DE1124485B - Process for the preparation of analeptically active phenylcycloalkylmethylamines - Google Patents

Description

It has been found that one can use phenylcycloalkylmethylamines of the general formula

Method of manufacture

of analeptically effective

Phenylcycloalkylmethylamines

R ₈

S VC
A - = / / \

VC-CH ₂ -N

CHj

CH R-3

where R ₁ and R _{2 represent} hydrogen, the hydroxyl group, the methyl or methoxy group or together represent the methylenedioxy group, X together with the methylene groups and the central carbon atom are a cycloalkane ring with 3 to 6 carbon atoms, R _{3 is} hydrogen or a low molecular weight alkyl group, R ₄ and R ₅ denote hydrogen, saturated or unsaturated, open-chain or ring-shaped, low molecular weight alkyl groups or, together with the nitrogen atom, members of a saturated ring, optionally interrupted by a further heteroatom, but R _{1 must} not denote a methoxy group if R ₂ and R _{3 are} hydrogen are, X together with the methylene groups and the central carbon atom forms a cyclohexylidene radical and R ₄ and R ₅ are either hydrogen or methyl at the same time, if nitriles of the general formula are obtained in a manner known per se

<Q VC-CN

CH ₂ CH - R ₃

in which R ₁ to R ₃ and X have the abovementioned meaning, reduced by catalytic hydrogenation to primary amines and, if appropriate, the phenylcycloalkylmethylamines obtained are treated in the customary manner with alkylating agents _{which donate the radicals R 4} and / or R _5.

The products of the process represent valuable medicaments with particularly good central analeptic properties Properties.

The substituents R ₁ and R ₂ can be identical or different. For example, R ₁ can stand for hydrogen, while R _{2 stands for} a low molecular weight alkyl group, preferably the hydroxyl group, which is methyl or methoxy group. Applicants can also:

Farbwerke Hoechst Aktiengesellschaft
formerly Master Lucius & Brüning,
Frankfurt / M., Brüningstr. 45

Dr. Walter Krohs, Bad Soden (Taunus),
Dr. Leopold Ther, Frankfurt / M.-Unterliederbach,
and Dr. Gerhard Vogel, Frankfurt / M.-Zeilsheim,
have been named as inventors

z. B. both radicals R ₁ and R ₂ together represent the methylenedioxy group. Their position in the benzene nucleus can be different, so that, for. B. a substitution in the o-, m- or p-position or a mixed substitution comes into consideration.

The radicals R ₄ and R ₅ can also be identical or different. Examples of saturated or unsaturated alkyl radicals R ₄ and R ₅ are: methyl, ethyl, isopropyl, η-butyl, isobutyl, secondary butyl, allyl; the cyclopentyl and cyclohexyl radicals may be mentioned as cycloalkyl radicals R ₄ or R _5. Both substituents R ₄ and R ₅ , together with the nitrogen atom, can also mean members of a saturated ring, optionally interrupted by a further hetero atom such as nitrogen, oxygen or sulfur. For example: acetidine, methylacetidine, pyrrolidine, dimethylpyrrolidine, piperidine, hexamethyleneimine, morpholine, thiamorpholine and piperazine.

Possible substituents R ₃ are hydrogen or low molecular weight alkyl groups such as methyl, ethyl or n-propyl. The cycloalkane ring formed from the central carbon atom, the methylene groups and the substituent X can have the following meanings in detail: cyclopropane, methylcyclopropane, ethylcyclopropane, cyclobutane, methylcyclobutane, cyclopentane and cyclohexane.

209 517/416

3 4

In particular, the following starting materials, for example, reaction of the amines with acylating agents are to be mentioned: speaking acyl compounds and reduction of the

l-phenyl-l-cyanocyclopropane, ^le ^ ¹ "* lithium aluminum hydride

,,. The alkylation with the help of halides or

1-Phenyl-1-cyanomethylcyclopropane, ₅ sulfonic acid esters is expediently effected by heating

l-phenyl-l-cyanocyclobutane, in a suitable solvent, e.g. B. in ethanol,

! - (S'-Methoxypheny ^ -l-cyancyclobutane, benzene, toluene or xylene, at temperatures between

l - ^ '- MethylphenylH-cyancyclobutane, 80 and 130 ⁰ C. The duration of the heating depends

l-e ^ '- DimethoxyphenyO-l-cyancyclobutane, according to the temperature and reactivity of the

, J ¹ F jyjj ·> ₁₀ ester component and is generally between

1- (2,4-Dimethylphenyl) -l-cyanocyclobutane, _{2 and} 20 hours. To intercept the educated

l-phenyl-l-cyanocyclopentane, hydrohalic acid or sulfonic acid can

l- (2'-methylphenyl) -l-cyancyclopentane, you also have an excess of the amine used

l - ^ '- MethoxyphenylH-cyancyclopentane, ^{in a} water-immiscible solvent

l- (2 ', 4 -dimethylphenylH-cyancyclopentane, _{oil and after} cooling by suction or

1- ^ S'-DimethylphenylH-cyancyclopentane, shaking the reaction solution with water removed

HS '^' - DimethylphenylM-cyancyclopentane, after which the desired reaction

HS'-methoxyphenylH-cyancyclohexane, ²⁰ product either by distilling off the solution

l-O '^' - methylenedioxyphenyD-l -cyanocyclohexane ^m i; ^te l ^s, _f ^ ° ^{of Cutout} £ ^{ütteIn. of the} solvent

^{v J} jfjj jj _{isolate with the} help of acids in the form of a salt

_mi ^and lets.

isolate from acids in the form of a salt

1-phenyl-1-cyanocyclohexane. Instead of a second mole of amine, however,

25 also other basic compounds, e.g. B. Sodium

The starting materials are advantageously obtained from bicarbonate, anhydrous sodium carbonate, or ter-

Implementation of the appropriately substituted benzylic amines, such as triethylamine or diethylamine, Use cyanide with twice the equimolecular amount to trap the acids formed.

