KR840002089B1 - Process for preparing phenoxy-amino propanol derivatives - Google Patents

Abstract

Phenoxy-aminopropanol derivs. of formula (I) and their acid addn. salts were prepd. by reacting epoxides of formula (II) with amines of formula (II). In the formulas, R is lower alkyl; X is O or S; n is 0 or 1; Y is methylene, ethylene, or propylene or, when n is 0, y can also be -CH=CH-C*H2-, where the double bond is trans and C* is linked to Z; Z is 1-imidazolyl, 1H-1,2,4-triazol1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-phenyl-1- pyrazolyl, 1-benzimidazolyl, 2H-benzotriazol-2-yl, 4,5,6,7- tetrahydro-2H-benzotriazol-2-yl, or 1H-indazol-1-yl; and Z is linked to Y at an N atom. The compds. have antihypertensive activity.

Description

Method for preparing substituted phenoxy-aminopropanol derivatives

The present invention relates to a novel process for preparing substituted phenoxy-aminopropanol derivatives of the general formula (I) below and pharmaceutically acceptable acid addition salts thereof.

In the above formula,

R is a lower alkyl group;

X is oxygen or sulfur atom;

n is an integer of 0 or 1;

의 그룹 (여기에서, 이중결합은 트랜스이고, *표로된 탄소원자는 Z에 연결된다)을 나타낼 수 있으며 ;Y is a methylene, ethylene or propylene group, or when n is 0, Y is a structural formula

May represent a group of wherein the double bond is a trans and a carbon atom with an asterisk is linked to Z;

또는

의 그룹으로 치환될 수 있는 5원 방향족 헤테로시클릭환을 나타낸다.Z contains one or more nitrogen atoms as the only hetero atom, is linked to Y by a nitrogen atom, and may be substituted by halogen, lower alkyl, lower alkoxy, aryl, cyano or carboxamido groups Structural formulas on adjacent carbon atoms

or

5-membered aromatic heterocyclic ring which may be substituted with a group of.

The term "lower alkyl" refers to a straight or branched chain alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl and tert-butyl). The term " lower alkoxy " means a straight or branched alkoxy group having 1 to 4 carbon atoms (e.g., mesoxy, epoxy, propoxy, iso-propoxy, etc.). The term "halogen" is fluorine, chlorine, bromine and iodine. Examples of the aryl group include phenyl group.

Examples of aromatic heterocyclic rings represented by Z include: 1-imidazolyl, 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1 , 2,3-triazol-2-yl, 1-pyrazolyl, 4-halo-1-pyrazolyl (eg 4-chloro-1-pyrazolyl), 4-aryl-1-pyrazolyl (eg 4 -Phenyl-1-pyrazolyl), 1-benzimidazolyl, 2H-benzo-triazol-2-yl, 4,5,6,7-tetrahydro-2H-benzotriazol-2-yl, 1H- Indazol-1-yl, and the like.

Preferred compounds of formula (I) include those in which R is isopropyl or tertiary butyl group, more preferably isopropyl group, X is an oxygen atom, n is 1 and Y is methylene group. And Z is 1-imidazolyl, 1H-1,2,4-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1-pyrazolyl or 4-halo-1- Preferred are compounds of the general formula (I) which are pyrazolyl groups, more preferably 2H-1,2,3-triazol-2-yl or 4-chloro-1-pyrazolyl groups.

From the foregoing, R is isopropyl, X is oxygen atom, n is 1 and Y is methylene group, Z is 2H-1,2,3-triazol-2-yl or 4-chloro- More preferred are compounds of formula (I) which are 1-pyrazolyl groups.

Particular preference is given to the following general formula (I) compounds:

1-isopropylamino-3- [4- [2- (1-pyrazolyl) ethoxy] phenoxy] -2-propanol,

1- [4- [2- (1-imidazolyl) ethoxy] phenoxy] -3-isopropyl-amino-2-propane,

1- [4- [2- (1-benzimidazolyl) ethoxy] phenoxy] -3-isopropyl-amino-2-propane,

1-isopropylamino-3- [4- [2- (1H-1,2,4-triazol-1-yl) ethoxy] -phenoxy] -2-propanol,

1-3-butylbutyl-3- [4- [2- (1-pyrazolyl) ethoxy] phenoxy] -2-propane,

1-isopropylamino-3- [4- [3- (1-pyrazolyl) propoxy] phenoxy] -2-propanol,

1-isopropylamino-3- [4- [3- (1H-1,3,4-triazol-1-yl) propoxy] phenoxy] -2-propanol,

1-isopropylamino-3- [4- [2- (4-phenyl-1-pyrazolyl) ethoxy] -phenoxy] -2-propanol,

1-isopropylamino-3- [4- [2- (4-chloro-1-pyrazolyl) ethoxy] -phenoxy] -2-propanol,

1- [4- [2- (1imidazolyl) ethyl] phenoxy] -3-isopropyl-amino-2-propane,

1-isopropylamino-3- [4- [2- (1-pyrazolyl) ethyl] phenoxy] -2-propane,

1-isopropylamino-3- [4- [2- (1H-1,2,4-triazol-1-yl) ethyl] -phenoxy] -2-propanol,

1-isopropylamino-3- [4-[(1-pyridazolyl) methyl] phenoxy] -2-propanol,

1- [4- [2- (1-imidazolyl) methyl] phenoxy] -3-isopropyl-amino-2-propanol,

1- [4- [2- (2H-benzotriazol-2-yl) ethoxy] phenoxy] -3-isopropylamino-2-propanol,

1- [4- [2- (4,5,6,7-tetrahydro-2H-benzotriazol-2-yl) -ethoxy] phenoxy] -2-propanol,

1-isopropylamino-3- [4- [3- (1-pyrazolyl) propyl] phenoxy] -2-propanol,

Trans-1-isopropylamino-3- [4-3- (1-pyrazolyl) -1-propenyl] -phenoxy] -2-propanol,

1-isopropylamino-3- [4- [2- (1-pyrazolyl) ethylthio] phenoxy] -2-propane and

1- [4- [2- (1H-indazol-1-yl) ethoxy] phenoxy] -3-isopropylamino-2-propane,

Especially preferred compounds of formula (I) are as follows:

1-isopropylamino-3- [4- [2- (2H-1,2,3-triazol-2-yl) ethoxy] -phenoxy] -2-propanol,

1-isopropylamino-3- [4-[(1-pyrazolyl) methoxy] phenoxy] -2-propanol

1- [4- [2-hydroxy-3- (isopropylamino) propoxy] phenoxymethyl] -4-pyrazolecarbonitrile,

1-isopropylamino-3- [4- [1H-1,2,3-triazol-1-yl) methoxy] phenoxy-2-propane and

1-isopropylamino-3- [4-[(1-pyrazolyl) methylthio] phenoxy] -2-propanol.

