PL166607B1 - Method of obtaining derivatives of 1,2-ethanodiole and their salts - Google Patents

Abstract

Methods for preparing 1,2-ethane derivatives from iols and their salts or optical isomers of the general formula 1b, in which R 1 denotes the phenyl, naphthyl groups a , ind yl , ind e n yl , hydro naphthyl tetra or h ether cyclic, optionally based on a selected method. this includes halogenated groups, hydroxyl groups, possibly protected acetyl groups, tetrahydroxyl yloxy groups, amino groups, possibly t u a l y b asic groups C 1-6 - alkyl m e n t s, groups C 1 - 6 - a l k y m e n t , po ssibly n u m e n t b a s i c a t i o n ca, phenyl groups, possibly based on at least one base selected from among halogens, groups C 1-6 - C 1-6-alk oxy groups, phenyl-C 1-4-alk yl groups, C 1- 6-alk oxy groups, e n ly based on at least one base selected from among the furyl, thienyl or pyridyl groups, phenyl -C 1- 4- oxyl alkyl alcohols, possibly based on at least one basis selected from among halogen atoms, h y d groups oxyl group, C 1-6 -alk oxy group, which may be based on the C 1-6 -alk oxy group and C 1-6 -alkyl group of phenoxy groups, optionally substituted with at least one substituent selected from among halogen,.... . . characterized by the fact that the compound of the general formula 4, in which m R 1, R ² , R 3, R 4, R 5 and m have the meaning given above, and Y denotes a removable group a, p reacts with the compound of formula 16 or its salt,... FORMULA 16 PL

Description

The subject of the invention is a process for the preparation of 1,2-ethanediol derivatives and their salts, used as agents that improve brain function. Brain improvers are used to treat cerebral palsy, senile dementia, Alzheimer's dementia, ischemic sequelae, and cerebral stroke.

1,2-ethanediol derivatives are known, for example, from U.S. Patent No. 2,928,845, J. Pharm. Sci., Vol. 50, pp. 769-771 (1961), Farmaco. Ed. Sci., Vol. 19, pp. 1056-1065 (1964) and other publications. These compounds are used as local anesthetics. However, they are not known to be used to improve brain function, as agents against memory loss or as nootropics.

WO 88/8424 teaches that 1,2-ethanediol derivatives can be used in the treatment of Alzheimer's disease and other degenerative neurological disorders. However, no example of such derivatives is given in the application.

Drugs such as agents that increase metabolism in the brain, cerebral vasodilators and the like are used to treat a variety of dementias, especially Alzheimer's dementia and cerebrovascular paralysis. However, no brain enhancer is known that would be useful in the treatment of cerebral vascular paralysis, senile dementia, Alzheimer's dementia, sequelae of ischemic encephalopathy, and cerebral stroke.

The process of the invention provides novel 1,2-ethanediol derivatives and their salts.

The inventors conducted research to solve the above problems. As a result of these studies, it was found that the 1,2-ethanediol derivatives of general formula 1b or their salts have an excellent action against memory loss and an excellent action against hypoxia, and are particularly useful as brain enhancers.

According to the invention, a process for the preparation of 1,2-ethanediol derivatives, their salts or optical isomers of the general formula 1b,

R1 is phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl or heterocyclic groups, optionally substituted with a substituent selected from:

- halogen atoms,

- hydroxyl groups, optionally protected with an acetyl group,

- tetrahydropyranyloxy groups,

- amino groups, optionally substituted with C1-4alkyl groups,

- C1-6alkyl groups optionally substituted with halogen atoms,

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- phenyl groups optionally substituted with at least one substituent selected from halogen, C1-6alkyl and C1-6alkoxy groups,

- phenyl-C 1-4 alkyl groups,

- C 1-6 alkoxy groups optionally substituted with at least one substituent selected from furyl, thienyl or pyridyl groups,

- phenyl-C1-4-alkoxy groups, optionally substituted with at least one substituent selected from halogen atoms, hydroxyl, C1-6-alkoxy that may be substituted by C1-6-alkoxy groups and C1-6-alkyl groups,

- phenoxy groups optionally substituted with at least one substituent selected from halogen atoms,

- C1-6-alkyl groups and C1-6-alkoxy groups,

- carbamoyloxy groups substituted with C1-6-alkyl groups or with phenyl groups which may be substituted with halogen atoms,

- C1-6-alkylthio groups,

- C2-6-alkenyl groups,

- C2-6-alkenyloxy groups,

- phenyl-C1-4-alkylthio groups,

- phenyl-C1-4-alkylsulfonyl groups,

- phenylsulfonyl groups,

- C1-4-alkylsulfonylamino groups,

- phenylsulfonylamino groups,

- thienyl groups,

- pyridyl groups,

- nitro groups,

- oxo groups

-1 C1-4-alkylenedioxy groups ,.

R ² represents a hydrogen atom, a C1-6 alkyl group or a hydroxyl protecting group;

R ³ is: hydrogen or a C1-6 alkyl group, a -R ⁴ 1 MR5 are the same or different and represent hydrogen or C1-6 alkyl, m is 0 or an integer from 1 to 6,

R 6 ^b is amino or nitrogen-containing heterocyclic, optionally substituted with at least one substituent selected from:

- C1-6 alkyl groups optionally substituted with a hydroxyl group or a C1-6 alkoxycarbonyl group,

- C3-6 cycloalkyl groups,

- Cus-acyl groups,

- phenyl-C1-4-alkyl groups,

- phenyl-C2-4-alkenyl groups,

- pyrimidinyl groups,

- pyridylcarbonyl groups,

- pyrrolidinecarbonyl groups which may be substituted with an oxo group,

- adamantyl groups,

- amino groups,

- hydroxyl groups that may be substituted with C1-6-alkyl groups,

- oxo groups,

- benzoyl groups substituted with halogen atoms,

- pyridyl groups,

- pyrimidinyl groups

-1 halogen atoms, the heterocyclic group is selected from imidazolyl, pyridyl, quinolyl, tetrahydroquinolinyl, thiazolyl, furyl, thienyl, benzothienyl, benzofuranyl, indolyl, benzomidazolyl, benzothiazolyl, 2,3-dirobenzofuranyl, 2,3-dihydrobenzofuranyl groups -dihydroindolyl and benz [b] pyrazinyl, and the heterocyclic group contains

166 607 Lesbians nitrogen is selected from pyrrolidinyl, piperidyl, piperazinyl, lmidazolilowej, pyridyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, tetrahydroizochinohnylowej, tetrazolyl and quinuclidinyl, excluding (a) compounds in which R ¹ represents a phenyl group optionally substituted by a halogen atom or C1-6-alkyl, C1-4-alkylenedioxy, C '-4 alkoxy or hydroxy and R 6 ^b is -NR ⁷ R ⁸ wherein R ⁷ stands for a phenyl-C1-4 alkyl and ^R8 is hydrogen or C1-6 alkyl or R7 and r8 form together with the nitrogen atom a group of formula 2, wherein R ⁹ is phenyl, pyridyl or pyrimidyl, ai is 0 or an integer from 1 to 3, a group of the formula 3 wherein R "is a phenyl, pyridyl or pyrrolidinyl group, and i is 01 (b) of compounds where R ¹ is an unsubstituted or C 1-6 alkyl substituted phenyl group and R 6b is a di-C 1-6 alkylamino group or formula 7, 8 or 9, consists in reacting a compound of the general formula 4, in which R ¹ , R ² , R ³ , R ⁴ , R ^{5 and} m are as defined above, and Y is a removable group, is reacted with a compound of formula 16 or a salt thereof, wherein R6b is as defined above and optionally the hydroxyl protecting group is removed with R2 to give a compound in which R2 is hydrogen.

Brain enhancement agent refers to an agent that improves brain function having not only the effects of conventional brain enhancers, e.g. for treating the sequelae of ischemic encephalopathy and cerebral stroke, but also a therapeutic or prophylactic effect for memory loss and dementia, e.g. cerebral vascular paralysis. , senile dementia and Alzheimer's dementia.

In this description, the following terms have the following meanings unless otherwise stated.

The term halogen means, for example, fluorine, chlorine, bromine and iodine. An alkyl group of 1-6 carbon atoms is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl and the like. An alkenyl group of 2-6 carbon atoms is a vinyl, propenyl, butenyl, pentenyl, hexenyl group and the like. A cycloalkyl group of 3-6 carbon atoms is a group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term alkylenedioxy group means a group such as an alkylenedioxy group of 1-4 carbon atoms such as methylenedioxy, ethylenedioxy and the like. The term acyl means a group such as formyl, acetyl, butyryl and the like. The term ammonium means a tri-lower-alkyl ammonium group such as trimethylammonium, triethylammonium.

Protecting groups for hydroxyl groups, carboxyl groups and amino groups include conventionally used protecting groups for hydroxyl, carboxyl and amino groups which are described in Protective Groups in Organic Synthesis, Theodra W. Green, 1981, John Wiley's Sons, Inc. More particularly, protecting groups for hydroxy groups include, for example, lower alkyl groups, lower acyl groups, tetrahydropyranyl groups, and aryl-lower-alkyl groups such as substituted or unsubstituted benzyl groups.

A salt of the 1,2-ethanediol derivative of formula 1b may be a pharmaceutically acceptable salt. Such salts include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like, salts with carboxylic acids such as formic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid and the like, salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like, and alkali metal salts such as sodium, potassium and the like.

When the 1,2-ethanediol derivative of Formula 1b or a salt thereof has isomers (e.g., optical isomers, geometric isomers, tautomers), all of these isomers are within the scope of the invention. Also hydrates, solvates, and all crystalline forms of the compound of the present invention are included in the invention.

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The preparation of the 1,2-ctanediol derivatives of general formula 1b is shown in schemes 1.21 3. In these reaction schemes R 1, R ³ , R ⁴ and R ⁵ 1m are as defined above, R ^2a is the same hydroxyl protecting group. as given in the definition of R 2, R ^6b represents the same substituted or unsubstituted nitrogen-containing heterocyclic group, provided that the nitrogen-containing heterocyclic group has a free valency at the nitrogen atom forming the heterocyclic ring or a substituted or unsubstituted amino group, R ⁿ is the same a hydroxyl protecting group as in the definition of R2, χΐ and χ2, which may be the same or different, are halogen atoms, Y is a removable group such as halogen, lower alkylsulfonyloxy, arylsulfonyloxy or the like, Ya is arylsulfonyloxy and m represents an integer 1-6.

In the process shown in Scheme 1, (1) a compound of general formula 10 is reacted with a compound of general formula 11 or a salt thereof in the presence or the absence of a base to obtain a compound of general formula 12 or a salt thereof.

The obtained compound of general formula 12 or a salt thereof can be used in the next reaction without isolation.

(2) The compound of formula 12 or a salt thereof is subjected to a conventional reaction to protect the hydroxyl group to provide a compound of formula 13. The obtained compound of formula 15 can be used in the next reaction without isolation.

The compound of formula 13 is then reacted to remove the selective hydroxyl protecting group to provide the compound of general formula 14 or a salt thereof. The obtained compound of general formula 14 or a salt thereof can be used in the next reaction without isolation. These reactions may be carried out according to methods known per se, for example the method described in Protective Groups in Organic Synthesis, TheodraG. Green (1981), John Wiley and Sons, Inc., or a method similar to this.

The combination of the hydroxyl protecting groups R 2a and ^n, which may be used in these reactions may be appropriately selected.

(3) A compound of general formula 14 or a salt thereof is reacted with a halogenating agent or a sulfonylating agent in a solvent in the presence or absence of a base to obtain a compound of general formula 15.

The solvent that can be used in the reaction may be any solvent, as long as it does not adversely affect the reaction. Suitable solvents include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxane and the like, nitriles such as acetonitrile and the like, amides such as N, N-dimethylformamide and the like. These solvents may be used alone or as a mixture of two or more.

As the base which can optionally be used, there can be mentioned, for example, organic and inorganic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, potassium t-butoxide, sodium carbonate, potassium carbonate, sodium hydride and the like.

As the halogenating agent, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride and the like can be mentioned.

As the sulfonylating agent, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride and the like can be mentioned.

The halogenating agent, the sulfonylating agent and the optional base are used in an amount of at least 1 mole, preferably 1-2 moles per mole of the compound of general formula 14 or salt thereof.

The reaction can be carried out usually at -10 ° C to 100 ° C, preferably 0 ° C to 40 ° C for 10 minutes to 30 hours. The resulting compound of general formula 15 can be used as is in the next reaction without isolation.

(4) A compound of formula 15 is reacted with a compound of general formula 16 or a salt thereof in the presence or absence of a catalyst, in the presence or the absence of a base, to obtain a compound of general formula 1b or a salt thereof.

The solvent that may be used in the reaction may be any solvent so long as it does not adversely affect the reaction. Suitable solvents can be

For example, mention the same solvents as mentioned under item (3) of reaction scheme 1.

As the optionally used catalyst, for example, potassium iodide, sodium iodide and the like can be mentioned. The catalyst is used in an amount of 0.1-1 mol per mol of the compound of general formula 15

As the base which can optionally be used, there can be mentioned, for example, the same bases as mentioned under item (3) of scheme 1.

Each compound of general formula 16 or a salt and base thereof as optional component is used in an amount of at least 1 mole, preferably 1-20 moles per mole of the compound of general formula 15. The reaction can be carried out usually at a temperature of 10-150 ° C, preferably 20 ° C. - 100 ° C for 1 minute for 20 hours.

In Scheme 2, (1) a compound of general formula 10 is reacted with a compound of general formula 17 or a salt thereof in the presence or the absence of a base to provide a compound of general formula 18 or a salt thereof.

(2) The compound of general formula 18 or a salt thereof is reacted with a sulfonylating agent in a solvent in the presence or absence of a base to obtain a compound of general formula 19 or a salt thereof.

A solvent that may be used in the reaction may be any solvent so long as it does not adversely affect the reaction. Suitable solvents are, for example, the same solvents as mentioned in the process described in item (3) of scheme 1.

As the base that can be used optionally, there can be mentioned, for example, the same bases as mentioned in the process described in item (3) of scheme 1.

As the sulfonylating agent, for example, p-toluenesulfonyl chloride and the like can be mentioned.

Both the sulfonylating agent and the base optional ingredient are used in an amount of at least 0.95 mol, preferably 1-2 mol, per mol of the compound of general formula 18 or salt thereof.

The reaction can be carried out usually at -10 to 100 ° C, preferably 0 to 40 ° C for 10 minutes to 30 hours. The obtained compound of formula 19 or a salt thereof can be used in the next reaction without isolation.

(3) A compound of general formula 18 or a salt thereof is subjected to a conventional hydroxyl group protection reaction to obtain a compound of general formula 20. The reaction can be carried out according to methods known per se, for example the method described in Protective Groups in Organic Synthesis, Theodra W. Green. (1981), John Wiley and Sons, Inc. or a method similar to it. The obtained compound of general formula 20 can be used in the next reaction without isolation.

(4) A compound of general formula 19 or a salt thereof or a compound of formula 20 is reacted with a compound of general formula 16 or a salt thereof, in the presence or absence of a base, to obtain a compound of general formula 1b or a salt thereof. The reaction can be carried out in the same manner as described in the process set forth in item (4) of scheme 1.

In the process shown in Scheme 3 (1), a compound of formula 3 (1) is reacted with a compound of formula 3 (1) to give a compound of formula 23 or a salt thereof.

The solvent that can be used in the reaction may be any solvent as long as it does not adversely affect the reaction. Suitable solvents include, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like, and aromatic hydrocarbons such as benzene, toluene and the like. These solvents may be used alone or as a mixture of two or more.

In this reaction, the compound of general formula 22 is used in an amount of 0.8-100 mol, preferably 0.8-10 mol, per mol of the compound of general formula 21. The reaction can be carried out usually at -78-100 ° C, preferably -78 to 50 ° C for 5 minutes to 24 hours. The obtained compound of general formula 23 or a salt thereof can be used in the next reaction without isolation.

The compound of general formula 22 used in this reaction can be produced according to a method known per se, for example the method described in Bull. Soc. Chim. Fr., 1967 (5), pp. 1533-40.

(2) A compound of general formula 23 or a salt thereof is reacted with a compound of general formula 16 or a salt thereof, in the presence or absence of a base, to obtain a compound of general formula 1c or a salt thereof.

The solvent that can be used in the reaction may be any solvent, as long as it does not adversely affect the reaction. Suitable solvents include, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxane and the like, alcohols such as ethanol, propanol, butanol and the like, nitriles such as acetonitrile and the like. These solvents may be used alone or as a mixture of two or more.

As the base that can be used optionally, there can be mentioned, for example, the same bases as mentioned in the process described in item (3) of scheme 1.

Each of the compounds of general formula 16, or a salt and base thereof, as an optional ingredient is used in an amount of at least 1 mole, preferably 1-20 moles, per mole of the compound of general formula 23 or salt thereof.

The reaction can be carried out usually at 10-150 ° C, preferably 20-100 ° C for 10 minutes to 20 hours.

The reagents or base may also be used as a solvent in the above-described production processes depending on the nature of the reactants or the base.

In the production processes outlined above, when the compounds of formula 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 and 23 have isomers, e.g. optical isomers, geometric isomers, tautomers, can be used in the form of isomers. Further, the compounds can be used in the form of a hydrate, solvate or in any crystalline form.

When the compounds of general formulas 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 22, 23, 1a, 1b and 1c have a hydroxyl group, amino group or carboxyl group, it is possible to protect these groups in advance with conventional protecting groups and removal of the protecting groups after reaction, if necessary, according to a method known per se. The resulting compounds can be subjected to conventional isolation and purification processes such as column chromatography, crystallization, distillation, extraction, and the like.