Sodium amide and the equivalent amount of a di- If you work with sodium carbonate or sodium

haloalkane in a bicarbonate which is immiscible with water, the reaction is expediently carried out

Solvent, such as benzene, at temperatures between, with good stirring in a water-immiscible

20 and 8O ⁰ C. bleed solvent and removed after completion

According to the method according to the invention, the sodium salt formed is heated, followed by the

the nitriles used as starting materials in the reaction products in the above first reaction stage by catalytic hydrogenation 35 can be worked up further,

reduced to the corresponding primary amines. When using tertiary amines for scavenging

With regard to the conversion of the acids formed, the process can also be carried out with water

conditions varied within wide limits and the miscible solvents such. B. Ethanol, work,

be adapted to current conditions. In this case, the catalyst is distilled for work-up

Lytic hydrogenation can e.g. B. with the help of metals 40 advantageous from the solvent, takes the return

of the VIII. Group of the Periodic Table, preferential stand in water, to the resulting salt of the

wise of cobalt or nickel catalysts, solubilized in tertiary amine, and isolated

The presence of solvents customary for this purpose, e.g. B. the reaction product by shaking with the help

Alcohols such as methanol. If the solvent is immiscible with water.

Use of nickel or cobalt as catalysts 45 But you can also use the alcoholic reaction

it is advisable to work at temperatures between the solution and immediately after cooling with water

60 and 120 ⁰ C and at 50 to 100 atm hydrogen thin until no further precipitation takes place, and

pressure. Instead of the above-mentioned catalyst, then the reaction mixture, as described above,

Sators can also process precious metals such as platinum or further.

Palladium can be used. For the success of the 50 The alkylation with halides or sulfonic acid

Conversion can be advantageous; the reaction ester can also pass through without a solvent

Mixture add ammonia to the formation heating the two components to temperatures

to push back secondary amines. perform between 80 and 130 ° C, whereby one

For those given in the second reaction stage, it is expedient to use the amine in a twofold molar overrun ensuing alkylation come the 55 shot used for this. After cooling down, you take that usual methods. For example, reaction product can be used for work-up in one with the primary amines obtained with halogen-water immiscible solvents, eg. B. ether hydrogen or sulfonic acid esters of the same or benzene, and continues in the already Alcohols or by hydrogenation with aldehydes or the manner indicated above. After a Alkylate ketones. Further come z. B. the following 60 further embodiment of the method according to FIG Methods under consideration: Heating the primary amines invention can also be used by the alkylation with dialkyl sulfates or with formaldehyde and hydrogenation of the primary amines with aldehydes or Carry out formic acid, addition of alkyl halides or ketones. The implementation is in one Dialkyl sulfates to the corresponding benzylidene or can be carried out in two stages. So you can e.g. compounds and cleavage of the alkylidene compounds that result from the primary form benzaldehyde formed with water by water amines and the aldehydes or ketones, Steam distillation (Decker method), isolate heating and then hydrogenate the double bond with alcohols and Raney nickel catalysts or or amine and aldehyde in one operation or

Dissolve ketone in the molecular ratio in a solvent and immediately the catalytic hydrogenation subject. If a ketone is used, an excess of this component can readily can also be used as a solvent, since the excess ketone in the catalytic hydrogenation is not attacked with precious metals. The metals of group VIII des are suitable as catalysts Periodic table, e.g. B. platinum, palladium, nickel or cobalt. If you work with precious metal catalysts, so temperatures of 40 to 50 ° C and low overpressure or increased pressure up to 50 atm proved to be appropriate. When using base metals, temperatures of 80 to 100 ° C are required and pressures between 30 and 100 atmospheres are appropriate.

For the monomethylation of the primary phenylcycloalkylmethylamines, z. B. the Decker alkylation method can be used. It is heated according to this embodiment of the process the benzylidene compound of the amine with an excess of dimethyl sulfate for 5 hours to 100 ° C., water is then added to the reaction mixture and the benzaldehyde formed is removed by steam distillation. The aqueous solution is obtained by adding sodium hydroxide solution the monomethyl compound, which is taken up in ether and after drying and distilling off of the solvent by vacuum distillation or via the corresponding acid addition salts, for example via the hydrochloride, can be purified.

Furthermore, for the alkylation, the amines used as starting materials can be _{heated with alcohols, which correspond to the meaning of the radicals R 4} and R ₅ , and Raney nickel. So you get z. B. from the 1 - (3 ', 4' - dimethylphenyl) -1 - aminomethylcyclopropane with excess secondary butanol and a lot of Raney nickel at 15 hours of heating with mechanical stirring at 100 to 120 ° C, the corresponding N-secondary butyl-l- (3 ', 4'-dimethylphenyl) -1-aminomethylcyclopropane.

Finally, corresponding acylamines, the acyl radical of which corresponds to the definition of the radicals R ₄ and / or R ₅ , can be converted into the desired process products by heating in an inert solvent with lithium aluminum hydride. The acyl compounds required as starting materials are obtained, for. By treating the primary amines with acylating agents such as acid halides.

If compounds are to be built up in which the radicals R ₄ and R ₆ together with the nitrogen atom form a saturated ring, the primary amines are expediently mixed with hydrohalic acid esters of dihydric alcohols in a water-immiscible solvent such as benzene, toluene or xylene at temperatures between 80 and 130 ° C and in the presence of anhydrous sodium carbonate as an acid-binding agent. The duration of the heating depends on the reactivity of the ester and is over when halogen is only weakly detectable in the solution.

