DE2220712A1 - Substituted naphthylene lactamimides and processes for their preparation - Google Patents

Description

RECMTSAHVVAiTc 2220/12

DR. J !!?. ! -; L .- ^ "M. V //. LTSR BEIL

ALFRlO .; "·; \ \\

I> R. juil. ,., Λ. . · ... --.- J. WOLFF

LAi jus. ι; λ; ο «, - .:» ·. BciL April 26, 1972

FRANKrIiRr AM MAIN-HOCHST

Our no. 17 797

Richardson-Merrell Inc. New York, N.Y., V.St.A.

Substituted naphthylalkylene lactamimides and processes for their preparation

The invention relates to new substituted naphthylalkylene lactamimides, especially those that are hypoglycemic and / or coagulation-inhibiting and / or diuretic properties, as well as methods for their Manufacturing.

The novel compounds have the general formula

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in which each radical R - in the same or different

Meaning present - a hydrogen atom, a halogen atom, such as a Chlorine, fluorine or bromine atom, a trifluoromethyl radical, a straight or branched-chain alkyl radical with 1 12 C atoms, an alkoxy radical with 1 3 C atoms or a nitro radical, Y a straight or branched alkylene chain with 1-6 carbon atoms, which are optionally substituted by a phenyl or substituted phenyl radical is, where the substituents of the substituted phenyl radical are halogen atoms, such as fluorine, chlorine, bromine or iodine atoms or lower alkyl radicals with 1 - represent 3 carbon atoms,

Rp is a hydrogen atom or a lower alkyl radical with 1 - H C atoms,

R, a hydrogen atom, a lower alkyl radical with 1 - U C atoms or a halogen atom, such as a chlorine, fluorine, bromine or iodine atom, and

η is an integer from 3 to 11

mean. Also included according to the invention are pharmaceutical permissible acid addition salts of these compounds and the individual optical isomers, insofar as they are applicable.

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The compounds according to the invention are novel and unfold biological effectiveness in one or more ways, which makes them interesting for pharmacy. Closest to the invention comes a class of substituted Iminopyrrolidines and iminopyrrolines, as described in the three U, S.A. Patents 3 Io9 848, 3 121 O93 and 3 132 are disclosed »The compounds described therein are intended to be used as fungicides, aphicides and mticides be. ■

For the sake of simplicity and uniformity, all of the present compounds are referred to as substituted 2-iminoperhydro-azacarbocyclic ones Compounds of the formula I shown and named. However, it is known that such compounds in the form of acid addition salts through the tautomeric form of formula II

R ²

■ ~ anion '

/ ¹ V

< ^CH 2>

2> n

can be represented. This tautomerism is dealt with in J. Org. Chem. _32, 7 ² Jo (1967) by R. Kwok and P. Pranc. Structures of this formula could also be named in other ways. In solution, under conditions of therapeutic utility, the ratio of each tautomeric form or the delocalization of the charge is between

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the two nitrogen atoms depending on numerous factors, including the nature of the substituents, the pH of the medium, and the like. This state of equilibrium is represented by the formula III below:

^Anion

III

Of course, the revelation refers to in
both tautomeric forms shown and named compounds.

Compounds of the following are preferred according to the invention

Fornel

R ³ IV

where R has the meaning given above,

R, a hydrogen atom,

X is a lower alkyl radical with 1-5 C atoms,
a phenyl radical or a halogen atom or a lower alkyl radical with 1-3 carbon atoms

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substituted phenyl radical and η is an integer from 3-6

mean.

In the compounds of the above-mentioned formulas I, II, III and IV, R denotes either a hydrogen atom, 'Halogen atom, such as a chlorine, bromine or fluorine atom, a trxfluoromethyl radical, a straight or branched chain Alkyl radical with 1-12 carbon atoms, such as a methyl, ethyl, propyl, butyl, octyl, decyl or dodecyl radical and the like., a nitro radical or an alkoxy radical with 1-3 carbon atoms, such as a methoxy, ethoxy or propoxy radical. R can each be the same or different and in any suitable Position on the naphthyl radical to be arranged.

The radical Y in the compounds denotes those mentioned above Formulas I, II and III have a straight or branched chain Alkylene radical with 1-6 carbon atoms, such as methylene, 1,1-ethylene, 1,2-ethylene, 1,3-propylene, 1,1-butylene, 1,4-butylene, 1,5-pentylene ,. 1,6-hexylene, 2-methyl-1,4-butylene, 2-ethyl-1,4-butylene or 3-methyl-1,5-pentylene radical or the like., These alkylene radicals by a phenyl radical or by halogen atoms, such as chlorine, fluorine, Bromine or iodine atoms, or a lower alkyl radical with 13 carbon atoms, such as a methyl, ethyl or propyl radical Phenyl radical can be substituted.

The radical Rp in the formulas I, II and III means a Hydrogen atom or a lower alkyl radical with 1-4 C atoms, such as a methyl, ethyl, propyl or butyl radical.