Particularly preferred compounds of formula (I) are as follows:

1- [4-[(4-chloro-1-pyrazolyl) methoxy] phenoxy] -3-isopropylamino-2-propanol and

1-isopropylamino-3- [4-[(2H) -1,2,3-triazol-2-yl) methoxy] -phenoxy] -2-propanol.

According to the preparation method of the present invention, the above-mentioned substituted phenoxy-aminopropanol derivatives (ie, the compound of formula (I) and pharmaceutically acceptable acid addition salts thereof),

(a) reacting an epoxide of general formula (II) with an amine of general formula (III),

(b) if necessary, dividing the racemate of formula (I) into optical isomers, and / or

(c) If necessary, a compound of formula (I) is prepared by converting it into a pharmaceutically acceptable acid addition salt thereof.

In the above formula,

R, X, Y, Z and n are as described above.

According to the production process (a), the reaction between the amine of general formula (III) (which is a known compound or can be prepared by a known method) and the epoxide of general formula (II) is carried out in the presence of an inert organic solvent, Or in the absence. When using an inert organic solvent, for example, lower alkanols such as methanol, ethanol and the like can be used. Alternatively, an excess of amine of general formula (III) can be used, whereby the amine can be used as a solvent. The reaction is carried out at atmospheric pressure, from 0 ° to room temperature, preferably at room temperature.

The above general formula (I) compound has an asymmetric carbon atom and thus may exist in racemate or optically active form. The present invention includes racemates and optically active forms in the scope of the invention. If necessary, racemates can be partitioned into optical isomers according to the preparation process (b) using known methods (eg, fractionally determining salts formed with optically active acids). The phenol of general formula (IV) as starting material can be used as an optically active form to obtain the desired compound of general formula (I) of the corresponding optically active form.

According to the preparation process (c), the compound of general formula (I) can be prepared by pharmaceutically acceptable inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.) and pharmaceutically acceptable organic acids (e.g. acetic acid, tartaric acid, citric acid). Fumaric acid, maleic acid, malic acid, methanesulfonic acid, paratoluenesulfonic acid, etc.) may be converted into pharmaceutically acceptable acid addition salts.

The epoxide of the general formula (II) used as a starting material in the manufacturing process (a) is new and prepared by reacting an alkali metal derivative of phenol of the general formula (VI) with epichlorohydrin or epibromohydrin. Can be.

(In the above formula,

X, Y, Z and n are as described above)

The process of reacting an alkali metal derivative of phenol of formula (IV) with epichlorohydrin or epibromohydrin, preferably epichlorohydrin, is carried out in an inert organic solvent. Examples of inert organic solvents that can be used are dimethylformamide, dioxane, dimethoxyethane and tetrahydrofuran, with dimethylformamide being preferred. The alkali metal derivatives of the phenols of formula (VI) are preferably formed in situ from the corresponding phenols and alkali metals, alkali metal hydrides or alkali metal amides, preferably alkali metal hydrides, in particular sodium hydride. . It is advantageous to carry out the reaction at elevated temperature, preferably at about 60 ° C.

The phenols of formula (VI) described above, most of which are new and belong to part of the present invention, can be prepared by various methods in accordance with the definitions of X, Y and n.

For example, a phenol of general formula (VI) wherein X is an oxygen atom, Y is an ethylene or propylene group, and n is 1 is represented by Scheme I (where Z is as described above and Y ² is ethylene or propylene) Group and Bz is a benzyl group).

In the scheme (I), 4-benzyloxyphenol of the formula (VII) is reacted with a compound of the formula (X) to obtain a compound of the formula (VII).

Br-Y ² -Br (X)

(Y ² in the general formula is as described above.)

This reaction is carried out by a known method at elevated temperature (about 100 ° C.) in an aqueous alkali medium (eg an aqueous solution of an alkali metal hydroxide such as an aqueous sodium hydroxide solution).

Subsequently, the compound of formula (VII) is reacted with a heterocyclic compound of formula (X) to convert the compound of formula (X).

H-Z (ⅩI)

(Z in the general formula is as described above.)

This reaction is carried out in a conventional manner in the presence of an inert organic solvent such as dimethyl formamide and the like and in the presence of a suitable alkali metal base such as an alkali metal hydride (eg sodium hydride). It is convenient for the reaction to proceed at an elevated temperature (about 60 ° C).

Finally, the compound of formula (VII) is debenzylated and converted to the desired phenol of formula (VIa). Debenzylation can be carried out by known methods using, for example, hydrogen in the presence of a catalyst (eg palladium / carbon etc.) or hydrogen bromide in glacial acetic acid.

A phenol of general formula (VI) wherein X is an oxygen atom and n is 1 is reacted with an alkali-metal derivative of 4-benzyloxy phenol of general formula (V) with a compound of formula (V) below (preferably chloride): The reaction product can be prepared by debenzylating in a similar manner as described above with respect to the debenzylation of the general compound.

R ¹ -Y ¹ -Z (V)

(In the above structural formula,

R ¹ is a leaving atom or group,

Y ¹ is methylene, ethylene or propylene group,

Z is as described above.)

The leaving atom or group represented by R ¹ in the general formula (V) compound is a common leaving atom or group, for example, chlorine or bromine atom, lower alkylsulfonyloxy group (eg methanesulfonyloxy) or arylsulfonyl Oxy group (eg, P-toluenesulfonyloxy). It is preferred that R ¹ is an arylsulfonyloxy group, in particular P-toluenesulfonyloxy.

Scheme (II) to be described later illustrates the preparation of phenol of formula (VI) wherein n is 0 and Y is an ethylene group. In this scheme Z and Bz are as described above and R ² is a lower alkyl or aryl group.