If the reaction products contain methoxy groups in the benzene nucleus, these can be demethylated by customary methods. A suitable method is that heating the methoxy derivatives with concentrated hydrochloric acid in the pressure vessel or with 48 ° / _o hydrobromic acid and heated with pyridine hydrochloride longer time to boiling.

The products of the process can be treated with inorganic or organic acids in the corresponding acid addition salts are converted. For example, they can be used for salt formation are: inorganic acids such as hydrochloric and hydrobromic acid, sulfuric acid, phosphoric acid or sulfamic acid.

The following organic acids come into question, for example: acetic acid, propionic acid, oxalic acid, malic acid, Succinic acid, lactic acid, maleic acid, fumaric acid, sorbic acid, citric acid, aceturic acid, Aspartic acid, p-aminobenzoic acid, salicylic acid and ethylenediaminetetraacetic acid.

The products of the process are particularly well tolerated by valuable central analeptic properties Properties. In the table below they are numerically determined Pharmacological comparative tests obtained information on the toxicity and action of a number of Process products specified.

link

toxicity
(~ LD ₅₀ )
at the mouse
intravenous
mg / kg Motuity
Paraldehyde be
100% =
10 mg / kg
Subcutaneous at the with
landed mouse
control
20 mg / kg
Subcutaneous 40 300 400 20th 250 350 20th 250 350 30th 300 350 25th 350 400 25th 250 350

1-phenyl-1-secondary-butylaminomethylcyclopropane I - phenyl -1 - secondary - butylaminomethylcyclobutane

1 - (3 ', 4' - dimethylphenyl) -1 - secondary - butylaminomethylcyclopentane

1 - (3 ', 4'-methylenedioxyphenyl) -1-diethylaminomethylcyclopentane

1 - (3 '- methoxyphenyl) - 1 - diethylaminomethylcyclopentane

1 - (3 ', 4' - methylenedioxyphenyl) -1 - pyrrolidinomethylcyclohexane

The compounds were tested for motility in the paraldehyde-treated mouse on white mice with an average weight of g according to that of L. Ther in Süddeutsche Apotheker-

newspaper, 1953, pp. 292 to 294, published test method, with the following test arrangement selected became:

For observation, three animals were placed in cylinder glasses and treated with paraldehyde, each mouse receiving 600 mg / kg paraldehyde subcutaneously. 15 minutes after this pretreatment the test preparation to be examined was also administered subcutaneously. the Tests were carried out against controls which had only been pretreated with paraldehyde. After a waiting time of 10 minutes, the evaluation followed, by taking a 1 hour Observation time was briefly registered once per minute whether and how many animals the Experimental group moved. Those obtained from the observations of the untreated controls Numerical values were designated as "motility of the paraldehyde controls" and equal to 100 try to examine their circulatory effects on anesthetized cats by measuring their blood pressure. The test values obtained are in the table below the corresponding data of the known 5 product, which was numbered with IV, compared.

number of
Initiations Average link
IV Dose in
mg / kg percentage
Increase in blood pressure 32 intravenous 1 link
II 66 0.2 3 18th 78 0.5 2 38 93 1 2 13th 2 47

Test groups in comparison to the untreated controls were calculated in percent and is approximated in the table.

The test results obtained show that the new process product II significantly increases the cycle less affected than the known product IV.

The products of the process are effective both orally and parenterally. You can, therefore, mixed with suitable solid or liquid pharmaceutical carriers, such as water, vegetable

Oils, starch, lactose, talc or auxiliaries, for example stabilizers, preservatives, wetting agents or emulsifiers, in the form of tablets, dragoes Find capsules, solutions, suspensions or emulsions use. The application is preferably carried out

The test results illustrated in the table clearly show that the process products are very well tolerated and are already in low dosage a significant motility

cause an increase. The test results give 30 per os in the form of tablets, all the more about the valuable properties of the
Compounds information, as their compatibility
is known to be considerably greater in the case of subcutaneous administration than in the case of intravenous administration.
The toxicity data contained in the table correspond to ₃₅
speak of the ascertained during the preliminary examination

Example 1 a) I-Phenyl-1-aminomethylcyclopropane

92 g of 1-phenyl-l-cyancyclopropane are poured into 250 ml Hydrogenated methanol at 60 to 80 ° C using Raney nickel as a catalyst. After finished That will be hydrogen absorption and cooling Reaction mixture separated from the catalyst, the

LD ₅₀ after intravenous administration.

The new process products have compared to the known / 9-phenylisopropylmethylamine

the advantage that it distills off methanol with significantly lower toxicity, and the residue is also dissolved in benzene taken a significantly lower circulation effectiveness and refer to the benzene solution; which is shaken out when the new diluted hydrochloric acid is administered. Remains in benzene The rise in blood pressure caused by bonds is from nitrile that is not hydrogenated in this way, which is recovered small extent that it has practically no meaning. can be. The acidic solution is separated and

The comparison of the experiments on the mouse 45 from this the base with dilute sodium hydroxide solution

determined toxicity data gives the following picture:

No. Exam preparation LD ₅₀
(intravenous) I.
II
III / 3-phenylisopropylmethylamine ..
1 - (3 ', 4' -Methylenedioxyphenyl) -
1 - diethylaminomethylcyclo-
pentane (see p. 8, table, ver
binding no. 4)
1 - phenyl - 1 - secondary - butyl-
aminomethylcyclopropane (cf.
P. 8, table, compound no. 1) ~ 5 mg / kg
~ 30 mg / kg
40 mg / kg

The compatibility of the new compounds is thus about a power of ten greater than that of the known commercial product. To demonstrate the therapeutic progress of the new process products compared to the cyclohexylisopropylmethylamine known from German patent specification 970 780, the above-mentioned new compound No. II was divorced in the context of pharmacological comparison. After taking up in benzene and separating off the aqueous phase, the benzene is distilled off and the remaining 1-phenyl-1-aminomethylcyclopropane is distilled under reduced pressure. Bp. ₁₂ 98 to 102 ° C, the yield is 72 g. The base hydrochloride melts at 175 ° C.

