FI77647B - FOERFARANDE FOER TILLVERKNING AV TERAPEUTISKT ANVAENDBARA FENETYLAMINDERIVAT. - Google Patents

Description

! 77647

A process for the preparation of therapeutically useful phenethylamine derivatives

The invention relates to the preparation of substituted phenethylamine derivatives which are central nervous system depressants.

From Mutak et al., Acta Pharm. Jugosl. 31 (1981) 17-26 2-aryl-2-cyclohexenyl-ethylamines and 2-aryl-2-cyclohexylethylamines are known.

These known compounds lack the group -OR 2, which is essential for the anti-depressant activity of the compounds of the invention. These known compounds are analgesic agents and not antidepressant compounds such as the compounds of the invention.

15 From Mutak et al., Acta Pharm. Jugosl. 31 (1981) 143-150 discloses cycloalkenylbutylamines which have also been reported to be analgesically active.

DE 1 124 485 discloses compounds of the formula: wherein and R 2 represent hydrogen, hydroxy, methylmethoxy or methylenedioxy; X forms a cycloalkane ring having 3 to 6 carbon atoms with a methylene group and a central carbon atom; R 1 is hydrogen or lower alkyl; and R 1 and R 5 represent hydrogen, saturated or unsaturated alkyl or cycloalkyl or together with the nitrogen atom form a heterocycle.

The structure of the compounds known from said DE differs from the compounds according to the invention in that the cycloalkyl moiety containing the group X has no acid-containing substituent and this cycloalkyl moiety is not a 2,77647 ethane substituent. In addition, these compounds are CNS stimulants, which is completely different from the antidepressant activity of the compounds of the invention.

FI patent publication 52 973 describes alkali-substituted tertiary butanols which have been reported to have, for example, a sedative, antiemetic and antiulcer effect. The therapeutic effect of these compounds thus differs from the antidepressant effect of the compounds of the invention.

The invention relates to a process for the preparation of therapeutically useful phenethylamine derivatives of the formula (I) and their pharmaceutically acceptable salts. wherein the dotted line represents an optional bond,: R 1 is hydrogen or alkyl of 1 to 6 carbon atoms; R 2 is alkyl of 1 to 6 carbon atoms; R 4 is hydrogen or alkanoyl having 2 to 6 carbon atoms; * R 5 is hydrogen, hydroxyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, trifluoromethyl, amino or nitro; R 6 is hydrogen, alkoxy of 1 to 6 carbon atoms, or a halo gene; R 7 is hydrogen or alkyl of 1 to 6 carbon atoms; and n is one of the integers 0, 1, 2, 3 or 4, R 1 is hydrogen or alkyl of 1 to 3 carbon atoms; or a pharmaceutically acceptable salt thereof.

Most preferred compounds are those wherein R5 and R8 are in the meta or para position and n is 2.

Il 3 77647

Compounds in which R 4 is alkanoyl having 2 to 6 carbon atoms are not as effective in the experimental methods used herein as the corresponding derivatives having a free hydroxy group. However, in the context of long-term treatment, acyl-5-oxy derivatives act as drug precursors when the acyl group is removed in vivo, either in the stomach by acid hydrolysis or enzymatically.

Pharmaceutically acceptable acid addition salts of the basic compounds of this invention are conveniently formed by reacting the free base with an equivalent amount of any acid to form a non-toxic salt. Illustrative examples of acids are either inorganic or organic acids, hydrochloric acid, hydrobromic acid, fumaric acid, maleic acid, succinic acid, sulfuric acid, phosphoric acid, tartaric acid, acetic acid, citric acid, oxalic acid and the like. For parenteral administration, water-soluble salts are preferred, although the free base of pharmaceutically acceptable salts is also suitable for oral or parenteral administration of the compounds. The halogen substituent represented by R 1 or R 2 is intended to include chlorine, bromine, iodine or fluorine substituents.

Compounds of formula (I) are prepared by a) reduction of an amide of formula “-Λ.

R6 (CH2'n where R1, R2, Ry and n are as defined above, the dotted line represents an unsaturated bond, R5 and R1 ·: * ·; 35 are as defined above and, when amino or hydroxyl, is N-protected amino or O-protected hydroxy, provided that said reduction is carried out selectively with aluminum hydride with a dotted line indicating an unsaturated ring bond, or 5 b) reduction of a nitrile of formula

CN

I ° H

Wherein R 5, R 9, R 7, n and the dotted line are as defined in a) above, for the preparation of a primary amine, followed by N-mono- or di-alkylation followed by deprotection when it is N- or O-protected and then, if desired, the product obtained by methods a or b is acylated with an active derivative of an alkanoic acid having 2 to 6 carbon atoms to give a compound of formula (I) wherein R 4 is alkanoyl or an Rg group ol-20. The amino is diazotized by treatment with nitrite or nitrile to give a compound of formula (I) wherein R 1 is nitro, or the resulting racemic compound of formula (I) is resolved into its optically active isomers by conventional methods.

The starting nitrile is prepared by reacting a cycloalkanone or cycloalkenone with an appropriately substituted (ortho or para) phenylacetonitrile anion according to the method of Sauvatre et al., Tetrahedron 34, 2135 (1978), followed by reduction of the nitrile (kata). hydrogenation, borane reducing agents, LiAlH 2, etc.) to the primary amine and alkylation of the amine to give a compound of formula (I). In the presence of a cycloaliphatic unsaturated bond, lithium aluminum hydride is the primary reducing agent. Subsequent oC-cycloaliphatic hydroxyl group and any hydroxyl group present; acylation of the wart group can be performed in the usual manner

II

s 77647 with alkanoic acid halide or anhydride. Symmetrical N-methylation can be performed by the modified Eschweiler-Clarke method using the largest excess of water, as reported by Tilford et al., J.A.C.S. 76, 5,2431 (1954); alternatively, the method of Borch and Hassid, J. Org. Chem., 37, 1653 (1972) using sodium cyanoborohydride and formaldehyde. Asymmetric N-alkylation or monoalkylation can be performed by stepwise alkylation of N-trifluoroacetate as described in R.A.W. Johnstone et al., J. Chem. Soc., (C) 2223 (1969).

Symmetrical Ν, Ν-dimethylation can be easily performed by reacting a primary amino derivative with formaldehyde and formic acid in a large excess of water. During the reaction, an intermediate, 3-at-sa-1-oxaspiro / 3 # 77undecane, is formed which can be isolated.

It is represented by the following structural formula: 20 R.

i1 r6 wherein the dotted line represents an optional unsaturated bond, R1 is methyl; and the other substituents have the same meaning as above.

. . These oxaspiro ε 5.7 / undecane intermediates have a similar effect to the corresponding open-ring tertiary amino-terminal compounds of formula (I). For example, the properties of the oxazine prepared in Example 3 are compared below to those of the corresponding dimethylamino final compound of Example 3. The final compound is prepared from the corresponding oxazine by boiling for a long time in the presence of aqueous formic acid.

6 77647

An alternative and preferred way to prepare compounds of formula (I) involves the reaction of a cycloalkanone or cycloalkenone with an appropriately substituted phenylacetamide anion following the method of Sauvetre et al., Same publication (preparation of the starting material), followed by reduction of the amide with lithium aluminum with a boron hydride reducing agent, except in the case of cycloaliphatic unsaturation mentioned above, to the corresponding amine. This method is preferred because it is considerably easier in the case of meta-substituted or halogen-substituted phenylacetamide reagents, which cause considerable problems in the preparation via the acetonitrile intermediate. This pathway to the desired end products also allows for easy conversion of R 1 sn and R 2 in the original reagent.