In Scheme (II), 4-benzyloxyphenethyl alcohol of general formula (XII) is reacted with lower alkyl sulfonyl or arylsulfonyl halide (preferably methanesulfonyl chloride) to give the general formula (XIII) Convert to compound. The reaction is usually carried out in the presence of an inert organic solvent (eg an ether such as diethyl ether) and an acid binder (preferably a tertiary organic base such as pyridine). desirable.

Subsequently, the compound of general formula (XIII) is reacted with the heterocyclic compound of general formula (XI) in a manner similar to the method of reacting the compound of general formula (VII) with the heterocyclic compound. Convert to compound.

Similar to the process of debenzylating a compound of formula (VIII), the compound of formula (XIV) is debenzylated to yield the desired phenol of formula (VIb).

Phenol of the general formula (VI), wherein n is 0 and Y is a propylene group, can be prepared as described in Scheme (III) (where Z and Bz are as described above).

In step 1 of Scheme (III), the heterocyclic compound of formula (XI) described above for 1-dimethyl-amino-3- (4-benzyloxyphenyl) -propan-3-one of formula (XV) Reaction with gives a compound of the general formula (XVI). This reaction is carried out in a conventional manner, for example by heating the reactants in a suitable alkanol (eg n-butanol). The heating is preferably carried out at the reflux temperature of the reaction mixture.

The product of formula (XVI) is then reduced by known methods to convert to a compound of formula (XVII). For example, the reduction may be carried out using alkali metal borohydride (eg sodium brohydride) at room temperature in the presence of an inert organic solvent such as lower alkanol (eg ethanol).

Finally, the desired phenol of formula (VIc) is obtained by catalytic hydrogenation of a compound of formula (XVII) under acidic conditions. Catalytic hydrogenation can be carried out in a conventional manner in inert organic solvents (eg lower alkanols such as ethanol) using, for example, palladium / carbon or similar catalysts. It can be made acidic using hydrochloric acid.

Phenol of the general formula (VI), wherein n is 0 and Y is a methylene group, 4-hydroxybenzyl alcohol together with the heteroerocyclic compound of the general formula (XI) described above by a known method (e.g., at about 160 ° C). It can be prepared by heating.

The phenol of general formula (VI) in which X is a sulfur atom and n is 1 can be prepared by reacting 4-mercaptophenol with the compound of general formula (V) described above.

Reaction of 4-mercaptophenol with a general formula (V) compound is carried out in the presence of an inert organic solvent such as dimethylformamide, alkali metal hydride (e.g. sodium hydride) or alkali metal carbonate (e.g. In the presence of a suitable alkali metal base such as potassium carbonate).

Phenol of the general formula (VI) wherein n is 0 and Y is the aforementioned -CH = CH-C * H ₂ -group is represented by the following scheme (IV) (where Z and Bz are as described above and Et is an ethyl group). It can be prepared according to the).

In Scheme (IV), a compound of Formula (XVII) prepared as described above in Scheme (III) is firstly lower alkylsulfonyl or atylsulfonyl chloride in the presence of a tertiary organic base (preferably pyridine). And dehydrated by heating together with the compound of formula (XVII). The heating is advantageously carried out at about 100 ° C.

The compound of formula (XVIII) is then converted to a compound of formula (XIX) by treatment with ethanethiol and borontrifluoride diethyl etherate. It is preferable to perform the said reaction at room temperature.

The reaction for oxidizing the compound of formula (XIX) to give the compound of formula (XX) is usually carried out using an organic peracid in the presence of an inert organic solvent. As the organic peracid, acetic acid peroxide, perbenzoic acid, halogenated perbenzoic acid, preferably m-chloroperbenzoic acid, mono perphthalic acid and the like are suitable. Inert container solvents are halogenated hydrocarbons (eg methylene chloride, etc.).

Finally, the compound of formula (XX) is heated in an inert solvent to convert it to the desired phenol of formula (VId). As the inert organic solvent, aromatic hydrocarbons, in particular toluene, are preferable. Heating is conveniently carried out at the reflux temperature of the mixture.

The starting materials required for the preparation of the phenol of formula (VI) in the above process are known compounds which can be prepared by conventional methods or homologues of known compounds.

The compound of general formula (V) is a known compound which can be produced by a conventional method, or a homologue of a known compound.

The substituted phenoxy-amino propanol derivatives of the present invention have cardiac selective β-adrenergic processing activity and can therefore be used to prevent and treat heart disease (eg angina and cardiac arrhythmias). It can also be used to treat high blood pressure.

It can be demonstrated by standard test methods that the substituted phenoxy-aminopropanol derivatives of the invention exhibit cardiacselective β-blocking activity at β ₁ -and β ₂ -adrenergic receptors. In this test method, this activity in rats was induced by the dose of test substance required to reduce 50% of isoprene-induced tachycardia (denoted as ED ₅₀ (HR)) and isoprenaline. It is determined by measuring the dose (expressed as ED ₅₀ (BP)) (μg / kg intravenously) required to reduce the suppressed response to 50%. If ED ₅₀ (BP) is significantly greater than the ED ₅₀ (HR), the test compound is β ₂ - and blocks more selective to the adrenergic receptors (i. E., A heart-selective) - β ₁ adrenergic receptor than.

The results obtained by testing the substituted phenoxy-aminopropanol derivatives of the present invention, and athenol, a well-known cardioselective β-adrenergic blocker widely used, are as follows.

[table]

Derivative A: 1-isopropylamino-3- [4- [2- (1-pyrazolyl) -ethoxy] phenoxy] -2-propanol hydrogen maleate

Derivative B: 1- [4-[(4-chloro-1-pyrazolyl) methoxy] -phenoxy] -3-isopropylamino-2-propanolhydrogen oxalate.

Derivative C: 1-isopropylamino-3- [4- [2H-1,2,3-triazol-2-yl) methoxy] phenoxy] -2-propanol hydrochloride.

Derivative D: 1-isopropylamino-3- [4- [2- [2H-1,2,3-triazol-2-yl) ethoxy] phenoxy] -2-propanol hydrochloride.