b) l-phenyl-l-secondary-butylaminomethyl-

cyclopropane

10 g of 1-phenyl-1-aminomethylcyclopropane will be under a hydrogen pressure of 50 atm in 100 g of methyl ethyl ketone at 50 ° C with palladium as a catalyst hydrogenated until the uptake of hydrogen ceases. Then the reaction mixture is separated from Catalyst and obtained after distilling off the excess methyl ethyl ketone in quantitative Yield the 1-phenyl-1-secondary-butylaminomethylcyclopropane, which forms a hydrochloride with a melting point of 97 ° C.

c) l-phenyl-l-pyrrolidinomethylcyclopropane

20 g of 1-phenyl-1-aminomethylcyclopropane will be in 250 ml of xylene with 29.5 g of 1,4-dibromobutane and 34 g

9 10

anhydrous sodium carbonate for 15 hours under the l- (3'-methoxyphenyl) - with methyl ethyl ketone

heated to reflux well stirring. After completion, I-secondary-butylaminomethylcyclobutane. The hy-

During heating, the reaction mixture is ab- drochloride melts at 109 ° C.

cooled, sucked from the inorganic salts,

and the xylene is distilled off under reduced pressure. 5 ^e > H3 -Methoxyphenyl) -l-pyrrohdinomethyl-

23 g of crude 1-phenyl-1-pyrrolidino-cyclobutane remain

methylcyclopropane, which is a hydrochloride from the reaction of l- (3'-methoxyphenyl) -

Melting point 170 ° C forms. l-aminomethylcyclobutane with 1,4-dibromobutane ana-

_R. log example l, c) the l- (3'-methoxyphenyl) -

Example Z _lo i.pyn-oijdinomethylcyclobutane, its hydrochloride

a) 1-Phenyl-1-aminomethylcyclobutane melts at 185 ° C.

89 g of 1-phenyl-l-cyanocyclobutane are, as in the 8 hour heating in the examples

Example 1, a) described, hydrogenated and worked up. 3, b), c), d), e) described methoxyphenylverbin-

This gives 79 g of crude 1-phenyl-1-aminomethylcyclo- fertilize with 48 ° / ₀ hydrobromic acid under

butane, which is obtained by distillation under reduced reflux, forms the methyl group

Print is cleaned. Kp. _Lo 115 to 117 ^° C. corresponding hydroxyphenyl derivatives are split off.

,,,,, For example, the following process products

b) 1 -phenyl- l-secondary-butylammomethyl- produced "
cyclobutane

Analogously to example 1, b) one obtains from the 1-phenyl- so l-O-hydrox ^ henyO-l-a ^ ylaminomethy ^ clo-

l-aminomethylcyclobutane by hydrogenation with butane, melting point of the hydrochloride 166 ° C;

Methyl ethyl ketone using palladium l-O'-hydroxyphenylH-diethylaminomethylcyclo-

as catalyst, the ^{1-phenyl-1-secondary-butylamino-butan} "melting point of the hydrochloride 162 ° C;

methylcyclobutane. The hydrochloride of the compound 1 - (3'-hydroxyphenyl) -! - secondary-butylamino-

melts at 113 ° C. 25 methylcyclobutane, melting point of the hydro-

c) 1-phenyl-1-ethylaminomethylcyclobutane,, ~, _TT ,! _1N , .....,,,

' 1- (3-Hydroxyphenyl) -l-pyrrohdmomethylcyclo-

24 g of l-phenyl-l-aminomethylcyclobutane are mixed with butane, the melting point of the hydrochloride is 182 ° C.

23.1 g of diethyl sulfate heated to 100 ° C. for 5 hours.

After completion of the heating is added to the 30 serving as the starting material l- (3'-Methoxy-reaction mixture with water, the base is precipitated with phenyl) -l-cyancyclobutan from Kp. _3136-138 ° C sodium hydroxide solution, the precipitation takes in ether and after drying and distilling off the cyanide with 2 moles of sodium amide and 1 mole of 1,3-di-ether, 28 g of 1-phenyl-1-ethylaminomethylcyclobutane are obtained by reacting 3-methoxybenzyl content. bromopropane at 30 to 35 ° C.
The compound's hydrochloride melts at 35
166 ° C. Example 4

a) 1-phenyl-1-aminomethylcyclopentane

a) 1- (3'-Methoxyphenyl) -l-aminomethyl- Corresponding to that given in Example 1, a)

cyclobutane _{40 procedure} is obtained from 148 g of 1-phenyl- 1-cyano-

According to the cyclopentane specified in Example 1, a) by hydrogenation 132 g of 1-phenyl

Provision is obtained from 294 g of l- (3'-Methoxyphenyl) - l-aminomethylcyclopentan from Kp _lo 130 to 132 ° C.

l-cyanocyclobutane by hydrogenation 249 g 1- (3'-Me-

thoxyphenyl) -l-aminomethylcyclobutane of bp. ₃ b) l-phenyl-l-dimethylaminomethylcyclopentane
12O ⁰ C. The hydrochloride melts at 128 ° C. 45

, _N , ",,,,,,, 87 g of 1-phenyl-1-aminomethylcyclopentane

b) l- (3-l--MethoxyphenyO äthylammomethyl- _{with 92 g ant} acid tert. and 150 g of 30 ° / ₀ sodium form

cyclobutane aldehyde heated on the steam bath for 3 hours.