The 1,2-ethanediol derivatives of general formula 1b or their salts can be converted into other 1,2-ethanediol derivatives of general formula 1 or their salts by subjecting the first compound to an appropriate combination of known reactions such as oxidation reaction, reduction reaction, addition reaction, acylation reaction, alkylation reaction, sulfonylation reaction, deacylation reaction, substitution reaction, dehydration reaction, hydrolysis reaction and the like.

The compound of formula 10, which is a starting material for the preparation of the compounds of the invention, can be prepared in a known manner, for example as described in JACS ⁿ , vol. 87, p. 1353 (1965) and as described in Shin Jikken Kagaku Koza, vol. 14, p. 579 (1977), Maruzen.

The compound of the invention, when used as a medicament, can be suitably mixed with excipients such as fillers, carriers, diluents and the like, and can be formed into tablets, powders, granules, fine granules, pills, suspensions, emulsions, liquids, etc. syrups, injection fluids, and the like, according to conventional methods. These drugs can be administered orally or parenterally. The method of administration, the dose, and the number of doses to be used may be suitably varied according to the age, weight and condition of the patient. In the case of oral administration, usually 0.01-500 mg of active compound is used daily in one to several portions for an adult patient.

Next, the pharmacological activity of representative compounds according to the invention is described. The test compound numbers given in the following pharmacological tests refer to the compound numbers given in the working examples.

1. Effect of the test compound on blood hypoxia.

Test compound dissolved in physiological saline (100 mg / kg) was orally administered to female ddY mice (5-6 weeks old, each group consisting of 10 mice). One hour (30 minutes) after administration, each mouse was placed in a 300 mL glass chamber and a gas mixture containing 4% oxygen and 96% nitrogen was purged through the chamber at a rate of 51 Lire / minute. The time from the beginning of gas flow to death of each mouse was measured. Groups of control mice were dosed orally with saline only.

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The effect of test compounds on blood hypoxia was calculated from the following formula, mean survival time of mice in the test group χ ^ o (%) mean survival time of mice in the control group The results are presented in the table and

Table i

Relationship no Impact for hypoxia (%) Relationship no Impact for hypoxia (%) and 2 and 2 io I65 i99 I39 23 I76 * 200 i48 24 i32 204 I76 * thirty i53 * 205 i94 3i I44 * 209 i50 * 38 i76 * 210 i65 * 40 i64 * 211 i60 46 i77 * 212 i5i 50 i36 * 2 and 7 I37 5i 242 * 2 and 8 207 52 I48 * 2 and 9 i82 54 I77 * 221 I33 56 149 224 i84 * 58 i97 225 i27 60 I52 * 230 247 * 6i i49 * 234 I47 62 I55, 246 I77 * 63 i57 * 247 i75 * 67 I55 * 249 i30 * 68 i24 250 I79 69 i26 25i I56 * 8i I83 255 I69 98 i82 * 258 I64 99 I68 259 I76 * i05 i98 * 260 I38 * and 06 I62 * 26 i i64 * i09 25i * 263 i7i * iiO 209 * 265 i40 * iii I47 * 267 i60 * ii4 i32 * 274 i23 i21 I55 * 275 i77 i24 i35 * 276 246 i25 i43 * 277 i50 i3i i56 * 28i I77 I33 221 * 282 i49 I39 293 * 283 i23 i4i i6i * 284 i50 i42 i69 * 288 i59 i43 228 * 29i i28 i44 2i3 * 292 I24 i45 248 * 295 i45 * I50 24i * 296 I86 * I52 3 and 6 * 297 I90 * I54 i7i * 304 i75 * i6i I37 * 305 I62 * i65 ii9 306 i49 * i66 245 * 307 i42 * i72 ii3 308 i40 * i77 I84 * 3i0 i72 * I78 i94 * 3ii i72 * I79 ii6 3 and 4 i58 * i82 i68 * 3 and 6 I67 * I86 24i * 3 and 7 i33 * i90 20i * 3 and 9 201 * i96 224 * 322 i63 * I97 221 324 I62 *

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1 2 1 2 335 180 376 144 * 336 185 377 163 * 340 150 * 379 157 * 341 185 * 380 160 * 344 155 381 268 * 347 198 382 185 * 350 160 * 387 182 351 154 * 390 157 * 358 212 * 391 222 * 361 157 * 392 183 * 363 217 * 393 183 * 365 160 * 394 144 368 242 * 397 154 370 230 * 403 221 * 372 246 * 404 131 * 374 224 * 408 189 * 375 309 * 409 211 *

Note * Mice were placed in the chamber 30 minutes after dosing instead of one hour after dosing

2. Effect of the test compound on memory loss (1) Memory loss induced by electrode convulsive shock (ECS).

Test compound dissolved in saline was administered to male ddY mice (5-6 week old mice, each group comprised 10 mice). The passive avoidance task acquisition trial was performed one hour after administration. Each mouse was placed in the clear space of a passive staged type two-space avoidance apparatus (MPA-100M manufactured by Muromachi Kikai). As mice entered the dark space, the sloping door to the dark space was closed. After 0.5 seconds, the feet were shocked (1.6 mA, 2 seconds). Immediately thereafter, the mice were applied with ECS (25 mA, 0.5 seconds) through both eyes. After 24 hours in a memory test, the mice were placed back in the bright space and the latency of the response to the stimulus upon entering the dark space was measured. If the mouse avoided for more than 300 seconds, the upper value of 300 seconds was determined.

A group of control mice that were administered saline only intraperitoneally were also measured latency times in the same way.

The anti-memory loss effect was taken as the middle of the latency times of the 10 mice's responses and expressed as the following symbols: 0-60 seconds; + 61 -100 seconds; + + 101 150 seconds; +++ 151-300 seconds.

The results are presented in Table 2

Table 2

Relationship no Dose mg / kg Effects on memory loss Relationship no Dose mg / kg Effects on memory loss 1 2 3 4 5 6 2 3 + 171 3 + 3 3 + + 178 3 +++ 13 3 + + 182 3 + 19 3 + + 186 10 + 32 3 +++ 192 3 + 69 3 + 207 10 + + 74 3 + + 211 3 + + 165 3 + 215 3 + 166 3 +++ 216 3 +++

io

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and 2 3 and 2 3 221 i0 J. + + 354 3 + 004 3 + + 357 io + + 030 3 + + 364 i0 + 033 3 + + 366 io + 039 3 + + 367 3 + 04i 3 + + 373 io + + 097 3 +++ 375 3 + + 300 3 + + 380 3 + + 353 3 + + 1

(0) The study effect of ua -cyclceximide induced memory loss.

Like dounsi Yamazaki and iu. (Drugs, Miud aud A-tiou, tnm 3, pp. I07 - i36 (i983)), -cyclic Ceximide interferes with memory recovery in mice. Hence, we performed the substitute test.

The test was performed using the npisau method in Drugs, Miud aud A-tinu, tnm 3, pp. I07 i36 (i983) and Fnlia PCarma-nlngi-a Japoui-a, tnm 89, pp. 043-050 (i987).

As the bottom apparatus, the torsion box was gradually reduced by the bottom of the uuikauia. It was a -zarue box of Vivid acrylic with a dimension of -C 00 -m X 00 -m X 0i -m (height), part of which had a stainless steel grating and which had a platform of the size of the C 7 m X 7 m X 0 m (height).

CycloCeximide rczpusz-znun in saline and injections into the skin at a dose of 20 mg / kg alone-nm ddY mice 5-6 weeks of age. Each group consisted of 10 mice. In the uabywauia trial, Mon i5 miut-C from the pod, each mouse put-zouo ua the platform in the above apparatus on the day of the study. Short side of the mouse only changed the platform, supplied current and mA for 0 seconds, tb / the delay after which the mouse returned to the cage. Test zz ^ joar ^ ii ^ tiu ^ ia a nd attempt to weaken memory. Each mouse that was treated orally with pndaun cycloceximide was tested for the compound dissolved in the physiological log. Pn 30 miuut-C from the administration of the mice pcunwuie putz-znun ua the platform and measured -times utajeuia responses ua changed-zeuie. If the mouse has elapsed for longer than 300 seconds, nzua-zouo will go up to 300 seconds.

A group of kcutrcluyyC mice dosed only with saline orally were also measured with the latency of response in the same manner.

The mice's answer was taken as mid-time and the term for pnm-ą is replaced by -y-C symbols: - 0-60 seconds; + 6i - i00 seconds; + + i0i -i 50 seconds; +++ i51-300 sec.

The results are presented in Table 3

Table 3

Relationship born Dose mg / kg Impact of ua memory loss Relationship born Dose mg / kg Impact of ua memory loss 1 2 3 and 2 3 8 i0 + 74 thirty + 21 3 +++ iii 3 + + 04 io + + ii2 3 + 37 3 + ii3 3 + + 39 3 +++ ii4 3 + 68 3 + ii6 i0 + 69 3 +++ i21 3 + 70 3 + i03 3 +++ 7i io + i04 3 +

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1 2 3 1 2 3 170 10 + 291 3 + + 172 10 + 293 3 + + 177 3 +++ 296 3 +++ 178 3 +++ 297 thirty +++ 179 10 + 300 3 +++ 188 '3 + 331 3 +++ 191 10 + 336 3 + + 205 3 + 344 3 + + 211 3 + + 348 10 + 212 3 + + 355 3 + + 217 3 + + 358 3 + + 219 3 + 362 10 + + 223 3 +++ 363 10 + 228 3 + + 363 10 + + 245 3 + + 371 3 + 246 3 + 372 3 + 247 10 + + 376 3 + + 263 3 + + 377 3 + 273 3 +++ 378 3 + 274 10 + + 380 10 + + 275 3 + 383 3 + 277 10 + + 385 3 + + 278 3 + 387 3 +++ 279 3 + 391 3 + 280 3 +++ 392 10 + + 283 3 + 393 10 + 285 3 + 394 3 + + 286 3 + + 398 3 + 287 3 + + 404 10 + 289 3 + + 409 10 + + 290 10 + + comparative relationship - -

3. Inhibitory effect for acetylcholinesterase.

The test was performed according to the method of Ellman et al., Biochem. Pharmacol., Vol. 7, pp. 88-95 (1961).

Acetylcholine (as vehicle) was added to the phosphate buffer solution containing 5,5'-dithiobis- (2-nitrobenzoic acid) (DTNB), test compound and mouse brain homogenate (as a source of acetylcholone esterase). The resulting mixture was incubated and the amount of 5-thio-2-nitrobenzoic acid obtained was measured photometrically at 412 nm.

The inhibitory activity for the acetylcholinesterase of the test compound was expressed as the percentage of inhibition when the final concentration of the test compound was 10 µg / ml. The results are presented in

Relationship no % braking Relationship no % braking 1 2 1 2 8 24 33 76 25 38 60 83

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61 74 233 91 62 36 234 87 63 43 235 92 68 43 236 89 98 38 241 90 111 42 246 93 113 26 249 50 128 thirty 251 44 133 23 253 52 142 47 260 38 161 59 266 36 169 13 275 25 193 22 278 59 197 26 282 44 200 45 284 22 201 36 286 31 203 26 291 thirty 210 38 292 26 211 51 ! 35 ⁴ thirty 217 83 '357 thirty 218 22 1 360 twenty 221 45 | 367 45 223 71 ! 374 21 224 89 1 378 61 225 78 379 67 228 62 385 45 230 90

4. Acute Toxicity.

A test compound dissolved in saline was intravenously administered to a group of (male) ddY mice (5-6 weeks old) to investigate the acute toxicity of the test compound.

As a result of the trial, tested compounds Nos. 2, 3, 13, 19, 21, 25, 33, 37, 52, 81, 105, 116, 124, 125, 131, 133, UI, 146, 1 ^: 2,165,166,169, Γ71, 172,119,188,193,196,197,201,203,205,207,209,215,

216,217,228,230,233,234,273,304,305,311 317,331,344,347,351,353,354,357,363,365,375, 387, 391, 392, 393, 397 and 403, did not result in any mortality at 50 mg / kg.

It is clear from the results of the above test that the compounds according to the invention have an excellent antihypoxic effect, an anti-memory loss and an acetylchohnoeeterase inhibitory effect, while having a low toxicity.

From the above results it is clear that the brain enhancer according to the invention is suitable for the treatment of cerebral palsy, senile dementia, Alzheimer's dementia, the sequelae of ischemic encephalopathy and cerebral stroke.

The invention is illustrated in the non-limiting working examples. In the examples, the ratios of the eluent mixtures are always by volume and the support in the column chromatography is silica gel (Kieselgel 60, Art. 7734) manufactured by Merck Co.

The abbreviations used in the examples have the following meanings: Methyl, Et-ethyl, i-Prtzopropyl, t-Bu - t-butyl, Ac - acetyl, Ph - phenyl, DPM - difenzlmethyl, Bz - benzyl, Tr - trityl, IPA alcohol isopropyl, IPE-isopropyl ether, PTS-p-toluenesulfonic acid.

In the following sentences and tables, substances in parentheses refer to the solvents used in crystallization.

166 607

Example I.

(1) A mixture of 10.8 g of (L) -dibenzoylcystine, 1.6 g of lithium borohydride, 2.4 g of t-butoxide and 180 ml of tetrahydrofuran was refluxed for one hour and then cooled to -60 ° C. 6.1 g of 4-benzyloxyphenacyl bromide were added to the mixture. The mixture was stirred for 30 minutes at the same temperature and further for 3 hours at -40 to -30 ° C. The reaction mixture was added to a mixture of 100 ml and 200 ml of diethyl ether. The organic layer was separated, washed with water, a saturated sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution in that order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using toluene as eluent to obtain 2.8 g of (S) -1- (4-benzyloxyphenyl) -2-bromoethanol.

(2) 2.8 g of (S) -1- (7-benzyloxyphenyl) -2-bromoethanol was dissolved in a solvent mixture of 20 ml of methanol and 10 ml of tetrahydrofuran. To this solution was added a solution of 0.8 g of potassium hydroxide dissolved in 4 ml of water under ice cooling. The mixture was stirred for 5 minutes at the same temperature and a further 10 minutes at room temperature. The reaction mixture was added to a mixture of 50 ml of diethyl ether and 50 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 25 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1.4 g of (S) -2- (4-benzyloxyphenyl) oxirane, mp 56-61 ° C and optical rotation [a] D ²⁵ = + 5.2 ° (c = 2, CHCl ₃ ) .

The following compounds were prepared in the same way: (S) -2- (methylphenyl) oxirane, [a] d ²⁵ = + 15.7 ° (c = 2, CHCl3), (S> 2- (4-phenoxyphenyl) oxirane, [a] D ²⁵ = + 12.5 ° (c = 4, CHCl 3).

Example II (1) A solution of 23 g of (+) -diisopinocamphenylchloroborane dissolved in 30 ml of tetrahydrofuran was cooled to -25 ° C. To my 12 g of 4-benzyloxyphenacyl bromide was added. The resulting mixture was stirred for 4 hours at -20 to -15 ° C. The reaction mixture was added to a mixture of 150 ml of diethyl ether and 100 ml of ice water. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 1: 2 mixture of hexane: toluene as eluent. 6.8 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol were obtained.

(2) 6.0 g of (R) -1- (4-benzyloxyphenyl) -2-bromoethanol was dissolved in a mixture of 50 ml of methanol and 25 ml of tetrahydrofuran. Thereto was added a solution of 1.5 g of potassium hydroxide dissolved in 5 ml of water under ice cooling. The resulting mixture was stirred for 5 minutes at the same temperature and further for 10 minutes at room temperature. The reaction mixture was added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted with 50 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water, a saturated aqueous sodium chloride solution in turn and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 3.7 g of (R) -2- (4-benzyloxyphenyl) oxirane, mp 58-67 ° C and optical rotation [α] d ²⁶ = -14.4 ° (C = 2, CHCla).

The following compounds were prepared in the same manner: (R) -2- (3-methylphenyl) oxirane, [a] D ²⁷ = -18.6 ° (C = 2, CHCl). (R) -2- (4-phenoxyphenyl) oxirane, [α R = -11.3 ° (C = 2, CHCl ₃ ).

Example III (1) 5.1 g of pntasium tert-butoxide were added to less than 10 ml of ethylene glycol mono-t-butyl ether. The mixture was heated to 80 ° C. 35.0 g of 2- (3-chlorufebyl) oesirabd was added dropwise thereto for an hour. The mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 100 ml of ice water and 100 ml of ethyl acetate. The organic layer of the club, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sulfate

166,607 of magnesium. The solvent was removed by distillation under reduced pressure. The residue thus obtained was further subjected to distillation under reduced pressure to obtain 37.7 g of colorless oily 1- (3-chlorofrnyl) -2- (2-t-butoxyrtoxy) ethanol, boiling point 140-146 ° C / 1.17 · 10- 1 kPa.

(2) 37.0 g of 1- (3-chlorofrnyl) -2- (2-t-butoxyethoxy) ranol was dissolved in 70 ml of methylene chloride. 12.9 g of pyridine and 16.9 g of acetic anhydride were added to the solution. The resulting mixture was stirred for 24 hours at room temperature. The reaction mixture was added to a mixture of 150 ml of ice water and 100 ml of methylene chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution and water in that order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 40.0 g of oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-t-butoxyrtoxy) ethane.