Amino substituents given by R 1. and / or Rg represent, are protected throughout the reaction sequence with a protecting group such as 1,1,4,4-tetramethyl-1,4-dichlorosilylethylene-20, which completely protects the amino nitrogen atom from undesired reactions. At the end of the reaction sequence, the amino group is deprotected and alkylation is carried out in the usual manner to obtain a mono- or di-alkylamine group having 1 to 6 carbon atoms in each case. Nitro-· '; The support represented by R 1 and / or R 8 is attached as an aromatic substituent by diazotization of the aromatic amine, followed by treatment with alkali metal nitrite in the presence of copper or formation of diazonium tetrafluoroborate and reaction with alkali metal nitrite, i.e.:

II

R 77 with acetic anion, salt, ester, aldehyde or alcohol vpnr - *

I OH

: “^ ^ 6 77647 s where Β denotes a carboxyl group or a salt or ester thereof or a CHO or reactive C ^ OH group.

The carboxylic acid group can be converted to an acid halide, active ester or anhydride and then reacted directly with the desired amine to give, after reduction of the amide formed, the final products of the invention. The carboxylic acid group can also be reduced with diisobutylaluminum hydride or lithium aluminum hydride to give the corresponding aldehyde.

10 The ester is easily converted to an aldehyde with diisobutylaluminum hydride or an alcohol with lithium aluminum hydride.

The aldehyde can be condensed with hydroxylamine to give the oxime -CH = NOH; with ammonium or a peripheral amine to give the imine -CH = NR 2, or the primary

With a trivalent or secondary amine to form OH

group, Alcohol -CH5OH can be converted to -CH-NR-j ^.

to the corresponding nitro derivative by preparation of the corresponding organic sulfonate (mesyl ester) or halide, followed by a substitution reaction with an inorganic nitrile. Reduction of these intermediates gives primary amine intermediates or secondary or tertiary amine end products. The alcohols can be converted to mesylates or tosylates, which are reacted with KCN to give the nitrile, converted to the amide, and then subjected to a Hoffman reaction reaction with bromine or chlorine and alkali metal hydroxide.

Other ways to obtain the desired products are the reaction of ammonia or HNR 2 R 2 with the compound

Z

ch9 I OR

I: 35 (5- (ΤμΓΊ) R6 9 77647, wherein Z is a leaving group such as halogen or an organic sulfonyloxy group (mesyl, tosyl and an age-like group) under conventional conditions. If desired, the amine reagent may be initially protected with a relatively labile acyl group such as trifluoroacetyl to give the reagent of formula 2 hnr1ccf3 prior to reaction with the alkylation reagent using KOH and a highly polar solvent such as dimethyl sulfoxide to give a tertiary amide. can be easily removed to prepare a compound for asymmetric N-alkylation to attach I 1. Instead of N-alkylation, the secondary amine may preferably be acylated or reacted with an aldehyde, followed by reduction of the amide or Schiff's base. Similarly, reaction of the amine with an alkyl chloroformate gives, after reduction, the N-methylated amine.

LiAlH 2 is a reducing agent well suited for these methods. Also by performing aldehyde 20

CHO

:: Reduction amination with ammonia, primary amine or secondary amine (Leuckart reaction) gives the desired end products.

During the synthesis of the compounds of formula (I), the hydroxy group represented by -OR 4 or R 4 may be in free form or in the form of hydroxy protected by a leaving group, except, of course, that the hydroxy group is not protected. in any case where it is intended to participate in the 10,77647 reaction. The protected form is preferred in the event that the hydroxy group may otherwise participate in an undesired reaction. Examples of hydroxy protecting groups are given in Protective Groups in Organic Chemistry, edited by J.F.W. McOmie, in Chapters 3 and 4 (pp. 95-182), published by Plenum Press (1973), and in Protective Groups in Organic Chemistry, T.W. Greene, in paragraphs 2 and 3 (pages 10-113), published by John Wiley and Sons (1981). The protecting group may be removed at a suitable later stage in the synthesis. Similarly, each amino or alkylamino group may be in protected form where it is preferred during the synthesis of the final compounds. The protecting groups for amino groups are described in Chapter 2 of McOmie's book (pages 43-94) and in Greene's book 15 in Chapter 7 (pages 218-286).

The final products have one or two asymmetric centers, depending on the saturation and unsaturation state of the cycloaliphatic ring, respectively. Individual stereoisomeric forms may be obtained or separated by conventional methods. For example, separation of the mixture in the case of an amine or carboxylic acid can be accomplished by neutralization with a suitable optically active compound to form salts that can be separated. Example 32 illustrates a typical separation of the product of Example 3, compound A.

The antidepressant activity of the compounds of formula (I) was demonstrated by showing that they (1) prevent the binding of H-imipramine to brain tissue in the experimental method described by Raisman et al., Eur. J. Pharmacol.

30 61, 373-380 (1980); (2) inhibit the synaptosomal absorption of norepinifrine (^ H-NE) 14 and serotonun (C-5-HT) using the experimental method of Wood et al., J. Neurochem.

37, 795-797 (1981); and have an antagonistic effect on reserpine-induced hypothermia when testing 35 compounds according to the method of Askew1, Life Sci. 1, 725-730 (1963).

Il n 77647 The results of these methods confirmed the antidepressant activity of the compounds of formula (I) to be in agreement with the most generally accepted theory of the antidepressant activity and the correlation of activity-5 with known tricyclic antidepressants. Namely, in at least two cases, in connection with the dimethylamino product of Example 3 and the 4-chlorine product of Example 1Q, the undesirable property of classical antidepressants is perceived as a peristaltic inhibitory property reflected by the muscarinic receptor ligand, 3H-quinuclidinyl suppression, and karbako-glycol-stimulated guinea pig ileum contraction suppression, does not occur. Also, there is no depression of the classic feature 15 medicines which can be seen as contrary to a feature of histamine, which is reflected in the histamine H ^ receptor lingandin, 3H-pyrilamine for the prevention, and histamine-stimulated contraction of the guinea pig ileum being prevented.

As typical examples of the activity profile of the compounds of formula (I), the following values are given for the dimethylamino product of Example 3, hereinafter referred to as Compound A, its oxazine variant, part of the compound hereinafter referred to as Compound B, the 4-chloro product of Example 10, hereinafter Compound C for the title compound, the 4-bromo product of Example 14, hereinafter referred to as Compound D, the 3-chloro product of Example 16, hereinafter the compound designated E, the 3-bromo product of Example 15, the compound designated hereinafter F and the 3,4-dichloro product of Example 18, hereinafter referred to as G: 3. . ...

Inhibition of H-imipramime binding: Compound A

The? 3 (HCl salt) contraceptive constant (K 2) against H-imipramine was 90 nm, making it a fairly potent ligand for this receptor. Compound B was somewhat more potent at K. 77 nm. Compound C was seemingly as effective as Compound A, with K 2 against H-imipramine at 100 nm. Although these were not as effective as imipramine (λ = 1.7 nm), these values are in the range of desmethyl imipramine (DMI) (Ki = 130 nm) and other tricyclic antidepressants. The K i values of the non-typical antidepressants tested (non-tricyclic) in this experiment are greater than 5000 nm. Compounds D, E, F and G eh-10 had fermentation constants of 62, 130, 52 and 37, respectively. Compounds A-G, compounds representing other compounds of this invention, are thus comparable in this experiment to known tricyclic antidepressants.

Inhibition of absorption of synaptosomal NE and 5-HT; The results of inhibition of the synaptosomal absorption of NE and 5-HT, expressed as the inhibitory concentration at which the rate of absorption was reduced to 50% (IC 50), are shown in the table below, comparing them with imi-20 pramin, DMI and amitriptyline: IC50 (».M)

Compound NE 5-HT

25 Imipramine 0.26 0.12 DMI 0.15 3r 0

Amitriptyline 0.50 0.60

Compound A 0.64 0.21

Compound B 4.7 2.9

Compound C 0.33 0.25

Compound D 0.21 0.11

Compound E 0.16 0.32: 35 '' - Compound F 0.11 0.23

Compound G 0.07 0.08

II

13 77647 These results indicate that compounds A and C-G are approximately as effective as impramine in inhibiting NE-5-HT association. Again, compound B is somewhat less effective.