Substituted phenoxy-aminopropanol derivatives of the present invention can be prepared in pharmaceutical form by mixing with a pharmaceutically acceptable carrier and used as a therapeutic agent. Inert organic or inorganic carriers which can be administered orally or parenterally may be used. Such carriers include water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene glycols, petroleum jelly and the like. Pharmaceutical formulations may be prepared by convenient methods and the finished dosage forms may be in solid dosage forms (e.g. tablets, dragees, suppositories, capsules) or in liquid dosage forms (e.g. solutions, suspensions, emulsions). have. The pharmaceutical preparations may carry out conventional pharmaceutical manipulations such as sterilization and / or may contain conventional adjuvants such as preservatives, stabilizers, wetting agents, buffers, salts to alter the osmotic pressure.

Substituted phenoxy-aminopropanol derivatives of the invention may be administered or aliquoted once daily to an adult in an amount of about 1 mg / kg to 10 mg / kg. This dosage range can be changed up and down depending on factors such as the type of the substituted phenoxy-aminopropanol derivative to be administered and to be administered), the route of administration, and the amount required by the patient.

The process of the invention is illustrated by the following examples.

Example 1

3.16 g (15 mmol) of 4- [2- (1-pyrazolyl) ethoxy] phenol are dissolved in 75 ml of dimethyl formamide and stirred with 0.72 g (15 mmol) of 50% sodium hydride suspension in mineral oil for 5 minutes. 10 ml of epichlorohydrin is added and the solution is stirred at 60 ° C. for 30 minutes. The solvent and excess epichlorohydrin are evaporated off under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to yield 4.1 g of crystalline epoxide which was dissolved in 100 ml of ethanol containing 15 ml of isopropylamine without purification. The mixture is then left overnight at room temperature. The solution is evaporated to dryness and the crystalline product is dissolved in 100 mL of ethanol containing 1.74 g (15 mmol) maleic acid. The solution was evaporated and the residue recrystallized from isopropanol to yield 1-isopropylamino-3- [4- [2- (1-pyrazolyl) -ethoxy] phenoxy] -2-propanol hydrogen having a melting point of 103 to 105 ° C. 5.0 g (76.5%) of maleate are obtained.

4- [2- (1-pyrazolyl) ethoxy] phenol used as starting material can be prepared as follows:

(a) 125 ml of a 1.6 N sodium hydroxide solution was added to a stirred mixture of 40 g (0.2 mol) of 4-benzyloxyphenol and 71.1 g (0.38 mol) of ethylenedibromide at 100 ° C. over 1 hour, and the stirring was continued at 100 ° C. overnight. . The cold mixture is partitioned between 20% sodium hydroxide and diethyl ether. The organic layer is separated, washed with water, dried over sodium sulfate, filtered and evaporated to dryness. Recrystallization of the residue gave 36 g (59%) of 1-benzyloxy-4- (2-bromoethoxy) benzene having a melting point of 77 to 80 ° C.

(b) 1.36 g (20 mmol) solution of pyrazole in 50 ml of dimethylformamide is treated with 0.96 g (20 mmol) of 50% sodium hydride dispersion in mineral oil and the mixture is stirred for 5 minutes. 6.14 g (20 mmol) of 1-benzyloxy-4- (2-bromoethoxy) benzene are added and the mixture is heated at 60 ° C. for 0.5 h with stirring. The solvent is evaporated off under reduced pressure and the residue is partitioned between ethyl acetate and water.

The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to yield 5.7 g of crystalline residue. This residue is dissolved in 250 ml of ethanol and hydrogenated overnight at atmospheric pressure and room temperature in the presence of 0.2 g of 10% palladium / carbon. The catalyst was filtered off, the solvent was evaporated and the residue recrystallized with toluene to yield 3.16 g (77.5%) of 4- [2- (1-pyrazolyl) ethoxy] phenol having a melting point of 74 to 77 ° C.

Example 2

Similar to the method described in the first paragraph of Example 1, 1- [4- [2- (1-imidazolyl) ethoxy]-from 4- [2- (1-imidazolyl) ethoxy] -phenol Phenoxy] -3-isopropylamino-2-propanol bis (hydrogen oxalate) is obtained (melting point: 147 to 148 ° C. (decomposition, from methanol)).

Starting materials are prepared as follows:

Similar to that described in Example 1 (b), 4- [2- (1-imidazolyl) having a melting point of 141 to 144 ° C. from 1-benzyloxy-4-(-2-bromoethoxy) benzene and imidazole. ) Ethoxy] phenol.

Example 3

In a manner similar to that described in the first paragraph of Example 1, 1- [4- [2- () having a melting point of 170 to 173 ° C. from 4- [2- (1-benzimidazolyl) ethoxy] -phenol. 1-benzimidazolyl) ethoxy] phenoxy] -3-isopropylamino-2-propanolbis (hydrogen oxalate) is obtained.

Starting materials are prepared as follows:

According to the method of Example 1 (b), 4- [2- (1-benzimidazolyl) -ethoxy] phenol was obtained from 1-benzyloxy-4- (2-bromoethoxy) benzene and benzimidazole. Obtained.

Example 4

1-isopropylamino-3- [4- [from 4- [2- (1H-1,2,4-triazol-1-yl) epoxy] phenol in a similar manner as described in the first paragraph of Example 1 2- (1H-1,2,4-triazol-1-yl) ethoxy] phenoxy] -2-propanol dihydrochloride is obtained (melting point: 153 to 158 ° C. from isopropanol / ethanol).

Starting materials can be prepared as follows:

In a similar manner to Example 1 (b), 4- [2- (1H-1,2,1) from 1-benzyloxy-4- (2-bromoethoxy) benzene and 1H-1,2,4-triazole 4-triazol-1-yl) ethoxy] phenol is obtained.

Example 5

Tert-Butylamino-3- [4- [2- (1-pyrazolyl) ethoxy] phenoxy] -2-propanol in a similar manner to Example 1 using tertiary butylamine instead of isopropylamine Hydrogen maleate is obtained (melting point: 145-148 ° C. from ethanol).

Example 6

In a manner similar to the first paragraph of Example 1, 1-isopropylamino-3- [4- [3- (1-pyrazolyl) -propoxy from 4- [3- (1-pyrazolyl) propoxy] phenol ] Phenoxy] -2-propanol hydrogen maleate is obtained (melting point: 89-91 ° C. from isopropanol).

Starting materials can be prepared as follows.