(3) 40.0 g of 1-acetoxy-1- (3-chlorophenyl) -2- (2-t-butoxyethoxy) ethane was dissolved in 40 ml of methylene chloride. 80 ml of mfluoroacetic acid was added to the solution under ice-cooling. The mixture was stirred for 12 hours at room temperature. After completion of the reaction, the solvent was removed by distillation under a reduced pressure. The residue was mixed with 100 ml of toluene. The solvent was further removed by distillation under reduced pressure. The residue thus obtained was dissolved in a mixture of 50 ml of ethanol and 10 ml of water. 10.7 g of sodium bicarbonate was added to the solution at room temperature. The mixture was adjusted to pH 6-7 with saturated aqueous sodium bicarbonate solution, then concentrated to about half its volume under reduced pressure. 100 mL of ethyl acetate was added to the concentrate. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using 3/1 toluene / ethyl acetate as eluent to give 19.4 g of oily 1-acetoxy-1- (3-chlorophenyl) -2- (2-hydroxyethoxy) rtane.

(4) To a mixture of 19.0 g of 1-acetoxy-1- (3-chlorofrnyl) -2- (2-hydroxyethoxy) ethane and 95.0 ml of methylene chloride containing 9.1 ml of methanesulfonyl chloride, 16.4 ml of methylamine was added dropwise over an hour. with ice cooling. The resulting mixture was stirred for 10 minutes at the same temperature and for an additional hour at room temperature. The reaction mixture was added to a mixture of 50.0 ml of methylene chloride and 150.0 ml of ice water. The resulting mixture was adjusted to pH2.0 with 6N hydrochloric acid. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 24.5 g of oily 1-acroxy-1- (3-chlorophenyl) -2- (2-methanesulfonyloxyethoxy) ethane.

(5) 1.40 g of 1-acetoxy-1- (3-chlorofrnyl) -2- (2-methanesulfonyloxyethoxy) ethane was dissolved in 7 ml of NN-dimethylformamide. 0.69 ml of N-methylpiperazine and 1.03 g of potassium carbonate were added to the solution. The mixture was stirred for 3 hours at the temperature of 80 ° C. The reaction mixture was cooled and added to a mixture of 30 ml of ice water and 30 ml of diethyl ether. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was mixed with 7 ml of methanol and 45 mg of sodium methoxide. The mixture was allowed to stand overnight at room temperature. The solvent was removed by distillation under reduced pressure. 20 ml of ethyl acetate and 10 ml of water were added to the residue. The organic layer was separated. The aqueous layer was extracted with 20 mL of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were washed with a saturated aqueous sodium chloride solution and then purified by column chromatography using a 10/1 chloroform / methanol system as eluent. To the obtained oily product were added 10 ml of ethanol and 1.2 ml of a 6N dry ethanol hydrochloride solution. 10 ml of diethyl ether were added to the resulting mixture. The mixture was stirred for 30 minutes.

166 607

The obtained crystals were collected by filtration, washed with a mixture of 2 ml of ethanol and 2 ml of diethyl ether, and dried to give 770 mg of 1- (3-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) ethoxy] ethanol hydrochloride (Compound No. 1) mp 211-213 ° C (MeOH-EtOH).

Compounds of general formula 25 shown in Table 5 were prepared in the same manner. Table 5

Compounds of formula 25

Relationship no R ¹ R ² R ³ R ⁴ R6b m Addition salt Melting point ° C 2 pattern 24 H. H. H. pattern 26 2 - Oil 3 pattern 24 H. H. H. pattern 27 2 - 134.4-136.5 (IPA) 4 pattern 24 H. H. H. pattern 28 2 - Oil 5 pattern 24 H. H. H. pattern 29 2 HCl 138-140 (IPA) 6 pattern 24 H. H. H. pattern 30 2 - Oil 7 pattern 24 H. H. H. pattern 31 2 HCl 164.5-166.5 8 pattern 24 H. H. H. pattern 32 2 HCl 169-171 (EtOH) 9 pattern 24 H. H. H. pattern 33 2 2HCl 169-171 (CH ₂ Cl ₂ -EtOH) 10 pattern 24 H. H. H. pattern 34 2 - 104.5-105.5 (EtOH) AT pattern 24 H. H. H. pattern 35 2 - Oil 12 * _a pattern 24 H. H. H. pattern 36 2 1/2 1,5-naphtha-208-210 (MeOH-Et ₂ O) lenedisulfonic acid

Note " ^A 1 mole of the dimethylamine form was reacted with 0.5 mole of dimethyl 1,5-naphthalenedisulfonate to give the desired product. Example IV. A mixture of 2.0 g of 1- (4-benzyloxyphenyl) -2- [2- (N, N-dimerylamino-toxyethanol) hydrochloride, 500 mg of 10% palladium on carbon and 10 ml of methanol was hydrogenated for 2 hours at room temperature under pressure. After completion of the reaction, the palladium on carbon was removed by filtration. The solvent was removed by distillation under reduced pressure to give 1.4 g of 1- (4-hydroxyphenyl) -2- [2- (N, N-dimethylamino] -oxyethanol hydrochloride (Compound # 13). ) mp 169.5-170.5 ° C (EtOH).

Compounds of Formula 25 shown in Table 6 were prepared in the same manner.

Table 6 Compounds of formula 25

Relationship no R ¹ R ² R ³ R ⁴ R6b m Addition salt Melting point ° C 14 pattern 38 H. H. H. pattern 39 2 HCl 150-152 (EtOH) 15 pattern 38 H. H. H. pattern 39 2 HCl amorphous 16 pattern 40 H. H. H. pattern 39 2 - Oil 17 pattern 24 H. H. H. pattern 41 2 HCl 145-147 18 pattern 24 H. H. H. pattern 42 2 2HC1 204.5-206.5 (MeOH) 19 pattern 44 H. H. H. pattern 43 2 - Oil twenty pattern 45 H. H. H. pattern 39 2 HCl 151-153 Example V. 0.65 ml of pyridine and 0.99 ml of anhydride vinegar added to 1 g 1- (3-

mrtylphenyl) -2- [2- (morpholm-4-yl) ethoxy] ethanol. The mixture was stirred for 3 hours at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent. 20 ml of ethyl acetate and 10 ml of water were added to the residue. The mixture was brought to pH 10 with potassium carbonate. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using a 30/1 chloroform / ethanol system as eluent, yielding 1 g of oily 1-acetoxy-1- (3-methylphenyl) -2- [2- (morpholin-4-yl) ethoxy] -ethane (compound no.21).

Compounds of general formula 25 shown in Table 7 were prepared in the same manner.

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Table 7 Compounds of formula 25

Relationship no R ¹ R ² R ³ R ⁴ _R 6b Addition salt Melting temperature ° C 22 pattern 44 Ac H. H. pattern 46 2 - Oil 23 pattern 44 Ac H. H. pattern 39 2 - Oil 24xd pattern 24 H. H. H. pattern 47 2 - Oil 25xe pattern 48 H. H. H. pattern 39 2 HCl 174.5-176.5 (EtOH) 26 pattern 49 Ac H. H. pattern 39 2 HCl 169.5-170.5 (EtOH) 27 pattern 50 Ac H. H. pattern 39 2 HCl 131.5-132.5 (Mó2CO) 28 pattern 51 Ac H. H. pattern 39 2 HCl Oil 29 pattern 52 Ac H. H. pattern 39 2 HCl Oil thirty pattern 53 Ac H. H. pattern 39 2 - 144.5-146.5 (EtOH-Et2O) 31 pattern 24 Ac H. H. pattern 54 1 HCl Oil

Note the indicated compound was obtained by reacting compound 17 with acetic anhydride ^x e the indicated compound was obtained by reacting compound 20 with boron sulfnnyl chloride in pyridine

Example VI. 50 ml of a 1: 1 mixture of chloroform and water was added to 3.30 g of 1-acetoZsz-1- (3-hzdroxyphenyl) -2- [2- (N, N-dimethylamino) ethoxide] ethane hydrochloride. 750 mg of sodium carbonate was added to the mixture under ice-cooling. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was mixed with 20 ml of benzene. The mixture was heated to 60 ° C. A solution of 870 mg of ethyl isocyanate dissolved in 5 ml of benzene was added dropwise over 10 minutes to the resulting solution. The mixture was stirred for 40 minutes at the same temperature. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The thus obtained residue was purified by column chromatography using a 10/1 chloroform / ethanol system as the eluent to obtain an oily product. The oily product was dissolved in 10 ml of ethanol. Hydrogen chloride gas was blown into the solution. The solvent was removed by distillation under reduced pressure to give 1.50 g of 1-acetnx-1- [3- (Netzl-carbamolloxy) fenzln] -2- [2- (N, N-dimethylnamino) ethnez] ethane hydrochloride (Compound No. 32 ) m.p. 111.5-113.5 ° C (Mo2CO).

In the same manner, oily 1-acotoxy-1- [3- (3-chlorofenzlcarbamollynxy) fenzin] -2- [2- (N, N-dimethylammonium) ethoxide] ethane hydrochloride (compound No. 33) was prepared.

Example VII. (1) 9.5 g of potassium butoxide was added to 92 ml of ethylene glycol. The mixture was heated to 80 ° C. A solution of 34.7 g of 2- (4-benzene-keyphenyl) -zelran dissolved in 220 ml of dimethylsulfoxide was added dropwise thereto over 3 hours. The resulting mixture was stirred for 30 minutes at the same temperature. The reaction mixture was cooled and added to a mixture of 1 liter of ice water and 600 ml of ethyl acetate. The resulting mixture was adjusted to pH 7 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 200 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 10/1 chloroform / ethanol system as eluent. 25 g of 2- (4-benzyl-xyphenyl) -2- (2-hydroxyethoxy) ethanol with a melting point of 116.5-117.5 ° C (MeCN) were obtained.

(2) 22.7 g of 1- (g-benzyloxyphenyl) r2- (2-hydroxyethkxy) nZezoiu dissolves about j4Zm1 of pimldine. The solution was cooled to -20 ° C. 19 g of p-toluernsulfonyl chloride was added to the solution. The resulting mixture was warmed to 0 ° C and stirred at this temperature for 15 hours. The reaction mixture was added to a mixture of 300 ml of ice water and 200 ml of diethyl ether. The resulting mixture was adjusted to pH2 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 100 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were washed with 1 N hydrochloric acid, water, and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under

166,607 under reduced pressure. The residue was purified by column chromatography using 3/1 toluene / ethyl acetate as eluent, yielding 20.5 g of 1- (4-benzyluxyphenel) -2- [2- (p-tolunbusdlfubelo) uesyetoese] ethanol.

(3) To a mixture of 20 g of it (4-benzyloxyphenyl) -2-t2 - (- totuenesulfonyloxy) ethoxy] ethabul and 40 ml of methylene chloride containing 8.2 g of 1Aciihydro4H-pyran was added 2.3 g of p-toluenesulfonate piredemoweg at room temperature. The resulting mixture was heated under reflux for 30 minutes. The reaction mixture was then added to a mixture of 100 ml of ice water and 100 ml of methylene chloride. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give 18.6 g of a slightly yellow oily oily ^ ^ benzyloxyphenyl) - (2-tetrahydroplranyloxy) t2- [2- (p-toldebusulfonylux) ethyl] ntPbu.

(4) A mixture of 2 g of 1- (4-benzyloxyphenyl) -1- (2-tetrahydrupirabylux) -2-t [2- (p-toluenebusdlphobylux) ethoxy] ethab, 5.9 ml of 40% aqueous methylamine and 20 ml of ethanol was heated in refluxing for 2 hours. The reaction mixture was handled and added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer of uDzinlubu. The aqueous layer was extracted twice with 20 ml of diethyl ether. The extracts were combined with the previously separated organic layer. The combined organic layers were mixed with 10 ml of water. DupruwaDzon mixture Up to pH 1.0 with 6 N hydrochloric acid. The aqueous layer of uDzinlubu was stirred for 30 minutes at room temperature. To it 30 ml of chloroform was added. The resulting mixture of dupruwpDzon to pH 12 using a 5% aqueous solution of sodium wuDurutlnbed. The organic layer was washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The empty wash was mixed with 10 ml of acetone. Hydrogen chloride gas was blown into the mixture under ice cooling. The resulting crystals were collected by filtration, washed with acetone, and dried to give 620 mg of Dured 1t (4-bnbzylphenyl) -2- (2-methylpmiboetux) ethanol (compound No. 34) chlorine, mp 173-173.5 ° C (EtOH).

Compounds of Formula 37 shown in Table 8 were prepared in the same manner.

Table 8 Compounds of formula 5

Relationship no R ¹ R ² R ³ R ⁴ a R ^4b R6b has m Addition salt Melting point ° C 1 2 3 4 5 6 7 8 9 10 11 35 pattern 52 H. H. H. H. pattern 109 1 1 HCl 158-158.5 (IPA) 36 pattern 52 H. H. H. H. pattern 55 1 1 HCl 170-170.5 (EtOH) 37 pattern 56 H. H. H. H. pattern 39 1 1 HCl 180-181 (EtOH-AcOEt) 38 pattern 50 H. H. H. H. pattern 33 1 1 2HC1 179-180.5 (MnCbtEt2O) 39 pattern 50 H. H. H. H. pattern 55 1 1 HCl 174.5-175 (IPA) 40 pattern 50 H. H. H. H. pattern 57 1 1 2HC1 212.5-213 (MeOH) 41 pattern 50 H. H. H. H. pattern 58 1 1 - Oil 42 pattern 50 H. H. H. H. pattern 59 1 1 2HC1 158.5-160.5 (EtOH) 43 pattern 50 H. H. H. H. pattern 60 1 1 - 55-58 44 pattern 50 H. H. H. H. pattern 61 1 1 - 36-38 45 pattern 50 H. H. H. H. pattern 62 1 1 - Oil 46 pattern 50 H. H. H. H. pattern 63 1 1 HCl 139-141 (IPA-AcOEt) 47 pattern 50 H. H. H. H. pattern 64 1 1 HCl 163-164 (EtOH-MeCN) 48 pattern 50 H. H. H. H. pattern 65 1 1 - Oil 49 pattern 44 H. H. H. H. pattern 66 1 1 - Oil 50 pattern 44 H. H. H. H. pattern 67 1 1 - Oil 51 pattern 44 H. H. H. H. pattern 64 1 1 HCl 148.5-149.5 (IPA-AcOEt) 52 pattern 24 H. H. H. H. pattern 64 1 1 HCl 173.5-175.5 (EtaGH-MeaCO) 53 pattern 24 H. H. H. H. pattern 69 1 1 PTS 198-200 (EtOH-AcOEt) 54 pattern 24 H. H. H. H. pattern 70 1 1 HCl 161-162.5 (IPA-AcOEt) 55 ^x1 pattern 44 H. H. H. H. pattern 39 1 1 HCl Oil 56 * 1 pattern 50 Me H. H. H. pattern 39 1 1 - Oil

Note * 'Metuxylwpme was carried out using boron diazomethane instead of 3,4-dlhydru-2H-piΓPbd, to prepare the desired product

166 607

Example VIII. A mixture of 500 mg of 2 - [(imίdazol-4-yl) methoxy] -1-phenylethanplium, 1.1 ml of pyridine, 1.1 ml of triethylamine and 11.1 ml of acetic anhydride was stirred for one hour at 100 ° C. The reaction mixture was cooled to room temperature. The solvent was removed by distillation under reduced pressure. 1.1 ml of methyl iodide and 5 ml of acetonitrile were added to the residue. The mixture was allowed to stand at room temperature for 24 hours. The solvent was removed under reduced pressure. 4 ml of ethanol and 6.8 ml of a 5% aqueous sodium hydroxide solution were added to the residue thus obtained. The resulting mixture was stirred at room temperature for 6 hours. The solvent was removed by distillation under reduced pressure. 30 ml of chloroform and 20 ml of water were added to the residue thus obtained. The organic layer was separated, washed with water, and dried over magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained oily product was purified by column chromatography using a system of chloroform / ethanol in the ratio 10/1 as eluent. Isopropyl ether was added to the obtained white crystals, and the resulting mixture was filtered to give 450 mg of 2 - [(1-methylpimidazol-5-yl) methoxy] -1-phenylpetanol (Compound # 57), mp 102-105 ° C.

The following compound was prepared in the same manner: 1- (4-benzyloxyphenyl) -2 - [(1-methylimidazpl-5-yl) methoxy] ethanol (compound No. 58), m.p. 148.5-150.5 ° C (IPAAcOEt ).

Example IX. 1.23 g of N, N'-dicyclphexylcarbidimide was added under ice cooling to a solution of 1.08 g of 2- (2-aminoethoxy) -1-phenylethanol, 730 mg of nicotinic acid, 810 mg of 1-hydroxybenzotnasole and 0.83 ml of triethylamine dissolved in 5 ml tetrahydrofuran. The resulting mixture was stirred at the same temperature for 5 minutes and further at room temperature for an hour. 11 ml of ethyl acetate was added to the reaction mixture. Insoluble matter was removed by filtration. 5 ml of water was added to the filtrate, and the mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted with 5 ml of water. The extract was combined with the previously separated aqueous layer. The combined aqueous layers were mixed with 20 ml of chloroform and adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a system of chloroform / ethanol in the ratio of 15/1 as eluent. 400 mg of oily 2- (2-mkptynpilpaminpetpksy) -1phenylethanol (compound No. 59), IR (pure) αηΛνο = at 1635 was obtained.