76.4 g of l-Q'-methoxyphenyrH-aminomethylcyclo- After cooling, the mixture is treated with

butane are etherified from sodium hydroxide solution in accordance with Example 2, c) and obtained after drying

given instructions with 61.6 g of diethyl sulfate and distilling off the ether 90 g of 1-phenyl-l-di-

Reaction brought and worked up. 84 g of methylaminomethylcyclopentane and its hydrochloride are obtained

l- (3'-methoxyphenyl) - 1-ethylaminomethylcyclobutane, melts at 230 ° C,
this is a hydrochloride with a melting point of 132 ° C

forms. 55 c) l-phenyl-l-ethylaminomethylcyclopentane

c) l- (3'-methoxyphenyl) -l-diethylaminomethyl _{analogous to example 2> c) one derives from the} μρ ^ ι.

cyclobutane l-aminomethylcyclopentane by reaction with di-

By reacting 44 g of l- (3'-methoxyphenyl) - ethyl sulfate, the l-phenyl-l-ethylaminomethylcyclo-

1-ethylaminomethylcyclobutane with 31 g of diethyl sulfate 60 pentane. The compound's hydrochloride melts

44 g of l- (3'-methoxyphenyl) -l-diethylamino- at 178 ° C.

methylcyclobutane obtained, its hydrochloride in. . _, ,,, - .. ,, ■ ",,

160 ° C melts) 1-phenyl-1-diethylammomethylcyclopentane

λλ WT η λ. u ni 1 λ-- u . ι Corresponding to that given in Example 3, c)

d) l- (3 -Methoxyphenyl) -l-secondary-butyl- _{65 procedure} is obtained from 1-phenyl-l-ethylamino-

ammomethylcyclobutane methylcyclopentandasl-phenyl-l-diethylaminomethyl-

As in Example 1, b), hydrogenation gives cyclopentane. The hydrochloride of the compound

of l- (3'-methoxyphenyl) -l-aminomethylcyclobutane melts at 165 ° C.

11 12

Example 5 Allyl bromide added. Then cooks manda's reaction

\ * / μ / »* ■■ ι. ι ι. η, ^. , t mix 8 hours under reflux, cool it down,

a) l- (4 -MethylphenyD-l-aminomethylcyclopentane _{separates y (m the formed} hydrobromide of the starting

Corresponding to the base specified in Example 1, a), the benzene solution was washed with water and distilled

Prescription is obtained from 50 g of 1- (4'-methylphenyl) - 5 from the solvent. 13 g of 1- (2 ', 5'-di-

1-cyancyclopentane by hydrogenation 42 g of 1- (4'-methylphenylj-l-allylaminomethylcyclopentane, its

thylphenyl) -1 - aminomethylcyclopentane of b.p. ₁₂ hydrochloride melts at 143 ° C. 146 to 148 ° C.

b) l - ^ '- methylphenylH-secondary-butylamino- ₁₀ ^d > l- (2', 5'-dimethylphenyl) -l-cyanocyclopentane

methylcyclopentane By converting 2,5-dimethylbenzyl cyanide

Analogously to Example 1, b), by hydrogenation with sodium amide and 1,4-dibromobutane, 1- (4'-methylphenyl) -! - aminomethylcyclopentane is used to give 1- (2 ', 5'-dimethylphenyl) -l -cyan with methyl ethyl ketone and palladium as a catalyst obtained cyclopentane from b.p. ₄ 144 to 146 ° C, the 1- (4'-methylphenyl) -! -secondary- butylamino- 15

methylcyclopentane, its hydrochloride at 169 ° C Example 8

melts. ■ _Λ . ■,. ,

The starting material l- (4'-methylphenyl) - a) l- (3 ^ -DimethylphenyO-l-aminomethyl-

L-cyanocyclopentane with a boiling point of ₁₂ 158 to 160 ° C can be cyclopentane

by reacting 1 mole of 4-methylbenzyl cyanide in accordance with the procedure given in Example 1, a) with 2 moles of sodium amide and 1 mole of 1,4-dibromo, 66 g of 1- (3 ', 4'-dimethylbutane in benzene) are obtained are prepared from 50 to 6O ⁰ C. phenyl) -l-cyancyclopentan by hydrogenating 60 g

1 - (3 ', 4' - dimethylphenyl) -1 -. Aminomethylcyclopentan Example 6, bp _u 163-165 ° C. The corresponding hydro-

\ 1 / τ Λ <rv Vu 1 u η ι · _Λ ι ² 5 chloiid melts at 17O ⁰ C.

a) l- (2, 4-dimethylphenyl) -l-ammomethyl-

cyclopentane b) l- (3 ', 4'-dimethylphenyl) -l-dimethylamino-

Corresponding to the methylcyclopentane specified in Example 1, a)

The procedure is obtained from 42 g of l- (2 ', 4'-dimethyl- corresponding to that given in Example 4, b) phenyFj-l-cyancyclopentane by hydrogenation 41 g 30 procedure is obtained by reacting l- (3 ', 4'-

1- (2 ', 4'-dimethylphenyl) -l-aminomethylcyclopentane, dimethylphenyl) -1 -aminomethylcyclopentane with

from which a hydrochloride with a melting point of 183 ⁰ C formaldehyde and formic acid form the l- (3 ', 4-dimethyl-

is obtained. phenyl) -1 - dimethylaminomethylcyclopentane, its

u \ 1 / τ A ' rv + u 1 u u t 1 j- u * 1 hydrochloride melts at 252 ° C,

b) l- (2, 4-dimethylphenyl) -l-secondary-butyl- ■ ₃ -

aminomethylcyclopentane c) l- (3 ', 4'-dimethylphenyl) -l-ethylaminomethyl-

As in Example 1, b), hydrogenation gives cyclopentane

of 1- (2 ', 4'-dimethylphenyl) -1-aminomethylcyclo- Analogously to Example 2, c) is obtained from the 1- (3', 4'-di-

pentane with methyl ethyl ketone the 1- (2 ', 4'-dimethyl-methylpheny ^ -l-aminomethylcyclopentane by umphenyl) -1 - secondary - butylaminomethylcyclopentane, 40 settlement with diethyl sulfate the I- (3', 4'-dimethylphenyl) -das a Hydrochloride with a melting point of 201 ⁰ C forms. l-ethylaminomethylcyclopentane, its hydrochloride