(a) 1-benzyloxy-4- (3-bromopropoxy) benzene is obtained from 4-benzyloxyphenol and 1,3-dibromopropane in a similar manner to Example 1 (a) (melting point 49 ° to 53 ° C. from methanol).

(b) In a manner similar to Example 1 (b), 4- [3- (1-pyra) having a melting point of 108 to 110 ° C. from 1-benzyloxy-4- (3-bromopropoxy) benzene and parasol. Zolyl) propoxy] phenol is obtained.

Example 7

1-isopropylamino-3- [4- [3 from 4- [3- (1H-1,2,4-triazol-1-yl) -propoxy] phenol in a similar manner to the first paragraph of Example 1 -(1H-1,3,4-triazol-1-yl) propoxy] phenoxy] -2-propanol dihydrochloride is obtained (melting point 158-160 ° C. from ethanol).

Starting materials can be prepared as follows:

Similar to Example 1 (b), 1-benzyloxy-4- (3-bromopropoxy) benzene (prepared by the method described in Example 6 (a)) and 1H-1,2,4-tria From the sol a 4- [3- (1H-1,2,4-triazol-1-yl) propoxy] phenol having a melting point of 141 to 144 ° C. is obtained.

Example 8

1-isopropylamino-3- [4- [with a melting point of 141 to 143 ° C. from 4- [2- (4-phenyl-1-pyrazolyl) -ethoxy] phenol according to the method of the first paragraph of Example 1 2- (4-phenyl-1-pyrazolyl) ethoxy] -phenoxy] -2-propanol hydrogen maleate is obtained. (Melting point 141-143 degreeC from isopropanol).

Starting materials can be prepared as follows.

Example 1 from 1-benzyloxy-4- [2- (4-phenyl-1-pyrazolyl) ethoxy] benzene [1-benzyloxy-4- (2-bromoethoxy) benzene and 4-phenylpyrazole Prepared by the method of (b). 5.7 g (15.4 mmol) is stirred in 20 ml of 48% hydrogen bromide in glacial acetic acid at 25 ° C. for 0.5 hour. The solution is evaporated to dryness and the residue is partitioned between 2N sodium hydroxide solution and diethyl ether. The aqueous layer is adjusted to pH 6 with concentrated hydrochloric acid and extracted with ethyl acedate. The ethyl acetate extract is washed, dried over sodium sulphate and filtered. Evaporate the filtrate. The residue was crystallized with toluene to give 3.24 g (75%) of 4- [2- (4-phenyl-1-pyrazolyl-ethoxy] phenol having a melting point of 146 to 150 ° C.

Example 9

1-isopropylamino-3- [4- [2- (4 from 4- [2- (4-chloro-1-pyrazolyl) -ethoxy] phenol according to the method described in the first paragraph of Example 1 -Chloro-1-pyrazolyl) ethoxy] phenoxy] -2-propanol P-toluenesulfonate is obtained (melting point 120 ° C., from methanol).

The extrudate can be prepared as follows.

By the method described in the second paragraph of Example 8, 1-benzyloxy-4- [2- (4-chloro-1-pyrazolyl) ethoxy] benzene [1-benzyloxy by the method of Example 1 (b) 4- [2- (4-chloro-1-pyrazolyl) ethoxy] phenol from 4- (2-bromoethoxy) benzene and 4-chloropyrazole); melting point 105 DEG C, from carbon tetrachloride ).

Example 10

1- [4- [2- (1-imidazolyl) from 2.82 g (15 mmol) of 4- [2- (1-imidazolyl) ethyl] phenol according to the method described in the first paragraph of Example 1 5.57 g (69%) of ethyl] phenoxy-3-isopropylamino-2-propanol (hydrogen maleate) are obtained (melting point 144-106 DEG C, from isopropanol).

Starting materials can be prepared as follows:

(a) A solution of 3.51 g (30.7 mmol) of methanesulfonyl chloride in 5 mL of diethyl ether was added to a stirred solution of 7.0 g (30.7 mmol) of 4-benzyloxy phenethyl alcohol in 20 mL of pyridine over 0.5 h at 0 ° C. It is appropriate. The mixture is allowed to come to room temperature with stirring for 2 hours. The mixture is then partitioned between 150 mL 2N hydrochloric acid and dichloromethane. The organic layer is separated, washed with water, dried over sodium sulfate, filtered and evaporated. The residue is triturated with nhexane to crystallize. The crystals were filtered off and dried to yield 8.9 g (95%) of 1-benzyloxy-4- (2-methanesulfonyloxyethyl) -benzene having a melting point of 60 to 64 ° C.

(b) 1.93 g (28 mmol) of imidazole in 100 ml of dimethylformamide are treated with a 50% sodium hydride dispersion in mineral oil and the mixture is stirred for 5 minutes. 8.65 g (28 mmol) of 1-benzyloxy-4- (2-methanesulfonyloxyethyl) benzene are added and the mixture is heated to 60 ° C. for 0.5 hour with stirring. The solvent is evaporated under reduced pressure, the residue is triturated with water, filtered off, washed with water and dried. The resulting solid (7.5 g) is dissolved in 200 ml of ethanol and the solution is hydrogenated overnight at room temperature and atmospheric pressure in the presence of 0.2 g of 10% palladium / carbon. The catalyst was filtered off and the solvent was evaporated to recrystallize the residue with ethanol to yield 3.36 g (67%) of 4- [2- (1-imidazolyl) -ethyl] phenol having a melting point of 158 to 161 ° C.

Example 11

1-isopropylamino-3- [4- [2- (1-pyrazolyl) -ethyl] phenoxy] -2- from 4- [2- (1-pyrazolyl) ethyl] phenol by the method of Example 1 Propanol P-toluenesulfonate is obtained (melting point 134 ° to 135 ° C. from isopanol).

Starting materials can be prepared as follows:

By the method of Example 10 (b), 4- [2- (1-pyrazolyl) having a melting point of 94 to 95 ° C. from pyrazole and 1-benzyloxy-4- (2-methanesulfonyloxyethyl) -benzene Ethyl] phenol is obtained.

Example 12

1-isopropylamino-3- [4- [2- (1H-1) from 4- [2- (1H-1,2,4-triazol-1-yl) ethyl] phenol in a similar manner to Example 1 , 2,4-triazol-1-yl) ethyl] phenoxy] -2-propanol This hydrochloride is obtained (melting point: 173 ° to 175 ° C. from ethanol).