EXAMPLE 10 (1) 1.19 g of 4-benzyl-benzaldehyde was dissolved in 20 ml of tetrahydrofuran. The solution was cooled to -10 ° C. To it, 10 ml of a tetrahydrofuran solution containing 2 N of 2-chlorinrpetoxymethylmagnesium chloride was added dropwise over 10 minutes. The resulting mixture was stirred for one hour under ice-cooling. The reaction mixture was added to a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 1 g of ammonium chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using toluene / ethyl acetate in the ratio 20/1 as eluent. 1.34 g of 1- (4-benzylthiphenylp) H 2- (2-chloroetpxy) ethanol with a melting point of 49.5-50.5 ° C (hexane-IPE) was obtained.

(2) A mixture of 600 m0 1-rglbenzblothiofpnyl- (2-chloroethoxyptayol, 4 ml of 50% aqueous diethylamine solution, 310 mg of potassium iodide and 5 ml of ethanol was refluxed for 4 hours. 4 ml of 50% aqueous) was further added to the reaction mixture. dimethylamine solution The resulting mixture was refluxed for 4 hours The reaction mixture was cooled to room temperature The solvent was removed by distillation under reduced pressure The resulting mixture was adjusted to pH 10.5 with potassium carbonate The organic layer was separated, washed with water and saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 15 ml of acetone. 0.4 ml of a 5N solution of ethanol dry hydrochloric acid was added to the solution. The obtained crystals were collected by filtration. yielding 590 mg of hydrochloride

166 607 0i

1- (4-Beusylthiofeuyl) -O- [O- (N, N-dimethylαmiuc) ethoxy] ethauol (compound 60) m.p. 73.5-14.5 ° C (EtOH).

In the same way, compounds with inclination 37 pnkazaue in Table 9 were maintained.

Table 9 Compounds of formula 5

Relationship born R ¹ R0 R ³ r4 < R4b K rria Temperature melts mb salt addy-yjua ° C 6i pattern 7i H. H. H. H. pattern 39 i and HCl i94-i95 (EtOH) 60 pattern 70 H. H. H. H. pattern 39 i and HCl 007-008 (EtOH-A-Et) 63 pattern 73 H. H. H. H. pattern 39 i and maleic acid 168-170 (decomposition) 64 pattern 74 H. H. H. H. pattern 39 i and HCl i59.5-i60.5 (EtOH-A-OEt) 65 pattern 75 H. H. H. H. pattern 39 i and HCl i4i-i40 (EtOH-A-OEt)

Example XI. (i) Mix 4.5 g of potassium t-butaunlauu and 45 ml of ethylene glycol, heated to 80 ° C. On my day, I added dropwise for an hour and 3.7 g of 0- (1-uaphthyl) octrauu. They will get a hammer and mix it over the socket at the same temperature. It was mixed with n-cooling reaction and added to the mixture 50 ml of ethyl o-tau and 50 ml of indium sodium. The orgam-layer layer has been peeled off. The indigo layer was extracted twice with 00 ml of ethyl n-tauu in portions. The extracts are combined with a pre-separated organic layer. Half of the crgaui-zue layers were washed with water and then mixed with sndu chloride in this sequence and dried with anhydrous maguezium. Rnzpusz-zaluik removed by distillation pnd zmuiejszouym -iśmernem. The n-zysz-zaun residue thus obtained by -Crn-columnmatography using the elueut of the toluene / n-tau ethyl system in the i / 3 ratio. There were obtained 8.3 g of 0- (O-hydroxyethoct2) -1- (1-naphth2) ethauol with a melting point of 9-190 ° C (IPE).

In the same way, 0- (O-hydroxyethoxy) -1- (O-naphth2) eth2lo was produced at a top temperature of 105-106 ° C (A-OEt).

(0) 8.3 g of 0- (0-hydroxyethnx2) -1- (1-uαft2ln) etαunlu dissolved in 5 ml of pyridine. O -Cooln solution to -05 ° C. To ui dndauo 6.8 g of p-toluene sulfouyl Clnride. The hammer was then put on the day of storage at 0-5 ° C for 04 hours and then at room temperature for 4 hours. The mixture was added to the mixture with 100 ml of 6 N soldgo acid, 50 ml of indium-indium and 100 ml of diethyl ether. The resulting mixture was adjusted to pH0.0 with pnmn ± 6N of snluy acid. The orgamic layer is dddouo. The water layer is ectPaCowau about 00 ml of diethyl ether. Clam-zouo extract with an opaque layer. The combined orgasmic layers were washed with water and with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The soluble-zalmk was removed by distillation under the mulletzouym-schmern. The oyz2tz-zαun residue thus retained by column chromatography uses the toluene / o-tau ethyl system in the 10 / i stack as the elueut. 6.3 g of colorless oily i- [i -uαft2lo (-O- / 0) -p-toluene sulfin2loct] etaunl were obtained.

In the same colorless colorless oily 1- () - naphth2) -O- [0- (p-toluene-sulfou2loct2ethoxy) ethoxy] ethaunl.

(3) 0.80 g of p-toluene sulfouiauu pyridine dndauo to a solution of 6.3 g 1- (1-naphth-2l) -0- [0- (ptnlueuotulfou2locty) -ethocty] ethauol and 0.97 ml 3,4-dihvdro-2H -pirauu dissolve in 63 ml -Methyl Clnride at room temperature. I mix the resulting mixture at the same temperature for 00 minutes and then at 35-40 ° C for 10 minutes. Hammer with an n-Clndzouo reaction, washed with a tub and dried with anhydrous maguezium thiαryzαuem. Dissolve-zalmk removed by distillation under zmuiejszouym -iśmeuiem. The residual residue thus obtained was isolated by column chromatography using the same toluene / o-tau ethyl system in a 10 / i stack. 7.53 g of colorless oily 1- (1-uaftyl) -1- (tetraCydropyran-O-ylox2) -O- [0- (p-toluemsulfou2inx2) ethnts] etαuu were obtained.

In the same way, it is colorless and oily i- (O-naphthyl) -i- (tetraCydropyran-2-yloxy) -2- [2- (p-toluene sulfouylxy) ethoxy] etau.

(4) Mixing 7.5 g 1- (1-uaίtyl) -1- (tetraCydroplran-O-yloxy) -0- [0- (p-toluotulfou2'loxy) ethocty] etαuu, 0.65 ml N-methylpiperase, 3.96 g of potassium carbon and 38 ml of N6-dimethyl 22

The formamide was stirred for 2 hours at 90-100 ° C. The reaction mixture was cooled and added to a mixture of 100 ml of diethyl ether and 100 ml of ice water. The organic layer was separated. The aqueous layer was extracted twice with 25 ml of diethyl ether each time. The extracts were combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 10/1 chloroform / ethanol system as eluent. 3.36 g of colorless oily 2- [2- (4-methylpiperazin-1-yl) ethoxy] -1 - (1-naphthyl) -1 - (tetrahydropyran-2-yloxy) ethane (compound 66) were obtained.

(5) 3.3 g of 2- [2- (4-methylpiperazin-1-yl) ethoxy] -1- (1-naphthyl) 1- (tetrahydropyran-2-yloxy) ethane were dissolved in 30 ml of acetone. 3.46 g of p-toluenesulfonic acid monohydrate and 7 ml of water were added to the solution at room temperature. The resulting mixture was stirred at the same temperature for 30 minutes and further at 40 ° C for an hour. The reaction mixture was added to a mixture of 60 ml of chloroform and 60 ml of ice water. The mixture was adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with 20 ml of chloroform. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 40 ml of acetone. Hydrogen chloride gas was blown into the solution under ice cooling. The resulting mixture was stirred at room temperature for 30 minutes. 40 ml of diethyl ether were added to my. The resulting mixture was stirred at the same temperature for 30 minutes. The resulting crystals were collected by filtration, washed with acetone, and dried to give 2.35 g of 2- [2 - ((2 - 4, 2 - (2 - 4) dihydrochloride] 2 - 2, 4, 4 - azin-1-yl) ethoxy] - dihydrochloride. 1- (1-naphthyl) ethanol (Compound No. 67), m.p. 230.5-231.5 ° C (MeOH).

Example XII. The process described in steps (4) and (5) of Example 11 was repeated, except that N-methylpiperazine was replaced with N- (p-fluorobenzoyl) piperidine to give the hydrochloride

2- {2- | (p-fluorobenzoyl) piperidin-1-yl] ethoxy} -1- (1-naphthyl) ethanol (compound No. 68), m.p. 204.5-205.5 ° C (MeOH).

Example XIII. 2 g of 1- (1-naphthyl) -1- (tetrahydropyran-2-yloxy) -2- [2- (p-toluenesulfonyloxy) etrxy] ethane were dissolved in 20 ml of ethanol. 6.60 g of a 40% aqueous methylamine solution was added to the solution at room temperature. The mixture was refluxed for one hour. The reaction mixture was cooled and added to a mixture of 20 ml of ice water and 50 ml of diethyl ether. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were processed further by adding 15 ml of water and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted twice with 10 ml of water. The extracts were combined with the previously separated aqueous layer. The combined aqueous layers were mixed with 25 ml of chloroform and adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted twice with 10 ml of chloroform each time. The extracts were combined with the previously separated organic layer. The combined organic layers were dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 1.27 g of an oily product. The oily product was dissolved in 10 ml of acetone. Hydrogen chloride gas was blown into the solution while cooling with ice. 10 ml of diethyl ether were added thereto. The obtained crystals were collected by filtration, yielding 0.72 g of 2- [2- (N-methylramino) etrxy] -1- (1-naphthyl) ethanol hydrochloride (compound No. 69), m.p. 137.5-539 ° C (IPA).

Compounds of Formula 37 shown in Table 10 were prepared in the same manner.

166 607

Table 10 Compounds of formula 5

Relationship no R ' R ² R ³ R4a R4b R ⁶ has mb Addition salt Melting point ° C 70 pattern 76 H. H. H. H. model 55 1 1 HCl 180-181 (EtOH) 71 pattern 76 H. H. H. H. model 64 1 1 - 159.5-162 72 pattern 76 H. H. H. H. model 70 1 1 1/2 acid maleic 184-185 (IPA-AcOEt) 73 pattern 77 H. H. H. H. model 41 1 1 HCl 170-171 (EtOH) 74 pattern 77 H. H. H. H. model 55 1 1 HCl 18 (0.5-181.5 (IPA-EtOH)

Example XIV. 7ml of water and 7ml of dioxane were added to 0.7g of 2- (2-aminoethoxy) -1- (1-naphthylthanol) to obtain a solution. 0.32g of potassium carbonate was added to the solution. The resulting mixture was heated to 50 ° C and added to 0. 35 g of 2-chloropyrimid6a The resulting mixture was heated under reflux for 3 hours, then 0.32 g of potassium carbonate and 0.35 g of 2-chloropyrimid6a were added to the mixture. The resulting mixture was refluxed for 2.5 hours. The reaction mixture was cooled and added to a mixture of 20 mL of ethyl acetate and 20 mL of ice water. The organic layer was separated. The aqueous layer was extracted with 10 mL of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were further processed by adding 15 mL thereto. and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated and the organic layer was extracted with 10 mL of water. The extract was combined with the previously separated aqueous layer. 50 ml of methylene chloride were added to the bottom, and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography, eluting with chloroform / ethanol in the ratio 20/1, to obtain an oily product. 4 ml of ethanol and 0.21 g of maleic acid were added to the oily product. The resulting mixture was stirred at room temperature for an hour. 2 ml of diethyl ether was added to the reaction mixture. The resulting mixture was stirred at the same temperature for an hour. The resulting crystals were collected by filtration and dried to give 0.53 g of 1- (1-6-naphthyl) -2- {2- [plrimid6-2-yl) amino] etpxy} eta6ol maleate (compound No. 75), m.p. 103 ° C (EtOH-AcOEt).

Example XV. 0.62 g of N, N'-dicyclic hexylcarbodiimide was added to the mixture of 0.7 g of 2- (2ammpetpxy) -1- (1-6aphthylp) ethanol, 0.37 g of nicotinic acid, 0.41 g of hydroxybenzotriazole, 0.42 ml of triethylamine and 4 ml of tetrahydrofuran with ice-cooling. The resulting mixture was stirred at the same temperature for 5 minutes and further at room temperature for an hour. 6 ml of ethyl acetate was added to the reaction mixture. Insoluble matter was removed by filtration. 15 ml of ethyl acetate and 20 ml of water were added to the filtrate. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated and the organic layer was extracted twice with 10 ml of water. The extracts were combined with the previously separated aqueous layer. 30 mL of chloroform was added to the combined aqueous layers, and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 10/1 chloroform / ethanol system as eluent to obtain an oily product. The oily product was dissolved in 7 ml of acetone. 0.43 ml of a 5N dry chlorohydrogen-ethanol solution was added to the solution. The resulting mixture was stirred at room temperature for an hour. 3 ml of diethyl ether was added to the reaction mixture. The resulting mixture was stirred at the same temperature for an hour. The resulting crystals were collected by filtration and dried to give 0.67 g of 1- (1-naphthylp) -2- [2- (nicotinoylpami6p) etpxy] ethanol hydrochloride (compound No. 76), m.p. 162.5-163.5 ° C ( EtOH-AcOEt).

Example XVI. 250mg of 2 - [(1,5-diformylpiperazin-2-methoxyphyl-O-naphthylthanol) was dissolved in 1.5 ml of methanol. 1.5 ml of a 5N dry solution was added to the solution.

Hydrogen chloride-ethanol, and the mixture was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with ethanol, and dried to give 180 mg of 1- (1-naphthyl) -2 - [(cerazin-2-methyl) methosy] ethanol dichloride (compound No. 80), m.p. 199-201 ° C (with decomposition).

Example XVII. 2- (1-methylimieazol-5-11) methoxy-1- (1-raftzl) ethanol was reacted with methyl iodide to give the oily 2- (1-methylimieazol-5-11) methoxy-1- (1-raftzlo) etharol (compound No. 81).

Example XVIII. (1) 6.0 g of 6-benzaline-2-raftylaldehyde was dissolved in 60 ml of tetrahydrofuran. The solution was cooled to -30 ° C, then 30 ml of a tetcahzecofucar solution containing 1.6 M 2-chloroethoxomethylmagnesium chloride was added to it over 10 minutes. The resulting mixture was stirred for one hour under ice-cooling. The reaction mixture was added to a mixture of 100 ml of ice water, 100 ml of ethyl acetate and 3.6 g of ammonium chloride. The mixture was brought to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using toluene / ethyl acetate in the ratio 20/1 as eluent. A solid was obtained to which 10 ml of isopropyl ether was added. The resulting mixture was stirred at room temperature for an hour. The resulting crystals were collected by filtration and dried to give 4.7 g of 1- (6-benzyloxy-2-naphthyl) -2 (2-chloroethoxy) etharol, mp 86-87.5 ° C (IPE).

(2) A mixture of 4.5 g of 1- (6-benzyloxy-2-naphthyl) -2- (2-chloroethox) ethannl, 1 g of potassium iodide, 10 ml of 500% aqueous dimethylamine solution and 22 ml of ethanol was heated in tow under a condenser. feedback for 3 hours. 10 ml of a 50% dry dimethylamine solution was added to the reaction mixture. The resulting mixture was further heated under reflux for 6 hours. The reaction mixture was cooled and concentrated to about half its volume under reduced pressure. 100 ml of ethyl acetate and 100 ml of water were added to the concentrate. The mixture was brought to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. 30 ml of diethyl ether was added to the residue. The resulting crystals were collected by filtration and dried to give 3.9 g of 1- (6-benzylZe-2-naphthyl) -2- [2- (N, N-diroethylamino) ethnxy] etharol (compound No. 82), m.p. 100-1OO. . 5 ° C (EtOH-H 2 O).

1- (6-benzyloxy-2-naphthyl) -2- [2- (N, N-d1-methylammo) ethoxy] ethanol was treated in the same manner as described in Example 9 to give 1- (6-bonzlnxy-2-) hydrochloride naphthalene) -2- [2 (N, N-dimethylamino) ethoxy] ethanol (compound No. 83) m.p. 220-220.5 ° C (EtOH)

Example XIX. In 12 ml of pyridine, 3.0 g of 1- (6-benzyloxy-2-naphthyl) -2- [2- (N, N-dimethinaminine) ethoxy] ethanol were suspended. 1.6 ml of acetic anhydride was added to the suspension. The resulting mixture was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. 60 ml of ethyl acetate and 60 ml of water were added to the residue thus obtained. The mixture was brought to pH 10.5 with potassium carbonate. The organic layer was separated. The aqueous layer was extracted with 30 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 30 ml of acetone. Added to the solution

1.5 ml of a 5N solution of dry hydrogen chloride and ethanol. The resulting mixture was stirred at room temperature for an hour. The resulting crystals were collected by filtration and dried to yield

2.6 g of 1-acetocez-1- (6-benzine-2-naphthyl) -2- [2- (N, N-dimethylnamino) ethylene] ethane hydrochloride (compound No. 84), m.p. 157-158 ° C (MeOH) .

Example XX. A mixture of 2.0 g of 1-acetoxy-1- (6-benzyloxy-2-naphthalene) -2 [2- (N, N-dimethylamino) ethoxy] nitrate hydrochloride, 0.5 g of 5% palladium on carbon and 40 ml of ethanol was subjected to hydrogenated at room temperature and atmospheric pressure. After the reaction was complete, the palladium on carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. Acetone was added to the residue. The resulting crystals were collected by filtration and dried to give 0.76 g of i-acetoxy-i- (6-hydroxy-2-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 85), m.p. and 50.5- and 51.5 ° C (EtOH).