Inhibition of 5 H-QNB binding; In the QNB receptor binding assay, compounds A and CG had an IC 50 of greater than 10 molar and were therefore substantially inactive (the Ki values of imipramine and DMI were 37 nm and 50 nm, respectively. These results suggest that unlike tricyclic antidepressants, compounds A and CG would have no inhibitory effects on muscarinic peristalsis at all.

carbachol-stimulated guinea pig ileum contraction inhibition imipramine After 15 l, um concentration of K is

/ B

about 100 nm carbachol-stimulated guinea pig ileum contraction in, Compound A was inactive at a concentration of lyum. This result supports the suggestion that Compound A lacks the effect of inhibiting muscarinic peristalsis.

3 Inhibition of H-pyrilamine binding: When DMI against 124 N-pyrilamine binding is 124 nm, Compound A was inactive. Compounds D-G had an IC 50 of greater than 10 μmolar. These results suggest that, unlike tricyclic antidepressants, compounds A and D-G have no anti-histamine property at all.

Histamine-stimulated guinea pig ileum contraction inhibition:

Imipramine prevents the concentration of l ^ um-30 Nin histamine-stimulated contraction of the guinea pig ileum Κβ: η of about 8 nm. Compound A, in contrast, has no effect in this experiment at a concentration of 1 μm.

This result supports the notion that Compound A has no anti-histamine activity at all.

14 77647

Effect against reserpine-induced hypothermia:

The lowest effective doses (M.E.D.) of Compounds A-G that were shown to have an anti-reserpine anti-heat effect in mice (n = 8 groups) compared to desmethylimipramine (DMI) were:

Compound Dose, mg / kg, i.p.

DMI 0.4 A 10.0 (and p.o.) 10 B 30.0 C 10.0 D 3.0 E 1.0 F 1.0 15 G 3.0

All mice received 5 mg / kg reserpine subcutaneously 18 hours before test compound administration. DMI and compounds A-G are approximately equally effective in restoring reserpii-20-induced hypothermia. In this experiment, Compound B was less effective than Compound A, Compound C was approximately as effective as Compound A, Compounds D and G were approximately three times as effective as Compound A, and Compounds E and F were approximately ten times more potent than Compound A. .

Y; The following table provides additional information on the specific antidepressant activity of the compounds of the present invention.

.... 30 / N (CH3> 2

OH

· ;: R * “jpM3

Re

II

15 77647

Table

Eg Compound Ki vs IC50 vs IC50 vs

Well. Rg Rg Imipramine norepinephrine 5-HT

5 5 HH 300 19 2.9 3A 4-MeO H 90 0.64 0.21 19 3-Cl 4-Cl 37 0.07 0.08 15 3-Br H 52 0.11 0.23 20 3-MeO H 150 0.62 0.19 10 35 3-Br 4 -Me 190 0.14 0.20 24 4-Me H 205 0.53 1.34 23 3 “CF3 h 360 ° ’36 2.2 10 4- C1 H 100 0.33 0.25 14 4-Br H 62 0.21 0.11 15 16 3-Cl H 130 0.16 0.32 25 4-OH H 60 1.16 0.34 22 4-CF3 Thus, the final compounds of this invention are useful in the treatment of a depressive disorder, for which purpose they may be administered orally or parenterally in amounts sufficient to alleviate the symptoms of depression. The actual amount of antidepressant used will vary depending on the severity and nature of the depressive disorder, the subject being treated, and the desired effect. In humans, an oral dose of about 2 to about 50 milligrams represents a suitable dosage. At an intramuscular dose of about 1 to about 25 milli-. . 30 grams, a dose comparable to the oral dose of 7764 7 is obtained. As with other antidepressants, treatment should be initiated at lower doses and increased until the desired symptomatic relief is obtained.

The following examples illustrate the preparation technique used in the preparation of the compounds of the invention.

Example 1 1- [4-Cyano (p-methoxyphenyl) methyl] cyclohexanol 10 p-Methoxyphenylacetonitrile (50 g, 0.3 mol) was added to dry tetrahydrofuran (250 ml) and the solution was cooled to -70 ° C under nitrogen. With stirring, n-butyllithium in hexane (210 mL, 0.3 mol) was added dropwise. The temperature was kept below -50 ° C and a yellow precipitate formed. After the addition was complete, the reaction mixture was kept below -50 ° C for 30 minutes and cyclohexanone (35 mL, 0.3 mol) was added. After the temperature was still below -50 ° C for 45 minutes, it was allowed to rise to 0 ° C and saturated ammonium-20 chloride solution was added. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated to dryness. The product crystallized (25.2 g mp 125-127 ° C).

Mass spectral analysis: molecular weight 245 (Tm + 1), C.I.M.Si? NMR analysis: δ 7.32, 6.95; (4H quartet, p-substituted aromatic) 3.8 (3H singlet, O-CH 2); 3.76 (1H, Singlet-ti, CH-CN); 1.56 (10H, multiplet, aliphatic cyclo... Hexyl) ppm.

;; Example 2 1- {2-Amino-1- (p-methoxyphenyl) ethyl] cyclohexanol • 1-Cyano (p-methoxyphenyl) methyl / cyclohexanol (12 g, 0.05 mol) was dissolved by heating in an ammonia-35 ethanol mixture (20 vol). .-%, 250 ml) and hydrogenated on a Parr apparatus with 5% rhodium alumina (2.8 g). The catalyst was filtered off, washed well with ethanol and the combined filtrate was evaporated to dryness and

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17,77647 was dried in vacuo to give an oil (12 g). Mass spectral analysis: molecular weight 249 (M + 1) +, C.I.M.S. TLC: single spot, ninhydrin-positive • chloroform-methanol-acetic acid (80:10; 10, ti 1. ratio.) _ 7.

Example 3 5- (4-Methoxyphenyl) -3-methyl-3-aza-1-oxaspiro (5.5) undecane and 1- (2-dimethylamino) -1- (4-methoxyphenyl) ethylcyclohexanol 1- N-2-amino-1- (p-methoxyphenyl) ethyl / cyclohexano-10 (12 g: 0.048 mol) was treated with a mixture of formaldehyde (11 ml), formic acid (14.5 ml 88%) and water (125 ml). ml) and heated at 100 ° C for five hours. The reaction mixture was cooled and extracted with ethyl acetate. This extract was discarded. The aqueous residue was cooled on ice, basified by the addition of solid potassium hydroxide, saturated with sodium chloride and extracted three times with ethyl acetate. The extract was washed with brine, dried over anhydrous potassium carbonate and evaporated to an oily residue (8 g). This mixture of products was chromatographed on 1 kg of Mallinckrodt

Silicar CC7 silica gel and the progress of the chromatography was monitored by thin layer chromatography using a mixture of ethanol: 2-norm. ammonia ethyl acetate: cyclohexane was 45: 8: 100: 100 (v / v).

Fractions containing the desired products were combined and prepared using the 4-norm hydrochloride salts.

HCl isopropanol solution. The yields of the free bases were 1.4 g (spiro compound) and 4.6 g (dimethylamine), respectively.

30 Compound B

5- (4-Methoxyphenyl) -3-methyl-3-aza-1-oxaspiro (5.5) undecane_

Melting point; 242-244 ° C.

1 - X

Mass spectral analysis: molecular weight 275 (M + 1), C.I.M.S.

[35 NMR analysis: δ 7.22 6.96 (4H quartet, p-substituted aromatic) 4.78 (2H quartet, O-CH2-NCH3) 3.8 (4H1: O-CH3, CH-CH2- NCH 3) 3.3 (2H, multiplet CH-CH 2 -NCH 3) 2.8 - f (3H, NCH 3) 0.9-1.8 (10H, broad multiplet, aliphatic cyclohexyl) ppm.

77647 BC

Compound A

1- (T2-dimethylamino) -1- (4-methoxyphenyl) ethyl / cyclohexanol

Hydrochlorides: m.p. 215-217 ° C.

Mass spectral analysis: molecular weight 279 (M + 1) +, C.I.M.S. (free base).

NMR analysis: δ 7.32, 6.98 (4H quartet, p-substituted aromatic) 3.78 (3H, O-CH 3) 3.64 (2H, multiplet CH 2 N (CH 3) 2) 3.06 (1H, multiplet CH-CH 2 (NCH 3) 2) 2.74 10 (6H, N (CH 3) 2) 1.38 (10H, broad multiplet, aliphatic cyclohexyl) ppm.

