DE2854595A1 - AMINOPHENYL ETHER COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND USE - Google Patents

Description

2854535

Aminophenyl ether compounds, process for their preparation as well as their use

Yaraanouchi Pharmaceutical Co., Ltd.

Kr. 5-1, ITihonbashi-Honcho 2-cliome, Chuo-ku, Tokyo (Japan)

This invention relates to new aminophenyl ether compounds or their pharmacologically acceptable salts with the formula I

I,

wherein R _{1 represents} a hydrogen atom or a lower alkyl group; Rp represents a cyclohexyl group which may be substituted by lower alkyl group (s), an alkyl group having 1 to 20 carbon atoms, a phenyl group or a benzyl group; R 1 represents a hydrogen atom, a lower alkyl group or a cyclohexyl group which may be substituted by lower alkyl group (s); R. denotes a hydrogen atom, a lower alkyl group or a lower alkoxy carbonyl group; and Rc represents a hydrogen atom, an aryl group, or the group represented by -CORg or -CH ₂ Rg, (wherein Rg represents a hydrogen atom, an amino group, an alkyl group, 1 to

909828/0662

-9- 2854535

Has 19 carbon atoms, a cyclohexyl group, an aryl group, an ax * alkyl group, an arallcenyl group, an amino group, substituted by lower alkyl group (s), a heterocyclic group substituted with a lower alkyl group may, or represents a bridged hydrocarbon group); Rp and R ~ can be used together with the neighboring carbon atom form a cyclohexane ring, which is replaced by lower alkyl group (s) substituted otiin can, and R ^ and Rc can be used together with the adjacent nitrogen atom form a pyrrolidine ring or a piperidine ring.

When in the aminophenyl ether compounds having the formula 1, the portion represented by

ι I

has a di-substituted cyclohexane ring, the cis ~ and trans stereoisomers of these exist, hence the Compounds of this invention also include these stereoisomers.

The term "lower alkyl group" used in this invention includes straight-chain and branched-chain alkyl groups containing 1 to 6 carbon atoms such as methyl group, ethyl group, isopropyl group, butyl group, isopentyl group, hexyl group, etc. As examples of the "aryl group" in this Invention, the phenyl group, naphthyl group, etc. are mentioned as examples of an "aralkyl group" are the benzyl group, phonetyl group, phenylpropyl group, etc. As examples of the "lower alkoxycarbonyl group" are mentioned the methoxycarbonyl group, ethoxycarbonyl group, butoxycarbonyl group, etc. Examples of the "aralkenyl" are the styryl group, cinnamyl group, etc. Examples of a "heterocyclic group" which PyrrοIyIgruppe, Furylgnippe, Ihienylgruppe, Oxazolynylgruppe, Pyridylgruppo _t thiazolyl, Thiadiazolylgruppo, Dithiaiiylgruppe, Pyrimidinylgrui pe, Piparadinylgruppe, morpholino etc. Furthermore cils "bridged carbon

90982 8/066 2

hydrogen group "for example the Bicyclononanylgruppe, Bicyclodecanylgruppe, Adamantyl group, pinanyl group, bornyl group etc. listed.

As pharmalcologically acceptable acid addition salts of the compounds of the formula I of this invention are exemplified by the acid addition salts of an inorganic acid such as hydrogen chloride acid, phosphoric acid etc. called. As acid addition salts with organic acids, formic acid, acetic acid, Lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, benzenesulfonic acid, etc. called. Even the quaternaries Ammonium salts, obtainable by reaction with an alkyl halide, such as methyl iodide, etc. are usable.

The compounds of formula I of this invention are hypolipidemic Activity and also particularly excellent cholesterol and triglyceride lowering activity; they are effective for prophylaxis and medical treatment of arteriosclerosis as well as coronary heart disease.

It is believed that atherosclerosis is caused in part by a content of unusually excessive amounts of lipids, such as cholesterol Triglycerides etc., caused in the blood. A hypolipidemic Means, namely p-chlorophenoxy-isobutyric acid ethyl ester (clofibrate) has so far been used for this. Still, however, it has been desirable to develop medicaments which have more effective hypolipemic activity and have fewer side effects.

As a result of the inventors' diligent studies, it has now been found that the compounds described by Formula I a cholesterol and triglyceride lowering activity and a selective effect for increasing the high concentrations of lipoprotein (UDL) has cholesterol.

It is known that the amount of HDL in blood in arteriosclerosis is lower than in normal human blood fcatus and that HDL also reduces the excess deposition of cholesterol on the ar- ⁺ hydrobromic acid,

909828/0662

- 11 - 28b4595

material wall prevents and the removal of cholesterol from the arterial wall in experimental animal experiments favored. Therefore, the increase in HDL cholesterol can be effective for the prophylaxis and drug treatment of atherosclerosis Find use. However, the conventional ones have hypolipidemic vision Gowns such as clofibrate etc. do not have selective activity to increase HDL cholesterol.

As a compound that increases the activity on HDL cholesterol, 17-j is p- (i-adamantyloxy) phenyl] piperidine (U-41,792) in U.S. Patent 4,036,977. However, the activity of the compounds of this invention is clearly beyond the properties of the known compound, as will be demonstrated below.

Experiment I.

Three week old male Sprague-Dawley rats were aged 7 days fed a semi-purified diet containing 1.5% cholesterol and 0.5% bile acid to induce hypercholesterolemia.

A compound of this invention suspended in an aqueous solution containing 0.25% 1-methylcellulose was administered to them by oral fattening for a full four days. After fasting overnight, the animals were anesthetized with ether and the blood was obtained from the peripheral vascular vein, then the HDL cholesterol (cholesterol of HDL) in the serum was determined. The results are given in the following tables. In addition, the determination of the total cholesterol was carried out according to the method described by Schettler G. & Rüssel ("Arbeitsmed. Sozialmed. Präventivmed.", 10 , 25 (1975)); the HDL cholesterol was determined according to the method described by TT Ishikawa et al ("Lipids", 11, 628 (1976)).

909828/0662

2354595

Table I.

link dose
(mg / kg / day) Reduction of
Cholesterol (%) Increase of
cholesterol
of HDL (%) (A)
control
- D Acquaintance
link
TJ-41,792 + I 25th -73 210 19.7 Connection ^
the inventor
manure,
At αρ. No,
1 1
100 -69 660 45 4th 25th -66 470 19th 18th 25th -75 460 30.7 19th 25th -77 380 33 31 25th -80 370 47.3 47 25th -80 460 47.7 53 100 -79 440 66 54 25th -76 490 39.3 55 25th -76 430 32.4 63 25th -77 430 34 67 25th -63 280 8th 70 25th -80 420 23 71 25th -77 450 35.3 72 25th -75 420 26.3

(A): cholesterol from HDL / cholesterol from (VLDL + LDL)

Table II

link dose
(mg / kg / day) Cholesterol / 'cholesterol _vo '
from HDL y ^ (VLDL + LDL)
(Control = 1) Acquaintance
link
U-41,792 25th 19.7

909828/0662

- 13 28b459S 45 Continuation: 30.7 links 33 the invention 47.3 Example no. 47.7 1 100 66 18th 25th 39.3 19th 25th 32.4 31 25th 34 47 25th 23 53 100 23 54 25th 35.3 55 25th 26.3 63 25th 70 25th 71 25th 71 25th 72 25th

N-p- (1-Adamantyloxy) phenylpiperidine (U.S. Patent 4,036,977)

- 0

2 VLDL: Pre-ß-lipoproteins (very low density lipoproteins) LDL: ß-lipoproteins (low density lipoproteins) HDL: oC "lipoproteins (high density lipoproteins). (After Jenkins, P.J .; Harper, R.W .; Nestel, P.J .: British Medical Journal 1978, 2, 388-391 is in the literature EDL also known as pre-ß-cholesterol and VLDL also called ß-alcoholesterol).

Experiment II

The same test procedure as described in Example 1 was used, except that five-week-old male Sprague-Dav / ley rats were used and the total serum cholesterol and HDL cholesterol were determined in the same manner and manner as in Experiment I. The results are given in Table III below.

909828/0662

- 14 Table III

Connection of
invention
Example Mr. dose
(mg / kg / day) Reduction of
Cholesterol {%) Increase of
HDl (50 31
48
49 12.5
25th
12.5
25th
12.5
25th -43
-69
-54
-68
-36
-69 119
280
212
308
154
277

Table IY

link
the invention
Example ITr.

Dose (mg / kg / olag)

Cholesterol of - ^^ tJholesterin of HDl ^^ (VLDL + LDL)

(Control = 1)

31

48

49

12.5 25

12.5 25

12.5 25

2.2 16.5

5.7 18.8

2.5 16

From the experimental findings described above, it is clear that the compounds of formula I of this invention not only have excellent cholesterol lowering activity but also greatly increase the amount of HDL, wa3 is known for its ability to remove cholesterol favored from the arterial wall. For this reason, the compounds of this invention are useful for prophylaxis and the drug treatment of atherosclerosis very effective.

909828/0662

28b4595

The compounds of formula I of this invention can be used in various ways Formulations such as powders, granules, tablets, capsules, injections and the like., Are processed, such Usual additives for formulations can be added. It is preferred that the compounds be administered orally. The dosage of the compounds depends on the condition, age, etc. of the patient; in the case of oral administration the dosage is usually 1 to 100 mg / kg, preferably 5 to 25 mg / kg, daily for adults.