Example XXI. A mixture of 360 mg of I-acetoxy-I- (6-hydroxy-2-naphthyl) -2β-CNN-dimethylamino-toxicane hydrochloride, 10 ml of water and 10 ml of chloroform was adjusted to pH 9 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with 10 ml of chloroform each. The extracts were combined with the previously separated organic layer. The combined organic layers were washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 6 ml of benzene. 0.2 ml of ethyl isocyanate was added to the solution. The resulting mixture was stirred for 4 hours at the temperature of 80 ° C. The reaction mixture was cooled. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 20/1 chloroform / ethanol system as eluent to obtain an oily product. The oily product was treated in the same manner as described in Example 15, yielding 150 mg of amorphous I-acetoxy- [2- (N, N-dimethylamino) ethoxy] ethane hydrochloride (Compound No. 86).

Example XXII. A mixture of 50 mg of 2- [2- (N, N-dimethylamino) ethoxy] -i (8-nitro-i-naphthyl) ethanol oxalate, 50 mg of 5% palladium on carbon and 3 ml of methanol was hydrogenated at room temperature for 30 minutes under pressure. atmospheric. After completion of the reaction, the palladium on carbon was removed by filtration. The filtrate was distilled under reduced pressure to remove the solvent. The obtained residue was added to a mixture of 30 ml of ice water and 30 ml of chloroform. The mixture was adjusted to pH ii with 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was dissolved in 1 ml of ethanol. 0.2 ml of a 5.9 N dry chlorohydrogen-ethanol solution was added to the solution. The obtained crystals were collected by filtration and dried to give 10 mg of 1- (8-ammo-1-nαphthyl) -2- [2- (NN-d-methylamino) ethoxy] ethanol dihydrochloride (compound No. 87) with a melting point of 95-198 ° C (from decomposition) (AcOT-EtOH).

Example XXIII. T-methylamine was added to 1- (8-amino-I-naphthyl) -2- [2 (NN-dimethylamino-toxylethanol) hydrochloride The resulting mixture was reacted with methanesulfonyl chloride to give the oily 2- [2- (N, N-dimethylamino) hydrochloride salt. ethoxy] -I- (8-methylsulfonylamino-i-naphthyl) ethanol (compound No. 88).

Example XXIV. The process described in (i) and (2) of Example 18 was repeated with the difference that 6-benzyloxy-2-naphthylaldehyde was replaced with 4- (N, N-dimethylamino) -1-naphthaldehyde to give oily I- [4- (N, N-dimethylamino) -I-naphthyl] -2- [2- (N, N-dimethylamino) ethoxy] ethanol (Compound # 89).

Example XXV. l 3 ml of ethanol was added to 1.3 g of i- (4-N, N-dimethylamino) i-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol dihydrochloride. The resulting mixture was refluxed for one hour. The reaction mixture was cooled and the solvent removed by distillation under reduced pressure. A mixture of 20 ml of ethyl acetate and 20 ml of water was added to the residue. The resulting mixture was adjusted to pH 10 with potassium carbonate. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give i. 3 g of oily i-ethoxy-I- [4- (N, N-dimethylamino) -1-naphthyl) -2- [2- (N, N-dimethylamino) ethoxy] ethane (compound 90).

Example XXVI. (i) 9.6 g of 5-bromo-i-hydroxyindane was dissolved in 100 ml of dry methylene chloride. 570 mg of pyridinium p-toluenesulfonate and 4.5 ml of 3,4-dihydro-2H-pyran were added to the solution at room temperature. The resulting mixture was stirred at the same temperature for 3 hours. The reaction mixture was added to ice water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous

166,607 in aqueous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using toluene / ethyl acetate in the ratio of 15/1 as eluent. 13.1 g of oily 5-bromo-1- (tetrahydropyran-2-ylxy) were obtained.

(2) 8.1 g of 5-brno-1f (tetrahydropπan-2-phyloxy) indano was dissolved in 100 ml of anhydrous tetrahydrofuran under nitrogen atmosphere. 20 ml of n-butyllithium hexane solution (1.5 N) was added dropwise to the solution over 10 minutes at -65 ° C. The resulting mixture was stirred at the same temperature for 5 minutes. 2.3 ml of anhydrous N, N-dimethylformamido were added thereto. The reaction mixture was warmed to room temperature and added to a mixture of 100 ml of ice water, 100 ml of diethyl ether and 2 g of ammonium chloride. The organic layer was separated, washed with water and a saturated sodium chloride aqueous solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography using toluene / ethyl acetate in the ratio of 15/1 as eluent. 6.5 g of 5-formyl-1- (tetrahydropyran-2-yloxy) indane are obtained.

(3) The process described in (1) and (2) of Example 18 was repeated except that 6-benzyloxy-2-naphtaldehyde was replaced with 5-formyl-1f (tetrahydropyran-2-yloxy) indane to give the oily 2- [ 2- (N, N-dimethylamino) ethoxy-1 - [1- (tetrahydropyran-2-yloxy) indan-5-yl] ethanol (compound 91).

(4) A mixture of 2.5 g of 2- [2- (N, N-dlmethylamino) ethoxy] -1- [1- (tetrahydro-pyran-2-yloxy) indan-5-yl] ethanol, 8 ml of acetic anhydride and 0.64 ml of pyridine was stirred at room temperature for one hour. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of diethyl ether. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography using a system of chloroform / methanol in the ratio 10/1 as eluent. 1.9 g of oily 1-phacetoxyf2- [2- (N, N-dimethylamino) etrxy] -1- [1- (tetrahydropyran-2-yloxy) indan-5-yl] ethane (compound 92) was obtained.

(5) 1.8 g of 1-phacetoxyf2- [2- (N, N-dlmethylamino) ethoxy] -1- [1f (tetrahydropyran-2-ylrxy) indan-5-yl] ethane was added to 30 ml of acetic acid, tetrahydrofuran and water in 4: 2: 1 ratio. The resulting mixture was stirred at 70 ° C for 2 hours. The reaction mixture was cooled and added to a mixture of 100 ml of water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography using a 10/1 chloroform / ethanol system as eluent, yielding 1.0 g of oily 1-acetoxy-1- (1-hydroxy / indan-1-yl} -1-N, N-dimethylamino). ethoxy] ethane (compound 93).

(6) 1.0 g of 1-phacetoxy-1f [(1H-hydroxy / indan55-yl) -2- [2- (N, N-dimethylamine-ethoxyethane) was dissolved in 5 ml of pyridine. 0.3 ml of methanesulfonyl chloride was added to the solution at room temperature. the mixture was stirred at the same temperature overnight. The reaction mixture was added to a mixture of 50 mL of ice water 150 mL of diethyl ether. The resulting mixture was adjusted to pH8.5 with potassium carbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue obtained was purified by column chromatography using a 10/1 chloroform / methanol system as eluent to give 80 mg of oily 1-acetoxy-1- (1H-inden-yl-β-dlNN-dimethylamino). toxyJetanu (compound No. 94).

(7) 80 mg of 1-acetoxy-1- (1H-inden-6-yl) -2- [2- (N, N-difmethylamino) ethoxy] ethane was dissolved in 0.5 ml of methanol. 80 mg of a 28% sodium methoxide solution in methanol was added to the solution under ice-cooling. The resulting mixture was stirred at room temperature for 20 minutes. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography, eluting with chloroform / methanol in the ratio 20/1. A yellow oily product is obtained which is dissolved in 0.1 ml of ethanol. 0.1 ml of a 5.9 N dry hydrogen chloride-ethanol solution was added to the solution at room temperature. The resulting crystals were collected by filtration to give 20 mg of 1- (1-indan-6-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethanol (compound 95), melting point 171 ^168-C with decomposition ( AcET-EtOH).

166 607 07

In the name of compounds 94 and 95, we use the term "Ludeu --- 2 In", because we know that the carbon at which the connection is bound is the ethoxy group.

Example XXVII In the same way as I will describe in the knob (5) of example XXVI and in example XV nholdaun -Clcrnwcdnrek 1 - [(1-C2drnks2) iudau-5-yln] -0- [0- (N, N-dimethylnamluc) etnx2] etaunlu (compound u 96) at tcpmeuia 150- and 52 ° C (IPA).

Example XXVIII. 0- [0- (N, N-dimethylamino) ethoxy] -1 - [(1-uaphthyl) ethauol in the form of pnddaun with n-tn in pyridinium in nbe-ins and triethyl amine are 1-a-etnx2-0- [2- (N, N-dlmethylamlun) etnct2] -1- (1-uαphylne) etαu (compound ur 97).

Example XXIX. The compounds n will recycle 05 in Table 11 in the same manner as I will describe in section-C (1) and (0) of Example 18.

Table 11 Compounds of formula 05

Relationship born Ri r0 R ³ R ⁴ R ⁶⁰ m Salt of addy-yjua Melt temperature ° C 98 pattern 76 H. H. H. pattern 79 2 0HCl 037-038 (decomposition) (EtOH-H0O) 99 pattern 78 H. H. H. pattern 39 2 HCl 191-191.5 (IPA) 100 pattern 76 H. H. H. pattern 86 2 0HCl 175-176.5 (decomposition) (EtOH) 101 pattern 76 H. H. H. pattern 81 2 0HCl 120-104 (EtOH) 102 pattern 76 H. H. H. pattern 41 3 - 119-100 (A-OEt) 103 pattern 76 H. H. H. pattern 55 3 HCl 139-140.5 (EtOH-A-OEt) 104 pattern 76 H. H. H. pattern 64 3 HCl 111.5-110 (EtOH-AeOEt) 105 pattern 80 H. H. H. pattern 39 2 HCl 186-187 (decomposition) (EtOH-A-OEt) 106 pattern 83 H. H. H. pattern 39 2 HCl 160-161.5 (EtOH-A-OEt) 107 pattern 84 H. H. H. pattern 39 Ί HCl 149-150 (EtOH-Me0CO)

Example XXX. (1) We mix 5.7 g of potassium t-butaunlauu and 57 ml of ethylene glycol ngrzaun dn 80 ° C, then dndaun dn, after 1.5 hours a solution of 18 g 0- (beige [b] tlofeu-5ylnjnksirauu rnzpusz-zouegn in 30 ml of dimethylsulfntleuk. The resulting hammer was stirred at the same temperature for 30 minutes. The hammer was reacted with a dndauo dn hammer2 with 100 ml of ice water and 80 ml of ethyl n-tauu. 30 ml of ethyl n-tauu. Extracts of combined n-tauu with a layer of nrgam-zue. The wet-nue layer of nrgaui-zue was washed with a tub and a thick aqueous solution of sodium Clnride in this knlein and dried with anhydrous magnesium sulfate. Solvent-zalmk was removed by distillate from mejszcu2m -smeuiem. Pnznstability of n-zytz-zauo by knlumunwa-chromatography using an eluent system -Clornform / etauol in the stack ^ u 00/1. Obtained 9.1 g 1- (beuzn) [b] thiophene, 5-yln) -O- (O-C2drcks2 ethers) etaunl at peu temperature 119-120.5 ° C (EtOH-A-OEt).

(0) In 54 ml of pyridine, 9.0 g of 1- (beuzn [b] thiofeu-5-2In) -2- (2-hydroxyethoct2) etaunl were dissolved. The solution was added at -05 ° C, 7.0 g of -p-trieuosulfouyl chloride. Confused? leave the day at 0-5 ° C for 4 hours and then at room temperature for 4 hours. The youngest reaction was mixed with 103 ml of 6 N solugo acid, 50 ml of indium salt and 100 ml of ethyl ether. The obtained mixture was adjusted to pH 0.0 with 6 N snluegnic acid. The layer is separated by an extraction and the end layer is extracted with 30 ml of ethyl ether. The climax extract from the prejudices was separated with an orgasmic layer. The tiers of the nrgam-zue layers were washed with a tub and uas2-cu2m deep sodium chloride solution in this order and dried with an anhydrous magnesium grease. Dissolve-zalmk was removed by a distillation under a dimmejsznuym -iśuieuiem. The solidity of c-zysz-zaun by column chromatography uses any elueu / n-tau ethyl system in a 10/1 ratio. There was obtained 7.7 g of a colorless oily 1- (beige [b] tinfeu-5-2In) -O- [0- (p-tinsulfin-2lnkt2) ethoxy] ethauol.

(3) 0.97 g of p-tnlueuntulfnmauu pyridyuinwegn dndauo at room temperature to solution

7.6 g of 1- (beuzn [b] phen-5-yl) -O- [0- (p-tcleunsulfoured) ethoxy] etaunl and 3.5 ml of 3,4-dihydroOH-pyrauu to powder in 40 ml - Clnrk methyluu. Stirring is carried out at the same temperature for 00 minutes and then at 40-45 ° C for 30 minutes. The hammer was washed with water and dried with absolute magnesium sulfate. Solvent-zalmk was removed by distillation-pnd with mishnyme-sweet -green -8.7 g of nleistegn colorless 1- (beige [b] thiofeu-5-2l) -1- (O-tetraCydroplranyloxy) -2- [0- (p- tnlueuctulfnu2lnksy) etnkty] etauu.

166 607 (4) 1.5 g of 1- (benzo [b] tlophen-5-yl) -1- (2-tetrahydropyranyloxy) 2- [2- (p-toluenesulfonyloxy) ethoxy] ethane was dissolved in 15 ml of ethanol. 4.9 ml of 40% aqueous methylamine solution was added to the solution. The resulting mixture was refluxed for one hour. The reaction mixture was added to a mixture of 20 ml of water and 20 ml of diethyl ether. The organic layer was separated and the aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layers were processed further by adding 20 ml of water. The resulting mixture was adjusted to pH 1.5 with 6 N hydrochloric acid and stirred at room temperature for 20 minutes. The aqueous layer was separated. The organic layer was extracted with 10 ml of water. The extract was combined with the previously separated aqueous layer. The combined aqueous layers were processed further by adding 30 ml of methylene chloride thereto. The resulting mixture was adjusted to pH 11 with 10% aqueous sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with 15 ml of methylene chloride. The extract was combined with the previously separated organic layer, and the combined organic layers were dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved in 7 ml of acetone. 0.5 ml of a 6N dry hydrogen chloride-ethanol solution was added to the solution. The resulting mixture was stirred at room temperature for an hour. The reaction mixture was combined with 7 ml of diethyl ether. The obtained crystals were collected by filtration to obtain 0.5 g of 1- (benzo [b] thiophen-5-yl) -2- (N-methylamylethoxy) rtane hydrochloride (compound No. 108), m.p. 201.5-202.5 ° C (EtOH- Me2CO).

Compounds of Formula 25 shown in Table 12 were prepared in the same manner.

T a b e l a 12

Compounds of formula 25

Relationship no R ¹ R ² R3 R ⁴ R6b m Addition salt Melting point ° C 109 pattern 85 H. H. H. pattern 64 2 HCl 196.5-197.5 (E ^ H-M ^ CO) 110 pattern 85 H. H. H. pattern 33 2 2HC1 232-234 (MeGH-MeiCO) 111 pattern 85 H. H. H. pattern 86 2 HCl 219.5-220 (EtGH-AcGEr) 112 pattern 85 H. H. H. pattern 87 2 oxalic acid 138-149 (EtGH-AcGEr) 113 pattern 85 H. H. H. pattern 80 2 HCl 170.5-171.5 (EtGH-AcGEr) 114 pattern 85 H. H. H. pattern 69 2 HCl 222.5-223 (EtGH-AcGEt)

Example XXXI. 0.46 g of 1- (benzo [b] thiophen-5-yl) -2- (2-aminoethoxy) ethanol was dissolved in a mixture of 5 ml of water and 5 ml of dioxane. 0.21 g of sodium carbonate was added to the solution. The resulting mixture was heated to 50 ° C, and 0.22 g of 2-chloropyrimidine was added thereto. The resulting mixture was heated to reflux for 3 hours. The reaction mixture was added to a mixture of 30 ml of ice water and 30 ml of ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 10 mL of ethyl acetate. The extract was combined with the previously separated organic layer. 20 ml of water was added to the combined organic layers, and the resulting mixture was adjusted to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated and the organic layer was extracted with 10 ml of water. The extracts were combined with the previously separated aqueous layer. 50 mL of methylene chloride was added to the combined aqueous layers, and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 20/1 chloroform / ethanol system as eluent. An oily product was obtained to which was added 2 ml of ethanol and 70 mg of maleic acid. The resulting mixture was stirred at room temperature for an hour. 2 ml of diethyl ether was added to the reaction mixture. The obtained crystals were collected by filtration and dried to give 0.28 g of 1/2 1- (benzo [b] tlophen-5-yl) -2 - {[2- (plrimidin-2-yl) amino] oxy} rtan1u maleate (compound No. 115), m.p. 113.5-114.5 ° C (IPA-AcOEt).

Example XXXII. 0.39 g of N, N'-dicyclohexylcarbodiimide was added under ice cooling to a mixture of 0.45 g of 1- (brnzo [b] thiophen-5-ylo) -2- (2-ammoethoxy) ethanol, 0.23 g of nicotinic acid, 0.26 g of 1-hydroxybenzotriazole, 0.26 ml of methylamine and 3 ml of tetrahydrofuran. The resulting mixture was stirred at the same temperature for 5 minutes and further at room temperature

166 607 for 2 hours. 20 ml of water and 20 ml of ethyl acetate were added to the reaction mixture. Insoluble matter was removed by filtration. Filter the dupruvadzobu to pH 1.5 with 6N hydrochloric acid. The aqueous layer in thigh and the organic layer was extracted twice with 5 ml of water. The extracts were combined with the previously separated aqueous layer. To the combined aqueous layers were added 30 ml of chloroform and the resulting duplex mixture to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a 10/1 chloroform / ethanol system as eluent. The obtained oily product was dissolved in 3 ml of ethanol. 0.24 ml of a 5N dry Doru chlorine solution in ethanol was added to the solution. The resulting mixture was stirred at room temperature for an hour. 1.5 ml of diethyl ether was added to the reaction mixture. The resulting mixture was stirred at the same temperature for an hour. The obtained crystals were collected by filtration and dried, yielding 0.31 g of 1- (bnbzo [b] tlophen-5-yl) -2- [2- (nicotinoylamino) ethoxy] etabul hydrochloride (compound No. 116), m.p. 152-153 ^° C ( EtGH-AcGET).