Example 4 1 - [(α-Aminomethyl) benzyl] -cyclohexanol

Phenylacetonitrile (10 g, 0.08 mol) was added to dry THF (100 mL) and the solution was cooled to -70 ° C under nitrogen. N-Butyllithium in hexane (64 mL, 0.1 mol) was added dropwise keeping the temperature below -40 ° C and a yellow precipitate appeared.

After the addition, the reaction mixture was maintained at about 20-70 ° C for 30 minutes and cyclohexanone (10 g, 0.1 mol) was added. After a further 45 minutes at -70 ° C, the temperature was allowed to rise to 0 ° C and saturated ammonium chloride solution was added. The layers were separated and the ee-success layer was extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated to dryness. The product, 1- [α] cyano-: benzyl-7-cyclohexanol, crystallized (4.93 g, mp 100-102 ° C).

Mass spectral analysis: molecular weight 215 (M +).

NMR analysis: 67.4 (5H, singlet) aromatic 3.8 (1H, 30 singlet, CH-CN) 1.6 (10H, multiplet aliphatic cyclohexyl) ppm.

A solution of 1- (α-cyanobenzyl) cyclohexanol (3.43 g, 0.02 mol) in a mixture of methanol and ammonia (9: 1, 60 ml by volume) was hydrogenated on a Parr apparatus. with alumina containing 2% rhodium (2 g). The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate, washed with brine, dried over magnesium sulfate and evaporated.

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19,77647 was dried. Hydrochlorides, m.p. 220-222 ° (1.2 g), crystallized from diethyl ether-acetone.

Analysis for C 18 H 19 N 2 O 2 • HCl: Calculated: C, 64.29; H, 8.67; N, 5.47%; Found: C, 65.74; H, 8.51; N, 5.56%.

NMR analysis (DMSO): δ 7.73 (5H singlet, aromatic) 3.46 (2H, multiplet Cl 2 -Ni 2), 3.0 (1H multiplet CH-CH 2 NH 2) 0.9-1.7 ( 10H, multiplet aliphatic cyclohexyl) ppm.

10 Mass spectral analysis by chemical ionization: 220 (M + M) + (mol. Weight 219) (free base).

Example 5 1- (α- [7-Dimethylamino) methyl] benzyl) cyclohexanol 1 (aminomethyl) benzyl cyclohexane I5 (1.38 g, 0.006 mol) was dissolved in a mixture of formaldehyde (2 ml), formic acid (2.6 ml) ) and water (25 ml), and boiled at 95 ° C for 18 hours. The reaction mixture was cooled, basified with solid KOH and extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate and evaporated to dryness. The hydrochloride (m.p. 225-227 ° C) was prepared using 3-norm. HCl isopropanol solution. Yield 589 mg.

Analysis for C 18 H 18 N 2 O 2 HCl: 25 Calculated: C, 67.36; H, 9.12; N, 4.88%; Found: C, 67.7; H, 9.23; N, 4.93%.

Mass spectral analysis: molecular weight 247 (M, free base). NMR analysis: (DMSO) δ 7.4 (5H, singlet, aromatic), 3.68 (2H, multiplet CH 2 -N (CH 3) 2, 3.18 (1H, multiplet CH-CH 2 N- (CH 3)) 2.68 (6H, .N (CH3) 2; 0.9-1.7 (10H multiplet aliphatic cyclohexyl) ppm).

20 77647

Example 6 1- (1- (7-Methylamino) methyl) benzyl) cyclohexanol 1- [E- (Aminomethyl) benzyl] cyclohexanol (1.59 g, 0.007 mol) was dissolved in diethyl ether 5 (10 ml) and cooled to 5 ° C. . Trifluoroacetic anhydride (2 g) was added and the mixture was stirred at 0 ° C for 30 minutes. The mixture was neutralized using saturated sodium hydrogen carbonate solution and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to dryness to give crystalline trifluoroacetamide, m.p. 78-80 ° C (975 mg). Trifluoroacetamide (975 mg) was dissolved in dry acetone (20 ml) and treated with methyl iodide (2 g). The solution was heated to reflux and powdered potassium hydroxide (1 g) was added, followed by excess methyl iodide. The mixture was boiled for five minutes, then cooled and the acetone evaporated. Water (20 ml) was added and the mixture was boiled for 15 minutes. It was cooled and extracted with ethyl acetate.

The extract was washed with water and brine, dried over magnesium sulfate and evaporated to a crystalline product, m.p. 92-94 ° C. This was converted to the hydrochloride using 3-norm. HCl isopropanol solution. Yield 235 mg, m.p. 208-210 ° C.

NMR analysis (CHCl 3), β7.3 (7H, aromatic, HCl and NH * CH 3); 3.9 (1H, multiplet CH-CH 2 NH 2), · 3.25 (2H, multiplet CH 2 -NH 2); 2.6 (3H singlet NH-CH3); 0.8-1.9 (10H multiplet, aliphatic cyclohexyl) ppm. Mass spectral analysis: molecular weight by chemical ionization.

M.S. 233 (M + 1 at 234, free base).

Il 21 77647

Example 7 1- (α- (7'-Dimethylamino) methyl) benzyl) cyclohexanol acetate [1- (α / 7 (dimethylamino) methyl] benzyl) cyclohexanol (0.5 g, 0.0025 mol) was treated with acetic anhydride (1 ml) and pyridine. (3 ml) and the mixture was at room temperature overnight The reaction mixture was poured into water, basified with solid KOH and extracted with ethyl acetate, the extract was washed with water and brine, dried over magnesium sulphate and evaporated to an oil. after azeotropic distillation, the oil was treated with 3N HCl in isopropanol and the title compound was obtained as crystalline hydrochloride (70 mg), mp 163-165 ° C.

NMR analysis: (CHCl 3) δ 7.35 85H singlet, aromatic); 4.2 (1H, multiplet CHCH2N (CH3) 2; 3.6 (2H multiplet CH2-N (CH3) 2); 2.65 (6H, singlet, N (CH3) 2); 2.1 (3H singlet, -O-C-CH 3): 0.9-1.7 (10H multiplet, aliphatic cyclohexyl) ppm.

Mass spectral analysis: molecular weight 289 (M +, free base). Example 8 1- [Cyano (4-chlorophenyl) methyl] cyclohexanol

Replacing p-methoxyphenylacetonitrile in Example 1 with 1 molar equivalent of p-chlorophenylacetonitrile gave 1-cyano (p-chlorophenyl) methylcyclohexanol (13.7 g), m.p. 115-117 °.

Mass spectral analysis: molecular weight 249 (M + 1) +, C.I.M.S. Example 9 1- [2-Amino-1- (4-chlorophenyl) ethyl] cyclohexanol

Lithium aluminum hydride (3.5 g) was suspended in ice-cold tetrahydrofuran (125 ml) and concentrated sulfuric acid (2.5 ml) was carefully added with stirring.

After 1 h, 1-cyano (p-chlorophenyl) methyl] -35 cyclohexanol (15 g, 0.06 mol) was dissolved in tetrahydrofuran (100 mL) and added dropwise dropwise with vigorous stirring and cooling. tetrahydrofuran-water (1: 1, 30 mL) followed by 10% sodium hydroxide solution (50 mL). Tetrahydrofuran decan-5 was removed and the residue was washed well with diethyl ether and ethyl acetate. The combined organic solution was dried over anhydrous potassium carbonate and evaporated to an oil (12 g).

Mass spectral analysis: molecular weight 253 (M + 1) +, C.I.M.S.

Example 10 1- (1- (4-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol-1- [2-amino-1- (4-chlorophenyl) ethyl] cyclohexanol (12 g, 04 moles) was treated with a mixture of formaldehyde (13.7 ml) formic acid (18.1 ml) and water (160 ml) and boiled at 100 ° C for four hours.The reaction mixture was cooled, extracted well with ethyl acetate and the extract The aqueous residue was cooled in ice and basified by the addition of solid potassium hydroxide, saturated sodium chloride and extracted three times with ethyl acetate, the extract was washed with brine, dried over anhydrous potassium carbonate and evaporated to dryness. normal HCl isopropanol solution, yield 4.7 g, mp 241-243 ° C.

