmaceutical use are those compounds of formula I wherein R ^{1 is} phenyl or substituted phenyl, R ^{2 is} phenyl and A ¹ is trimethylene or tetramethylene. Especially preferred are the ether derivatives of formula (I) wherein R ^{1 is} phenyl or halophenyl, R ^{2 is} phenyl, A ^{1 is} trimethylene or tetramethylene, and Z ¹ is dimethylamino or piperidino. .

The novel compounds of formula (I) according to the invention may be prepared by:

a) (II) compound of formula (wherein R ⁶ and R ⁷ are independently selected from furyl, thienyl or pyridyl optionally substituted by one or two halogen, C1-4 alkyl, C1-4 alkoxy, nitro -, di- (C 1-4 alkyl) amino, benzyloxy, C 1-4 alkylthio and / or -N (- (C 1-4 alkyl) -N (C 1-4 alkanoyl) amino- phenyl and A ¹ is as defined above) is reacted with a halogen derivative of general formula (III) wherein Z ² is as defined for Z ¹ , except for unsubstituted piperazino, amino and -NMR ³ or -NMR ⁴ identical; D ¹ is halogen and A ² is as defined above); obsession

b) reacting a compound of formula IV (wherein D ² is halogen and A ¹ , A ² , R ^e and R ⁷ are as defined above) with an amine derivative of formula V (wherein Z ¹ is a above);

and optionally subjecting the compound (I) thus obtained to one or more of the following optional conversions: reducing the nitro group; debenzylating the benzyloxy group of the benzyloxy group; acylating or alkylating the amino group; the C 1-4 alkylthio group is oxidized and / or the N- (C 1-4 alkyl) -N-methylamino group is phoxoxycarbonylated, and the resulting N- (C 1-4 alkyl) -N - cleaving the alkoxycarbonyl group from (C1-C4 alkoxy) carbonylamino; then, if desired, burn in this way

-2182667 is converted to a non-toxic pharmaceutically acceptable acid addition salt.

The reactions listed above are described in detail below.

(a) Preparation of compounds of formula (I) by reaction of compounds of formula (II) and (III):

The compounds of formula (II) are usually in the presence of an alkali (e.g., alkali metal hydride, alkali metal alkoxide, alkali metal amide or alkali metal) in an inert solvent (such as benzene, toluene, xylene, dimethylformamide or dinethylsulfoxide). The reaction is carried out at a temperature of from about 0 ° C to the reflux temperature of the reaction mixture (preferably from about 50 ° C to about 150 ° C).

(b) Preparation of compounds of formula (I) by reaction of compounds of formula (IV) and (V):

The compounds of the formula (TV) are usually reacted with the compounds of the formula (V) in an inert solvent at a temperature between 0 ° C and the boiling point of the reaction mixture. Examples of inert solvents are alcohols (such as methanol or ethanol), ethers (such as tetrahydrofuran or dioxane), amides (such as dimethylformamide or dimethylacetamide), aromatic hydrocarbons (such as benzene, toluene or xylene), ketones (such as methyl ethyl ketone). or methyl isobutyl ketone) or dimethylsulfoxide. the reaction is preferably carried out in the presence of a base such as alkali metal hydroxide, alkali metal carbonate, alkali metal bicarbonate, triethylamine or pyridine.

Reduction of nitro group and debenzylation of benzyloxy or benzylamino group:

The reactions may be carried out by reduction methods known per se, for example hydrogenation in the presence of palladium on charcoal. The benzyloxy group may also be debenzylated by acid treatment; as the acid, for example, acetic acid, hydrochloric acid or Lewis acids.

Dimethylation of N- (C 1 -C 4 alkyl) -N-methylanevine:

The reaction may be carried out in a manner known per se, for example by reacting the methyl derivative with ethyl chloroformate and hydrolyzing the resulting product with alkali.

Acylation of the amino group:

The amino group may be acylated in a manner known per se, for example by reacting the corresponding amino compound in the presence of a base at 0-30 ° C with the appropriate acid halide (such as acetyl chloride, propionyl chloride or butyryl chloride).

Alkylation of the amino group:

The amino group may be alkylated in a manner known per se, for example by reacting the amino compound in the presence of a base at a temperature from 20 ° C to the boiling point of the reaction mixture with the appropriate alkyl halides such as methyl bromide or ethyl bromide.