Example XXXIII. (1) 1.6 g of 4-mntyl-2-formylutlPzuld was dissolved in 30 ml of tntrahydrufdran. The solution was cooled to -30 ° C and 10 ml of a tetrahyDrofuran solution containing 1.6 N 2-chloruntuxymntylumpg anhydrous chloride was added dropwise to the ning over 10 minutes. The mixture was stirred for one hour under ice-cooling. The reaction mixture was added to a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 2 g of ammonium chloride. The resulting mixture of duplicate to pH 2 with 6 N hydrochloric acid and stirred at the same temperature for 5 minutes. The reaction mixture is duplicated to pH6 with saturated aqueous sodium bicarbonate solution. The organic layer of the separation was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using toluene / ethyl acetate in the ratio 4/1 as eluent. 1.3 g of oily 1- (4-methyl-2-tlazohl) -2- (2-chloroethoxy) etabulide were obtained.

(2) A mixture of l. ^ G 1- (Utm (thyme-2-tlazolyl) -2- (U) chloroethuk-n) utayol, oml 30 (¾ aqueous from dimethylamine solution, 0.45 g of potassium iodide and 20 ml of ethanol) was heated to reflux After refluxing for 3 hours, 3 ml of 50% aqueous dimethylamine solution was added to the reaction mixture. The resulting mixture was heated under reflux for 3 hours. The solvent was removed by distillation under reduced pressure. To the thus obtained residue were added 30 ml of ethyl acetate and 30 ml of ethyl acetate. The resulting DuprowpD mixture was taken to pH 1.5 with 6N hydrochloric acid. The aqueous layer was separated and washed with 10 mL of ethyl acetate. To this was added 30 mL of ethyl acetate. The resulting mixture was dupruwpDubo to pH 10.5 with potassium carbonate. The organic was separated, washed with 10 mL of water and 10 mL of a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was dissolved. in 6 ml of ethanol. To the solution was added 0.6 ml of a 5N solution of dry Doru chlorine in ethanol and 6 ml of diethyl ether. The mixture was stirred at room temperature for one hour. The resulting crystals were collected by filtration, washed with 2 ml of a 1: 1 mixture of diethyl ether and ethanol, and dried to give 390 mg of 1- (4-methyl-2-thiazolyl-2 [2- (N, N-dimethylammu) ethoxy] ethabol hydrochloride. (compound No. 117), m.p. 159-160 ° C (IPA-AcOEt).

Compounds of Formula 25 shown in Table 13 were prepared in the same manner.

Table 13 Compounds of formula 25

Relationship no R ¹ R ² R ³ R ⁴ R6b m Addition salt Melting point ° C 1 2 3 4 5 6 7 8 9 118 pattern 88 H. H. H. pattern 39 2 - Oil 119 * 1 pattern 89 H. H. H. pattern 39 2 2HC1 185-186.5 (EiOH-AcOEt) 120 pattern 90 H. H. H. pattern 39 2 - Oil 121 * ² pattern 91 H. H. H. pattern 39 2 - Oil

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1 2 3 4 5 6 7 8 9 122 pattern 92 H. H. H. pattern 39 2 HCl 175-176 (EtOH-AcOEt) 123 pattern 93 H. H. H. pattern 39 2 2HC1 Oil 124 pattern 94 H. H. H. pattern 39 2 HCl 182.5-183 (EtOH-AcOEt) 125 pattern 95 H. H. H. -NH2 2 1/2 fumaric acid 170-173 126 pattern 96 H. H. H. pattern 39 2 2HC1 116-117 (EtOH-Me2CO) 127 pattern 97 H. H. H. pattern 39 2 2HC1 179-179.5 (EtOH-AcOEt) 128 pattern 98 H. H. H. pattern 39 2 2HC1 155-156 (EtOH-AcOEt) 129 pattern 99 H. H. H. pattern 39 2 2HC1 184-186 (EtOH-AcOEt) 130 pattern 100 H. H. H. pattern 39 2 2HC1 196-197 (MóOH) 131 * 1 pattern 103 H. H. H. pattern 102 2 HCl 193-193.5 (EtOH-AcOEt) 132 ^x3 pattern 101 H. H. H. pattern 39 2 HCl 162-163 (IPA) 133 pattern 104 H. H. H. pattern 39 2 HCl 153.5-154 (IPA) 134 pattern 105 H. H. H. pattern 39 2 2HC1 176-179 135 pattern 95 H. H. H. pattern 107 2 - Oil 136 pattern 108 H. H. H. pattern 39 2 - Oil 137 pattern 103 H. H. H. pattern 64 2 HCl 194.5-195 (EtOH-AcOEt) 138 pattern 85 H. H. H. pattern 109 3 - 109-111 (AcOEt) 139 pattern 85 H. H. H. pattern 64 3 HCl 133.5-134.5 (EtOH-AcOEt) 140 pattern 85 H. H. H. pattern 110 3 HCl 136.5-139.5 (EtOH-AcOEt) 141 pattern 112 H. H. H. pattern 39 2 HCl 193-193.5 (EtOH-AcOEt) 142 pattern 113 H. H. H. pattern 39 2 HCl 171.5-172 (EtOH-AcOEt) 143 pattern 85 H. H. H. formula 8 3 HCl 137.5-139.5 (EtOH-AcOEt) 144 pattern 85 H. H. H. pattern 107 2 HCl 1313.5-139 (EtOH-AcOEt) 145 pattern 112 H. H. H. pattern 110 2 HCl 184-184.5 (EtOH-AcOEt) 146 pattern 106 H. H. H. pattern 109 3 - 68.5-69.5 (hexane) 147 pattern 85 H. H. H. pattern 79 2 2HC1 200-202.0 (decomposition) (MeOH-H 2 O) 148 pattern 85 H. H. H. pattern 114 2 2HC1 155-157 (EtOH) 149 pattern 95 H. H. H. pattern 41 3 - 65-67.5 (IPA-IPE) 150 pattern 95 H. H. H. pattern 79 2 2HC1 234-234.5 (MeOH-AcOEt) 151 pattern 95 H. H. H. pattern 41 2 HCl 178-180.5 (IPA-AcOEt) 152 pattern 115 H. H. H. pattern 39 3 - 52-53 (IPE) 153 pattern 115 H. H. H. pattern 41 3 - 81.5-83 (IPA-IPE) 154 pattern 115 H. H. H. pattern 41 2 HCl 196-198 (EtOH-AcOEt) 155 pattern 115 H. H. H. pattern 64 2 HCl 190-192.5 (EtOH-AcOEt) 156 pattern 85 H. H. H. pattern 36 2 1/2 naphthalene-eulfonic acid amorphous 157 pattern 85 H. H. H. pattern 39 2 HCl Oil 158 pattern 54 H. H. H. pattern 116 1 - Oil 159 pattern 54 H. H. H. pattern 117 1 1/2 maleic acid 110-117

Note * '- The compound can be obtained by hydrolyzing compound No. 118 with hydrochloric acid * 2- The compound can be obtained by subjecting compound No. 120 to hydrolysis with sodium hydroxide quenching * ³ - The compound can be obtained by subjecting compound No. 130 to a conventional hydrogenation reaction

Example XXXIV.

(1) A mixture of 9.2 g of 1- (2-thienyl) -2- [2 - (N, N-dimethylamino) ethoxy] etharol and 18 ml of acetic anhydride was heated under reflux for 10 minutes. The reaction mixture was added dropwise to the mixture. , 8 ml of concentrated nitric acid and 27 ml of acetic anhydride at 0 ° C for 30 minutes. The resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, adjusting the resulting mixture to pH 7 with 40% aqueous sodium hydroxide solution. The resulting mixture was adjusted to pH 10 with 40% aqueous sodium hydroxide solution, and 300 ml of chloroform was added thereto. The organic layer was separated and 300 ml of water was added thereto. The resulting mixture was adjusted to pH 2 with 6N sodium acid. The water was separated and added to my 300m-chloroform. The resulting mixture was adjusted to pH 10 with 40% aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 10.4 g of oily 1- (O-ritro-2-thiounyl) -1-acetoxene-2- [2- (N, N-dimethylamino) ethnez] ethane (Compound No. 160) ( 2) 320 mg of 1- (5-mtro-2-thienyl) -1-acetokey-2- [2- (N, N-dimethylammonitoxide) was dissolved in 10 ml of methanol. 1.27 ml of a 1N aqueous solution was added to the solution. sodium hydroxide The resulting mixture was stirred at room temperature for 1 hour to the mixture

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In the reaction, 40 ml of chloroform and 40 ml of water were added. The organic layer was separated and 30 ml of water was added to it. The resulting mixture was adjusted to pH2 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of chloroform was added thereto. The resulting mixture was adjusted to pH ii with 10% aqueous sodium hydroxide solution. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. To the residue thus obtained were added 3 ml of methanol and 1 ml of a 5N solution of dry hydrogen chloride in ethanol. The solvent was removed by distillation under reduced pressure. 5 ml of ethanol was added to the obtained residue. The resulting crystals were collected by filtration and dried to give 170 mg of I- (5-mtro-2-thienyl) -2 [2- (N, N-dimethylamino) ethoxy] ethanol (compound No. 6i), m.p. 189-19I, 5 ° C with breakdown.

Example XXXV (1) 3.4 g of 2- [2- (N, N-dimethylamino) ethoxy] -I- (6-benzyloxybenzo [b] furan-2-yl) ethanol were dissolved in 10 ml of pyridine. To the solution was added and. 8 ml acetic anhydride. The resulting mixture was stirred at room temperature for 7.5 hours. The solvent was removed by distillation under reduced pressure. 4 ml of ethyl acetate and 40 ml of water were added to the residue thus obtained. The resulting mixture was adjusted to pH 7 with sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with 20 mL of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layers were washed with water and a saturated aqueous sodium chloride solution in this order and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography using a chloroform / ethanol system in the ratio i / i as eluent. 3.25 g of oily I-acetoxy-I- (6-benzyloxybenzo) [b] furan-2-yl) -2- [2- (N, N-dimethylammo) ethoxy] ethane (compound No. I62) were obtained; IR (clean) cm ^ ν c = o I740.

(2) A mixture of 3.2 g of I-acetoxy-I- (6-benzylyoxybenzo [b] furan-2-yl) -2- [2- (1N, N-dimethylamino) ethoxy] ethane, 0.6 g of 5% palladium on carbon, 0.67 ml of concentrated hydrochloric acid and 30 ml of methanol were hydrogenated at room temperature under atmospheric pressure for 1.5 hours. After completion of the reaction, the palladium on carbon was removed by filtration. The solvent was removed by distillation under reduced pressure. 20 ml of chloroform and 20 ml of water were added to the obtained residue. The resulting mixture was adjusted to pH 7 with sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with 10 ml of chloroform. The extract was combined with the previously separated organic layer. The combined organic layers were washed with 5 ml of water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography using a chlorine system as an eluent. orm / methanol in the ratio 7/1. There was obtained 1.57 g of oily i-acetoxy-1- (6-hydroxybenzo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) ethoxy] ethane (compound No. I63); IR (pure) cm '\ vC = O ^ ™.

(3) 0.65 g of I-acetoxy-I- (6-hydroxybenzo [b] furan-2-yl) -2 [2-N, N-dimethylamino) ethoxy] ethane was dissolved in 3.5 ml of benzene. 0.33 ml of ethyl isocyanate was added to the solution. The resulting mixture was stirred for 30 minutes at 80 ° C. The solvent was removed by distillation under reduced pressure. The obtained residue was purified by column chromatography using 6: chloroform / ethanol as the eluent to give an oily product. The oily product was treated with dry hydrogen chloride in a conventional manner to obtain 0.58 g of oily i-acetoxy-1- (6-N-ethylcarbamoyloxybenoo [b] furan-2-yl) -2- [2- (N, N-dimethylamino) ethoxy] hydrochloride. of ethane (compound No. I64) IR (pure) cm ^d : vC = O4 ™ ⁰ .

Example XXXVI. The compounds shown in Table and 4 were obtained in the same manner as shown in Examples I-XXXV.

In table i4, Ri, R2, R3, R4a, R4b, R6b have the same meaning as the substituents and integers in formula 5.

166 607

Table 14 Compounds of formula 5

Relationship no R1 R2 R3 R4 * R46 R ^6b has m Addition salt Melting point ^J C 1 2 4 5 6 7 8 9 10 1 lft < pattern 24 H. H. H. H. pattern 39 1 1 HCl 184-185 (EtOH) 166 '* R-configuration - —- - “ _- -— -—- 17-4.5-175 (Me2CO-EtOH) 167 '° design 25S-kp6 configuration 17-4.5-175 (Me2CO-EtOH) 168 pattern 24 - —- pattern 107 - Oil 169 pattern 24 —- —— pattern 7 HCl 113-174 (EtOH-Et2O) 170 pattern 24 - - —— formula 8 - 163.5-164.5 (EtOH-Et2O) 171 pattern 24 pattern 9 - _u 153 ^ 154.5 (EtOH-Et2O) 172 pattern 24 pattern 46 - * - Oil 173 pattern 24 pattern 6 174 pattern 24 —_ " pattern 119 175 pattern 24 —_ " pattern 39 2 1 - Oil 176 pattern 24 H. H. H. H. pattern 39 3 3 HCl Amorphous 177 pattern 120 1 1 198199 (EtOH) 178 pattern 44 —— · * · * _ “ 165-166 (IPA) 179 pattern 121 181.5-183 (EtOH) 180 pattern 122 —- “ · * _ “ —_ " 201.5-203 (IPA) 181 pattern 123 —_- —_- 194.5-196.5 (EtOH) 182 pattern 124 - _u 251-252 (EtOH) 183 pattern 44 —_ · * —_ " pattern 9 —_- 141-143 (EtOH-Et2O) 184 pattern 44 formula 8 —_ " 136.5-137.5 (EtOH-Et2O) 185 pattern 44 ——- pattern 6 —_ " - Oil 186 pattern 44 —— “ —_ " pattern 39 2 2 -_ * 187 pattern 44 H. H. H. H. pattern 39 1 2 - Oil 188 pattern 44 —— “ pattern 46 —_ « 1 —_- 189 pattern 125 —_ · * ——- pattern 39 —_ " HCl 184-185 (EtOH) 190 pattern 126 —— * - _u —_ " 158-159 (IPA) 191 pattern 44 Me —— “ pattern 39 - Oil 192 pattern 44 H. Me pattern 39 193 pattern 24 Me —— “ H. pattern 39 HCl 1 ^ 191 (MeOH-EtzO) 194 pattern 127 H. “_ · * - ^ —_ " —_ " 203-204 (EtOH) 195 pattern 128 H. H. H. H. pattern 39 1710-171 (MezCO) 196 pattern 129 —-— " 1 ^ 18.5-190 (MeOH-EtsO) 197 pattern 130 —_ · * —— “ —— “ —- * —_ " —_ " 1 ^^> 157.5 (EtOH-Et2O) 198 pattern 131 H. H. H. H. pattern 39 1 1 HCl 184-184.5 (EtOH) 199 pattern 128 —— “ - · - ** formula 8 131-132 (Et0) H-Et23) 200 pattern 130 —— “ 178.5-179.5 (EtOH-Et2O) 201 pattern 205 —— “ pattern 39 171-172 (EtOH) 202 pattern 132 —_- 182-182.5 (EtOH) 203 pattern 133 —— “ 228-229.5 (EtOH-EtzO) 204 pattern 134 "-" u_u —— ^u —_ " 1 ^^, 5 ^ 194.5 (EtOH) 205 pattern 135 —_- 1 ^ (8.5 ^ 169 (EtOH) 206 pattern 136 - * - " 146-147 (EtOH) 207 pattern 137 H. H. H. H. pattern 39 1 1 HCl 171-173 (EtOH) 208 pattern 138 -— " PTS 140-141 (EtOH) 209 pattern 139 - * - · * —_ « HCl 179.5 ^ 181.5 (ETOH-Et2O) 210 pattern 140 —_ " 169-171 (EtOH) 211 pattern 141 —— “ · * _ “ * · _ “ 18: 6-186.5 (EtOH) 212 pattern 142 at_" 188-188.5 (EtOH) 213 pattern 235 - * - " “_ · * 1 ^ 19 ^.5 (MeOH-EtOH) 214 pattern 143 - · - · * - Oil 215 pattern 144 "-" —- HCl 149.5-151 (MezCO) 216 pattern 145 · * _ “ · * _ —S 140-141 (EtOH-EtzO) 217 pattern 52 H. H. H. H. pattern 39 1 1 HCl 17.4, ^ 176.5 (MeCN) 218 pattern 146 - * - * · - u_u —._- 229-231 (MeCN) 219 pattern 53 - · - “ -_ * 217.5-218.5 (EtOH) 220 pattern 147 - · _ · * 138-140 (EtOH-Et2O) 221 pattern 148 ^u _ " 153-154 (EtOH) 222 pattern 149 179-181 (EtOH) 223 pattern 24 pattern 151 - Oil 224 pattern 44 “_ · * _AT * " 225 pattern 150 - * _ “ 50-52 226 pattern 150 formula 8 - · _ “ HCl 160-161 (EtOH-Et2O) 22 ^ί pattern 150 H. H. H. H. pattern 9 1 1 HCl 151-152.5 (EtOH-Et2O) 228 pattern 152 -— pattern 39 —_ " 223-225 (EtOH-IPA) 229 pattern 153 * 215-216 (MeOH-EtOH) 230 pattern 154 —_ " 1 ^ (0.5-181.5 (MeCN)