Mass spectral analysis: molecular weight 281 (M + 1), C.I.M.S.

NMR analysis: δ 7.35 (4H singlet, typical for 4-chloro substitution) 3.65 (2H multiplet, CH 2 -CHN (CH 3) 2) / 3.0 (1H multiplet CH 2 CHN (CH 3) 2 1 .4 (10H multiplet, aliphatic cyclohexyl) ppm.

Example II 1- [L- (4-Methoxyphenyl) -2- (methylamino) ethyl] cyclohexanol 33 By replacing 1- [α- (aminomethyl) benzyl] cyclohexanol in Example 6 by an equivalent molar amount of 1- [2-amino-1-

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23,77647 (p-Methoxyphenyl) ethyl] cyclohexanol were obtained 1- [N- (4-methoxyphenyl) -2-methylamino) ethyl] cyclohexanol hydrochloride (m.p. 164-166 ° C).

Mass spectral analysis: molecular weight 263 (M + 1) +, C.I.M.S.

Δ NMR analysis: δ 7.28, 6.92 (4H quartet, p-substituted aromatic) 3.76 (3H singlet, OMe) 3.4 (2H multiplet, CH 2 -CHNCH 3) 2 2.9 (1H multiplet, CH 2 CHN (CH 3) 2) 2.54 (3H, NCH 3) 1.4 (10H broad multiplet, aliphatic β-isohexyl) ppm.

Example 12 4-Bromo-N, N-dimethylbenzene acetamide

Para-bromophenylacetic acid (50 g, 0.233 mol) was dissolved in methylene chloride (500 mL) and treated with oxalyl chloride (23.3 mL, 0.27 mol) and D.M.F. (0.5 mL) at room temperature. The mixture was stirred for four hours until gas evolution ceased. The solvent was evaporated and the residue was dried in vacuo to remove excess oxalyl chloride. The residue was dissolved in methylene chloride (300 mL) and treated with more than 20 g of dimethylamine gas.

The mixture was stirred overnight and the solvent was evaporated. The residue was redissolved in methylene chloride and the solution was washed with saturated sodium hydrogen carbonate solution, 1-norm. hydrochloric acid, water, brine, dried over magnesium sulfate and evaporated to dryness. The skin-colored crystals were filtered with hexane and air-dried.

Yield 51.2 g, m.p. 73-76 ° C.

Analysis for C 18 H 18 NO 2 Br: 30 Calculated: C, 49.59; H, 4.96; N, 5.79; Found: C, 48.98; H, 5.14; N, 5.77.

NMR analysis (CHCl 3): δ7.55 (4H quartet, aromatic) 3.65 (2H singlet) 2.95 (6H singlet, N (CH 3) 2) ppm.

24 77647

Example 13 1- (14-Bromophenyl) (dimethylamino) carbonyl-methyl-cyclohexanol-4-bromo-N, N-dimethylbenzeneacetamide (15 g, 0.06 mol) was added to dry THF (250 ml) and the solution was cooled to -78 °. To C under nitrogen protection. Straight-chain butyllithium in hexane (43.3 mL, 0.06 mol) was added dropwise, keeping the temperature below -70 ° C throughout. An orange precipitate formed.

After the addition was complete, the reaction mixture was maintained at -70 ° C for 20 minutes and cyclohexanone (7.5 mL, 0.07 mol) was added. After a further 50 minutes at -78 ° C, the reaction mixture was poured into stirred saturated ammonium chloride solution. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic solution was washed with brine, dried over magnesium sulfate and evaporated to dryness. The product crystallized and was filtered off with isopropanol (9.8 g mp. 140-144 ° C).

Analysis for C 18 H 22 NCl 2 Br: 20 Calculated: C, 56.47; H, 6.47; N, 4.12; Found: C, 57.22; H, 6.66; N, 4.21.

NMR analysis (CHCl 3) δ 7.35 (4H, aromatic) 3.63 (1H singlet CH-CON 1 CH 2) 2) 2.95 (6H singlet, F- (CH · ^)); 1.45 (10H multiplet, aliphatic cyclohexyl) ppm.

Example 14 1- {1- (4-Bromophenyl) -2- (dimethylamino) ethyl] cyclohexanol

Lithium aluminum hydride (0.7 g) was suspended in dry THF (25 mL), cooled to 0 ° C, and concentrated sulfuric acid (0.5 mL) was carefully added to the in situ prepared aluminum hydride. The mixture was stirred for 1 h at 0 ° C and the amide, 1- (14-bromophenyl) / dimethylaminocarbonyl-methyl-cyclohexanol (4 g, 0.012 mol) was dissolved in THF (35 mL) and added rapidly by dropwise addition. The reaction mixture was stirred at 0 ° C for 1 hour. A mixture of THF and water (1: 1 v / v, 11 25 7 7 6 4 7 6 ml) was added slowly followed by 10% sodium hydroxide (10 ml). The mixture was filtered and the residue was washed well with ethyl acetate. The combined filtrate was dried over anhydrous potassium carbonate and evaporated to an oil (3.5 g) which was converted to the hydrochloride salt using 4-norm.

HCl isopropanol solution.

Analysis for c16H24NOBr. HCl: Calculated: C, 52.97; H, 6.9; N, 3.86; Found: C, 52.71; H, 6.63; N, 3.71.

NMR analysis: (DMSO): δ 7.4 (4H aromatic) 3.55 (2H doublet CH-CH2N (CH3) 2); 3.05 (1H, triplet, CH-CH 2 N (CH 3) 2; 3.05 (1H, triplet, CH-CH 2 N (CH 3) 2); 2.63 (6H singlet, N- (CH 3) 2 1.30 ( 10H multiplet, aliphatic cyclohexyl) ppm.

Example 15 1- [N- (3-Bromophenyl) -2- (dimethylamino) ethyl] cyclohexanol

Substitution of p-bromophenylacetic acid in Example 12 with a molar equivalent of m-bromophenylacetic acid, 20 and following the procedures described in Examples 13 and 14 gave 1- [1- (3-bromophenyl) -2- (dimethylamino) ethyl] cyclohexanol as the hydrochloride, m.p. 198-201 ° C. Analysis for C 1 H 2 NOBr. HCl: Calculated: C, 52.97; H, 6.90; N, 3.86; Found: C, 52.84; H, 6.92; N, 3.99.

Example 16 1- [1- (3-Chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol

Substituting p-bromophenylacetic acid in Example 30 with 12 molar equivalents of m-chlorophenylacetic acid and following the procedures described in Examples 13 and 14 gave 1- [N- (3-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol as the hydrochloride. 214-216 ° C Analysis for C 18 H 18 N 2 O 2 HCl: 35 Calculated: C, 60.38; H, 7.86; N, 4.4; Found: C, 60.07; H, 7.79; N, 3.93.

26 7 7 6 4 7

Example 17 1- [N- (2-Chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol

Replacing p-bromophenylacetic acid in Example 5 with 12 molar equivalents of o-chlorophenylacetic acid, and following the procedures described in Examples 13 and 14, gave 1- [N- (2-chlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol as the hydrochloride.

205-206 ° C.

Analysis for C 1-4 NOCl. HCl: Calculated: C, 60.38; H, 7.86; N, 4.4; Found: C, 60.45; H, 7.71; N, 4.79.

Example 18 i-Zi- (3,4-Dichlorophenyl) -2- (dimethylamino) ethyl] -cyclohexanol

Substitution of p-bromophenylacetic acid in Example 12 with a molar equivalent of 3,4-dichlorophenylacetic acid, and following the procedures described in Examples 13 and 14, gave 1- [N- (3,4-dichlorophenyl) -2-20 (dimethylamino) ethyl] cyclohexanol as hydrochloride. 241-244 ° C.