The compounds of formula I of this invention can be according to various Processes are produced, for example, these can be according to the processes denoted by numbers 1 to 5 can be prepared according to the following reaction equations:

Procedure 1

A-OH III strong base

-NO «

(A: IV

Ti

R ₉ -G-

> C.

reduction

II

Method 4 XR ₈ -X

Π \ R ₇ or his re-x. active derivatives

-NHCO-Rc

Method 5 reduction

AO ^ Jy NHCH ₂ -R ₆ XII

909828/0662

The compounds of formula I of this invention also include the compounds of formulas II, V, VII, VIII, X and XII.

The five procedures described above are then followed will be described in detail.

Procedure 1:

In this invention, the compounds having the formula II

R ₁
R * C 0- (/ \ NHo. II

R * C ν 1

wherein IL, R ₂ and R- have the same meaning already mentioned, by reacting an alcohol compound with the formula III

Eg O OH III,

'ν. Λ

wherein R ^, R ₂ and R, have the same meaning already mentioned, with the p-halonitrobenzene of the formula IV

IV,

wherein X represents a halogen atom, can be obtained in the presence of a strong base and then by reducing the product.

It is preferred that the reaction be carried out with heating in an organic ! solvents, such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dioxane, individually or in a mixture. Preferred examples of the strong base used in this invention are sodium, Potassium, lithium, sodium hydride, potassium hydride, lithium hydride and like that. In this case, it is preferred that the alcohol compound of the formula in is reacted beforehand with the strong base and then the product obtained with the p-halonitrobenzene of formula IV is implemented.

909828/0662
ORIGINAL INSPECTED

28b4595

The reduction can be carried out in the usual way, for example by catalytic reduction in a hydrogen atmosphere using a catalyst such as Raney nickel catalyst, platinum, palladium, etc. or by reduction under acidic conditions using a metal such as iron, zinc, tin and the like. The catalytic reduction can be carried out not only by reducing the nitro group, but also by hydrogenating the double bond which is present in the group R. _D I

² ι

R * Procedure 2: ^J

In this invention, the compound having the formula VR ₁

Rg — C 0 (^ ^ IiHCO-R ₆ V,

in which R ^, R ^ , R * and Rg have the same meaning already mentioned, which is achieved by reacting the compound of the formula II (which has already been explained in process 1)

with the carboxylic acid of formula VI

R ₆ - COOH VI,

wherein R _{6 has} the meaning already mentioned, or its reactive derivative is obtained.

It is preferred to carry out the reaction under cooling or at room temperature in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, pyridine, dioxane, etc. or in a mixed solvent of these. If the carboxylic acid of the formula VI is used in this reaction, it is better to carry out _{the reaction in the presence of a condensing agent, v / ie dicyclohexylcarbodi-ImId 5.} As reactive derivatives of the carboxylic acid

909828/0662

Formula VI has been exemplified by the satire halides, such as acid chlorides, Acid bromides, etc .; Mixed acid anhydrides, such as benzyl phosphate, Alkyl carbonate, pivalic acid, etc .; active esters such as p-l-nitrophenyl ester, thiophenyl ester, etc .; and acid anhydrides.

Procedure 3:

In this invention, the compounds having the formula VII

ir, ν VJ ν 7 ^NHR 7 VII

or with the formula VIII

VIII,

wherein R _{7 is} an alkyl group having 1 to 20 carbon atoms, an aryl group, an aralkyl group or a lower alkoxycarbonyl group; R ₇ ^{1 represents} a lower alleyl group; and R ^, R2 and Rz have the meaning already mentioned, by reacting the compound with the formula II, (which has already been explained in process 1)

II

^X 3
with the compound rait of the formula IX

R ₇ -X IX,

wherein R ₇ and X have the meaning already mentioned, are obtained.

Preferred examples of the halogen atom in the method are the bromine atom and iodine atom, E3 is preferred, at room temperature or with heating in an organic solvent such as benzene, toluene, xylene, dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran, Pyridine, methanol, ethanol and the like. Or in one

909828/0662

28 ^ 585

Solution with a mixture of these in the presence of a basic agent, v / ie sodium carbonate, potassium carbonate and the like. To perform.

Procedure 4:

In this invention, the compound of formula X

R ₁ R5 — CO— (/ \ N

U ₃

2 ν ^υ ^ v 'y — f % ^x »

wherein R _{8 is} the group - (CH ₂ ), - or - (CH ₂ ) C- and R ₁ , R ₂ and R ^ have the meaning already mentioned, by reacting the compound of the formula II (which was already used in process 1 has been explained)

R ₁

II

with the compound of formula XI

XR ₈ -X 'XI,

in which R ₈ and X have the meaning already mentioned, under the same reaction conditions as described in process 3, obtained.

Procedure 5s

In this invention, the compound of formula XII

XII,

wherein R ₁ , R ₂ , R, and Rg have the meaning already mentioned, by reducing the compound of the formula V

: co - R ₆

R ₂ CO— </ ^s ) —NHGH ₂ -

909828/0662
ORIGINAL INSPECTED

obtained by using as reducing agent, such as lithium aluminum hydride, Diborane and the like, in an organic solvent such as tetrahydrofuran, ether, etc., with preferably heating is used.

Further, the following reactions can be carried out using the compounds obtained in the above processes will.

In addition, the letter A in the following formulas means the grouping

ν. JL

1) A-0

A-O-

ITHCO - lower alkyl

Alkyl - X

(same condition as in procedure 3) l

CO - lower-alkyl, in which X has the meaning already mentioned.

NHCO - ar alkenyl

catalytic reduction

(same condition as in procedure 1)

NHCO - aralkyl

3) A - 0

NHCOO - lower alkyl

reduction

(same condition as in procedure 5)

// Vs. NHCH,

Y AO

lower - alkyl - COOH or its reactive derivatives I (same condition as in method 2) τ r. —Λ ^ CO- loweroo - alkyl A - 0 (/ \\ ^

909828/0662

- 21 - 2 Ο b A 5 9 p

Vfenn "in the above methods the GIs connection of the alcohol connection of formula III is used, the cis isomer obtained the compound of formula I and if d.Lo Vrans * Compound of the alcohol compound of the formula III is used, the trans isomer of the Vex 'bond of the formula I is obtained. Likewise, if a mixture of the cis-trans isomors of the alcohol compound of the formula III is used, a mixture of the cis-trans isoraere of the compound of the formula I is obtained »In this The case can be the Ois connection or the Trans connection of each other be separated by a common separation method such as fractional crystallization.

Htm are the production methods of the compounds of this invention with reference to the following examples.

example 1

, -NH ₂

In 120 ml of a mixture of dimethylformamide and benzene im Volume ratio 1: 2, 5.1 g of p-l-lenthen-S-ol were dissolved. After adding 1.6 g of sodium hydride (50% suspension in mineral oil this was refluxed by heating for 50 minutes. After cooling the reaction mixture, 4.7 g p-Fluoronitrobenaol was added dropwise to the mixture. That The resulting mixture was refluxed by heating for six hours. After cooling the reaction mixture were 200 ml of benzene are added. The mixture was then washed successively with water and then with aqueous sodium chloride solution.

The benzene layer was separated and dried over wauserfroic.m sodium sulfate dried. The Lösiuu ^ nittol wur.Lo under v Pressure distilled off. The residue was subjected to chromatography, .I): if5 gowüri '.'. C.ite product was processed Use an equivalent mixture of benzene and hexane

909828/0662

eluted.

Then was prevented by / ^ distilling the solvent Pressure from the eluate 7.2 g of 4- (1-p ~ llenthen-8-yloxy) nitrobenzene obtain. A mixture of this product and 0.7 g lO ^ ige Palladium carbon in 100 ml of ethyl acetate v / urden under hydrogen shaken "until the theoretical amount of hydrogen had been absorbed. Nö.ch filtering off the palladium-carbon became the solvent distilled off under reduced pressure. The residue was distilled under reduced pressure. There were 5.07 g of 4- (p-menthan-8-yloxy) aniline were obtained. Boiling point: 146 - 148 ° C / 0.3 mm Hg

Elemental analysis e for C ₁₆ H, H( JO N 00 COO 10, 19th 5 , 66 Calculated: 77.68 10, 20th 5 , 64 Found: 77.73

/ Y *

Example 2 3

31.2 g of ois-p-menthan-8-ol are dissolved in 670 ml of a mixture of dimethylformamide and benzene in a volume ratio of 1: 2 v /. After adding 8.0 g of sodium hydride (60-3 suspension in mineral oil) the mixture was refluxed for 30 minutes by heating. Then 28.2 g of p-fluoronitrobenzene was added dropwise added to the mixture. The resulting mixture was refluxed again for 6 hours. After cooling down 400 ml of benzene was added to the mixture. Da3 obtained mixture was added sequentially with water and aqueous sodium chloride solution washed. The Bonaolschichfc was over anhydrous Sodium sulfate to dry. After distilling off the The obtained solvent under reduced pressure was obtained Residue of a £ i'Llil: a; '; elsäulenchron; a't "O £ raphle subjected. D«: j desired product was made using an equiyalenteu

Π C) 9828/0662

BATH ORIGINAL

Eluted mixture of benzene and hexane. Then the solvent was distilled off from the eluate under reduced pressure. 49 g of cis-4- (p-menthan-8-yloxy) nitrobenzene with a boiling point of 180-183 ° G / 0.7 mm Hg were obtained.

A mixture of 44 g of the product and 2 g of 10% palladium carbon in 200 ml of ethyl acetate were shaken under hydrogen until the theoretically required amount of hydrogen had been absorbed. After filtering off the palladium carbon, the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure. 39.4 g of cis-4- (p-menthan-8-yloxy) aniline were obtained.
Boiling point: 152 - 154 ° 0/1 mm Hg
_{Elemental analysis} for C _ir H 9q ITO:

O( %) H (Si) TO) Calculated: 77 68 10.19 5.66 Found: 77 70 10.22 5.65 Example 3 CH ₃ r \ W. ( \ mz /

Mr.