166 607

1 2 3 '4 5 6 7 8 9 10 11 21 pattern 155 - - ““ _- - -_ 168 5-169.5 (IPA) 232 pattern 156 - —— ——- 177 5-178 5 (MeCN) 233 pattern 157 - 194.5-195 (MeCN) 234 pattern 158 --- - 162-162 5 (IPA) 235 pattern 159 - 171-172 (IPA) 2'6 pattern 160 - 162-162.5 (IPA) 231 pattern 161 H. H. H. H. pattern 39 1 l HCl 147 5-148 5 (Me ₂ CO-Et ₂ O) 238 pattern 52 ——- 2 1 - Oil 239 pattern 52 formula 8 1 1 HCl ^^ 160 5 (IPA) 240 pattern 52 pattern 9 ——- -—- 192.5-193 (MeCN) 241 pattern 52 pattern 151 Oil 242 pattern 162 “_ · * pattern 39 HCI ^^ 4-125 (MeCN) 243 pattern 50 pattern 39 2 1 - ^^ 1.5-123 (AcOEt-EtjO) 244 pattern 163 —_ · * pattern 39 1 · * Oil 245 ' ^c pattern 164 —_ · * HCl 179-181 (EtOH) 246 pattern 165 ^^ '9.5-190 (IPA) 247 pattern 166 H. H. H. H. pattern 39 1 1 2HC1 157-158 (EtOH) 248 pattern 167 - · _ “ ** - " HCl 161-162.5 (IPA) 249 pattern 168 - 2HCl 157.5-159.5 (EtOH) 250 pattern 169 · * - “ HCl 172-173 (IPA) 251 pattern 50 —— * pattern 107 1 1 - Oil 252 pattern 170 ——- pattern 39 - _u HCl 222.5-223.5 (EtOH) 253 pattern 44 “- · * pattern 107 ^u - " - Oil 254 pattern 171 - pattern 39 HCl 204.5-205 (EtOH-Me2CO) 255 pattern 172 168.5-169 (EtOH-AcOEt) 256 Pattern 173 H. H. H. H. pattern 39 1 1 HCl D3-194 (EtOH-AcOEt) 257 pattern 174 - _u 154.5-156 (MeCN) 258 pattern 172 ^^, 5-169.5 (EtOH-AcOEt) 259 Pattern 236 ^^ 7-198 (IPA-AcOEt) 260 Pattern 237 · * “_ · * · * 17 ^ 178 (EtOH) 261 pattern 175 —— * - 140.5-142 (IPA) 262 pattern 176 --- 181.5-182.5 (EtOH) 263 pattern 50 ——- pattern 9 17 ^ 170.5 (EtOH-Me ₂ CO) 264 pattern 177 —— “ pattern 39 ^^ 199.5 (EtOH) 265 ' pattern 24 H. H. H. H. -NH2 1 1 1/2 fumaric acid 181-182.5 266 " pattern 50 pattern 39 HCl 194-194.5 (R-configuration) pattern 39 HCl 19 * 4-194.5 (EtOH-Me2CO) 267 ’ pattern 44 pattern 39 16 ^ 165 (R-configuration) —— “ (EtOH-Me2CO) 268 '' pattern 52 - -—- D3-194 (MeCN) (R-configuration) 269 '" pattern 50 -—- D5-196 (EtOH-Me2CO) (S-configuration) 270 pattern 44 ^^ 3-164.5 (EtOH-Me2CO) (S-Configuration) 271 * ' pattern 52 -—- 187.5-188.5 (MeCN) (S-Configuration) 272 pattern 106 “_ · * - Oil 22 pattern L2 pattern 77 H. H. H. H. pattern 39 1 1 HCl ł ^ l ^ M) ^EuO 275 pattern 179 149-150 (Me2CO-EtOH) 276 pattern 180 - —— “ 178-179 (Me2CO-EtOH) 277 pattern 181 184-185 (Me2CO-EtOH) 278 * pattern 76 _- " 2 1 _ Oil 279 * pattern 76 2 -_- "_" 280 pattern 182 1 1 HCl 213-214 (IPA) 281 Pattern 183 - 205-205.5 (MeOH-EtOH) 282 pattern 76 ** formula 8 —— “ 174-174.5 (EtOH-Et10) 283 pattern 77 —- ** - " formula 8 156.5-158 (EtOH-Et2O) 284 pattern 184 H. H. H. H. pattern 39 1 1 HCl 157-158 (IPA) 285 * pattern 76 pattern 46 —- - Oil 286 * pattern 87 287 ’ _- -_ pattern 185 -_- -_- 288 pattern 76 —— pattern 107 155.5-157 (IPA) 289 pattern 186 pattern 39 151.5-153.5 (IPA) 290 pattern 187 —_- - 193.5-196.5 (EtOH) 291 pattern 188 -—- 1 «1.5-168 (IPA) 292 pattern 189 —- 161-163 (EtOH) 29 3 pattern 77 —— - " pattern 107 100.5-101.5 (IPA-AcOEt) 294 pattern 76 H. Me H. H. pattern 39 1 1 HCl 186.5-188 (EtOH-Me2CO) 295 pattern 76 H. Me —- pattern 39 fumaric acid 197-198.5 (EtOH-AcOEt)

166 607

and 2 3 4 5 6 7 8 9 10 ii 296 pattern I90 H. -—- HCl i99.5-20i (IPA-AcOEt) 297 pattern 222 -_- I98-I99 5 (IPA) 298 i9i pattern H. H. H. H. pattern 39 and and HCl I57-I59 (IPA)

Note a Optical rotation -43.3 ° (27 ° C, C = 3, EtOH) b Optical rotation + 43.3 ° (24 ° C, C = 3, EtOH) c Obtained by treating compound No. 244 with p-toluenesulfonic acid d Trityl was used as the amino-protecting group e Optical rotation -38.9 ° (28 ° C, C = i, 5, MeOH) f Optical rotation -45.8 ° (25 ° C, C = i, 5, MeOH) g Optical rotation -37.5 ° (25 ° C, C = i, 5, EtOH) h Optical rotation + 37.3 ° (23 ° C, C = i, 5, MeOH) and Optical rotation + 40.2 ° ( 23 ° C, C = i, 5, MeOH) j Optical rotation + 28.4 ° (23 ° C, C = i, 5, EtOH) * These compounds were not converted to their hydrochloride

Example XXXVII.

The compounds shown in Table i5 were obtained in the same manner as shown in Examples I-XXXV.

In table i5, Ri, R2, R3, R4, R6b and m have the same meaning as the substituents and integers in formula 25.

Table i5 Compounds of formula 25

Relationship no Ri R ² R3 R ⁴ R ^6b m Addition salt Melting point ° C and 2 3 4 5 6 7 8 9 299 pattern 44 H. H. - i5i pattern 0 HCl I80-I8i, 5 (IPA) 300 · _ “ pattern i92 220-204 30i pattern 94 "-at pattern i93 —— “ - II9-I20 302 pattern 24 H. pattern i94 and I53-I55 (Me ₂ CO-EtOH) 303 pattern 24 _ « pattern 195 Oil 304 pattern 24 pattern i96 - 92-95 305 pattern 24 _ « "-" pattern 54 ·· _ · HCl Oil 306 pattern 50 pattern 54 and - 78-8I (AcOEt-IPE) 307 pattern 24 _ « "-" pattern 97 HCl i29.5-i3i, 5 (AcOEt-IPE) 308 pattern 24 pattern 99 i57.5- i59.5 309 pattern 24 pattern i97 _- i3-7-I38.5 (Me _a CO) 3i0 pattern 44 pattern 54 and HCI Oil 3ii pattern i28 _ " "-" 3i2 pattern 24 H. H. H. model i99 and HCI Oil 3i3 pattern 24 pattern i93 - 3i4 ^x2 pattern 24 (S configuration) - "-" "-" pattern 54 "-" - 6i-6i.5 (EtOH-IPE) 3 and 5 ^x2 pattern 24 R-configuration - - - pattern 54 - - 6i-6i.5 (EtOH-IPE) 3 and 6 pattern i37 7i, 5-72 (EtOH-IPE) 3 and 7 ^x3 pattern 24 pattern 200 ii8-ii9.5 3 & 8 * 3 pattern 211 -_at pattern 201 and HCI i47.5-i49 (IPA-AcOEt) 3 and 9 ^x3 pattern 24 (IR-configuration) "-" ´ - " "-" pattern 202 "-" - Oil 320 ^X3 pattern 24 pattern 203 i04.5-i06.5 (IPA-AcOEt) 32ix3 pattern 24 ´ _ ´ pattern 204 220-22I (EtOH-AcOEt) 322 _X3 pattern 50 H. H. H. pattern 200 and - I54-I56 (IPA-AcOEt) 323 pattern 24 - ' pattern 206 2HCl 24I-242 decomposition 324 pattern i45 pattern 54 53.5-54.5 (Et _s O) 325 pattern 24 3 Oil 326 pattern 52 pattern 54 and 84.5-85.5 (EtOH-IPE) 327 pattern I21 - ⁱ 65.5-66.5 (EtOH-IPE) 328 pattern I50 ⁱⁿ - ' 68-69 (EtOH-IPE) 329 pattern 44 H. H. H. pattern and i8 and - Oil 330 pattern i28 33i pattern 52 332 pattern 50 "-" - formula ii6 - "-" "-"

166 607

1 2 3 4 5 6 7 8 9 333 pattern 136 "-" "-" '- “ pattern 116 1 - "-" 334 pattern 150 "-" "_" 335 pattern 44 pattern 117 1 fumaric acid 155-156 (EtOH) 336 pattern 128 "-" HCl Amorphous 337 pattern 52 - ' 1 ^ 2 fumaric acid 142-142.5 (EtOH-Me ₂ CO) 338 pattern 50 "-" 1/2 fumaric acid 147-148.5 (EtOH) 339 pattern 150 ⁴ '_ " 126-127 (IPA) 340 pattern 76 - ' pattern 195 1 98-100 (AcOEt) 341 pattern 77 - ' pattern 54 "_" 83-85 (AcOEt-IPE) 342 Pattern 233 H. H. H. pattern 54 1 72-73.5 (AcOEt-IPE) 343 pattern 76 pattern 194 1 HCl 162-164 (EtOH-Et2O) 344 pattern 199 "-" 143-146 345 “- __ pattern 193 0 151.5-154 (EtGH-Er2G) 346 - ' H. pattern 54 1 154-156 (EtOH-IPA) 347 pattern 76 pattern 207 1 - Oil 348 - - ' 1/2 fumaric acid 167.5-170 (EtOH) 349 pattern 77 - 122-123 (M ^ CO-AcOEt) 350 pattern 182 "-" - 138-139 (MesCO-AcOEt) 351 pattern 208 H. H. H. pattern 34 2 HCl 139-141 352 pattern 209 "_" 165.5-166 (EtOΟ-Et ₂ O) 353 pattern 54 "-" 2HCl 143-146 (EtOH) 354 pattern 210 HCl 128.5-130 (EtOH) 355 pattern 211 pattern 39 2 2HCl 185-185.5 (EtOH-IPA) 356 pattern 212 “_” HCl 128-130 357 formula 213 fumaric acid 136-136.5 (IPA) 358 pattern 214 "_" "_" HCl 166.5-167.5 (IPA-AcOEt) 359 pattern 215 “__“ 168.5-169.5 (IPA) 360 pattern 216 pattern 39 2 169-170 361 pattern 217 H. H. H. pattern 39 2 HCl Oil 362 pattern 103 "-" “_‘ 188.5-189 (EtOM-AcOEt) 363 pattern 95 '_ “ “__“ 168-169.5 (IPA-AcOEt) 364 pattern 198 "_" 169-172 (EtOH) 365 pattern 85 pattern 9 2 HCl 166.5-167.5 (EtGΟ-Mr2HG) 366 pattern 218 - ' pattern 39 - Oil 367 pattern 219 "_AT "" " 2HCl "-" 368 pattern 85 formula 8 “__“ HCl 167.5-169 369 Pattern 234 pattern 39 2HCl Oil 370 pattern 220 pattern 39 2 HCl 207.5-210 (EtOH) 371 pattern 221 "-" 1905-192 (EtOH-IPA) 372 pattern 115 H. H. H. pattern 39 2 HCl 171-172 (IPA-AcOEt) 373 pattern 85 pattern 37 "_" - Oil 374 pattern 39 3 - 81.5-85 375 pattern 85 pattern 39 4 HCl 105-107 (EtOH-AcOEt) 3/6 377 pattern 111 pattern 85 H. H. H. pattern 54 1 fumaric acid (EtGO-AcGEr) 106.5-107.5 (AcOEt-IPA) 378 pattern 216 "_" HCl Oil 379 pattern 85 pattern 151 2 - "-" 380 pattern 85 pattern 117 1 - 121.5-125 (AcOEt) 381 pattern 194 "-" 127-129.5 (EtOH-IPE) 382 '" pattern 195 “_» 95.5-98 (AcOEt) 383 '' "" " pattern 193 0 HCl 181-185 (EtGH-AcGEr) 384 pattern 68 ““ '' pattern 9 2 HCl H ^^ - 165 385 pattern 24 "_" - pattern 224 0 "-" 193-195 386 H. pattern 225 1 - Oil 387 "-" "-" pattern 226 1 / 2CHCOOH || 148.5-147 388 pattern 223 H. H. H. pattern 226 1 AT CHCOOH 1 / 2CHCOOH II CHCOOH 122-123.5 389 pattern 24 pattern 227 Oil 390 (configuration-1S, 2'S) pattern 24 pattern 226 COOH 130-132 391 (configuration-1S, 2'S) pattern 24 COOH CHOOOH 136-136.5 392 (configuration-1R, 2'S) pattern 24 CHCOOH 136-136.5

(configuration-1S, 2'R)

166 607

1 2 3 4 5 6 7 8 9 393 pattern 24 (R, 2'R-configuration) '- COOH COOH 131-132.5 394 pattern 76 '- pattern 39 2 HCl 196-197 395 pattern 77 pattern 227 1 - Oil 396 pattern 76 pattern 54 ' ^i— - "-" 397 pattern 77 H. H. H. pattern 226 1 1 / 2CHCOOH // CHCOOH 141-144 398 pattern 76 HCl amorphous 399 pattern 76 -NH2 2 - 89.5-92 400 pattern 230 1 - Oil 401 pattern 228 - ' - '' - '' pattern 39 2 COOH COOH 150-158.5 402 pattern 229 · __ ·· Pattern 231 1 - Oil 403 pattern 85 - pattern 39 2 HCl 191.5-192.5 404 pattern 95 - pattern 54 1 - 85-86 405 pattern 85 '- pattern 230 - Oil 406 - Pattern 231 "-" 2HCl 216-218 decomposition 407 '- -NH2 2 - 87-90.5 408 1 / 2CHCOOH 2 CHCOOH 204.5-205.5 409 pattern 85 pattern 232 1 - 128-129

Note * 1 Optical rotation + 23.3 ° (25 ° C, C = 1, MeOH) * ² Optical rotation -22.5 ° (25 ° C, C = 1, MeOH) * Reaction was performed using the amino-protecting group trityl group * Reaction was performed using a formyl amino-protecting group as the amino-protecting group

A compound can be obtained by subjecting Compound No. 366 to a conventional uwuDormema reaction

The following examples show pharmaceutical preparations containing the compounds of the present invention.

Example XXXVIII Tablets.

Tablets each containing 50 mg of 1t (4-bnzyluxyphenyl) -2- [2- (N, Nt dimethylupmib) ethylxy] ethanol hydrochloride (Compound # 211) were prepared from the following ingredients according to the following method:

1.

2.

compound 211 50 mg lactose 20 mg Kullidub CL (BASF product) 15mg corn starch 30 mg AVICELPH 101 (Asahi Kasei product) 50 mg puliwlbyloplrolldon K-90 5 mg lightweight silica 3 mg magnesium stearate 2 mg

©

Total 175 mg

Ingredients from group (1) of the crease with an aqueous solution containing 8% polyvinylpyrrolite don K-90. The pre-bent product was dried at 40 ° C and mixed with the ingredients of group ©. The resulting mixture was formed into round tablets weighing 175 mg and having a diameter of 8 mm.

Example XXXIX. Capsules.

Capsules each containing 50 mg of Chlurhydride 2- [2- (N, N-dimethylpmmu) ethylxy] 1t [4- (4-phenyloxy) phenyl] ethanol (Compound No. 217) were prepared from the following ingredients according to the following method.

166 607 mg 00 mg 53 mg ¹ mg 2 mg of 5 ml 0 ©

1. Compound ur 017 lactose corn starcha

Knllidnu CL (BASF product) polyvinylpyrrolidine K-90 0. AVICEL PH 300 (AsaCi Kasei product) magnesium steary

Total 150 mg

Ingredients from the group (1) of the thickened solution containing 8% of K-90 liquid. Zagme-iouy product is dried at 40 ° C and mixed with ingredients from group (0). They will be placed in Zelatyuowy-C capsule-C ur 3 in the amount of 150 mg in each capsule.