Analysis for C 18 H 18 N 2 O 2 • HCl: Calcd: C, 54.47; H, 6.81; N, 3.97; Found: C, 54.8; H, 6.83; N, 399.

Example 19 1- [N- (3,4-Dichlorophenyl) -2- (dimethylamino) ethyl] cyclohexanol

The product of the previous example was prepared in a similar manner according to the following procedure: Lithium diisopropylamide was prepared by dissolving diisopropylamine (69 mL) in THF (500 mL), followed by the addition of n-butyllithium (325 mL). After stirring for 10 minutes, the straw-colored liquid was cooled to -78 ° C and a solution of 3,4-dichloro-N, N-dimethylbenzamide 35 (110.9 g, crude) was dissolved in 300 mL of THF and added slowly. A dark red slurry was obtained. The mixture was

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27,77647 was further stirred for 20 minutes and cyclohexanone (55.7 ml) was added. After 60 minutes at -78 ° C, the reaction mixture was poured into saturated ammonium chloride solution. The aqueous layer was extracted with diethyl ether and the combined organic solution was washed with brine, dried over CH 2 Cl 2 and evaporated to dryness. The product, 1 - [- (3,4-dichlorophenyl) (dimethylaminocarbonyl) methyl / cyclohexanol, crystallized and was filtered off. The crystals were washed with isopropanol and petroleum ether and air-dried. Yield 73.6 g, m.p. 118-120 ° C.

To an ice-cold solution of the borane-THF complex (152 mL, 152 mmol) was added a solution of 1 - [(3,4-dichlorophenyl) (dimethylaminocarbonyl) methyl] cyclohexanol (30 g, 90 mmol) in THF. The mixture was boiled for 2 hours and re-cooled in an ice bath. 2-norm was added. HCl (23 mL) and the mixture was boiled for 1.5 h. It was allowed to cool overnight. The reaction mixture was basified to pH 14 with solid potassium hydroxide and the layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to a solid. This was filtered off and washed with diethyl ether and air dried. Yield: 15.4 g; mp. 128-130 ° C.

This product was converted to the hydrochloride, which was identical to the product of Example 18.

Example 20 1- {2- (Dimethylamino) -1- (3-methoxyphenyl) ethyl] cyclohexanol

Replacing p-bromophenylacetic acid in Example 30 with 12 molar equivalents of m-methoxyphenylacetic acid, and following the procedures described in Examples 13 and 14, gave 1- [2- (dimethylamino) -1- (3-methoxyphenyl) ethyl] cyclohexanol as the hydrochloride, m.p. 166-168 ° C. Analysis for C 16 H 25 NO 2 * HCl: 35 Calculated: C, 64.11; H, 8.68; N, 4.67; Found: C, 63.12; H, 8.54; N, 4.46.

28 7 7 6 4 7

Example 21 1- [N- (3,4-Dimethoxyphenyl) -2- (dimethylamino) ethyl] cyclohexanol _______

Replacing p-bromophenylacetic acid in Example 5 with 12 molar equivalents of 3,4-dimethoxyphenylacetic acid and following the procedures described in Examples 13 and 14 gave 1- {1- (3,4-dimethoxyphenyl) -2- (dimethylamino) ethyl] cyclohexanol as the hydrochloride.

Analysis for C 18 H 19 N 2 O 6. HCl: 10 Calculated: C, 62.88; H, 8.74; N, 4.08: Found: C, 62.42; H, 8.56; N, 3.98.

Example 22 1- [2- (Dimethylamino) -1- (4-trifluoromethylphenyl) ethyl] cyclohexanol By replacing p-bromophenylacetic acid in Example 12 with a molar equivalent of p-trifluoromethylphenylacetic acid and following the procedures described in Examples 13 and 14 for 2-, ) -1- (4-trifluoromethylphenyl) ethyl] cyclohexanol hydrochloride, m.p. 238-240 ° C.

Analysis for C 17 H 25 NOF 3 .HCl: Calculated: C, 58.03; H, 7.16, N, 3.98; Found: C, 58.47; H, 7.16; N, 4.07.

Example 23 1- [2- (Dimethylamino) -1- (3-trifluoromethylphenyl) ethyl] cyclohexanol

Substituting p-bromophenylacetic acid in Example 12 with a molar equivalent of m-trifluoromethylphenylacetic acid, and following the procedures described in Examples 13 and 14, 1- [2- (dimethylamino) -1- (3-trifluoromethylphenyl) ethyl] cyclohexanol hydrochloride was prepared. 194-196 ° C.

Analysis for C 27 H 25 NOF 3 * HCl: Calculated: C, 58.03; H, 7.16; N, 3.98; 35 Found: C, 58.31; H, 7.09; N, 4.09.

Il 29 7 7 6 4 7

Example 24 1- / 2- (Dimethylamino) -1- (4-methylphenyl) ethyl] cyclohexanol

By substituting 12 molar equivalents of p-methylphenylacetic acid in Example 5 for p-bromophenylacetic acid, and following the procedures described in Examples 13 and 14, 1- [2- (dimethylamino) -1- (4-methylphenyl) ethyl] -cyclohexanol was prepared as the hydrochloride.

Analysis for C 18 H 18 NO.HCl: 10 Calculated: C, 68.54; H, 9.17; N, 4.70; Found: C, 68.37; H, 9.31; N, 4.83.

Example 25 1- [2- (Dimethylamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol By replacing p-bromophenylacetic acid in Example 12 with a molar equivalent of p-benzyloxyphenylacetic acid, and following the procedures described in Examples 13 and 14, (4-benzyloxyphenyl) -2- (di-methylamino) -etyyli7sykloheksanolia.

Hydrogenolysis of this product to remove the benzyl protecting group from the 4-hydroxyphenyl group was performed by dissolving 1.0 gram of the product in 10 ml of ethanol. One gram of 10% Pd / C was added followed by cyclohexa-1,4-dienone (5 mL). The mixture was stirred for 25 ninety minutes at ambient temperature. The catalyst was removed by filtration and the solvent was removed by evaporation to dryness to give 800 mg of a solid. This solid 4-hydroxyphenyl product was converted to its fumarate salt with acetone-ethanol solution, 30 m.p. 140-142 ° C.

Analysis for C 16 H 25 NO 2 * C 4 H 4 O 4: Calculated: C, 63.30; H, 7.70; N, 3.69; Found: C, 62.18; H, 7.90; N, 3.63.

30 77647

Example 26 1- / 2- (Dimethylamino) -1- (3-hydroxyphenyl) ethyl] cyclohexanol

Replacing p-bromophenylacetic acid in Example 5 with 12 molar equivalents of m-benzyloxyphenylacetic acid, and following the procedures described in Examples 13 and 14, gave 1- [N- (3-benzyloxyphenyl) -2- (dimethylamino) ethyl / cyclohexanol.

This product (2.3 g) was hydrogenolyzed in 200 mL of ethanol using a Paar bomb, 300 mg of 10% Pd / C until hydrogen bonding was complete. The catalyst was removed by filtration and the solvent was evaporated to give a solid which was converted to its hydrochloride salt at 5-norm. with isopropanol solution of hydrogen chloride, 15 m.p. 162-164 ° C.

Analysis for C 16 H 25 NO 2 · HCl: Calculated: C, 64.08; H, 8.74; N, 4.67; Found: C, 62.78; H, 8.55; N, 4.55.

Example 27 1- [1- (4-Bromophenyl) -2- (dimethylamino) ethyl] cyclobutanol

Replacing the cyclohexanone in Example 13 with a molar equivalent of cyclobutanone, and following the procedure described in Example 14, gave 1- [1- (4-bromophenyl) -2- (dimethylamino) ethyl] octobutanol.

It was converted to the hydrochloride salt, m.p. 220-222 C.

Analysis for C 18 H 18 N 2 O 2 NHCl.HCl: Calculated: C, 50.22; H, 6.28; N, 4.19; Found: C, 50.26; H, 6.11; N, 4.13.