Oxidation of C 1-4 alkylthio:

The C 1-4 alkylthio group can be oxidized with hydrogen peroxide in an inert solvent medium at 20-50 ° C.

The starting compounds of formulas II and IV can be prepared by the process outlined in Scheme ¹ , wherein R ^e , R ⁷ A ¹ , A ² and D ² are as defined above.

Compounds of formula (VI) may be converted into compounds of formula (II) by reduction. The reducing agent may be, for example, a metal hydride (such as sodium borohydride or calcium borohydride), but the compounds of formula VI may also be hydrogenated in the presence of a catalyst (e.g. palladium on charcoal, nickel or platinum oxide). The compounds of formula (II) are then reacted with the compounds of formula (VII), wherein D ^{3 is a} halogen atom, A ² and D ² are as defined above, to give the corresponding compounds of formula IV. The reaction may be carried out in an inert solvent (such as benzene, toluene, xylene, dimethylformamide or dinethylsulfoxide) in the presence of a base at a temperature between 30 ° C and the boiling point of the reaction mixture (preferably 50-150 ° C). Suitable bases are, for example, alkali metals, alkali metal alkoxides, alkali metal amides or alkali metal hydrides.

The therapeutic activity of the compounds of formula I is confirmed by the following test:

Determination of Ant i-Barium Chloride Activity:

1- [3- (N, Ndinethylamino) propoxy] -1,5-diphenylpentane is used as the test chemical of formula (1) and barium chloride antagonist activity is measured in guinea pig ileum isolated as a standard test for vasodilator activity. .

Pieces of ileum about 2 cm long were cut out and immersed in a bath containing 10 ml Tyrod's solution. The solution was kept at 30 ° C and air was bubbled through. The concentration is measured isotonic. Muscle tension is approx. 0.5 g. The concentration of barium chloride is 3 to 10 ^-4 g / ml. The test compound is added to the bath and kept in contact with the tissue for 3 minutes prior to the addition of barium chloride. The anti-barium chloride activity was 91% (10 µg / ml).

The compounds of formula (I) may be formulated into pharmaceutical compositions by known methods of pharmaceutical manufacture.

Further details of the process of the invention are set forth in the following examples, without limiting it to these examples.

Example 1

A mixture of 5.0 g of 1- (p-chlorophenyl) -4-phenyl-1-butanol, 10 g of γ-dimethylaminopropyl chloride, 2.0 g of 65% sodium hydride in 100 ml of toluene was added. reflux for a minute. After cooling, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and chromatographed on silica gel. 1- [3- (N, N-dimethylamino) propoxy] -1- (p-fluorophenyl) -4-phenylbutane is obtained; product fumarate at 80-83 ° C

-3182667 melt. NMR δ (CDCl ₃ ): 2.17 (6H, s), 3.28 (2H, t), 4.16 (1H, 6), 6.8-7.4 (9H, m).

Example 2

By following the procedure described in Example 1, the following compounds were prepared:

- [3- (N, N-dimethylamino) propoxy] -1-thienyl-4-phenylbutane, m.p. 70-75 ° C (fumarate). NMR δ (CDCl ₃ ): 2.17 (6H, s), 2.60 (2H, t), 3.36 (2H, t-d), 4.45 (1H, t), 6.8-7 , 3 (8 H, m);

1- [3- (N, N-dimethylanino) propoxy] -1- (p-benzyloxyphenyl) -4-phenylbutane, a reddish oil. NMR δ (CDCl ₃ ): 2.18 (6H, s), 3.28 (2H, t), 4.14 (1H, t), 5.04 (2H, s), 6.8-7.5 (14 H, m);

1- [3- (Ν, Ν-dimethylamino) propoxy] -1,4-diphenylbutane, m.p. 105-107 ° C (oxalate), 89-92 ° C (citrate). NMR δ (CDCl ₃ ): 2.22 (6H, s), 3.25 (2H, t), 4.14 (1H, t), 7.0-7.3 (10H, m);

1- [3-N, N-dimethylamino) propoxy] -1,5-diphenylpentane, m.p. 81-85 ° C (oxalate). NMR δ (CDCl ₃ ): 2.18 (6H, s), 3.30 (2H, t), 4.17 (1H, t), 7.1-7.3 (10H, m); 1- [3- (N, N-dimethylanino) propoxy] -1- (p-methoxyphenyl) 4-phenylbutene, m.p. 70-73 ° C (fumarate). NMR δ (CDCl ₃ ): 2.15 (6H, s), 3.25 (2H, t), 3.76 (3H, s), 4.10 (1H, t), 6.7-7.3 (9 H, m);