It has been described by use of the \ ^r crfahrens in Example 2, but using trans-p-menthane-8-ol in place of cis-p-menthane-8-ol, trans-4- (p-menthane-8 yloxy) nitrobenzol with a boiling point of 168 - 171 ° C / 1 mm HG. By treating the product as described in Example 2, was. Tran3 ~ 4- (p-menthan-8-yloxy) aniline. Boiling point: 141 - 143 ° 0 / 0.6 mm Hg
Elemental analysis for Cjg-HgcNO:

0 (90 H (90 H (Ji)

Calculated: 77.68 10.19 5.66

Found: 77.86 10.31 5.64

909828/0662

-24- 28Ü4595

CH ₃

CH, /> CO V  \ NHCOCH,

³ \ _ / I XJ ³

In 100 ml of an equivalent mixture of tetrahydrofuran and Pyridine, 10 g of 4- (p-Hentban-8-yloxy) aniline were dissolved in solution. ITach dropwise addition of 8 ml of acetic anhydride to the solution below The Cemi3Ch was allowed to cool overnight at room temperature stirred. The reaction mixture was poured over 300 g of ice and worked for about two and a half hours. The unusual y: rintalle were separated off by filtration, washed with water and cus 50 ml of ethanol uiukristalliciert. It was 6.7 g lines 4 ~ (p-henthan-8-yloxy) acetanilide obtained.

Melting point: 119-120 ° C
Elementary analysis for

Bereclinet: 74.70 9.40-4.84 Found: 74.61 9.65 4.73

Using the same Ver driving, but instead of p-I-Ienthr.n-8-ol, as in the example 1, now other alcohol bonds are used were obtained aniline derivatives, these were unoccupied with acetic anhydride in the same manner as in Example 4 is described. Thus, the compounds of Examples 5 to 19 were obtained.

Example 5
Alcohol compound used as starting material

CH ,.

menthol

909828/0662

281.4595

- 2.0 -

Established connection
GIL

NHCOCH,

4- (p-Henthan-3 ~ yloxy) acetanilide Melting point: 133-134 ° C
Elemental analysis for ΟΛοΗογΙΓΟρί

C (? 5) H (Ji) N (#)

Calculated: 74.70 9.40 4.84 Found: 74.45 9.64 4.56

Example 6

Alcohol compound used as the starting compound CH, OH

I ³ I.

OH ₇ C = CH (CH ₂ J ₂ C-CH: = CH ₂

3,7-Dinethyl-3-oxy-1,6-octadiene Established connection

OH, CH,

Γΐττ pi f ΠΤΤ ι Π.— f \ // W. -... Τ.ΤΤΤΓΆΡΤΤ

^{3 2 5} I \ = / ⁵

C ₂ H ₅

4- (3,7-Dimethylo.c t-3 "yloxy) ac e tanilide Melting point: 50 - 51 ° C
Elemental analysis for CigHpgNO ,,:

C (%) E (%) N (%) Calculated: 74.18 10.03 4.81 Found: 74.19 9.89 4.54

Example 7 Alcohol Compound Used as Starting Material

909 828/0662 ORIGINAL BATHROOM

.26-28US95

OH

CH ₅

1.1 "bimethylpropanol Established connection

—NHCOCH

4- (1 »1-Dimethylpropoxy) aeetanjLlid Melting point: 116 - 117 ° C Elemental analysis _{for C 15} H _{1 QNO 2}

Calculated: 70.56 8.65 6.33 Found: 70.54 8.80 6.33

Example 8 Alcohol Compound Used as Starting Material

/ I -CH ₂ -OH

Cyclohexylmethanol

Established connection

f / ^

NHCOCH,

4- (Cyclohexylraethoxy) acotanilide Melting point: 118 - 119 ° C Elementary analysis for C ₁

Calculated: 72.84 8.56 5.66 Found: 72.66 8.57 5.82

909828/0662

ΓGi , pet 9

_{Alcohol compound CH 3} used as starting material

- OH

1-Oyclohexyläthanol Manufactured compound

/ V-GH - O (/ \ NHCOCH ₅

4- (1-Cyclohexyläthox3 ^r) acetanilide Schiselzpunlct: 94 - 95 ° C

Eleßientaraio aly s e for C ₁₆ H ₂₅ I. TO ₂ : 10 N (? 0 c (sO H (Ji) 5.36 Calculated: 73.53 8.87 5.30 Found: 73.41 9.08 example

Alcohol pre-binding used as starting material

- OH

1-cyelohexyl-1-methylethanol Established connection

NHCOCH,

4- (1-Cyclohexyl-1-methylethoxy) ac e taniIi d

909828/0662

Melting point: 122 - 123 C H 11 (O/\ N (Ji) Eleinentaraualy oe for Cj ^ ILjt-I 9 , 15 5.09 ff ο'Λ 9 , 41 4.93 Calculated: 74.14 Found: 74.07 example

Alcohol compound used as starting material

CH,

CH ₂ C OH

5H,

1-Bonzyl-1-methylethanol
Established connection

HHOOCH ₅

4- ( ■ :: '■. , ■? ■
Elemental analysis for C ₁₈ H ₂ ^ NO ₂ :

Calculated: 76.30 12th 7th , 47 4th , 94 Found: 76.38 7th , 47 4th , 91 example

Alcohol compound used as starting material

1-methylcyclohexanol

909828/0662

Established connection

/ V_o ft \

NHCOCH

4- (1 -methylcyclohexyloxy) ac etanilide Melting point: 125 - 124 ° C Elemental analysis for Cj kILj-jITOv ,:

72.84 H( %) N (?O) Calculated: 73.15 8th, 56 5 , 66 Found: example 8th, 65 5 , 76 13th

Alcohol compound used as starting material

3-methyl menthol
Established connection

NHCOCH,

4- (3-methyl-p-menthan-3-yloxy) acetanilide Melting point: 133-134 ° C

909828/0662

Elemental analysis for C

Calculated: 75.21 9.63. 4.62 Found: 74.69 9.96 4.93

Example 14 Alcohol Compound Used as Starting Material

OC-OH
JL

1-cyclohexyl-1-phenylethanol Established connection

NHCOCH ₃

4 - (.-.>"Cyclohexyl- .λ -methyl" benzyloxy) acetanilide Melting point: 102-103 ° C
Elemental analysis for

H (Ji)

Calculated: 78.30 8.06 4.15 Found: 78.01 8.34 4.36

Example 15 Alcohol Compound Used as Starting Material

H - OH

Dicyclohexylmethanol
Established connection

C ~ \ - CH - 0 £ \ NHCOCH ₃

4- (dicyclohexylmethoxy) acetanilide

909828/0662

Melting point: 187 - 188 ° O Elemental analysis for C ₂ ^ H ₅ -

Calculated: 76.55 9.48 4.25 Found: 76.61 9.84 4.15

Example Alcohol compound used as starting material

C-OH

t -DimethyTbenzyl alcohol Compound produced

NHCOCE

4- ( Ii-, (κ -dimethyl "benzyloxy) acetanilide. Melting point: 130-131 ° C

Elemental analysis for C ₁₇ H ₁₉ NC ) ₂ : H (Ji) O (Ji) H (Ji) 5.20 Calculated: 75.81 7.11 5.44 Found: 76.05 7.18 example 17th

Alcohol compound used as starting material

Cyclohexanol
Established connection

NHCOCH ₅

4- (Cyclohexyloxy) acetanilide 909828/0662

-32- 28B4595

Melting point: 158-159 ° O

Eleraental analysis iur o ^ n-j glT0 ₂ : H (Ji) c (%) H (Ji) 6.00 Calculated: 72.07 8.21 6.33 Found: 71.72 8.30

The compounds in Examples 18 and 19 were made by using prepared from isobutyric anhydride or benzoic anhydride instead of acetic anhydride in Example 4,

Example 18 Connection established

N-Isobutyryl-4- (p-menthan-8-yloxy) aniline. Melting point: 127-128 ° C
Element ar analysis for ^σ 20 ^Η 31 ^1ί0 2 ^ί

σ ( %) H , 84 N (Ji) Calculated: 75 67 9 , 10 4.41 Found: 75 54 10 19th 4.21 example

Established connection

CH ₅

4- (p-Menthan-8-yloxy) benzanilide Melting point: 121-122 ° C
Elemental analysis for CpeHpqlTOp ⁵

C (Si) H (5i) H (Ji)

Calculated: 78.60 8.32 3.98

Found: 78.31 8.46 3.69

909828/0662

Example 20

1 g of 4- (p-Kenthan-8-yloxy) aniline was dissolved in 10 ml of an equivalent mixture of tetrahydrofuran and pyridine. After the dropwise addition of 0.65 g of cyclohexyl carbonyl chloride to the solution with ice cooling, the mixture was stirred overnight at room temperature. The reaction mixture was poured over 60 ° g of ice and stirred for about two hours. The deposited crystals were separated by filtration and washed with water. These were recrystallized from 10 ml of ethanol. 1.02 g of white crystalline N-cyclohexylcarbonyl-4- (p ~ menthan-8-yloxy) aniline was obtained. Melting point 171-172 ° C
Element ar analysis for C ₂₅ H ₅₅ ITO ₂ :

G (Ji) H (%) - N (#)

Calculated: 77 | 27 9.87 3.92 Fimden: 77.27 10.13 3.74

By the same procedure as described in Example 20, but using cinnamoyl chloride, 1-adamantanylcarbonyl chloride or Ν, Ι ^ -dimethylcarbamoyl chloride instead of Cyclohexylcarbonyl chloride in Example 20, the compounds in Examples 21-23 were obtained.