Example 28 1- [2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclopentanol

Substituting p-bromophenylacetic acid in Example 12 with a molar equivalent of p-methoxyphenylacetic acid gave 4-methoxy-N, N-dimethylbenzeneacetamide. Thereafter, following the procedure outlined in Example 13, substituting a molar equivalent of cyclohexanone for

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3i 77647 cyclopentanone / gave the corresponding cyclopentanol derivative. This intermediate was converted, following the procedure described in Example 14, to the hydrochloride of the title compound, m.p. 194 ° C.

Analysis for C 18 H 28 NO 2 .HCl: Calculated: C, 64.07; H, 8.76; N, 4.67; Found: C, 64.19; H, 8.72; N, 4.33,

Example 29 1- / 2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] cycloheptanol

Replacing the cyclopentanone in Example 26 with a molar equivalent of cyclopentanone gave the title compound as the hydrochloride, m.p. 175-177 ° C.

Analysis for C 18 H 28 NO 2 .1 / 4 1 H 0:15 Calculated: C, 65.03; H, 9.26; N, 4.21; Found: C, 65.25; H, 9.16; N, 4.29.

Example 30 1- [2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] -cyclooctanol By replacing the cyclopentanone in Example 28 with a molar equivalent of cyclooctone, the title compound was obtained as the hydrochloride, m.p. 178-180 ° C.

Analysis for C 18 H 31 NO 2 .HCl.1 / 4 H 2 O: Calculated: C, 65.87; H, 9.48; N, 4.04; Found: C, 65.79; H, 9.08; N, 3.95.

Example 31 1- [2- (Dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohex-2-en-1-ol

Substitution of 4-bromo-N, N-dimethylbenzeneacetamide in Example 13 with 4 molar equivalents of 4-methoxy-N, N-dimethylbenzeneacetamide, and cyclohexanone with 2-cyclohexen-1-one gave the corresponding cyclohexenone derivative. This intermediate was converted to the fumarate of the title compound following the procedure described in Example 14, m.p. 128-130 ° C.

Analysis for C 17 H 25 NO 2 * C 4 H 4 O 4: 32 7 7 6 4 7 Calculated: C, 64.4; H, 7.31; N, 3.58; Found: C, 63.8; H, 7.46; N, 3.88.

Example 32

Separation of racemic 1- [2- (dimethylamino) -1- (4-methoxyphenyl) -5-ethyl] -cyclohexanol 1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl? cyclohexanol (48.0 g, 0.173 mol) dissolved in ethyl acetate (350 ml) was treated with a solution of di-p-toluoyl-d-tartaric acid (33.5 g, 0.082 mol-10 mol) dissolved in ethyl acetate ( 250 ml). After the mixture was in place overnight, the solid was filtered off. The solid was recrystallized three times by dissolving in boiling ethyl acetate (300 mL) and methanol (50 mL), concentrating by boiling to initiate crystallization, and cooling. Yield 31.7 g, m.p. 126-128 ° C. -? 25 Lä / p = -50.51; c = 1.03 ethanol.

The salt was converted to the free base by shaking to 2-norm. in sodium hydroxide and diethyl ether. The ether layer was washed with brine, dried over anhydrous sodium carbonate, evaporated to dryness and dried in vacuo. Yield 16.4 g, 68.5%, m.p. 104-5 ° C.

/ ä7p ^ = + 27.95; c = 1.15, 95% ethanol.

The base was dissolved in ether (500 mL) and treated with 4.5 NM. with a solution of hydrogen chloride in isopropanol (20 ml).

The hydrochloride salt formed was recrystallized from warm methanol (75 ml) by dilution with ether (400 ml) and cooling. Yield 16.6 g, m.p. 239-241 ° C. δ 7 ^ 5 = -4.38; c = 1.01, 95% ethanol.

The filtrate of the original di-p-toluoyl-d-tartrate salt 30 and the washings were evaporated to dryness. The free base was obtained by shaking the solid to 2-norm. with sodium hydroxide (400 mL), extracting with diethyl ether (3 x 250 mL), washing the extracts with brine and drying. Yield 24.2 g. The base was dissolved in ethyl acetate (150 mL) and treated with di-p-toluoyl-1-tartaric acid (16.75 g, 0.0435 mol) which was

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33 7 7 6 4 7 dissolved in ethyl acetate (150 ml). After standing overnight, the salt was filtered off and recrystallized twice from ethyl acetate (300 ml) and methanol (50 ml) as described. Yield 5 29.4 g, m.p. 124-127 ° C. * +50.77, c = 0.845 ethanol.

The base was obtained as described. Yield 14.7 g m.p. 104-105 ° C.

Zfl / p5 = -26.56, c = 1.22%, 95% ethanol.

The free base was converted to the hydrochloride salt. Yield 10 14.5 g, m.p. 239-241 ° C. / ^ 5 = + 4'98 'c = 1'01' 95% ethanol.

Example 33.

1- [3- (4-Aminophenyl) -2-dimethylaminoethyl] cyclohexanol 17.0 g (0.095 mol) of p-aminophenylacetic acid, dimethylamide, was dissolved in 500 ml of tetrahydrofuran, protected under a nitrogen atmosphere, and cooled to -20 ° C. 23.6 g (1.15 equivalents) of 1,1,4,4-tetramethyl-1,4-dichlorosilylethylene were added, followed by dropwise addition of a solution of 42 g (2.4 equivalents) of sodium bis (trimethylsilyl) amide 250 in ml of THF.

The mixture was allowed to warm to room temperature and stirred for 18 hours.

The mixture was then cooled to -78 ° C and 71.6 mL (1.2 equivalents) of 1,6-norm, n-butyllithium in hexane was added. The reaction mixture was stirred for 45 ml to 25 minutes and then 20 ml (2.0 equivalents) of cyclohexanone were added. The mixture was stirred for an additional hour at -78 ° C and then poured into saturated aqueous ammonium chloride solution. The organic phase was removed and the aqueous phase was extracted with diethyl ether. The combined organic phases were dried over sodium sulphate, filtered and evaporated to dryness in vacuo to give 20 g of crude 1/74-aminophenyl) (dimethylaminocarbonyl] methyl / cyclohexanol. Twice from ethanol again, the crystallized sample of m.p.

Analysis for C 18 H 20 O 2 N 2: Calculated: C, 69.51; H, 8.77; N, 10.14; Found: C, 69.69; H, 8.96; N, 10.26.

5.0 g (0.018 mol) of the above amide were dissolved in 300 ml of dry tetrahydrofuran and added dropwise to a mixture of 1.1 g of lithium aluminum hydride and 8.0 ml of concentrated sulfuric acid in 200 ml of tetrahydro-furan at 0 ° C. :in. The mixture was stirred at 0 ° C for 5 hours, then the excess reagent was destroyed by the dropwise addition of 4 ml of a 50:50 aqueous THF mixture, then 4 ml of 15% aqueous sodium hydroxide solution and finally 4 ml of water. The mixture was filtered and the precipitate was washed several times with THF. The combined filtrates were evaporated to dryness and the residue was recrystallised from isopropanol to give 3.8 g of the title compound as the free base. Treatment with excess oxalic acid in ethyl acetate gave the dioxalate, m.p. 105 ° C (decomposition).

Analysis for C 20 H 30 N 2 O 9: Calculated: C, 54.28; H, 6.84; N, 6.33; Found: C, 53.96; H, 6.83; N, 6.24.

Example 34 1- [1- (4-Nitrophenyl) -2-dimethylaminoethyl] cyclohexanol 2.0 g (7.6 mmol) of 1- [N- (4-aminophenyl) -2-dimethylaminoethyl] cyclohexanol were dissolved in 50 ml. methylene chloride and added dropwise to a stirred solution of 2.2 g (2.5 equivalents) of nitrosonium tetrafluoroborate. The reaction mixture was stirred at room temperature for four hours. The methylene chloride was then removed in vacuo and replaced with 100 mL of water. This solution was slowly added to a mixture of 2.0 g of copper in 200 ml of 1-norm. sodium nitrite and the combination was stirred for 2 hours at room temperature. Extraction with methylene chloride, drying and evaporation to dryness in vacuo gave 2.0 g of the free base of the title compound.