1- [3- (N, N-dimethylamino) propoxy] -1- (4-pyridyl) -4-phenylbutane, m.p. 103-106 ° C (fumarate). NMR δ (CDCl 3): 2.19 (6H, s), 3.24 (2H, t), 4.19 (1H, t), 7.1-

7.3 (7H, m); 8.5-8.7 (2H, m);

1- [3- (N, N-dimethylamino) propoxy] -1- (2-pyridyl) -4-phenylbutane, m.p. 92-94 ° C (oxalate). NMR δ (CDCl ₃ ): 2.18 (6H, s), 3.38 (2H, t), 4.36 (1H, t), 7.0-7.7 (7H, m), 8.4 -8.6 (1H, m);

1- [3- (N, N-dimethylamino) propoxy] -1- (p-dinethylaminophenyl) -4-phenylbutane, m.p. 77-80 ° C (fumarate. NMR δ CDCl 3): 2.17 (6H, s), 2.90 (6H, s), 3.28 (2H, t), 4.10 (1H, t), 6.6-7.3 (9H, m) );

1- [3- (N, N-dimethylamino) propoxy] -1- (p-methylphenyl) 4-phenylbutane, m.p. 98-102 ° C (fumarate). NMR δ (CDCl ₃ ): 2.17 (6H, s), 2.30 (3H, s), 3.28 (2H, t), 4.15 (1H, t), 7.1-7.3 (9 H, m);

1- [3- (N, N-dimethylamino) propoxyl-1- (m, p-dimethoxyphenyl) -4-phenylbutane, m.p. 79-85 ° C (oxalate). NMR δ (CDCl ₃ ): 2.16 (6H, s), 3.28 (2H, t), 3.84 (6H, s), 4.10 (1H, t), 6.7-7.3 (8 H, m);

1- [3- (N, N-dimethylamino) propoxy] -1,3-diphenylpropane, m.p. 103-105 ° C (fumarate). NMR 8 (CDCJ _3): 2.20 (6H, s), 3.32 (2H, t), 4.19 (1H, t), 7.1-7.4 (10H, m);

1- [3- (N, N-dimethylamino) propoxy] -1-furyl-4-phenylbutane, m.p. 75-85 ° C (oxalate). NMR δ (CDCl ₃ ): 2.20 (6H, s), 3.71 (2H, t), 5.47 (1H, t), 6.3-6.5 (2H, m),

7.2-7.4 (6 H, m);

1- [3- (N, N-dimethylamino) -propoxy] -1- (o-chlorophen = 4-phenyl-butane, m.p. 65-70 ° C (fumarate). NMR δ (CDCl ₃ ): 2.18 (6H, s), 3.32 (2H, t), 4.73 (1H, t), 7.0-7.5 '(9H>m);

1- (3-piperidinopropoxy) -1,5-diphenylpentane, m.p. 112-118 ° C (oxalate). NMR δ (CPC ₁₃ ): 1.3-2.1 (14H, m),

2.1-2.8 (8H, ni), 3.28 (2H, t), 4.16 (1H, t), 7.1-7.4 (10H, m);

1- (3-piperidinopropoxy) -1,4-diphenylbutane, m.p. 81-84 ° C (fumarate). NMR δ (CDCl ₃ ): 1.4-2.0 (12H, m),

2.2-3.0 (8H, m), 3.30 (2H, t), 4.17 (1H, t), 7.0-7.4 (10H, m);

1- [2- (N, N-diethylamino) ethoxy] -1,5-diphenylpentane, m.p. 109-112 ° C (oxalate). NMR δ (CDCl ₃ ): 0.97 (6H, s),

2.3-2.8 (8H, m), 3.34 (2H, t), 4.18 (1H, t), 7.1-7.3 (10H, ro);

1- [2- (N, N-dimethylamino) oxy] -1,4-diphenylbutane, m.p. 80-81.5 ° C (oxalate). NMR δ (CDCl ₃ ): 1.4-1.9 (4H, m), 2.20 (2H, t), 2.3-2.8 (4H, m), 3.36 (2H, t) , 4.17 (1H, t), 7.0-7.3 (10H, m);