Serving as starting material l- (2 ', 4'-dimethyl melts at 138 ° C. Phenyrj-1-cyancyclopentan from Kp. _4146-148 ° C,

can be obtained by reacting 2,4-dimethylbenzyl ^{cyanide d} > H ³ ' ⁴ -DxmethylphenyD-1-diethylammomethyl with 2 moles of sodium amide and 1 mole of 1,4-dibromo-45 cyclopentane

butane in benzene at 50 to 60 ° C. Corresponding to that given in Example 3, c)

. . _{7 procedure} is obtained from l- (3 ', 4'-dimethylphenyl) -

Example / 1-aminomethylcyclopentane the l- (3 ', 4'-Dimethylphe-

a) 1- (2 ', 5'-dimethylphenyl) -l-aminomethyl-nylH-diethylaminomethylcyclopentane. The hydro

cyclopentane ₅₀ chloride of the compound melts at 147 ° C.

Corresponding to that given in Example 1, a)

Prescription is obtained from 50 g of 1- (2 ', 5'-dimethyl-e) 1- (3', 4'-dimethylphenyl) -l-n-butylaminomethylphenyl) -1-cyanocyclopentane by hydrogenation 45 g of cyclopentane

1 - (2 ', 5'-dimethylphenyl) -1 -aminomethylcyclopentane,

its hydrochloride at 208 ⁰ C schmikt. 55 The above process product was both

u \ ι / Ό'-c'Ti · * t. 1 1. η 1 1 λ- 1. 1 by hydrogenation with n-butyraldehyde as well as by

b) 1- (2,5-D ₁ methylphenyl) -l-secondary _S -butyl- i _{heating for 5s} with excess n-butanol

ammomethylcyclopentane _{and vM Raney} . _{Nickel or by} reducing the

Analogously to Example !, b), the corresponding n-butyryl compound is obtained by hydrogenation with lithium from 1- (2 ', 5'-dimethylphenyl) -1-aminomethylcyclo-aluminum hydride. The hydrochloride of pentane with methyl ethyl ketone the 1- (2 ', 5'-dimethyl compound melts at 124 ^° C. The hydrogenation with phenyl) -1-secondary-butylaminomethylcyclopentane. n-Butyraldehyde was carried out under the reaction conditions given in the embodiment The hydrochloride melts at 181 ° C. Example 1, b).

c) l- (2 ', 5'-dimethylphenyl) -l-allylaminomethyl- ₆ f) l- (3', 4'-dimethylphenyl) -l-isobutylaminomethyl-

cyclopentane cyclopentane

25 g of l- (2 ', 5'-dimethylphenyl) -l-aminomethylcyclo- Corresponding to those given in Example 1, b)

pentane are dissolved in 60 ml of benzene and with 7.5 g of reaction conditions, 1- (3 ', 4'-di-

13 14

Methylphenyl) -1-aminomethylcyclopentane by means of the instructions given in Example 3

tration with isobutyraldehyde the l- (3 ', 4'-dimethyl- the following process products are obtained:

phenyO-l-isobutylaminomethylcyclopentane, whose 1- (3'-hydroxyphenyl) -1-diethylaminomethylcyclo-

Hydrochloride melts at 158 C. _{te melting point of the} hydrochloride 175 ° C;

g) By hydrogenation with acetone, methyl ethyl ketone, 5 ι. (3'-Hydroxyphenyl) -1 -pyrrolidinomethylcyclo-

Cyclopentanone and cyclohexanone were corresponding to the _{melting point of the} hydrochloride 146 ° C;

corresponding to the reaction indicated in Example 1, b) * · ₁ . _{(3 ,. Hydroxyphenyl)} . _λ _piperidmomethylcyclo-

conditions the following compounds are established: _pentane) Melting point of the hydrochloride 201 ⁰ C.

l. (3 \ 4'-Dimethylphßnyl) -l-isopropylminome. ₁₀ serving _{as the} starting material l- (3'-Methoxythylcyclopentan, melting point of the hydrochloride phenyl) -l-cyancyclopentan from Kp. _2O 186-188 ° C 'was prepared by reaction of 3-Methoxybenzylcyanids

l- (, 4'-dimethylphenyl 3 ') _{-l-secondary-butyl-m} i _t sodium amide and 1,4-dibromobutane produced aminomethylcyclopentan, melting point of the hydrochloride 168 ⁰ C; i ₅ Example 10! - (S '^' - Dimethylpheny ^ -l-cyclopentylaminome-., thylcyclopentane, melting point of the hydrochloride ^a ) H3 ' ⁴ -DimethoxyphenylM-aminomethyl-172 ° C- cyclopentane 1 - (3', 4 '- Dimethylphenyl) -1 - cyclohexylaminome- Corresponding to the vorthylcyclopentane given in Example 1, a), melting point of the hydrochloride ³ ° font is obtained from 123 g of 1- (3 ', 4'-dimethoxy-174 ° Q phenyl) -1-cyancyclopentane through Hydrogenation HOg

1- (3 ', 4'-dimethoxyphenyl) -1-aminomethylcyclopentane

h) l- (3 ', 4'-dimethylphenyl) -l-pyrrolidinomethyl- TSS ^ί Ρ Τ - ^ ^ ¹⁵⁶ ° ^{C' H} y ^{its hydrochloride with}

1-? 9 C melts.