Il 35 77647

Recrystallization from HCl isopropanol solution gave the hydrochloride, m.p. 211-212 ° C.

Analysis for C 16 H 24 O 3 N 2: Calculated: C, 58.42; H, 7.37; N, 8.52; Found: C, 58.03; H, 7.53; N, 8.69.

Example 35 1- (2-Dimethylamino) -1- (3-bromo-4-methoxyphenyl) ethyl? sykloheksanoli_

Substituting 1- [2-amino-1- (p-methoxyphenyl) ethyl? 10 cyclohexanol in Example 3 with 1 molar equivalent of 1- [2-amino-1- (3-bromo-4-methoxyphenyl) ethyl] cyclohexanol and boiling overnight gave the title compound, m.p. 218-220 ° C.

Analysis for C 18 H 18 N 2 O 2 Br.HCl: Calcd: C, 57.98; H, 6.92; N, 3.56; Found: C, 51.57; H, 6.79; N, 3.46.

Example 36 2- [N- (dimethylamino) -2- (4-methoxyphenyl) propyl? cyclohexanol_ 14.7 g (0.10 mol) of p-methoxyphenylacetonitrile were dissolved in 250 ml of dry tetrahydrofuran and placed in a dry ice / isopropanol bath under N 2 protection. 69.0 ml of a 1.6 molar solution of n-butyllithium (0.11 mol) were added dropwise over 30 minutes, and the mixture was stirred at -78 ° C for 1 hour. The lithium salt of the nitrile precipitated during this time as a yellow solid.

71.0 g (0.50 mol) of methyl iodide were then added and stirring at -78 [deg.] C. was continued for a further hour. The mixture was then poured into saturated ammonium chloride solution and the product was extracted into diethyl ether, washed with saturated sodium chloride solution and dried over sodium sulfide. Filtered and evaporated to dryness, redissolved in methylene chloride and passed through Floriser®. Evaporation to dryness gave 15.0 g of α (p-methoxyphenyl) propionitrile as an orange oil.

36 77647

The α- (p-methoxyphenyl) propionitrile prepared above was redissolved in 250 mL of tetrahydrofuran and cooled to -78 ° C in a dry ice / isopropanol bath. 69.0 ml of 1.6 mol were added over 30 minutes. n-bu-5 from lithium lithium solution and the mixture was stirred for 1 hour under nitrogen. Then 20 ml of cyclohexanone were added and stirring at -78 ° C was continued for another hour. The mixture was poured into saturated ammonium chloride solution and the product was extracted with diethyl ether. It was washed with water, saturated sodium chloride solution and dried over sodium sulfate. Filtration and evaporation to dryness gave 21.5 g of a white solid. After recrystallization twice from benzene, the sample m.p. was 129 ° C and the analysis was as follows: Analysis calculated for the compound: C, 74.10; H, 8.16; N, 5.40; Found: C, 73.95; H, 8.04; N, 5.29.

4.0 g (15 mmol) of the β-hydroxynitrile prepared above were dissolved in 200 ml of tetrahydrofuran and 50 ml of 1 mol were added. borane tetrahydrofuran complex.

The mixture was boiled for 2 hours and allowed to cool. 200 ml of 2-norm were added. HCl and THF were removed in vacuo. The aqueous solution was basified by the addition of solid potassium carbonate and the product was extracted into 500 ml of ethyl acetate, washed with saturated sodium chloride solution and dried over sodium sulfate. This was filtered off and evaporated to dryness and treated with a solution of HCl in isopropanol with diethyl ether to give 3.3 g of the primary amine, m.p. 209 ° C.

Analysis for C 16 H 26 NO 2 Cl 2: Calculated: C, 64.09; H, 8.74; N, 4.67; Found: C, 63.70; H, 8.60; N, 4.59.

3.0 g (10 mmol) of primary amine hydrochloride was dissolved in 200 ml of absolute ethanol. 5.0 ml of a 37% aqueous solution of formaldehyde and 1.0 g of 10% palladium on carbon were added, and the mixture was treated

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37 77647 at 50 psi hydrogen pressure on a Parr shaker for 3 days. The mixture was then filtered and evaporated to dryness and the solvent was replaced with 300 ml of water and washed with 300 ml of ethyl acetate. The aqueous solution was then basified with solid sodium carbonate and re-extracted with ethyl acetate. The organic extract was washed with saturated brine and dried over sodium sulfate. It was filtered and evaporated to dryness and the title compound was precipitated as the hydrochloride from isopropanol / ether by the addition of 10% HCl in isopropanol. Recrystallization from isopropanol gave 2.0 g of a white solid, m.p. 271 ° C.

Analysis for C 18 H 19 N 2 O 2 Cl 2: Calculated: C, 65.93; H, 9.22; N, 4.27; Found: C, 65.73; H, 8.93; N, 4.20.

Example 37.

Following a procedure similar to Examples 12-14, using (a) 3,4-dibromophenylacetic acid, (b) 3-methylphenylacetic acid, (c) 4-bromophenylacetic acid and (d) 3-methoxyphenylacetic acid and p-bromophenylacetic acid instead of p-bromophenylacetic acid (a) cyclohexanone, (b) cyclohexanone, (c) cyclobutanone and (d) cyclopentanone, were prepared from (a) 1 (1- (3,4-dibromophenyl) -2- (dimethylamino) ethyl] cyclohexananol, (b) ) - {2- (dimethylamino) -1- (3-methylphenyl) ethyl] cyclohexanol, (c) 1- [N- (4-bromophenyl) -2- (dimethylamino) ethyl] cyclobutanol and (d) 1- [2- (dimethyl-amino) -1- (3-methoxyphenyl) etyyli7syklopentanolia.

Claims (5)

A process for the preparation of therapeutically usable phenethylamine derivatives of formula (I) and pharmaceutically acceptable salts thereof, S ° R 4 (I) <in which formula the dashed line represents an optional bond, R 4 is hydrogen or alkyl of 1-6 carbon atoms; R 1 is alkyl of 1-6 carbon atoms; R 2 is hydrogen or alkanoyl of 2-6 carbon atoms; Rt is hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl, amino or nitro; R 9 is hydrogen, alkoxy of 1-6 carbon atoms or halogen; R 7 is hydrogen or alkyl of 1-6 carbon atoms; and n is any of the integers 0, 1, 2, 3 or 4; characterized in that one a) reduces an amide of the formula R 1 R 2 C = O OH R 5 -C 3 H 2 n R 6 where R 2, R 2, R 7 and n are as defined above, the dashed the line represents an optional bond, R 9 and 42 7 7 6 4 7 R 9 are as defined above and where R 9 is amino or hydroxyl, it is N-protected amino or O-protected hydroxy, provided that said reduction is selectively carried out with aluminum hydride in the dashed line denotes an unsaturated bond in the ring; or b) reduces a nitrile of the formula CN OH, -ΠΓμπι R6 wherein Rg, Rg, Ry, n and the dashed line are as defined above under (a), to obtain a primary amine, which is then mono- or di-alkylated, and thereafter, the protection is removed from the group Rg where it is N- or O-protected, and then, if desired, acylates the product obtained according to processes a or b with an active derivative of an alkanoic acid having 2- 6 carbon atoms to give a compound of formula (I) wherein R 2 is alkanoyl, or d & R g is amino, diazotizing by treating it with nitrite or nitrile to give a compound of formula (I) wherein R 9 is nitro , or divides the obtained racemic compound of formula (I) into optically active isomers thereof by conventional methods. 2. A process according to claim 1, characterized in that 1- [cyano (methoxyphenyl) methyl] cyclohexanol is catalytically hydrogenated to give 1 a mixture of formaldehyde and formic acid to give 1- [2- (dimethylamino) -1- (4-methoxyphenyl) ethyl] cyclohexanol. 35 3. Process according to claim 1, characterized in that 1 - [(3-bromo-4-methoxyphenyl) (dimethylaminocarbonyl) methyl] cyclohexanol is reduced with aluminum.