1- [2- (N, N-dimethylamino) ethoxy] -1,3-diphenylpropane, m.p. 125-126 ° C (oxalate). NMR δ (CDCl ₃ ): 2.22 (6H, t), 2.4-2.9 (4H, m), 3.40 (2H, t), 4.24 (1H, t), 7.1 -7.4 (10 H, m);

1- [3- (N, N-dimethylamino) propoxy] -1- (p-isopropylthiophenyl) -4-phenylbutane, m.p. 96-97 ° C (fumarate). NMR δ (CDCl3): 1.30 (6H, d), 1.53-1.87 (6H, ni), 2.20 (6H,

s), 2.60 (2H, t), 3.1-3.5 (3H, m), 4.14 (1H, t), 7.0-7.4 (9H, ni);

1- [4- (N, N-Dinethylamino) butoxy] -1,4-diphenylbutane, m.p. 98-99 ° C (oxalate). NMR δ (CDCl ₃ ): 2.20 (6H, s),

3.27 (2H, t), 4.17 (1H, t), 7.0-7.3 (10H, m); 1- (2-pyrrolidinoethoxy) -1,5-diphenylpentane, m.p.

92.5 ^° C (oxalate), NMR δ (CDCl ₃ ); 1.2-1.9 (10 H, m),

2.2- 2.7 (8H, m), 3.35 (2H, t), 4.14 (1H, t), 7.0-7.4 (10H, m);

1- (2-morpholinoethoxy) -1,5-diphenylpentane, m.p. 107.5-109.0 ° C (oxalate), NMR δ (CDCl ₃ ): 1.0-1.8 (6H) , m), 2.0-2.6 (8H, m), 3.40 (2H, t), 3.5-3.8 (4H, m), 4.18 (1H, t), 7, 0-7.4 (10 H, m);

1- (2-piperidinoethoxy) -1,5-diphenylpentane, m.p.

130.5 ° C (oxalate), NMR δ (Cl) Cl ₃ ): 1.0-2.0 (12H, m)

2.3-27, (8H, ni), 3.38 (2H, t), 4.15 (1H, t), 7.0-7.4 (10H, m);

1- (3-piperidinopropoxy) -1- (m-nitrophenyl) -4-phenylbutane, NMR δ (CDCl ₃ ): 1.2-2.0 (12H, m), 2.2- 2.6 (6H, m), 2.6 (2H, t), 3.32 (2H, t), 4.25 (1H, t), 7.0-8.3 (9H, m);

1- (3-piperidinopropoxy) -1,5-bis (3,4-dimethoxyphenyl) pentane, NMR δ (CDCl ₃ ): 3.28 (2H, t), 3.84 (12H, s) .

4.12 (1H, t);

1- (3-piperidinopropoxy) -1,5-bis (3,4-dimethylphenyl) pentane, NMR δ (CDCl ₃ ): 2.20 (6H, s), 2.22 (12H, s) .

3.28 (2H, t), 4.14 (1H, t), 7.1-7.3 (8H, m);

1- (3-piperidinopropoxy) -1-phenyl-4- (p-methoxyphenyl) butane, NMR δ (CDG ₃ ): 3.29 (2H, t), 3.80 (3H, s), 4.17 • 1H, t);

1- (3-piperidinopropoxy) -1-phenyl-4- (m-methylphenyl) butane, NMR δ (CDCl ₃ ): 2.40 (3H, s), 3.30 (2H, t) , 4.18 (1H, t);

1- (3-piperidinopropoxy) -1-phenyl-4- (3,4-dichlorophenyl) butane, NMR δ (CDCl ₃ ): 3.30 (2H, t), 4.16 (1H, t); 1- (3-piperidinopropoxy) -1,5-bis (4-fluorophenyl) pentane, NMR δ (CDCl ₃ ): 3.28 (2H, t), 4.16 (1H, t), 6.8-7.2 (5H, m).