25 From l- (3 ', 4'-dimethoxyphenyl) -l-aminomethyl ~

The following compounds were prepared in accordance with the cyclopentane given in Example 1, c)

Regulation was made by converting 1- (3 ', 4'-Di-:

methylphenyO-l-aminomethylcyclopentane with 1 4-di- _b) i. (3 ' _{) 4} ' .Dimethoxyphenyl) -l-ethylaminomethyl-

brombutandasl-CS ^ _{-DimethylphenyD-l-cyc} pyrrolidmo- _O i-pentane, melting point of the hydrochloride

methylcyclopentane obtained, its hydrochloride at 30 ₁₆₆ o _{C; obtained by reaction with} diethyl

211 C melts. _{sulfate analogous example 2) c} ).

The starting material l- (3 4 -dimethyl- _{The implementation of the} i- (3 ', 4'-dimethoxyphenyl) -

phenyl) -l-cyancyclopentane (bp. ₄ 154 to 157 C) was l-äthylaminomethylcyclopentans with diethylsul-

by reaction of 3 ^ 4-dimethylbenzyl _{cyanide with fat anaJo example 3 c) gave the} i. (3 ', 4'-di-

Sodium amide and 1,4-dibromobutane are produced. 35 methoxyphenyl) -1 - diethylaminomethylcyclopen-

-, ο ^tan > whose hydrochloride melts ^{at 161 0 C.}

^Bels P ^{iel 9} c) l- (3 ', 4'-dimethoxyphenyl) -l-pyrrolidinomethyl-

a) 1- (3'-Methoxyphenyl) -l-aminomethylcyclopentane cyclopentane, melting point of the hydrochloride ",,,.". . _,, ^, xr 206 ⁰ C, obtained by reaction with 1,4-di-Corresponding to the pre-bromobutane given in Example 1 a) analogously to Example 1, c).

font is obtained from 60 g of l- (3-methoxyphenyl) -

1-cyanocyclopentane by hydrogenation 47 g of l- (3'-meth- The l- (3 ', 4'-dimeth-

oxyphenyl) -1-aminomethylcyclopentane of bp. _e 161 oxyphenyl) -1-cyancyclopentane of b.p. _Oll 178 bis

up to 162 ° C. 180 ⁰ C was by reaction of 3,4-dimethoxy

In addition, I-iS'-methoxyphenyty-l-ammomethylcyclobenzyl cyanide with sodium amide and 1,4-dibromobutane

pentane, the following compounds were produced: obtained.

b) l-P'-methoxyphenylJ-l-ethylaminomethylcyclo- Example 11

pentane, melting point of the hydrochloride 138 ° C, a) l- (3 ', 4'-methylenedioxyphenyl) -l-amino-

obtained by reaction with diethyl sulfate “methylcyclopentane

analogous to example 2, c). Corresponding to that given in Example 1, a)

The implementation of the 1- (3'-methoxyphenyl) rule is obtained from 140 g of 1- (3 ', 4'-methylenedi-

1-äthylaminomethylcyclopentans with diethylsul- oxyphenyl) -1-cyancyclopentane by hydrogenation 125 g

fat analogous to Example 3, c) gave the l- (3'-methoxy- 1 - (3 ', 4' - methylenedioxyphenyl) -1 -aminomethylcyclo-

phenylH-diäthylaminomethylcyclopentan, the _{55 pen} tan melting point of 6O ⁰ C. hydrochloride at 98 ⁰ C melts.

c) l-CS'-methoxyphenylH-pyrrolidinomethylcyclo- ^b ) l- (3 ', 4'-methylenedioxyphenyl) -l-methylpentane, melting point of the hydrochloride 204 ° C, aminomethylcyclopentane

obtained by reaction with 1,4-dibromobutane 33 g of the base are in 100 ml of methanol with 18 g

analogous to example 1, c). 60 added benzaldehyde, and the reaction mixture

d) 1- (3'-Methoxyphenyl) -1-piperidinomethylcyclo- is heated on the steam bath for ¹ _{1/2 hours.} After pentane, melting point of the hydrochloride 176 ^° C., cooling, the benzylidene compound obtained precipitates by reaction with 1,5-dibromopentane, which is filtered off with suction and washed with cold methanol analogously to Example 1 c). The yield is 41 g of

6 ₅ Melting point 59 ° C.

By heating in the examples 41 g of the benzylidene compound for 8 hours, 35 g

9, b), c), d) described methoxyphenylverbindun- dimethyl sulfate ^{heated to 100 0} C for 5 hours. After 48% hydrobromic acid was added to the mixture, the heating was stopped

with water and eliminates the benzaldehyde released during the reaction by steam distillation. From the remaining aqueous solution is precipitated die_ base with sodium hydroxide solution from, taking the precipitation into ether to give, after drying and distilling off the solvent, 27 g of 1 - (3 ', 4' - methylenedioxyphenyl) - methylaminomethylcyclopentan whose hydrochloride at 25O ⁰ C melts. The following compounds were also obtained from l- (3 ', 4'-methylenedioxyphenyl) -l-aminomethylcyclopentane:

c) 1 - (3 ', 4' - methylenedioxyphenyl) -1 -ethylaminomethylcyclopentane, Melting point of the hydrochloride 174 ° C, obtained by treatment with diethyl sulfate analogous to example 2, c).

The reaction of diethyl sulfate with Monoäthylaminoverbindung analogously to Example 3, c) gave the l- (3 ', 4'-methylenedioxyphenyl) -l-diäthylaminomethylcyclopentan whose hydrochloride melts at 146 ⁰ C.

d) 1 - (3 ', 4'-methylenedioxyphenyl) -1 -secondary-butylaminomethylcyclopentane, Melting point of the hydrochloride 184 ° C, obtained by hydrogenation with methyl ethyl ketone as in Example 1, b).

e) 1- (3 ', 4'-methylenedioxyphenyl) -1-pyrroh'dinomethylcyclopentane, melting point of the hydrochloride 228 ⁰ C, obtained by reaction with 1,4-dibromobutane analogously to Example 1, c).