Starting materials can be prepared as follows:

Similar to Example 10 (b), 4- [2- (1H-1,2,4) from 1H-1,2,4-triazole and benzyloxy-4- (2-methanesulfonyloxyethyl) benzene -Triazol-1-yl) ethyl] phenol is obtained.

Example 13

By the method of Example 1, 1-isopropyl-amino-3- [4-[(1-pyrazolyl) methyl] phenoxy] -2- from 3.3 g of 4-[(1-pyrazolyl) -methyl] phenol Propanol hydrogen maleate 4.09 (54%) is obtained (melting point: 103 ° to 105 ° C., from isopropanol).

Starting materials can be prepared as follows:

4.96 g (40 mmol) of 4-hydroxybenzyl alcohol and 2.72 g (40 mmol) of pyrazole are heated together at 160 ° C. for 30 minutes. The resulting solid is cooled and dissolved in 150 ml of boiling toluene. The solution is tilted from a small amount of black tar and evaporated to dryness. The residue was recrystallized from ethyl acetate to give 3.3 g (47%) of 4-[(1-pyrazolyl) methyl] phenol having a melting point of 113 to 115 占 폚.

Example 14

According to the method of Example 1, 1- [4-[(1-imidazolyl) methyl] phenoxy] -3-isopropylamino-2-propanol from 4-[(1-imidazolyl) methyl] phenol Bis (hydrogen oxalate) is obtained (melting point 105-107 ° C., from methanol).

Starting materials can be prepared as follows:

By the method described in step 2 of Example 13, 4-[(1-imidazolyl) methyl] phenol is obtained from 4-hydroxybenzyl alcohol and imidazole.

Example 15

By the method of Example 1, 1- [4- [2- (2H-benzotriazol-2-yl) ethoxy from 1.26 g of 4- [2- (2H-benzotriazol-2-yl) ethoxyphenol 1.23 g (62%) of] phenoxy] -3-isopropylamino-2-propanol hydrochloride are obtained (melting point 175-176 ° C., from methanol).

Starting materials can be obtained as follows:

(a) 5.95 g (50 mmol) solution of benzotriazole in 100 ml of dimethylformamide is treated with 2.40 g (50 mmol) of 50% sodium hydroxide suspension in mineral oil and the mixture is stirred for 5 minutes. 15.35 g (50 mmol) of 1-benzyloxy-4- (2-bromoethoxy) -benzene (prepared by the method of Example 1 (a)) are added and the mixture is heated at 60 ° C. for 20 minutes with stirring. The solvent is evaporated off under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated to give 17.5 g of crystalline solid. This solid is chromatographed on a silica gel column using 10% ethyl acetate / hexane as eluent. The eluate is recrystallized from ethanol and evaporated to yield 6.18 g of 1-benzyloxy-4- [2- (2H-benzotriazol-2-yl) ethoxy] benzene having a melting point of 105 to 107 ° C.

(b) 3.1 g (8.9 mmol) of 1-benzyloxy-4- [2- (2H-benzotriazol-2-yl) ethoxy] benzene at 48% hydrogen bromide according to the method described in paragraph 2 of Example 8; Dibenzylation with acetic acid yields 1.26 g (55%) of 4- [2- (2H-benzotriazol-2-yl) ethoxy] phenol (melting point 98 ° C., from isopropanol).

Example 16

2.8 g of 4- [2- (4,5,6,7-tetrahydro-2H-benzotriazol-2-yl) ethoxy] phenol according to Example 1 1- [4- [2- (4, 3.15 g of 5,6,7-tetrahydro-2H-benzotriazol-2-yl) -ethoxy] pentoxy] -3-isopropylamino-2-propanol hydrochloride are obtained (melting point 157 ° to 158 ° C., From acetonitrile).

Starting materials can be prepared as follows:

1-benzyloxy-4- [2- (2H-benzotriazol-2-yl) ethoxy] benzene [prepared by the method described in Example 15 (a)] 5.5 g (16 mmol) is no longer absorbed by hydrogen 2.8 g (69) of 4- [2- (4,5,6,7-tetrahydro-2H-benzotriazol-2-yl) ethoxy] phenol until hydrogenated by the method of Example 1 (b) until %) Is obtained (melting point 93 ° C., from toluene).

Example 17

1-isopropylamino-3- [4- [3- (1-pyrazolyl) propyl] phenoxy] from 8.5 g of 4- [3- (1-pyrazolyl) propyne] phenol according to the method of Example 1 10.90 g (60%) of 2-propanol hydrogen maleate is obtained (melting point 126-130 ° C., from isopanol).

Starting materials can be prepared as follows:

(a) 20 g (71 mmol) of 1-dimethylamino-3- (4-benzyloxyphenyl) -propane-3-one in 250 ml of n-butanol and 6.8 g (100 mmol) of pyrazole were heated under reflux for 15 hours. The solution is then evaporated to dryness. The residue is partitioned between ethyl acetate and water. The organic layer was separated, dried over sulfuric sodium, filtered, doubled and recrystallized from ethyl acetate to give 1- (1-pyrazolyl) -3- (4-benzyloxyphenyl) -propan-3-one 15.1 having a melting point of 111 to 114 ° C. g (70%) is obtained.

(b) The catone is dissolved in 500 ml of ethanol and the solution is stirred with 2.0 g sodium borohydride at room temperature for 16 hours. The solvent is evaporated off and the residue is partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, filtered and evaporated to yield 14.9 g (98%) of 1-benzyloxy-4- [1-hydroxy-3- (1-pyrazolyl) propyl] benzene having a melting point of 80 to 85 ° C. .

(c) The alcohol is dissolved in 600 ml of ethanol with 8 ml of concentrated hydrochloric acid and the solution is hydrogenated at atmospheric pressure in the presence of 10% palladium / 0.4 g of carbon. The catalyst is filtered off, the filtrate is evaporated and the residue is partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to yield 8.5 g (87%) of 4- [3- (1-pyrazolyl) propyl] phenol in the form of colorless oil that could be used without purification.