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Example 3

1.5 g of 1- [3- (N, N-dimethylamino) propoxy] -1- (p-benzyloxyphenyl) -4-phenylbutane prepared in Example 2,

A mixture of 0.5 g of 10% palladium on charcoal catalyst (wet mass with 50% solids), 1 g of acetic acid and 50 ml of ethanol is kept under hydrogen at room temperature under vigorous stirring until the amount of hydrogen is taken up. The reaction mixture was poured into water, basified with aqueous ammonia solution and extracted. The catalyst is filtered off, the organic phase is washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 1- [3- (N, N-dimethylamino) propoxy] 1- (p-hydroxyphenyl) -4-phenylbutane is obtained; 91.5—

94.5 ° C (oxalate). NMR δ (CDCl ₃ ): 2.22 (6H, s), 3.27 (2H, t), 4.08 (1H, t), 6.6 7.3 (9H, m).

Example 4

a) A mixture of 30 g of 1,4-diphenyl-1-butanol, 42 g of 1-bromo-3-chloropropane, 9.5 g of 65% sodium hydride and 400 ml of toluene is refluxed for 2 hours. The reaction mixture was cooled, poured into water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo. 1- (3-chloropropoxy) -1,4-diphenylbutane is obtained.

b) A mixture of 1- (3-chloropropoxy) -1,4-diphenylbutane (1.5 g), morpholine (7 ml), potassium carbonate (1.5 g) and dimethylformamide (15 ml) was heated at 100 ° C for 1 hour. After cooling, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic solution was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the concentrate was chromatographed on silica gel. 1- (3-morpholinopropoxy) -1,4-diphenylbutane is obtained; the oxalate of the product melts at 138-139 ° C. NMR δ (CDCl ₃ ): 1.5-2.1 (6H, m), 2.2-2.9 (8H, m), 3.33 (2H, t), 3.69 (4H, t) , 4.17 (1H, t), 7.0-7.4 (10H, m).

Example 5

The following compounds were prepared according to the procedure described in Example 4:

1- [3- (4-methylpiperazino) propoxy] -1,4-diphenylbutane, m.p. 219-221 ° C (oxalate), NMR δ (CDCl ₃ ): 1.4-2.0 (6H, m), 2.23 (3H, s), 2.40 (8H, s), 3.31 (2H, t), 4.20 (1H, t), 7.0-7.4 ( 10 H, m);

1- (3-benzylaminopropoxy) -1,4-diphenylbutane, m.p. 97-98 ° C (oxalate), NMR δ (CDCl ₃ ): 1.4-2.0 (6H, m), 2.4-2.8 (4H, m), 3.32 (2H, t), 3.73 (2H, s), 4.14 (1H, t), 7.0-7.4 (15H, m);

1- (3-methylaminopropoxy) -1,4-diphenylbutane, m.p. 138-140 ° C (oxalate), NMR δ (CDCl ₃ ): 1.5-2.0 (6H, m), 2.39 (3H, s), 3.34 (2H, t), 4.20 (1H, t), 7.1-7.4 (10H, m);

(1- (3-isopropylaminopropoxy) -1,4-diphenylbutane, m.p.

107-108 ° C (oxalate), NMR δ (CDCl ₃ ): 1.0 (6H, d),

1.4-2.0 (6H, m), 2.4-2.9 (5H, m), 3.34 (2H, t), 4.20 (1H, t), 7.0-7.4 ( 10 H, m);

1- (3-aminopropoxy) -1,4-diphenylbutane, m.p. 143-147 ° C (oxalate), NMR δ (CDCl ₃ ): 1.4-2.0 (6H, m), 2.4-2.9 (4H, m), 3.32 (2H, t), 4.17 (1H, t), 7.0-7.4 (10H, m); 1- (3-pyrrolidinopropoxy) -1,5-diphenylpentane, m.p. 78.5-79.5 ° C (citrate), NMR δ (CDCl ₃ ): 1.0-2.0 (12H , m), 2.4-2.8 (8H, m), 3.31 (2H, t), 4.16 (1H, t), 7.0-

7.4 (10 H, m);

1-3-hexamethylene-iminopropoxy) -1,5-diphenylpentane, m.p. 110-112 ° C (oxalate), NMR δ (CDCl ₃ ): 1.1-1.9 (16H, m) , 2.4-2.7 (8H, m), 3.30 (2H, t), 4.15 (1H, t), 7.0-7.4 (10H, m);

1- (3-morpholinopropoxy) -1,5-diphenylpentane, m.p. 78-80 ° C (fumarate), NMR δ (CDCl ₃ ): 1.1-1.95 (8H, m),

2.2-2.7 (8H, m), 3.30 (2H, t), 3.67 (4H, t), 4.14 (1H,

t), 7.0-7.4 (10 H, m);