Example 21

Established connection

CH ^

-NHCOCH = CH- ^ M

N-cinnamoyl-4- (p-menthan-8-yloxy) aniline

Melting point: 75-76 ° C

909 828/0662

- 34 - 2854595 D ₂ : Elemental analysis e for C ₂₅ H ₅ .j 1T ( vfo / \ vtfci \
a. \ / o) a \ iv) cOO 8.28 3.71 Calculated: 79.54 8.37 3.52 Found: 79.31 22nd example Established connection
nu - / ~) NHCO- ^?) ^CH 3 O C 0 -
CH,

IT- (Adamant-1 -yl-carbony 1) -4- (p-menthan-8-yloxy) aniline Melting point: 105-106 ° C
Elemental analysis for CgoHzgNO ,,:

G ( ⁰ A) E (%) II (%) Calculated: 79.19 9.60 3.42 Found: 79.32 9.64 3.26

Example 23 Established connection

^CH 3 Ar \ ^ / CH ₃

NHGON,

-CH ₃

1- J4- (p-menthan-8-yloxy) phenyl] -3,3-dimethyl urea f Melting point: 112-114 ° C
Elementary analysis for

Calculated: 71.66 9.50 8.80 Found: 71.56 9.81 8.65

By the same procedure as given in Example 1, but using other alcohol compounds instead of p-menthen-8-ol in Example 1, aniline derivatives were obtained and these were treated with FjN-dimethylcarbamoyl chloride or I-adamantanyl carbonyl chloride in the same way as im

909828/066 2

Example 20 "described, implemented. Thus the connections were made of Examples 24 to 26 are obtained.

Example 24

Alcohol compound OH used as starting material

menthol

Established connection
CH ₃

/OH

NHOON.

1 -il4- (p-menthan-3-yloxy) phenyl_; -3,3-dimethylurea f melting point: 154-156 ° C
Elemental analysis for C-iq ^ oNoOp *

0 (%) H (%) N (? 0 Calculated: 71.66 9.50 8.80 Found: 71.53 9.69 8.58

Example 25 Alcohol compound used as a starting material

Cyclohexylmethanol

CH ₂ OH

909828/0662

Established connection

CHo

0 ~ / XS

-inicoii.

1 - (4-0yclohexylinetlioxyphenyl) "3,3-diniethylurea f Melting point: 158-159 ° C

Element ar analysis for CjgHgili , O ₂ : N ( Of ι
/ Q J σΟΟ H (Ji) 10, 14th Calculated; 69.53 8.75 9, 90 Found: 69.21 8.81 example 26th

Alcohol compound used as starting material

menthol

Established connection

NHCO-

N- (Adamant-1-ylcarbonyl) -4- (p-menthan-3-yloxy) aniline Melting point: 194-195 ° C Elementary glass for C ₂ YH

909828/0662

Calculated:
Found: C.
79
79 (Ji)
, 17th
, 40 example H (Ji)
9.60
9.86 3 0 H (Ji)
3.42
3.37 CH
"Λ- A- 27 OH ₅ - < -J L ^ \ / \ /

2.0 g of 4- (p-menthan-8-yloxy) aniline were added to 10 ml of anhydrous tetrahydrofuran dissolved. 5 ml of anhydrous pyridine was added. Then 1.55 g of N-döcanoyl chloride (OqH ^ qCOCI) was added dropwise added to the mixture with ice cooling. The resulting mixture was stirred overnight at room temperature.

The reaction mixture was poured over 50 g of ice and then Stirred for about 3 hours. The oily product thus deposited was separated by decantation and dissolved in 100 ml of ether dissolved «The ether solution was successively with 3 & Lger Hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and then washed with an aqueous sodium chloride solution. The ether solution was poured over anhydrous sodium sulfate dried, then the solvent was distilled off under reduced pressure. 3.2 g of crystalline 4- (p-menthan-8-yloxy) -N "decanoylaniline were obtained obtain. Recrystallizing the product from ethanol gave white crystals with a melting point from 31 - 32 ° C.

Elemental analysis C (Ji) H (Ji) H (Ji) 77.75 10.79 3.49 Calculated: 77.55 11.07 3.41 Found:

Example 28

NHCOC ₁₅ H ₂₇

909828/0662 ORIGINAL INSPECTED

The same procedure as described in Example 27 was carried out, except that kyristoyl chloride (C ₁₅ H ₂₇ OOOl) was used instead of li-decanoyl chloride, so that 4- (p-menthan-8-yloxy) -Ii-myristoylaniline was obtained v / urde. Melting point: 51-52 ° C
Elemental analysis for O ₃₀ II ₅₁ NO ₂ :

C (50 E (%) N (tf)

Calculated: 78.72 11.23 3.06 Found: 78.54 11.56 2.90

Example 29

The same procedure as described in Example 27 was carried out, but using palmitoyl chloride (C ₁ CHa ₁ 000l) instead of N-decanoyl chloride, so that 4- (p-menthan-8-yloxy) -N-palraitoylaniline was obtained v / urde. Melting point: 61 - 62 ° C
Elemental analysis for 032 ^ 55NO ₂ :

Calculated: / 79.12 CH,
~ \ I ³ 11 41 2 , 88 Found: 79.45 > —O-
OH ₃ 11 79 2 , 71 example 30th —NHOOO 17 ^H 35

2.0 g of 4- (p-menthan-8-yloxy) aniline were added to 20 ml of anhydrous tetrahydrofuran and 4.5 g of anhydrous stearic acid suspended. After dropwise addition of 5 ml of anhydrous pyridine under Stirring and ice cooling v / the mixture is stirred overnight at room temperature

909828/0662

-39- 2 Β 5 /, 5 9 5 "

The reaction mixture was poured over 100 g of ice and still etv / a Stirred for two hours. The deposited white crystals were separated off by filtration, three times with 50 ml each time Washed petroleum ether. Then was twice with 25 ml Recrystallized ethanol. White crystals of 4- (p-menthan ~ 8'yloxy) -H ~ 3tearoylaniline became received »a total of 3.1 g. Melting point: 72-73 ° C

Elemental analysis IUT W * Il _r J ₉ NO ₂ : N (Ji) c (ji) HW) 2.73 Calculated: 79.47 11.57 2.44 Found: 79.71 11.93

Example 31

6.2 g of 4- (p-menthan-8-yloxy) aniline, 7 g of anhydrous potassium carbonate and 5.75 ^V g of 1,5-dibromopentane were added successively to 150 ml of anhydrous ethanol. The mixture was refluxed with heating for 40 hours. After the reaction mixture was cooled, the solvent was distilled off under reduced pressure. 200 DiI dichloromethane and 150 ml of water were added to the residue. The dichloromethane layer was separated, washed with water and then rewashed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography. The product produced was then eluted using benzene saturated with ammonia; the solvent was then distilled off from the eluate under reduced pressure. 5.77 g of crystalline 1-i.4- (p-ienthan-8-ylo3cy) phenyl 'piperidine were obtained. After recrystallization of the product from ethanol, white crystals with a melting point of 53 ° -54 ° C. were obtained. Elemental analysis for Cg-jBWliO:

909828/0662

ceo HOO N0O Calculated: 79.95 10.54 4.44 Found: 79.90 10.83 4.37

By the same procedure as described in Example 1 is, -but using other alcohol compounds instead from p-Mcnthen-8-ol as in Example 1, aniline derivatives were obtained, these were made with 1.5 ~ l) ibromopentane in the same way implemented as described in Example 31. There were thus obtaining the compounds described in Examples 32-46.

Example 32
Alcohol compound used as starting material

Established connection

1 - [. 4- (p-Henthan-3-yloxy) phenyr piperidine
Melting point: 93-94 ° C
Elemental analysis for C ₂₁ H ₃

909828/0662

c (50 H (JO N (JO Calculated: 79.95 10.54 4.44 Found: 79.91 10.75 4.41 example 33

_{Alcohol compound CH 3} CH ₃ used as starting material

CH _2: =: C- (CHg) ₅ CH (CHg) ₂ OH

3,7-Dimethyl 1-7 octene-i-oil

Established connection

CH

^^ "** ·. Rrafrrti \ A

1- [4- (3,7-Dimethyloctyloxy) phenyl] piperidine
Melting point: 174-178 ° C / 0.4 mm Hg
Elemental analysis for C ₂ ^ H ₃₅ NO:

C (JO H (JO. N (JO Borochnet: 79.44 11.11 4.41 Found: 79.40 11.43 4.19

Example 34
Alcohol compound used as a starting material

CH,

OH

CH ₃ Cr =: CH (CHg) ₂ C CH = CH ₂

CH-Z

3,7-dimethyl-3-oxy-1,6-octadiene Established connection

CH ₃

CH ₃

CH, CH (CH ^ UC 0

\ C ₂ H ₅

N- [4- (3,7-dimethyloct-3-yloxy) phenylj [piperidine

909828/0662

Melting point: 174 - 176 ° 0 / 0.5 mm Hg Elemental analysis for C ₂ -j H ^ clTO:

C (%) H (Ji) Ii (Ji)

Calculated: 79.44 11.11 4.41 Found: 79.74 11.23 4.13

Example 35

Alcohol compound used as a starting material

- OH

Octadecanol
Established connection

- 0

F- (4-octadecanyloxyphenyl) piperidine

Melting point: 54-55 ° C
Elemental analysis for C _{2 0Hc 1} NO:

Calculated: 81.06 11.96 3.26 Found: 80.92 12.27 3.00

Example 36

_{Alcohol compound CH 5} used as starting material

I ₅ CH ₂

CII ₅ CH ₂ C OH

^H 3

CH ₅

1,1-dimethylpropanol
Established connection

c:

CH ₅ CH ₂ C

N- [4- (1,1-Dimethylpropoxy) phenyl] piperidine

909828/0662

Boiling point: 120 - 122 ° C / 1mm Hg element ar analysis for C ₁ ^ -H ₉ C-NOs

595

Calculated: 77.68 10.19 5.66 Found: 77.32 10.24 5.39

Example 37 Alcohol compound used as a starting material

{ V-CH ₂ - OH
Cyclohexylmethanol
Established connection

K- [4- (Cyclohexylmethoxy) phenyl] piperidine. Melting point: 63-64 ° C
Elemental analysis for CjgHgaNO:

Calculated: 79.07 9.95 5.12 Found: 78.88 10.22 5.00

Example 38

_{Alcohol compound CH 3} used as starting material

-CH- OH
1-cyclohexyl ethanol

Established connection

3-O

N- [4- (1-cyclohexylethoxy) phenyl] piperidine Boiling point: 147 - 148 ° C / 0.3 mm Hg

909828/0662

~ ⁴⁴ ~

Elemental analysis Tiyv Π λ _Λ Η _Α TTO H (Ji) N ( Ji) C (Ji) 10.17 4, 87 Calculated: 79.39 10.51 4, 87 Found: 79.28 39 example

Alcohol compound used as the starting material

C OH

CH ₃

1-cyclohexyl-1-methylethanol Established connection

IT-r4- (1-cyclohexyl »1-meth.ylethoxy) phenyl | piperidine melting point: 66 - 67 ° C elemental analysis for C ₂₀ H, ^ ITO:

0 (%) H (? QN (Ji)

Calculated: 79.68 10.36 4.65

Found: 79.54 10.58 4.41

Example Alcohol compound used as starting material

H ₂ C-OH 1-benzyl-1-methylethanol

909828/0662 ORIGINAL INSPECTED

Established connection

U-J4- ( _v v, J * -Dimethylphenetyloxy) phenyl] piperidine Melting point: 68 - 69 ° C Elemental analysis for

Calculated: 81.51 8.79 4.53 Found: 81.33 8.95 4.52

Example Alcohol compound used as a starting material

1-methylcyclohexanol Manufactured compound

O-O

• HC1

N- [4- (1-methylcyclohexyloxy) phenyl] piperidine hydrochloride Melting point: 150 - 151 ° C Elemental analysis for

Calculated: 69 , 77 9, 11 4th , 52 Found: 69 , 39 9, 42 4th , 64 example 42

Alcohol compound used as a starting material

909828/0662

28SA595

3-methylmenthol
Established connection

If- / _4- (3-Kothyl-p-nienthan-3-yloxy) phenyl I piperidine Boiling point: 140 - 145 ° C / 0.3 mm Hg Elementary analysis for C ₂₂ H ^ cHO:

C (Si) H (JS) N (Ji) Calculated: 80.19 10.71 4.25 Found: 80.14 10.42 3.92

Example 43 Alcohol compound used as a starting material

CH,

O-

OH

cL -Cyclohexyl- οι -me thy! benzyl alcohol

909828/0662

Established connection

N- [4- (3C-Cyclohexyl- <? (. -Methylbenzyloxy) phenyl] piperidine Boiling point: 178 - 183 ° C / 0.25 mm Hg elemental analysis for CgcH ^ M):

0 (%) 'H (Si) H (Ji)

Calculated: 82.60 9.15 3.85 Found: 82.66 9 _f 35 3 _f 65

Example 44 Alcohol compound used as a starting material

CH - OH

Dicyclohexylmethanol
Established connection

N- (4-Dieylohexylmethoxyphenyl) piperidine

Melting point: 57 -58 ° C. H (Si) H (Si) Elemental analysis for Cr
C. 10.49 3.94 Ö (Si) 10.83 3.73 Calculated: 81.07 28/0662 Found: 81.16 90 98

-48- 28b4b95

Example Alcohol compound used as starting material

c <-, ^, -dimethylbenzyl alcohol Compound produced

N- | 4- (oC, ^ - dimethylbenzyloxy) phenyl] piperidine Melting point: 92 - 93 ° C Elemental analysis for C ₂

Calculated: 81 , 31 8th, 53 ' 4th , 74 Found: 81 , 09 9, 69 4th , 98 example 46

Alcohol compound used as starting material

OH

Cyclohexanol
Established connection

N- (4-Cyclohexyloxyphenyl) piperidine Melting point: 50 - 51 ° C Elemental analysis for C ₁₇ IL ₇ C-NO:

c ( %) H (Yo) 62 N (%) Calculated: 78 72 9.71 5.40 Found: 78 51 9.92 5.56 90 9828/06

Example 47

CE

rv

1.23 g of 4- (p-menthan-8-yloxy) aniline, 1.4 g of anhydrous potassium carbonate and 1 »1 g of 1,4-dibronobutane were added successively to 50 ml of anhydrous ethanol, and the mixture was kept for 42 hours Held at reflux. The reaction product was then subjected to the extraction and purification procedures as described in Example 31. 1.1 g of crystalline N- / 4- (p-menthan-8-ylo.xy) phenyl] pyrrolidine was obtained. After recrystallization of the product from ethanol, white crystals with a melting point of 92-93 ° 0 were obtained. Elemental analysis for O ₂₀ Ez ₁ NO:

Calculated:
Found:

C (Ji)

79.68
79.43

H (Ji)

10.36 10.65

Example 48

N (tf)

4.65 4.37

To 150 ml of anhydrous ethanol, 30 g of cis-4- (p-mcnthan-8-yloxy) aniline, 25.2 g of anhydrous potassium carbonate and 33.5 g of 1.5 ~ dibromopentane were added and then the mixture was made Refluxed for 15 hours by heating. After cooling the reaction mixture under reduced pressure 500 ml dichloromethane and 500 ml v / water were added to the residue added. The dichloromethane layer was separated by decantation, washed with water and then with aqueous sodium chloride solution washed and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue obtained was then a silica gel

909828/0662

subjected to column cliroraatography. Then the produced product was eluted using benzene saturated with ammonia. The solvent of the eluate was distilled off under reduced pressure aMG3. 23 g of cis-1- J4- (p-menthan-8-yloxy) .phenyl] piperidine were obtained. After recrystallization of the product from ethanol, white crystals with a melting point of 78-79 ° C. were obtained.
Elementary analysis for Cp-iH-r ^ lTO:

Calculated: 79 , 95 10, 54 / 4, 44 Found: 79 , 83 10, 98 - < 4, 36 example 49 / \ I ³ CIl |> -I -0- >

CH.

The same procedure as described in Example 48 was carried out, but using trans-4- (p-nienthan-8-yloxy) aniline instead of cis-4- (p-menthan-8-yloxy) aniline. Crystals of Irans-1- [4- (p-menthan-8-yloxy) phenyl | - piperidine were obtained.
Melting point: 62-63 ° C
Elemental analysis for C ₂₁ EVjIiO:

Calculated: Found:

79.95 80.00

10.54
10.87

4.44 4.39

CI

Example 50

In 47 ml of 95 # Iger ethanol solution of 1 normal potassium hydroxide were 2.1 g of trans-ir-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline

909828/0662

-51- 28bA595

The solution was then refluxed by heating for 6 hours. Thereafter, ethanol was distilled off under reduced pressure from the reaction mixture to give the rud formed. 50 ml of ether and 50 ml of water were added and then it was extracted with ether. The extract was washed with water and then with aqueous sodium chloride solution ge \ _e 7aschen After drying over anhydrous magnesium sulfate was Äthr. distilled off from the reaction mixture. 1.75 g of Tran; "4- (p-menthan-8-yloxy) aniline were obtained.

1.7 g of the product were added to 50 ml of anhydrous ethanol together with 2 g of anhydrous potassium carbonate and 1.7 g of 1,5-dibronpentane added. The mixture was then refluxed by heating for 16 hours. By treating the Raakticv. Product as indicated in Example 48, 0.95 g of crystalline trans-1-4- (p-menthan-8-yloxy) phenyl / piperidine was obtained. Melting point: 62-63 ° C

The infrared absorption spectrum, nuclear magnetic resonance spectrum (H, C) and the mass spectrum of the crystals stir ::: it <? coincides with the spectra of the crystals shown in the example '/. were obtained.

Example 51

The same procedure was described as in Example 50 .; but using cis-N-ethoxycarbonyl-4- (p-menfc}. ¹ 8-yloxy) .anilin instead of trans-N-ethoxycarbonyl-4- (p-mcn. 8-yloxy) aniline used. Crystals of cis-1- [4 ~. menthan-8-yloxy) phenylj piperidine obtained · Melting point: 78-79 ° C

The infrared absorption spectrum, nuclear magnetic resonance spectrum (H, C) and mass spectrum of the crystals agreed with those spectra of the crystals, which in example A <-

909828/0662

BATH ORIGINAL

-52- 28S4595

were obtained.

Example 52

'HCl

2.5 g of 4- (p-menthan-8-yloxy) aniline, 1.4 g of anhydrous potassium carbonate and 1.7 g of benzyl bromide were successively added to 100 ral v / an rs of ethanol. The reaction mixture was then allowed to react for 4 hours at room temperature, then refluxed by heating for 40 hours. Thereafter, the reaction mixture was subjected to the extraction and purification procedures as described in Example 31. 0.95 g of oily IT-benzyl-4 were obtained - (p-menthan-8 ~ yloxy) aniline. The product was dissolved in 25 ml of anhydrous ether, after the addition of 1 ml of 5 normal hydrochloric acid with cooling, the mixture was allowed to cool. 0.8 g of IT-benzyl- . 4- (p-menthane-0-yloxy) aniline hydrochloride obtained Ho.ch dam recrystallization of the hydrochloride from a mixture of ethyl acetate and Dichlonaethan white crystals having a melting point at 137 - 138 ° C obtained..