Example 18

Trans-1-isopropylamino-3- [4- [3- (1- from 0.55 g of 4- [3- (1-pyrazolyl) prop-1-enyl] phenol by the method of the first paragraph of Example 1 Pyrazolyl) -1-propenyl] phenoxy] -2-propanol hydrogenmaleate 0.76 g (64%) is obtained (melting point 121-125 ° C., from isopropanol).

Starting materials can be prepared as follows:

(a) 8.8 g (28.5 mmol) of 1-benzyloxy-4- [1-hydroxy-3- (1-pyrazolyl) propyl] benzene and 3.27 g of methanesulfonyl chloride were heated under reflux for 15 hours in pyridine To this, methanesulfonyl chloride equivalent (3.27 g) is added, and further heated at reflux for 15 hours. Pyridine is evaporated off and the residue is partitioned between ethyl acetate and water. The organic layer is separated, dried over sodium sulphate and filtered. After evaporation of the filtrate and the residue recrystallized from methyl cyclohexane, 4.8 g (58%) of 1-benzyloxy-4- [3- (1-pyrazolyl) prop-1-enyl] benzene having a melting point of 91 to 93 ° C was obtained. Obtained.

(b) 4.5 ml (15.5 mmol) of 1-benzyloxy-4- [3- (1-pyrazolyl) -prop-1-enyl] benzene in 25 ml of ethanethiol and boron trifluoride diethyl etherate 25 Dissolve in ml of the mixture and stir the resulting mixture at 25 ° C. for 0.75 h. Excess thiol is evaporated off and the residue is partitioned between ethyl acetate and water. The organic layer is separated, dried over sodium sulfate and filtered. The filtrate is evaporated and the residue is chromatographed on silica gel using chloroform as eluent. The eluate is evaporated to yield 3.5 g (86%) of 4- [1-ethylthio-3- (1-pyrazolyl) propyl] phenol in oil form.

(c) 3.5 g of 4- [1-ethylthio-3- (1-pyrazolyl) propyl] phenol are dissolved in 100 ml of dichloromethane and the solution is stirred with 2.81 g of m-chloroperbenzoic acid for 0.25 h. The mixture is washed with saturated sodium bicarbonate solution, the dichloromethane layer is separated, dried over sodium sulfate and filtered. The filtrate is evaporated to yield 3.5 g of the corresponding sulfoxide and dissolved in 100 ml of these toluene. The solution is heated at reflux for 24 hours and then evaporated to dryness. The residue is chromatographed on silica gel using chloroform / hexanes (9: 1) as eluent. The eluate is evaporated to yield 0.55 g (22%) of 4- [3- (1-pyrazolyl) prop-1-enyl] phenol as a yellow crystalline solid having a melting point of 146 to 152 ° C.

Example 19

By the method of Example 1, 1-isopropylamino-3- [4- [2- (1-pyra) having a melting point of 84 to 86 DEG C from 2.6 g of 4- [2- (1-pyrazolyl) ethylthio] phenol Zolyl) ethylthio] phenoxy] -2-propanol hydrogen maleate is obtained 2.45 g (46%).

Starting materials can be prepared as follows:

3.15 g (25 mmol) of 4-mercaptophenol in 75 ml of dimethylformamide were treated with 1.2 g (25 mmol) of 50% sodium hydride dispersion in mineral oil and the mixture was stirred for 5 minutes. 6.65 g (25 mmol) of 1- (2-P-toluenesulfonyloxyethyl) pyrazole in 20 ml of dimethylformamide are added and the mixture is stirred at room temperature for 3 hours. The solvent is evaporated off and the residue is partitioned between ethyl acetate and water. The organic layer is separated, dried over sodium sulfate and filtered. The filtrate was evaporated and the resulting solid was recrystallized from toluene to yield 2.6 g (47%) of 4- [2- (1-pyrazolyl) ethylthio] phenol having a melting point of 87-91 ° C.

Example 20

According to the method of the first step of example 1, 1- [4- [2- (1H-indazol-1-yl) from 1.9 g of 4- [2- (1H-indazol-1-yl) ethoxy] phenol 1.50 g (49%) of) ethoxy] phenoxy] -3-isopropylamino-2-propanol hydrochloride are obtained (melting point 121 to 123 DEG C, from ethyl acetate).

Starting materials can be prepared as follows:

(a) 2.95 g (25 mmol) of indazole was reacted with 1-benzyloxy-4- (2-bromoethoxy) benzene (prepared according to Example 1 (a)) by the method described in Example 15 (a). Reaction with g (25 mmol) yielded 4.5 g (52%) of 1-benzyloxy-4- [2- (1H-indazol-1-yl) ethoxy] benzene having a melting point of 81 to 83 ° C. 81-83 ° C., from hexane),

(b) The benzyloxy compound obtained above was dibenzylated with 48% hydrogen bromide in glacial acetic acid according to the method of Example 8 to obtain 4- [2- (1H-indazol-1-yl) ethoxy] phenol 1.9. g (58%) is obtained (melting point 124-125 ° C., from toluene).

Example 21

According to the method of Example 1, 1-isopropylamino-3- [4- [2- from 5.1 g of 4- [2- (2H-1,2,3-triazol-2-yl) ethoxy] phenol 4.50 g (51%) of (2H-1,2,3-triazol-2-yl) ethoxy] phenoxy] -2-propanol hydrochloride are obtained.

Starting materials can be prepared as follows:

(a) 5.0 g (72.5 mmol) of 1,2,3-triazole was mixed with 22.25 g (72.5 mmol) of 1-benzyloxy-4- (2-bromoethoxy) benzene according to the method of Example 15 (a). Reaction yields 21.6 g of a solid containing an isomer mixture.

The solid was extracted with boiling petroleum ether (60-80 ° C.), the extract was filtered and crystallized by cooling the filtrate to give 1-benzyloxy-4- [2- (2H-1, 9.54 g (45%) of 2,3-triazol-2-yl) ethoxy] benzene are obtained.

(b) The benzyloxy compound obtained above was dehydrogenated by catalytic hydrogenation by the method of Example 1 (b) to 4- [2- (2H-1,2,3-triazol-2-yl). 5.3 g (81%) of oxy] phenol are obtained (melting point 63 ° to 66 ° C., from diethyl ether).