1- (3-pyrrolidinopropoxy) -1,4-diphenylbutane, m.p. 110-112 ° C (cifrate), NMR δ (CDCl ₃ ): 1.4-2.0 (10H, in),

2.4-2.75 (8H, m), 3.31 (2H, t), 4.19 (1H, t), 7.0-7.4 (10H, m);

1- (4-piperidinobutoxy) -1,4-diphenylbutane, NMR δ (Cl> Cl ₃ ): 1.2-2.0 (12H, m), 2.1-2.76 (8H, m), 3.25 (2H, t), 4.17 (1H, t), 7.0-7.4 (10H, m);

- [3- (4-Benzyl-piperazino) -propoxy] -1,4-diphenyl-butane, NMR δ (CDCl ₃ ): 3.32 (2H, t), 3.43 (2H, s), 4, 25 (1H, t); 1- [3- (4-Phenyl-piperazino) -propoxy] -1,4-diphenyl-butane, NMR δ (CDCl ₃ ): 3.32 (2H, t), 4.20 (1H, t).

Example 6

a) 1.0 g of 1- [3- (N, N-dimethylamino) propoxy] -1- (fluorophenyl) -4-phenylbutane, 2.75 g of potassium carbonate, 11 ml of chloro- a mixture of ethyl formic acid and 20 ml of toluene was refluxed for 2 hours. After cooling, the reaction mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 1- [3- (N-Methyl-N-ethoxycarbonylamino) propoxy] -1- (p-fluorophenyl) -4-phenylbutane is obtained.

b) 0.9 g of 1- [3- (N-methylN-ethoxycarbonylamino) -propoxy] -1- (p-fluorophenyl) -4-phenyl-butane, 0.9 sodium hydroxide prepared as described above. and 10 ml of dimethylsulfoxide were heated at 110 ° C for 1 hour. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. 1- (3- (N-methylamino) propoxy) -1- (p-fluorophenyl) -4-phenylbutane was obtained as a reddish oily residue; NMR (CDC1 _3): δ = 2.43 (s), 3.30 (t), 4.01 (t).

Example 7

0.2 g of 1- (3-piperidinopropoxy) -1- (m-nitrophenyl) -4-phenylbutane prepared in Example 2, 0.07 g of 5%

A mixture of -5182667 palladium on carbon (50% moisture) and 15 mL of ethanol was stirred vigorously at room temperature under hydrogen atmosphere until the theoretical amount of hydrogen was taken up. The reaction mixture was poured into water and extracted with ethyl acetate. The catalyst is filtered off, the organic phase is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. 1- (3-piperidinopropoxy) -1- (m-aminophenyl) -4-phenylbutane is obtained. NMR δ (CDCl ₃ ): 1.1-2.1 (12H, m), 2.4-2.9 (6H, m), 3.30 (2H, t), 4.06 (1H, t) , 6.45-7.60 (9 H, m).

Example 8

Acetyl chloride (0.08 g) was added to a mixture of 1- (3-piperidinopropoxy) 1- (m-aminophenyl) -4-phenylbutane (0.36 g), potassium carbonate (0.15 g) and tetrahydrofuran (5 ml) at room temperature. . The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel. 1- (3-piperidinopropoxy) -1- (m-acetylaminophenyl) -4-phenylbutane is obtained. NMR δ (CDCl _a): 2.1 (3H, s), 3.32 (2H, t), 4.10 (1H, t), 7.0-7.8 (9H, m).

Example 9

In a manner analogous to that described in Example 8, 1- (3-piperidinopropoxy) -1- [m- (N-acetyl-N-ethyl) ananino phenyl] -4-phenylbutane was prepared. NMR δ (CDCl ₃ ); 1.3 (3H, t), 2.1 (3H, s), 3.32 (2H, t). 4.12 (1H, t), 7.0-7.8 (9H, m).

Example 10

A mixture of 1- (3-piperidinopropoxy) -1- (m-aminophenyl) -4-phenylbutane (370 mg) and ethyl bromide (110 mg) was stirred at room temperature. The reaction mixture was poured into water, basified with aqueous ammonium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, evaporated in vacuo and the residue chromatographed on silica gel. There was thus obtained 1- [3-piperidinopropoxy) -1- (m-ethylaminophenyl) -4-phenylbutane. NMR δ (CDCl 3): 3.28 (2H, t), 4.14 (1H, t), 6.6-7.3 (9H, m).