El OEiont ar analysis OH ₃ / for C ₂₃ II ₃₂ ITOi Cl: N , 75 v_ O(%) H (Ji) 3 , 54 Calculated: 73.87 8.63 3 Found: 73.55 8.72 ₂ ) ₅ example 53 H (CH V-0 -CH - ^ CH ₃

It was described by the same procedure as in Example 52, implemented, but 1-bromobutane was used instead of benzyl bromide used. It was N-Butyl-4- (p-menthan-8-yloxy) aniline Obtain hydrochloride.

909828/0662
ORIGINAL INSPECTED

28SA535

Melting point: 138-159 ° G
Elemental analysis for C _9n Ez _A NOÖl: ■

C (Si) H (5i)

Calculated: 70.66 10.08 4.12

Found 70.46 10.28 5.91

Example 54 CH ·? C.

NHCOOC ₂ H ₅

5 g of 4- (p-menthan-8-yloxy) aniline were dissolved in 50 ml of anhydrous pyridine. Thereafter, 4 ml of ethyl chlorocarbonate were added dropwise to the solution while stirring and cooling with ice. After stirring the mixture further overnight at 4 ° C., the reaction mixture was poured into 300 ml of ice water. The oily product formed was extracted with ether. The extract was washed successively with water, aqueous hydrochloric acid, water and with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crystals formed were recrystallized from 20 ml of methanol. 3.5 g of white crystalline N-xthoxycarbonyl-4- (p-menthan-8-yloxy) aniline were obtained.
Melting point: 65 - 66 ° C

Elemental analysis for C ₁₉ H ₂ «NO. *: (%) H( JO O (Ji) H , 15 4, 38 Calculated: 71.44 9 , 37 4, 54 Found: 71.46 9

In addition, a further 1.5 g of the product produced could be obtained by recrystallization from the mother liquor.

Example 55

ITKCOOC ₂ H ₅

909828/0662

285459S

21 g of trans-4- (p-menthan-8-yloxy) aniline were dissolved in a mixture of 40 ml of anhydrous pyridine and 100 ml of anhydrous dichloromethane. Then, 18.5 g of ethyl chlorocarbonate was added dropwise to the solution while stirring and cooling with ice. The mixture was stirred over laughing at 4 ° C. The reaction mixture was poured into 300 ml of ice water. The dichloromethane layer formed was separated. The aqueous layer was extracted with 80 ml of dichloromethane. The extract was combined with the previously obtained dichloromethane solution, and the mixture was washed successively with water, 2 liters of hydrochloric acid, water and sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the crystals formed were converted from 80 ml of methanol. 19.5 g of trans-N-ethoxy carbonyl-4- (p-menthan-8-yloxy) aniline were obtained. Melting point: 76-77 ° C
Elementary analysis for CjgH ₂ glT0 ,:

Calculated: 71.44 9.15 4.38 Found: 71.87 9.43 4.35

ITHCOOC ₂ H ₅

The same procedure as given in Example 55 was followed, but using cis-4- (p-menthan-8-yloxy) -aniline instead of trans-4- (p-menthan-8-yloxy) aniline. Cis-li-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline with methanol was obtained in the crystal c

Drying under reduced pressure gave crystal methanol removed and it was cis-N-ethoxycarbony1-4- (p-menthan-8-yloxy) -aniline obtained as an oily material.

909828/0662

-55- 28bA595

Elemental analysis for O-qHgqNO *:

0 (90 HOO N (Ji)

Calculated: 71.44 9.1 4.38

Found: 71.15 9.37 4.36

Nuclear magnet! See resonance spectrum (CDCl,) (inner standard THS) (f (PPm): 0.99 (CH ₅ ^ Q-., 3H, d)

1.20 (-C-, 6Η, s) OH ₅

1.30 (011, -CH ₀ -O-, 3Η, t)

I ?? a

1.0-2.1 ( PiJ ^ ii » ^1OH » ^m )

^H HH ^H

4.24 (CH ₅ -CH ₂ -O-, Zh, q.) 6.72 (-NHC0-, 1H, s)

^H M ^H 6.95, 7.3 (Λ>, 4Η,

H Example 57

-NHC ₁₆ H ₅₅

To 100 ml of anhydrous ethanol were added successively 2.0 g of 4- (p-menthan-8-yloxy) aniline, 1.2 g of anhydrous potassium carbonate and 2.6 g of hexadecyl bromide (C ^ gH ₅₅ Br). The mixture was refluxed with heating for 48 hours. After the reaction mixture was cooled, the solvent was distilled off under reduced pressure. The residue was dissolved in 160 ml of dichloromethane and 100 ml of water. The dichloromethane layer was separated. The dichloromethane solution was washed with v / water and then with aqueous sodium chloride solution and dried over anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure, and the residue formed was subjected to silica gel column chromatography. The product made was made using ammonia

909828/0662

28b459S

saturated benzene eluted. The solvent was from your Eluate distilled off under reduced pressure. It was 1.6 g N-hexadecyl-4- (p-menthan-8-yloxy) aniline. After the Umla? of the product from ethyl acetate, white crystals with a melting point of 42-43 ° C. were obtained.

Elemental analysis • fill "O TT H (Ji) N 00 C (JS) 12.18 2 , 97 Calculated: 81.46 12.42 2 , 69 Found: 81.20

By using the same procedure as in Example 1 described, but using a different alcohol compound instead of p-henthan-8-ol of Example 1, aniline derivatives obtained, these v / urden reacted with hexadecyl bromide according to the method described in Example 57 to obtain the Examples 58-61 to produce compounds mentioned.

Example 58
Alcohol compound used as starting material

menthol
Established connection

N-hexadecyl ~ 4- (p-menthan-3-yloxy) aniline

4 ° C
909828/0662

Melting point: 43-44 ° C

Elemental analysis for Ο ^ Η, -οΝΟ:

σ OO hOO nOO

Calculated: 81.46 12.18 2.97 Found: 81.68 12.53 3.13

Example 59 Alcohol compound used as a starting material

CH _3-0 OH

Ah ₃

1-cyclohexyl-1-methylethanol

Established connection

CH ₃

C 0— < ) —NHC ₁ ,

4- (1 -Cycloliexyl-1-methylethoxy) -N-hexadecylaniline

H (Ji) 3.06 3.17

Alcohol compound used as starting material

Melting point: 31 - 32 ° C ): H (Ji) Elemental analysis for C ₃₁ H ₅₅ IK 12.11 Λ f (j / \
\ j V / 0 J 12.65 Calculated: 81.32 60 Found: 81.00 example

CH-OH

1-Cyclohexylethanol Manufactured compound

4- (1-Cyclohexylethoxy) -N-hexadecylaniline

909828/0662

Melting point: 32 - 33 ° C 3: H( JS) N (Ji) Elemental analysis for C ₃₀ H ₅₃ Ni 12, 04 3 , 16 C (Ji) 12, 55 3 , 16 Calculated: 81.19 61 Found: 81.15 example

Alcohol compound used as starting material

H ₉ C OH

N = / l

1-benzyl-1-methylethanol Manufactured compound

N-Hexadecyl-4- ( oL t ⁰⁰ -dimethylphenetyloxy) aniline Melting point: 45 - 46 ° C Elemental _{analysis for C 32} Hc ₁ NO:

w V / v J H (Ji) H (Ji) Calculated: 82.52 11.04 3.01 Found: 82.56 11.46 3.02 example 62

.HCl

2.5 g of 4- (p-menthan-8-yloxy) aniline were added to 80 ml of anhydrous ethanol dissolved. After adding 2.8 g of anhydrous potassium carbonate, a solution of 2.8 g of methyl iodide in 10 ml of anhydrous Ethanol is added dropwise to the mixture with stirring

909828/0662

Room temperature added. After refluxing the mixture overnight, the solvent was reduced under reduced pressure Distilled off pressure, the residue was treated with dichloroethane extracted. The extract was washed with water / water, then washed with aqueous sodium chloride solution and washed over dried anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was washed with Ether extracted. Insoluble ammonium salts were removed. After distilling off the ether, oily material was obtained, which was subjected to silica gel column chromatography. Then the produced product was saturated with ammonia Benzene eluted. From this eluate, the solvent was distilled off under reduced pressure. The oily material obtained was dissolved in 50 ml of dry ether, 1 ml of a mixture of 5 normal hydrochloric acid and ethanol was added to the Solution added. 1.8 g of crystalline 4- (p-menthan-8 ~ yloxy) -N $ N-dimethylaniline hydrochloride were obtained obtain. After recrystallization of the product from a mixture of dichloromethane and ethyl acetate, white crystals with a melting point of 148-149 ° 0 were obtained.