The used l- ( ', 4'-MethylendioxyphenylH-cyancyclopentan obtained by Kp. ₂ 158 to 16O ⁰ C was prepared by reacting 3,4-Methylendioxybenzylcyanid with sodium amide and 1,4-dibromobutane 3 as the starting material.

Example 12 a) 1-Phenyl-1-aminomethylcyclohexane

According to the procedure described in Example 1, a) is obtained from 160 g of 1-phenyl-1-cyanocyclohexane by hydrogenating 140 g 1-phenyl-l-aminomethylcyclohexane, bp. 144 ° C. _lo 142 bis

From the l-phenyl-l-aminomethylcyclohexane obtained the following derivatives were produced:

b) l-phenyl-l-ethylaminomethylcyclohexane, melting point of the hydrochloride 208 ° C (analogous to Example 2, c)).

By reacting the Monoäthylaminoverbindung with diethyl sulfate analogously to Example 3 c) was the 1-phenyl-1-diäthylaminomethylcyclohexan whose hydrochloride melts at 201 ^C C.

c) l-Phenyl-l-pyrrolidinomethylcyclohexane ^ melting point of the hydrochloride 220 ⁰ C, obtained by reaction with 1,4-dibromobutane analogously to Example 1, c).

Example 13

a) 1- (3'-Methoxyphenyl) -l-aminomethylcyclohexane

According to the instructions given in Example 1 a) one obtains g l- (3'-methoxyphenyl) -1-cyanocyclohexane of 66 by hydrogenation 62 g l- (3'-methoxyphenyl) -l-aminomethylcyclohexane, its hydrochloride at 148 ⁰ C melts.

From the l- (3'-methoxyphenyl) -1-aminomethylcyclohexane thus obtained the following connections were established:

b) l-ß'-methoxypheny ^ -l-diethylaminomethylcyclohexane, Melting point of the hydrochloride 115 ° C., obtained analogously to Example 2, c).

Employed as a starting compound l- (3'-methoxyphenyl) -l-cyanocyclohexane, bp. _2158-160 ° C was prepared by reaction of 3-methoxybenzyl cyanide with sodium amide and 1,5-dibromopentane.

Example 14

a) 1- (3 ', 4'-methylenedioxyphenyl) -l-aminomethylcyclohexane

According to the instructions given in Example 1, a), from 86 g of l- (3 ', 4 -methylenedioxyphenyl) -l-cyanocyclohexane by hydrogenation, 70 g of - (3', 4 '- methylenedioxyphenyl) -1 - aminomethylcyclohexane of bp. _n 196 to 198 ⁰ C.

From the l- (3 ', 4'-methylenedioxyphenyl) -l-aminomethylcyclohexane obtained in this way the following connections were made:

b) 1 - (3 ', 4' - methylenedioxyphenyl) -1 - ethylaminomethylcyclohexane, Melting point of the hydrochloride 226 ° C., obtained analogously to Example 2, c).

The reaction of the monoethylamino compound with diethyl sulfate gave the 1- (3 ', 4'-methylenedioxyphenyl) -1 - diethylaminomethylcyclohexane, the hydrochloride of which melts at 159 ° C.

c) 1- (3 ', 4'-methylenedioxyphenyl) -l-pyrrolidinomethylcyclohexane, melting point of the hydrochloride 225 ^° C., obtained by reaction with 1,4-dibromobutane analogously to Example 1, c).

d) 1 - (3 ', 4' - methylenedioxyphenyl) -1 - piperidinomethylcyclohexane, Melting point of the hydrochloride 241 ° C., obtained by reaction with 1,5-dibromobutane analogous to example 1, c).

The used 1- (3 ', 4'-MethylendioxyphenylH-cyanocyclohexane as a starting material, bp. 198 to 203 ° C _n was obtained by reacting 3,4-Methylendioxybenzylcyanid with sodium amide and 1,5-dibromopentane.

Claims (1)

PATENT CLAIM: Process for the preparation of analeptically active phenylcycloalkylmethylamines of the general formula > - C-CH ₂ -N CH ₉ - CH, wherein R ₁ and R _{2 represent} hydrogen, the hydroxyl group, the methyl or methoxy group or together represent the methylenedioxy group, X together with the methylene groups and the central carbon atom are a cycloalkane ring with 3 to 6 carbon atoms, R _{3 is} hydrogen or a low molecular weight alkyl group, R ₄ and R ₅ denote hydrogen, saturated or unsaturated, open-chain or ring-shaped low molecular weight alkyl groups or, together with the nitrogen atom, members of a saturated ring, optionally interrupted by a further heteroatom, but R _{1 may} not denote a methoxy group if R ₂ and R _{3 are} hydrogen , X forms a cyclohexylidene radical together with the methylene groups and the central carbon atom and R ₄ and R ₆ simultaneously denote either hydrogen or methyl, characterized in that nitriles of the general formula are used in a manner known per se reduced to primary amines and, if appropriate, the phenylcycloalkyhnethylamines obtained are treated in the customary manner with alkylating agents _{which donate the radicals R 4} and / or R _5. XC-CN
CH ₂ CH-R ₃ in which R ₁ , R ₂ , R ₈ and X have the abovementioned meaning, by catalytic hydrogenation.
German Patent Nos. 970 480, 937 952, 205; Ber. German, chem. Ges., Vol. 56 B, 1923, p. 1988 ίο by 2001; J. pharm. chim. (8), Vol. 10, 1929, pp. 478 to 479 (reported in Chem. Abstracts, Vol. 24, 19, column 42868); Chem. Pharm. Bl. (Japan), Vol. 7, 1959, pp. 917-920.