Example 11

100 mg 1- [3- (N, N-din] ethylamine) propoxy] -1- (p-isopropylthiophenyl) -4-phenylbutane, 64 mg sodium periodate, 7 ml water and 10 ml of methanol at room temperature

Stir for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, evaporated in vacuo and the residue chromatographed on silica gel. 1- [3- (N, N-dimethylamino) propoxy] -1- (p-isopropylsulfinylphenyl) -4-phenylbutane is obtained. NMR δ (CDCl ₃ ): 1.20 (6H, t), 1.4-2.0 (6H, m), 2.22 (6H, s), 2.62 (2H, t), 3.30 (2H, t), 4.23 (1H, t), 7.0-7.7 (9H, m).

Claims (8)

Patent claims: A process for the preparation of diphenylalkane ethers of general formula (I) wherein: R ¹ is furyl, thienyl or pyridyl, or optionally with one or two halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, amino, nitro, di- (C 1-4 alkyl) amino- , benzyloxy, hydroxy, C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkanoylamino, C 1-4 alkylamino, and / or N- (1-) Phenyl substituted with C4 alkyl) -N- (C1-C4 alkanoyl) amino; R ² is phenyl optionally substituted with one or two halogen atoms, C 1-4 alkyl and / or C 1-4 alkoxy; Z ¹ is a group of formula -NR ³ R ⁴ wherein R ³ and R ⁴ are each independently hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or R ³ and R ⁴ together with the adjacent nitrogen atom to which they are attached form a 5-7 membered saturated heterocyclic group optionally containing oxygen or other nitrogen atoms, wherein the additional nitrogen atom is optionally hydrogen, C 1-4 alkyl, phenyl- C1-C4 alkyl) or phenyl; A ¹ is C 2 -C 6 alkylene and A ² is C 2 -C 4 alkylene) and its non-toxic pharmaceutically acceptable acid addition salts are characterized in that a) (II) compound of formula (wherein R ⁶ and R ⁷ are independently selected from furyl, thienyl or pyridyl optionally substituted by one or two halogen, C1-4 alkyl, C1-4 alkoxy, nitro with di- (C 1-4 alkyl) amino, benzyloxy, C 1-4 alkylthio and / or N- (C 1-4 alkyl) -N- (C 1-4 alkanoyl) amino. substituted phenyl group and A ¹ is as defined above) is reacted with a halogen derivative of general formula (III) (wherein Z ² is as defined for Z ¹ , except for unsubstituted piperazino, amino and -NHR ³ or -NHR ⁴ identical; D ¹ is halogen and A ² is as defined above); -brain b) reacting a compound of formula IV (wherein D ² is halogen and A ¹ , A ² , R ⁸ and R ⁷ are as defined above) with an amine derivative of formula V (wherein Z ¹ is as defined above); -6182667 and optionally subjecting the compound (I) thus obtained to one or more of the following optional conversions: reduction of the nitro group; debenzylating the benzyloxy or benzylamino group; acylating or alkylating the amino group; the C 1-4 alkylthio group is oxidized and / or the N- (C 1-4 alkyl) -N-methylamino group is alkoxycarbonylated and then the N- (C 1-4 alkyl) -N- cleaving the alkoxycarbonyl group from (C1-C4 alkoxy) carbonylamino; and optionally converting the compound of formula (I) thus obtained into a non-toxic pharmaceutically acceptable acid addition salt. (Priority: March 28, 1980) A process for the preparation of the compounds of formula (I) and their non-toxic pharmaceutically acceptable acid addition salts according to claim 1, wherein R ¹ is furyl, thienyl or pyridyl or optionally substituted with one or two halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, nitro, amino, di- (C 1-4 alkyl) amino- phenyl substituted with benzyloxy and / or hydroxy; Z ¹ is a group of formula -NR ³ R ⁴ wherein R ³ and R ⁴ each independently represent hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or R ³ and R ⁴ together with the adjacent nitrogen to which they are attached are pyrrolidino, piperidino or morpholino, or form on the nitrogen atom a piperazino group optionally substituted with C 1-4 alkyl, phenyl (C 1-4 alkyl) or phenyl; and R ² is as defined in claim 1), wherein appropriate starting materials are used wherein R R is furyl, thienyl or pyridyl or optionally substituted with one or two halogen atoms, C 1-4 alkyl, phenyl substituted