Elemental analysis for C ₁₈ H ₅₀ NOC Jl: 4.49 E (%) 4.51 Calculated: 69.32 9.70 Found: 69.02 9.92 example 63 -NHCH ₂ C f \ CH ₅ - / \ / \ / CH ₅

A solution of 580 mg 4- (p-menthan-8-yloxy) acetanilide in 10 ml Anhydrous tetrahydrofuran was added dropwise with stirring to a suspension of 100 mg of lithium aluminum hydride in 1 ml anhydrous tetrahydrofuran added. The mixture was refluxed for 5 hours. To the reaction mixture were successively 0.1 ml of water, 0.1 ml of aqueous 15%

909828/0662

Sodium hydroxide solution and 0.3 ml of water were added with cooling. After the insoluble matter was filtered off, the solvent was distilled off under reduced pressure. The residue formed was subjected to silica gel column chromatography. The product made was benzene saturated with ammonia eluted. The eluate was concentrated under reduced pressure Distilled residue under reduced pressure. 300 mg of N-ethyl ~ 4- (p-menthan-8-yloxy) aniline were obtained. Melting point: 143-145 ° C / 0.35 mm Hg

5.09 5.41

Elemental analysis for CjgHpn NO: Calculated:
Found: CW
78.49
78.31 H (50
10.61
10.75 Example 64 yc

VS NHCOOC ₂ H ₅

In a mixture of 225 ml of anhydrous pyridine and 450 ml of anhydrous Tetrahydrofuran was 4915 g of 4- (p ~ menthan-8-yloxy) aniline (Cis isomer: trans isomer = 45:55) resolved. To By adding dropwise 48 g of ethyl chlorocarbonate to the solution while stirring and cooling with ice, the mixture became overnight at 4 ° C stirred. The reaction mixture was poured into 1 liter of ice water and extracted with 500 ml of ether. The extract was made one after the other with water, 4% hydrochloric acid, water, washed aqueous sodium hydrogen carbonate solution and water, then dried over anhydrous magnesium sulfate. Ether was distilled off under reduced pressure. The residue formed was left to stand under ice-cooling. The crystals formed were recrystallized from methanol, the volume of the Methanol was four times the volume of the crystals to be recrystallized. There were 31 g of N-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline obtained with a high proportion of trans isomers. The crystals were repeated three times from methanol in theirs

909828/0662

Two to three times the volume of uracrystallized, 14.5 g of trans-N-ethoxyl-carbonyl-4- (p-iiienthan-8-yloxy) aniline were obtained.
Melting point: 75 - 76 ° σ

The purity of the (Erans isomers was nuclear magnetic nuclear magnetic with 98.9% by the. ^Y G Resonansspektrum, dae infrared absorption spectrum H! 3che resonance spectrum and Macsenspektruia agrees with. In addition, these spectra were the product well with the spectra of pure material match.

Example 65

COOC ₂ E ₅

The mother liquors that were used in isolating the crystals from! Erans-N-ethoxycarbonyl-4- (p-menthaji-8-yloxy) aniline in Example 64 were combined and methanol was reduced under reduced pressure Distilled pressure. The residue formed was again recrystallized four times from methanol, the volume of the methanol was three times the volume of the crystals to be recrystallized. There were 16.2 g of methanol-containing Crystals of Cis-iT-athoxycarbonyl ^ -Cp-menthan-S-yloxy) aniline obtain. The product was stored under reduced pressure to remove methanol. This turned oily cis-N-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline obtain.

The purity of the cis isomer thus obtained was found to be 80%

\ Q resonance]

Example 66

13th
the C nuclear magnetic resonance spectrum is confirmed.

A solution of 2.57 g of 4- (p-menthan-8-yloxy) -N-stearoylaniline in 25 ml of anhydrous tetrahydrofuran was added dropwise

909828/0662

added to a suspension of 0.25 g of lithium aluminum alydride in 3 ml of anhydrous tetrahydrofuran with stirring and with ice-cooling. The mixture was refluxed for 6 hours. After cooling the reaction mixture with ice, 0.3 ml of water, 0.3 ml of aqueous 15% sodium hydroxide solution and then 1.0 ml of water were successively added to the mixture with stirring. After further stirring the mixture for about 30 minutes, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained concentrate was dissolved in 50 ml of ether, after washing the solution with saturated sodium chloride aqueous solution, the solution was dried over anhydrous sodium sulfate. Then the solvent was distilled off under reduced pressure, and the residue formed was subjected to silica gel column chromatography. The produced product was eluted with benzene saturated with ammonia. The solvent was distilled off from the eluate under reduced pressure. 1.49 g of crystals of 4- (p-menthan-8-yloxy) -N-octadecylaniline were obtained. After recrystallization of the product from ethanol, white crystals with a melting point of 38-39 ° C. were obtained.
Elemental analysis for 03, Hg ₁ NO:

C (SO H (Ji) H (Ji)

Calculated: 81.70 12.30 2.80 Found: 81.49 12.73 2.85

By the same method as described in Example 66 , but using the compounds obtained in Examples 27 and 28 instead of 4- (p-menthan-8-yloxy) -N-stearoylaniline in Example 66 , the compounds according to Examples 67 and received 68.

Example 67

Alcohol compound 4- (p-menthan-8-yloxy) -N-decanoylaniline used as the starting compound
(Product obtained according to Example 27)

909823/0662

b A 5 9 5

Established connection

N-Oecyl-4- (p-menthan-8-yloxy) aniline Boiling point: 172-175 ° C / 0.2 mm Hg

Elemental analysis for C ₂₆ H ₄₅ N0: H (J6) N (%) C (Y) , 11.70 3 , 61 Calculated: 80.56 12.06 3 , 67 Found: 80.35 Example 68

Alcohol compound used as starting material 4- (p-Monthan-8-yloxy) -il-myri is toylaniline (Product obtained according to Example 28)

Established connection

4- (p-menthan-8-yloxy) -N-tetradecylaniline Boiling point: 195 - -200 ° C / 0.25 mm Hg Elemental analysis for C ^ Hc ^ NO:

C. (° / o) H (Ji) 3.16 Calculated: 81 , 20 12.04 3.17 Found: 81 , 01 12.40 Example 69

CH,

H,

COCH,

In 20 ml of anhydrous ethanol, 1 g of 4- (p-menthan-8-yloxy) -

909828/0662

acetanilide dissolved. After adding 0.4 g of potassium tert-butoxide and 0.6 g benaylbronide for 24 hours Stirred through at room temperature. The solvent was taking distilled off under reduced pressure, the residue was washed with dichloromethane and water treated. The dichloromethane layer formed was separated, with water and then with aqueous Sodium chloride solution and washed over anhydrous magnesium sulfate dried. The solvent was distilled off under reduced pressure, the oily matter obtained became one Subjected to silica gel column chromatography. The produced product was eluted with benzene saturated with ammonia. the end the solvent was distilled off from the eluate under reduced pressure. The residue present as a syrup was under distilled under reduced pressure. 1.15 g of N-benzyl-4- (p-menthan-8-yloxy) acetanilide were obtained obtain. Boiling point: 195 - 200 ° C / 0.6 mm Hg

3.69 3.94

Elemental analysis e for %) H( %) c ( 11 8th, 76 Calculated: 79 49 8th, 96 Found: 79 example 70

CH

NHOOCH ₂ CH;

In 20 ml of anhydrous ethanol, 750 mg of N-cinnamoyl-4- (pmenthan-8-yloxy) aniline, obtained according to Example 21, dissolved. After adding 350 mg of 10% palladium-on-carbon, the mixture became Shaken in a hydrogen atmosphere until the theoretically calculated amount of hydrogen has been absorbed. After filtering off the palladium carbon, the solvent was distilled off under reduced pressure. The residue obtained was recrystallized from 85% ethanol. 0.7 g of white crystalline 4- (p-menthan-8-yloxy) -N- (3-phenylpropionyl) aniline were obtained obtain.

909828/0662

Melting point: 96 - 97 "C _? : %) NOO Elemental analysis for C ₂₁ -H- ^ NO, H( 76 3.69 0 (30 8th, 91 3.68 Calculated: 79.11 8th, Found: 78.99 71 example

NHCH.

A solution of 3.2 g of N-ethoxycarbonyl-4- (p ~ menthan-8-yloxy) aniline in 60 ml of anhydrous tetrahydrofuran was added dropwise to a suspension of 0.5 g of lithium aluminum hydride in 6 ml of anhydrous tetrahydrofuran with stirring over the course of added about 2 hours. The mixture was then refluxed for 5 hours. After cooling the reaction mixture with ice, 0.6 ml of water, 1 ml of 15.6% aqueous sodium hydroxide solution, and then 2 ml of water were sequentially added to the mixture in small portions. After the insoluble matter had been filtered off, the solvent was distilled off under reduced pressure, and the residue was extracted with ether. The extract was washed with water and dried over anhydrous magnesium sulfate. Then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, the produced product was eluted with benzene saturated with ammonia. The solvent of the eluate was distilled off under reduced pressure. The oily residue obtained was distilled under reduced pressure. 1.22 g of 4- (p-menthan-8-yloxy) -N-methylaniline were obtained. Boiling point: 148 - 151 ° C / 0.6 mm Hg
Elemental analysis for Cj7H ₂ ^ NO:

G(%) hOO nOO

Calculated: 78.11 10.41 5.36

Found: 78.08 10.80 5.51

909828/0662

Example 72

_C_ / VN _x

430 mg of N-methyl-4- (p-menthan-S-yloxy) aniline were dissolved in 5 ml of anhydrous tetrahydrofuran. After adding 300 mg of acetic anhydride and 0.8 ml of anhydrous pyridine, the resulting mixture was stirred overnight at room temperature. The reaction mixture was poured into 30 ml of ice water, and the white crystals obtained were recrystallized from 5 ml of petroleum ether. 350 mg of white crystalline 4- (p-menthan-8-yloxy) -N-methylacetanilide were obtained.
Melting point: 70-71 ° C

Elemental analysis for C ₁ qH ₂ qN0 ₂ -c ο
CH ₅ : 63 4.62 COO H( 96 4.41 Calculated: 75.21 9, Found: 75.01 9, CH ₅
-N ^ -CH ₅ example 73 N CH ₅ CH ₅ - / > ■ γ /