Example 22

According to the method of the first paragraph of Example 1, 1-isopropylamino-3- [4-[(2H from 333 mg of 4-[(2H-1,2,3-triazol-2-yl) daoxy] phenol 350 mg (59%) of -1,2,3-triazol-2-yl) methoxy] phenoxy] -2-propanol hydrochloride are obtained (from 141 ° to 144 ° C., isopropanol).

Starting materials can be prepared as follows:

(a) 4.0 g (58 mmol) of 1,2,3-triazole and 15 ml of 40% formalin solution were left at 25 ° C for 2 hours. The solution is then extracted 10 times with 50 ml of dichloromethane. The combined dichloromethane extracts are dried over sodium sulfate, filtered and evaporated to dryness. The semisolid residue was dissolved in a small amount of boiling dimethyl ether and left at 0 ° C. for 2 days to yield 1.55 g (27%) of 2-hydroxymethyl-1,2,3-triazole having a melting point of 63 to 67 ° C.

(b) 0.99 g (10 mmol) of 2-hydroxymethyl-1,2,3-triazole are dissolved in 5 ml of thionyl chloride. After 5 minutes the solution is evaporated to dryness under reduced pressure and below 25 ° C. The resulting crude 2-chloromethyl-1,2,3-triazole hydrochloride was dissolved in 2 ml of dimethyl formamide and the solution was mixed with dimethylformamide [0.96 g (20 mmol) of 50% sodium hydride suspension in mineral oil. Stirred for minutes] is added to 2.0 g (10 mmol) of 4-benzyloxyphenol in 20 ml. The mixture is stirred at 60 ° C. for 0.5 h and evaporated to dryness. The residue is partitioned between 2N sodium hydroxide solution and ethyl acetate. The organic layer is separated, dried over sodium sulfate, filtered and evaporated. The residue is dissolved in boiling petroleum ether (60-80 ° C.) and crystallized by cooling the filtrate when hot. The crystals were filtered to yield 1.03 g (37%) of 1-benzyloxy-4-[(1H-1,2,3-triazol-1-yl) methoxy] benzene having a melting point of 69 to 73 ° C. The filtrate was evaporated to yield 613 mg (22%) of 1-benzyloxy-4- [2H-1,2,3-triazol-2-yl) methoxy] benzene in oil form.

(c) dibenzylating the 1-benzyloxy-4-[(2H-1,2,3-triazol-2-yl) methoxy] benzene by catalytic hydrogenation according to the method of Example 1 (b) To yield 390 mg (94%) of 4- [2H-1,2,3-triazol-2-yl) methoxy] -phenol.

Example 23

According to the method of Example 1, 1-isopropyl amino-3- [4- [1H-1,2 from 577 mg of 4-[(1H-1,2,3-triazol-1-yl) methoxy] phenol 350 mg (27%) of, 3-triazol-1-yl) methoxy] phenoxy] -2-propanol hydrogen maleate are obtained (from isopropanol / ethanol at melting point 98-101 ° C.).

Starting materials can be prepared as follows.

The 1-benzyloxy-4-[(1H-1,2,3-triazol-1-yl) methoxy] benzene prepared in Example 26 (b) was catalytically prepared according to Example 1 (b) and the method. Dibenzylation by hydrogenation afforded 690 mg (99%) of 4-[(1H-1,2,3-triazol-1-yl) methoxy] phenol having a melting point of 157 to 163 ° C.

Example 24

As a method of the first step of Example 1, 1-isopropylamino-3- [4-[(1- (pyrazolyl) having a melting point of 83 to 87 ° C. from 4-[(1-pyrazolyl) methylthio] -phenol ) Methylthio] phenoxy] -2-propanol hydrogen maleate is obtained (from 83 to 87 ° C., isopropanol).

4-[(1-pyrazolyl) methylthio] phenol used as starting material is prepared by reacting 4-mercaptophenol and 1-chloromethyl pyrazole in dimethylformamide in the presence of potassium carbonate at room temperature. 4-[(1-pyrazolyl) methylthio] phenol is dissolved at 119-122 ° C.

Example 25

According to the method of Examples 1 to 24, the following compounds can be prepared:

1-isopropylamino-3- [4-[(1-pyrazolyl) methoxy] phenoxy] -2-propanol hydrogen maleate (melting point 84 ° to 87 ° C., from isopropanol).

1- [4-[(4-chloro-1-pyrazole) methoxy] -phenoxy] -3-isopropylamino-2-propanol hydrogen fumarate (melting point 82 ° to 85 ° C., from ethanol).

1- [4-[(4-chloro-1-pyrazolyl) methoxy] -phenoxy] -3-isopropylamino-2-propanol hydrogenoxalate (melting point 71 ° to 75 ° C., decomposition, from acetonitrile ) And

1- [4- [2-hydroxy-3- (isopropylamino) -propoxy] phenoxymethyl] -4-pyrazolecarbonitrile P-toluene-sulfonate (melting point 97 ° to 100 ° C., isopropanol / ethanol from).

Representative agents containing substituted phenoxy-aminopropanol derivatives provided by the present invention are described in the Examples below.

Example A

Tablets containing the following components can be prepared by conventional methods.

Example B

Capsules containing the following components can be produced by conventional methods.

The capsule formulation is preferably filled into hard gelatin capsules of NO 4.

Claims (1)

Next, the epoxide of the general formula (II) is reacted with the amine of the general formula (III) to prepare a substituted phenoxyaminopropanol derivative of the general formula (I) and a pharmaceutically acceptable acid addition salt thereof. Way.

R-NH ₂ (III) In the above general formula R is a lower alkyl group; X is oxygen or sulfur atom; n is an integer of 0 or 1; Y is a methylene, ethylene or propylene group, or when n is 0, Y represents a group of the formula -CH = CH- * CH _2-, where the double bond is trans and the * carbon atom is linked to Z ; Z is 1-imidazolyl, 1H-1,2,4-triazol-1-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2 -Yl, 1-pyrazolyl, 4-chloro-1-pyrazolyl, 4-phenyl-1-pyrazolyl, 1-benzimidazolyl, 2H-benzotriazol-2-yl, 4,5,6,7 Tetrahydro-2H-benzotriazol-2-yl, 1H-indazol-1-yl and 4-cyano-1-pyrazolyl represent a 5-membered aromatic heterocyclic ring wherein heterocyclic ring is nitrogen It is connected to Y by an atom.