with C 1-4 alkoxy, nitro, di- (C 1-4 alkyl) amino and / or benzyloxy; and, if desired, converting the compound of formula (I) thus obtained into a non-toxic pharmaceutically acceptable acid addition salt. (Priority: April 2, 1979) A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is optionally C 1-4 alkylthio, C 1-4 alkylsulfinyl, C 1-4 alkanoylamino, C 1-4 alkylamino, or N- (C 1-4 alkyl) -N-. phenyl substituted with (C 1-4 alkanoyl) amino; Z ¹ is a group of the formula -NR ³ R ⁴ wherein R ³ and R ⁴ are independently hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or R ³ and R ⁴ together with the adjacent nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; form on the nitrogen atom a piperazino group optionally substituted with C 1-4 alkyl, phenyl or phenyl (C 1-4 alkyl); and R ² is as defined in claim 1), wherein appropriate starting materials are used wherein R R is optionally a C 1-4 alkylthio, nitro or N- (C 1-4 alkyl) -N- Phenyl substituted with (C 1-4 alkanoyl) amino. (Priority: March 28, 1980) A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is phenyl optionally substituted with one or two halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, nitro, amino, di- (C 1-4 alkyl) amino, benzyloxy and / or hydroxy. ; Z ¹ is a group of formula -NR ³ R ⁴ wherein R ³ and R ⁴ are each independently hydrogen, C 1-4 alkyl or phenyl (C 1-4) alkyl, or R ³ and R ^{4 taken} together with the adjacent nitrogen to which they are attached are pyrrolidino, piperidino or morpholino. or form on the nitrogen atom a piperazino group optionally substituted with C 1-4 alkyl, phenyl (C 1-4 alkyl) or phenyl; R ² is as defined in claim 1), wherein appropriate starting materials are used wherein R R is optionally substituted with one or two halogen atoms, C 1-4 alkyl, C 1-4 alkoxy, nitro, di- ( phenyl substituted with C 1-4 alkyl) amino and / or benzyloxy. (Priority: April 2, 1979) A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is furyl, thienyl or pipridyl; R ² is phenyl; Z ¹ is a group of formula -NR ³ R ⁴ wherein R ³ and R ⁴ are independently hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or R ³ and R ⁴ together with the adjacent nitrogen to which they are attached are pyrrolidino, piperidino or morpholino; optionally substituted on the nitrogen atom with a C1-4 alkyl, phenyl (C1-C4) alkyl or phenyl substituted piperazino group) using appropriate starting materials wherein R @ 4 is furyl, thienyl or pyridyl and R ⁷ is phenyl. (Priority: April 2, 1979) -7182667 A process for the preparation of a compound of formula (I) according to claim 1, wherein R ¹ is phenyl or halophenyl; R ² is phenyl; f A ¹ is trimethylene or tetramethylene; Z ¹ is a group of formula -NR ³ N ⁴ wherein R ³ and R ⁴ are independently hydrogen, C 1-4 alkyl or phenyl (C 1-4 alkyl) or R ³ and R ⁴ together with the adjacent nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino, or piperazino substituted with 1 to 4 carbon atoms, optionally substituted with 1 to 4 carbon atoms, phenyl (C 1 -C 4 alkyl), or 1 phenyl), using appropriate starting materials wherein R ^e is phenyl or halogen phenyl, R ⁷ is phenyl and A ¹² is trimethylene or tetramethylene. (Priority: April 2, 1979) 7 for the preparation of pharmaceutical compositions, characterized in that a compound of the general formula in claim 1 sze5 Rint (I) (wherein R ^1, R ^2, Z ^1, A ¹ and A ² are as defined in claim 1; ) or a pharmaceutically acceptable acid addition salt thereof with an inert solid or liquid pharmaceutical carrier. 0 and mixed into a pharmaceutical composition. (Priority: March 28, 1980) A process for the preparation of a pharmaceutical composition comprising the compound of formula (I) according to claim 2 (wherein R ¹ , R ² , Z ¹ A ¹ and A ² are as defined in claim 2). or a pharmaceutically acceptable acid addition salt thereof as an active ingredient in admixture with inhaled solid or liquid pharmaceutical carriers and forming a pharmaceutical composition. (Priority: April 2, 1979)