1 g of 4- (p-menthan-8-yloxy) -Ν, ΪΤ-dimethylaniline was added to 30 ml of anhydrous ethanol dissolved. The compound was prepared from the hydrochloride obtained in Example 62. To the solution 5 ml of methyl iodide was added and the mixture was over Refluxed overnight. The solvent and excess Methyl iodide was distilled under reduced pressure. The residue formed was extracted with dichloromethane. Of the The extract was washed with water and then with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure. Abundant ether was added to the concentrate. The precipitates formed were separated by filtration and from a

909828/0662

" ^6Ί " 28bA595

Mixture of diehlomethane and ether recrystallized. 0.9 g of white crystalline 4- (p-menthan-8-yloxy) -N, N, N-trimethylanilinium iodide are obtained.
Melting point: 179-180 ° C
Elemental analysis for Cj QK ₇₂ NOJ:

0 (96) H (J6) NW Calculated: 54.68 7.73 3.36 Found: 54.34 7.91 3.25

Example 74

1.4 g of ethyl chlorocarbonate were added dropwise to a solution of 1.6 g of nicotinic acid and 1.31 g of triethylamine in 30 ml of methylene chloride with stirring and cooling. A solution of 2.5 g of cis-4- (p-menthan-8-yloxy) aniline in 20 ml of methylene chloride was added dropwise to the resulting solution for further reaction. After stirring the mixture to carry out the reaction for 30 minutes at the same temperature, the mixture was poured into ice water. The formed organic layer was washed successively with an aqueous 5% sodium carbonate solution and an aqueous saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue formed was subjected to silica gel column chromatography. The produced product was eluted using chloroform. The solvent was distilled off from the eluate. After recrystallization from ethanol, 2.3 g of white crystals of cis-4- (p-menthan-8-yloxy) -N-nicotinoylaniline were obtained. Melting point: 122-123 ° C
Elemental analysis for

Calculated: 74.96 8.01 7.95 Found: 74.53 7.98 7.99

909828/0662

Example 75
Tablets:

One thousand tablets for oral administration, each containing 100 mg of 1- [4- (pillenthan-S-yloxy) phenyl] piperidine are made from made of the following components:

1- | 4- (p-Monthan-8-yloxy) phenyl-piperidine: 100 g

Methylc ellulo se J.P. (Japanese Phannalcopoe): 6.5 g

Lactose: 25 g

Talc: 5 g

Calcium biatearate: 3> 5 g

The 1- [4- (p-methan-8-yloxy) phenylJpiperidine is 7.5% Weight / volume aqueous solution of methyl cellulose granulated by a sieve ITr. 8 driven and carefully dried. The dry granulate is passed through a sieve ITr. 12 sieved, with talc, lactose and calcium stearate mixed and compressed into tablets.

909828/0662

Claims (1)

Patent claims:
1J aminophenyl ether compounds with the formula I. where R ^ is a V / ass off atom or a lower alkyl group; Rp denotes a cyclohexyl group which may be substituted by the lower alkyl group (s), an alkyl group having 1 to 20 carbon atoms, a phenyl group or a Benayl group; R ^ denotes a hydrogen atom, a lower alliyl group or a cyclohexyl group which may be substituted by a lower alkyl groupj Ri denotes a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group; and R, - represents a hydrogen atom, an aryl group, or the group represented by -CORg or -CH ₂ Rg, (wherein Rg is a carbon atom, an amino group, an alkyl group having 1 to 19 carbon atoms, a cyclohexyl group, an alkyl group , represents an aralkyl group, an aralkenyl group, an amino group substituted by lower alkyl group (s), a heterocyclic group which may be substituted by a lower alkyl group or a bridged hydrocarbon group); R ₂ and 11, together with the adjacent carbon atom 909828/0662 Form a cyclohexane ring "which can be substituted by lower alkyl group (s), and R. and R, - together with the adjacent nitrogen atom can form a pyrrolidine ring or a piperidine ring, as well as their pharmacologically acceptable acid addition abav /. quaternary ammonium salts. Compounds according to claim 1, in which R ^ is a lower alkyl group, R _{2 is} a lower alkyl group-substituted cyclohexyl group and R- is a hydrogen atom or a lower alkyl group. 3. Compound according to claim 1: 4- (p-menthan-8-yloxy) aniline. 4. Compound according to claim 1: 1-4- (4-Kenthan-8-yloxy) phenylpipcridine. 5. A compound according to claim 1: cis-1- [4- (p-menthan-8-yloxy) -phenyl ") piperidine or its pharmacologically acceptable salts. 6. Compound according to claim 1: Trans-1- [4- (p-menthan-8-yloxy) -phenyIjpiperidin. 7. Compound according to claim 1: N-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline. 8. A compound according to claim 1: 0is-N-ethoxycarbonyl-4- (p-menthan-8-yloxy) aniline. 9. Compound according to claim 1: Trans-N-ethoxycarbonyl-4- (pmenthan-8-yloxy) aniline. 10. A compound according to claim 1: 4- (p-menthan-8-yloxy) -IT-methylaniline. 11. Compound according to claim 1: N-ethyl-4- (p-menthan-8-yloxy) -aniline. 12. Compound according to claim 1: N-butyl-4- (p-menthan-8-yloxy) aniline. 13 · Compound according to claim 1: N- [4- (p-menthan-8-yloxy) phenyl! - pyrrolidine. 909828/0662 14. Compound according to claim 1: 4- (p-menthan-8-yloxy) -N-methylacetanilide. 15. Compound according to claim 1: 4- (p-menthan-8-yloxy) acetanilide. 16. Compound according to claim 1: N ~ isobutyryl-4- (p "-menthan-8-yloxy) aniline. 17 Compound according to Claim 1: 4- (p-Menthan-8-yloxy) -N- (3-phenylpropionyl) aniline 18. Compound according to claim 1: 4- (p-menthan-8-yloxy) benzanilide. 19. Compound according to claim 1: 4- (p-menthan-8-yloxy) -N, N-dimethylaniline. 20. A method for the preparation of aminophenyl ether compounds according to claim 1, characterized in that an alcohol compound with the formula Γ- R | Ö OH wherein R ^, R. ^ and R, have the meaning already mentioned, and a p-halonitrobenzene with the formula v / orin X represents a halogen atom, in the presence of a strong one Base reacted and then the product is reduced or that the reduction product with a compound (a) selected from compounds with the formula RgCOOH, (in which Rg has the meaning already mentioned) or one of their reactive derivatives, (b) selected from compounds with the formula R ^ -X, (where Rrj represents an alkyl group containing 1 to 20 carbon atoms), an aryl group, an aralkyl group or a never- 909828/0662
ORIGINAL INSPECTED -4- 23 ^r - dore Alko ^ cnrbonylsruppe and X represents an Ilalogenatom, and (c) selected from compounds with the formula X-Rg-X, (in which R _{8 represents} the grouping - (CH ₂ ) ^ - or - (CH ₂ J ₅ - and X has the same meaning as above) is reacted and, if appropriate, the obtained compound of general formula I is converted into its non-toxic acid addition salt with a pharmaceutically suitable acid or into the quaternary ammonium salt with an alkyl halide. 21 · Process for the preparation of a compound having the formula wherein R ₁ , R ₂ and R _{5 have} the meaning already mentioned, according to claim 20, characterized in that an alcohol compound with the formula R ₂ - C - OH, J. wherein R ₁ , R ₂ and R _{5 have} the meaning already mentioned, with p-halo-nitrobenzene with the formula HO wherein X is a halogen atom, reacted in the presence of a strong base and then the product is reduced. 22. Procedure cure Preparation of a compound with the formula I ¹ Rs C 0- _7 NHCO-R ₆ 909828/0662 ÖÄiGJNÄt iNSPECTED Β υ 4 5 9 p wherein R ^, R ₂ , R * and Rg have the meaning already mentioned, according to claim 20, characterized in that a compound with the formula wherein R ^, R ₂ and R _{7 have} the meaning already mentioned, with a compound of the formula R ₆ - COOH, wherein Rg has the same meaning as above, or theirs reactive derivative is implemented. 25. Process for the preparation of a compound having the formula wherein R ^, R ₂ and R-, which have the meaning already mentioned, and Ry is an alkyl group having 1 to 20 carbon atoms, an aryl group, an aralkylgimppe or a lower alkoxy carbonyl group
or a compound with the formula R, wherein R7 'is a lower alkyl group and R ₁ , R ₂ and R ~ have the meaning already mentioned, according to claim 20, characterized in that a compound with the formula R.i 909828/0662 wherein R ^, R ₂ and R ^ have the same meaning as above with a compound having the formula R ₇ - is reacted, wherein X represents a halogen atom, and has the meaning already mentioned. 24. Process for the preparation of a compound of the formula wherein RJ, R ₂ and R ^ have the meaning already mentioned, according to claim 20, characterized in that a compound with the formula C 0- wherein R .., R ₂ and R, have the meaning already mentioned, with a compound of the formula XR ₈ -X wherein X represents a halogen atom and R _{Q has} the meaning already mentioned, is implemented. 25. Process for the preparation of a compound having the formula NHCH ₂ -Rg wherein R. |, R ₂ , R * and Rg have the meaning already mentioned, according to claim 20, characterized in that a compound of the formula 909828/0662 where RJ, R «, R * and Rg have the meaning already mentioned, is reduced. 26. Use of the compounds according to the invention according to claim as therapeutically active ingredients for the production of pharmaceuticals for humans and animals. 909828/0662