Example XL. Pills

CClnrnindor 0- [0- (N, N-dimethylnammn) ethoct2] -1-beuzn [b] tinfen-5-yl / etaml (compound ur 144) and di-Clnrnndor 0- [2- (4-benzylpperazin-1- I process 2lo) ethyl] -1- (beuzo- [b] furau-5-yl) ethauol (compound ur 150) in the manner of the first npisauy in example 1, get - tablets, each of which contains 50 mg of one of the udieuinuy-C above compounds.

Example XLI. Capsules.

CClnrnwndnrek 0- [0- (N, N-lnamun) ethoxy] -1- (beuzn [b] tofeu-5-2l) ethauol (compound ur 144) and di-hydrohydrate 0- [0- (4-benzylpiperaz2u-1 -yl) eth2lo] -1- (beuzo- [b] furau-5-yl) ethαuolu (compound ur 150), processed into npisauy in example 2, get- capsules, with C each containing 50 mg of one udder -C above unions.

166 607

R ³ R ⁴

R ¹ -CHCH-O-fCVR ^6b OR ² R ⁵

Formula 1b

-n ^ n-kf ^ R ⁹

Formula 2

-N N4CH ₂ tC0R ^w

Formula 3

166 607

R ³ R ⁴

R ^ CHCH-O-tC ^ Y 'o' r

OR ² R ⁵

Formula 4

R ³ fj ^4b

R'-oH-CH-O-thHUCHfeR "

OR ² R ^4q Formula 5

λ- Pr r, \, _ p _r - »□ Formula 6 Formula 7 -about 3 \ _t Formula 8 and Formula 9 Pattern 24

t? ³

R'-CH-CH-CH-Ot-fc-R ^{61> 1} 9

OR ²

Pattern 25

-N

CH ₂ OH

-N, Me 'C-Z3-0 and NOH

Pattern 26

Pattern 27

166 607

Me

-N ^ N-DPN -N> Pattern 34 Me Pattern 35

Me -N — Me blah p Pattern 36 Pattern 37 ^Ht V b Me χ ' -N Me Pattern 38 Pattern 39

HO ^h0_ ^ 3> “ Me - N ^ H. MODEL 40 MODEL 41 -nJih ABOUT MODEL 42 MODEL 43 Me nh ₉ b-

MODEL 44

MODEL 45

166 607

Ο

PATTERN 46 PATTERN 47

MODEL 48 DESIGN 49 ^Bz0

MODEL 50

MODEL 52

T0

N

MODEL 54

AcO-Az Ac O

MODEL 51

MODEL 53

-N-i-Pr

H.

PATTERN 55 r ° Xr --0 ^ 0

DESIGN 56 DESIGN 57

166 607

Ν (^ - ΌΗ) ₂ -ν ^ ν ^^ ^οη MODEL 58 MODEL 59 -Ν ^ \ - νη ₂ ^ Me - ν '' ^ ΟΗ MODEL 60 MODEL 61 Me -Ν ^X Et Me 1 -Ν- <]

MODEL 62 MODEL 63 Η -Ν— <1 Me -N-CH ₂ COOMe Pattern 64 Pattern 65

NN XJ ^N k Me N-, -d Pattern 66 Pattern 67

V -K ^ Pattern 68 Pattern 69

Ν -1 - Bu Η

MODEL 71

A GOOD DEATH: 70

MODEL 72

Et

MODEL 77

- N Ν-βζ

Me

PATTERN 78 r- \ N

- 'w-O

MODEL 79

-N ^ N

MODEL 80

MODEL 81

Me

166 607

MODEL 84

MODEL 85

PATTERN

Me

N ^ Bz

A GOOD DEATH: 87

Tr

MODEL 88

H.

MODEL 91

MODEL 92

π-Ń 1} l \ u AND l and 1 Ph

MODEL 93 MODEL 94 Oh? C ^ OMe. MODEL 95 MODEL 96 ABOUT. N N U '1 CA 1 Bz MODEL 97 MODEL 98 -n £> MeO N Tl A MODEL 99 PATTERN 100 Cerium MeO N Me -N MODEL 101 MODEL 102 Cu ^F xr MeNH N Cl MODEL 103 MODEL 104

IN

MeNH N and "Pr

Pattern 105

Pattern 106

-N

Et

Et

Pattern 108

Pattern 107

-N

-N

Me

H i - Pr

Pattern 109

Pattern 110

.Me

Me

Pattern 112

Pattern 113

166 607

Pattern 115

Tr

Pattern 116

b H. Pattern 117 -b ^ \ from Formula 118 Me -n ^ n ύ- Pattern 119 Pattern 120 ^Me_ O- ^e O Pattern 121 Pattern 122 '-Pr-O ^- 7-Bu-O ^- Pattern 123 Pattern 124

Me ^Me ^> Me Me Pattern 125 Pattern 126 Cl & Cl Pattern 127 Pattern 128

Cl ^cl X0

Style 129 Style 130

Cl F. ^you Xz5 ~ ^f_ O Pattern 131 Pattern 132 NO2 ^F 3 ^F O Pattern 133 Pattern 134 ^c k 0- MeO O ^-

Pattern 135

Pattern 136

166 607

Formula 137 Formula 138 ^θ ζΟ κ ^Mes- O ~ oWzór 139 Formula 140

0CH ₂ + Q + Ct ^Bz0 “O

Pattern 141 Pattern 142 BzO Bz ° ^ Q- Pattern 143 Pattern 144 PhO b- Μθ ° - <θ / θ “ Pattern 145 Pattern 146 Ph ΒΖ _χ Pattern 147 Pattern 148

^Βζ ΧΖΧ

Pattern 149

Ο- ^Βζ

Pattern 151

Pattern 150

Me

Pattern 152

Pattern 155

Pattern 156

Pattern 157

Pattern 160

OPh OBz & ó Pattern 161 Pattern 162

OCH2OMe ^CH 2 ° ~ O ·

Pattern 163

HO

Pattern 164 ^MG eight-opp Pattern 165 pw

N

Pattern 166

Me

PhO ^ J Formula 167

Formula 1 (i9

Pattern 170

Pattern 172

MeO

MeO

Pattern 173

Formula 174 ^Bz ° C>

OMe Model 175

Cl

Pattern 176

Pattern 177

OH Me ' ^hg

Pattern 178

Cl

Pattern 181

F (θφ

Pattern 180

MeO

Pattern 183

OMe (οφ

Pattern 184

II O

Pattern 185

^Cl in

Pattern 187

Cl

Pattern 189

Pattern 190

Pattern 193

Me

Pattern 194

Me

Model 195

N

Me

Pattern 196

Pattern 197

Br

Pattern 199

Pattern 200

Pattern 201

166 607

H. V H. Pattern 202 Pattern 203

H. ^F ' ^H CX Pattern 204 Pattern 205

H. and) H. About ^NH Pattern 206 Pattern 207 ąi ęr Pattern 208 Pattern 209 σ © d Model 210 Pattern 211 Ol θ ' Pattern 212 Pattern 213

cpgr Pattern 214 Pattern 215 H. Pattern 216 1 Me Pattern 217 1 Bz Pattern 218 H. Pattern 219 ę + r fp Pattern 220 Pattern 221 σ§ι c ^ o Pattern 222 Pattern 223

O ^CH 2 ^>

Pattern 224

166 607

^CH 2 - @> Pattern 225

.0

Pattern 227 '3

Pattern 228

CHO

CH3 in

Pattern 229

Pattern 230

Pattern 231

Style 233 Style 234

166 607

0CH2 - <§b ⁰ Me

V

Pattern 235

Pattern 236

Cl

Pattern 237

O and / \ -3

Ri-CHCHR ' ³

PATTERN 10 f ⁴

HCH--ferOR ^{13 1} 5 ^m

R ° MODEL 11

R 'i

R ² * or His sdl

R '

R-CHCH-Of C-hr-OR ^{3 1} and c ^m

OH R ⁵ or its sel

MODEL 12

R '

AND

R ^

R ^ CHCH-O-fC U ~ OR ¹³

I 1 ^rn > 2a

OR ^rcl R '

MODEL 13

R '

R ¹ -CHCH-Of-C 1 2 OH

And "| β or sullonylating agent halogenating agent

R ⁴ i

0R2a R MODEL U or its sel

R ^ CHCH-OiCirwY OR ^2a R ⁵

MODEL 15

HR ^6b or a salt thereof

PATTERN 16> 1

R ³ i

R-CHCH-OCC-LrR ¹ and J ⁷¹

OR ^2a R5 or a salt thereof

SCHEME 1

6b

MODEL 1a

PATTERN 20 or his set PATTERN Ib

SCHEME 2

R ¹ —CHO

PATTERN 21

HR ^6b or its sol MODEL 16

R ³ R ⁴

And '2 x'MgCH-O-EC ^ X

R ⁵ R ³ R ⁴

MODEL 22 1 I 2

--- R '-CH-CH-OłC -fcr * ¹ k

OH R ⁵ or its sel FORMULA 23

R ³

RCCHCH-O + Cfe- R ^6b

I and

OH R ⁵ or its sel FORMULA 1c

SCHEME 3

Publishing Department of the Polish Patent Office. Mintage 90 copies. Price PLN 1.00.

Claims (12)

Patent claims 1. A method for the preparation of 1,2-ethanediol derivatives and their salts or optical isomers of the general formula 1b, wherein R 1 npuoypa: pheuyl, uaphyl, iudauyl, iudeuyl, tetrahydrinaphthylic or Cetern-ykli-substituent groups - atnmas -Clnrnw-a, - Cydroxy-C groups, possibly protected by an alpha-ethyl group, - tetraCydrnpyranyloxy-h. - amiunwy-C groups, optionally a 2-C substituent with C 1-6 alkyl groups, - C1-6-alkylcyC groups, optionally substituting -C-Clopo atoms, - pheuylnwy-C groups, eweutuolme substitute wiouy-C -n with one substitute selected from among the-Clornw-a groups, C 1-6 -alkyl-C groups and C 1-6 -alkoxy-C groups, - pheuyl-C1-4alkyl-C groups, - C 1-6 alkyxy-C, eweutuoluie-C-n groups with one substituent selected from furyl, thieuyl or pyridine groups, - pheuylc-Cl-4-alkyxy-C groups, eweutuoluie-C -o substitution with one substitution selected from among the-Clornw-a atoms, the Cydroxyl group, the C 1-6 -alkyxy group, which can be substituted by C1-6-alkyxyl groups C1-6alkyl-C groups, - phenyl-C groups, optionally we substitute -C-n by one substituent selected from the -C11-a group, C 1-6 -alkyl-C and C 1-4 -alkoxy-C groups, - carbamoyloxy-C groups are substituted by C 1-6 alkyl groups or phenyl groups which can be substituted by -Clnrnw-a atoms, - C1-6-alkylthio groups, - Co-e-alkeyl-C groups, - C2-6-alkeuylnxylcwyyC groups, - pheuyln-C1-4alkylntin groups, - phenyln-C 1-4 alkylsulfoulyl-C groups, - feuylnsulfouylnwy-C groups, - Cl-4-alkylsulfurium-C groups, - feuylnsulfnuylnamlUowyyC groups, - thieuylnwy-C groups, - pyridyl-C groups, - uitrnwy-C groups, - nksn groups - and C 1-4 alkylenedioxy groups. R is a hydrogen atom, a C 1-6 alkyl group or a protected group by a Cydrnxyl group; R ³ feels α-za. atnm wndnru or C1-6-alkyl group, mR ⁴ 1 mR ^{5 groups} are the same or pink and nzua-take hydrogen atoms or C1-6-alkyl groups, m is 0 or nzua-after-total from 1 up to 6, R6 ^b nzua-za: the groups amiunwa or Cetern-ykli-zuą include -ą aznt, eweutualuie pndstawinue -n with one base selected from among others. - C1-6-alkyl groups, eweutual substitution of C-C with a Cydroxy group or a C1-6-alkyxycarbouyl group - groups C 3-6 -y2klcalkllnwy-C, - Ci-6-acyl-C groups, - the group b 1-yln-C 1-4 -alkyl-C, 166 607 - phenyl-C2-4-alkenyl groups, - pyrimidinyl groups, - pyridylcarbonyl groups, - pyrrolidinecarbonyl groups which may be substituted with an oxo group, - adamantyl groups, - amino groups, - hydroxyl groups that may be substituted with C1-6-alkyl groups, - oxo groups, - benzoyl groups substituted with halogen atoms, - pyridyl groups, - pyrimidinyl groups -1 halogen atoms; the heterocyclic group is selected from imidazolyl, pyridyl, quinolyl, tetrahydroquinolinyl, thiazolyl, furyl, thienyl, benzothienyl, benzofuranyl, indolyl, benzimidazolyl, benzothiazolyl, 2,3-dihydrobenzofroindolynyl, 2,3-dihydrobenzofuranyl, 2,3-dihydro-benzofuranyl, 2,3-dihydrobenzofurinyl-benzoyl groups b] pyrazinyl, and nitrogen-containing heterocyclic group is selected from pyrrolidinyl, piperidyl, piperazinyl, imidazolyl, pyridyl, tetrahydropyridyl, morpholinyl, thiomorpholinyl, tetrahydroquinolinyl, tetrazolyl, and quinuclidinyl, excluding (a) compounds in which R ¹ represents a phenyl group, optionally substituted by halo or Ci-6 alkyl, -C 4 alkylenedioxy, Ci-4-alkoxy or hydroxy, and R ^6b represents a -NR7r ⁸ wherein R7 is phenyl-Ci-C4-alkyl and R ⁸ is is hydrogen or Ci-6-alkyl or r7 and r8 form together with the nitrogen atom a group of formula 2, wherein R ⁹ is a phenyl, pyridyl or pyrimidyl group, and i is 0 or an integer from 1 to 3, a group of formula 3 in which R ^w is phenyl, pyridyl or pyrrolidinyl, and i is 0 and (b) compounds where R ™ is unsubstituted or substituted Ci-6-alkyl phenyl group, and R ⁶ b is a di-Ci-6-alkylamino or a group of the formula 7, 8 or 9, characterized in that the compound of formula 4, wherein R ™ R ^R2, R3, ^{R4, R5} 1 m are as defined above and Y is a leaving group, is reacted with a compound of formula 16 or a salt thereof, wherein R6b is defined as above, and optionally removing the hydroxy protecting group R2 to give a compound where R2 is hydrogen. 2. The method according to p. and, characterized in that compounds are used in which R represents a benzothienyl, benzofuranyl or 2,3-dihydrobenootienylową which may be substituted with Ci-6 alkyl or hydroxy, R ² is hydrogen, R ³ is hydrogen , -R ⁴ and -R ⁵ are hydrogen, R 6 ^b is a pyridyl group, a piperidinyl which may be substituted by a Ci-6 alkyl group, and 2,5,6-tetrahydropyridyl which may be substituted by a Ci-6 alkyl , an imidazolyl group, a piperazinyl group substituted with a phenyl C 1-4 alkyl group or an amino group which may be substituted with a C 1-6 alkyl group or a C 3-6 cycloalkyl group, the pipidyl, piperidyl, and 2,5, 6-tetrahydropyridyl, imidazolyl or piperazinyl have three open valences on the ring-forming carbon, and m is an integer from i to 4. 3. The method according to p. and, characterized in that the compounds in which Ri is 4-benzyloxyphenyl, R2, R3, R4, R5 are hydrogen, R6b is N, N-dimethylamino and m is 2. 4. The method according to p. and, characterized in that compounds are used wherein R 1 is a 4-benzyloxyphenyl group, R2, ^R3, R4 and ^R5 are hydrogen, and R 6b represents a methyl-5imidazolilową, and m has a value of i. 5. The method according to p. and, characterized in that the compounds in which R1 is i-naphthyl, R2, R3, R4 and R5 are hydrogen, R6b is imidazolyl and m is i. 6. The method according to p. and, characterized in that the compounds in which R1 is i-naphthyl, R2, R3, R4 and R5 are hydrogen, R6b is i-methyl-5-imidazolyl and m has the value i. 166 607 7. The method according to p. 2. The process of claim 1, wherein R ¹ is benzo [b] thiophen-5-yl, R ² , R ³ , R ⁴ and R ⁵ are hydrogen, R ^6b is N, N-dimethylamino, and has the value 2. 8. The method according to p. The process of claim 1, wherein R 1 is benzo [b] thiophen-5-yl, R, R, R and R are hydrogen, R is N, N-diethylamino and m is 2. 9. The method according to p. 1, characterized in that compounds are used wherein R 1 is benzo [b] thiophen-5-yl, R2, R3, R4 and ^R5 are hydrogen atoms, R 6 ^b is a N, Ndietyloaminową and m is 3. 10. The method according to p. The process of claim 1, wherein R 1 is benzo [b] thiophen-5-yl, R ² , R ³ , R 4 and R 5 are hydrogen, R 6b is imidazolyl and m is 1. 11. The method according to p. 1, characterized in that compounds are used wherein R 1 is benzo [b] thiophen-5-yl, R2, R3, R4 and ^R5 are hydrogen atoms, R 6b represents a 1-tetrahydropyridin-metylo1,2,5,6 -3-yl, and m is 1. 12. The method according to p. 1, characterized in that compounds are used wherein R ¹ is benzo [b] furan-5-yl, R2, R3, R4 and R5 are hydrogen atoms, R 6b is a N, Ndimetyloammową and m is 2.