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In the formulas I, II and III the radical R ^ means a water st off atom, a lower alkyl radical with 1-4 carbon atoms, such as a methyl, ethyl, propyl or butyl radical, or a halogen atom such as a chlorine, fluorine, bromine or iodine atom.

The alkylene lactamimide function, viz

• - f

H / ^Ν Λ.

of formulas I, II and III, or the remainder

H
X

/ ¹ N

-CH-N = C (CH ₂ )

Formol IV 3 can be found in any position on the naphthalene ring are located.

Examples of compounds according to the invention are:

Hexahydro-2- Cl-naphthylmethylin> ino) -azepine hydrochloride, HexahyJro-2- / l- (2-methyl) -naphthylmethylimino_7-azepine hydrochloride,

2- / I- (l-naphthyl) -äthylimino_7-piperidine hydrochloride, 2 ~ / 'L - (l-Maphthyl) -äthylimino_7-o ^ tahydroazocin hydrochloride, 2- (6 - Bromo-2-methoxy-1-naphthylmethylimino) azacyclotridecane and

2- / I- (5,3-Dimethyl-l-naphthyl) -äthylimino_7-hexahydroazepirihydr "· Nhlornd.

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Examples of preferred compounds are:

Hexahydro-2- / l- (l-naphthyl) ~ ethylimino-7-azepine hydrochloride _; 2- / l- (2-naphthyl) -äthylimino_7-hexahydroazepine hydrochloride, 2- / I- (4-chloro-l-naphthylJ-ethylimino_7-hexahydroazepine-

hydrochloride,

2- / l- (5,8-dimethyl-l-naphthyl) -äthylimino_7-hexahydroazepine hydrochloride,

2- / 2-methyl-l- (l-naphthyl) propylimino7-hexahydroazepine hydrochloride,

lävo-2 ~ / l- (l-naphthyl) ethylimino7-octahydroazoein hydrochloride,

Hexahydro-2 - / ^ - methyl-o- / i-naphthy l7-benzyl) -inm ^ -azepihhydrochlorid,

2- / ä- / i-fluoro-1-naphthyl7-benzyl) -imino7-piperidine hydrochloride.

Pharmaceutically acceptable acid addition salts of the invention Compounds are those salts formed with a suitable inorganic or organic acid vererden. Inorganic acids for this purpose include, for example, hydrochloric and hydrobromic acid, and sulfuric acid or phosphoric acid and the like. Suitable organic acids are, for example, carboxylic acids such as acetic acid. Propionic acid. Glycolic acid, lactic acid, pyruvic acid, Malonic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, Benzoic acid, Ilydroxybenzoic acid, phenylacetic acid, Cinnamic acid, salicylic acid, 2-phenoxybenzoic acid and derpl. or sulfonic acids "such as methanesulfonic acid, 2-hydroxyethane sulfonic acid etc.

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It has been found that the novel Compounds including acid addition salts and the individual optical isomers - as far as this applies, hj'poglycemic and / or have anti-coagulation and / or diuretic activity and they are in the form of pjlhrmaaeuti & cher Preparations containing the new ones suitable for oral or parenteral administration. Compounds contain, used can be. The amount of compound in unit dose; can fluctuate within a wide range, so that to ore the desired effect from about 1.0 to c tv; a 100 mg / kg body weight of the person treated per dose may exist. For example, if the person being treated (patient) weighs 70 kg, the desired effect can be achieved through administration Achieve from 25 - 500 mg of active ingredient one to four times or more a day.

The mode of action of the compounds according to the invention is explained below:

The compound of Example 1 exhibited 80 # inhibition in vitro of adenosine diphosphate-induced platelet accumulation in human platelet-enriched plasma after adding 100 mg of compound per ml of plasma. When 25 mg / kg of body weight of the compound of Example 13 was orally administered to rats, the urine excretion measured in ml increased - compared to a control group - by 203 % in five hours. When the third compound of Example 5 clv rats was administered in an amount of 50 mg / kg body weight, there was a 38 % reduction in plasma glucose compared with the control group.

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The compounds of the invention are made by reaction an excess of lacci ether of the formula

lower alkyl-O- (

with a primary amine of the formula

Y-NH ₀

^d VI

following the procedure of R. E. Benson and T.L. Cairns, J. Am. Chem. Soc. 70, 2115-8 (1948). The one in it Symbols n, R 1, R and Y used have those above mentioned meaning and the lower alkyl radical means a methyl or ethyl radical or the like. The reaction can with or without using a solvent. If a solvent is used, it is preferred a lower alcohol such as methanol or ethanol. However, other solvents such as benzene and toluene are also suitable and the like. The reaction mixture may contain a basic or acidic catalyst, e.g. a tertiary amine or hydrogen chloride can be added. Generally one uses preferably the hydrochloride salt of the amine in the reaction. The reaction temperature can vary from -40 to 180 ° C and is preferably from about 15 to 25 C. The reaction ·

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- Io -

time is about one hour to about 60 days and depends on the reaction temperature and the reactant used primary amine and even more on the degree of steric hindrance of the amine, since it is sterically hindered Amines react very slowly.

The lactimethers to be used for this reaction can be commercially available according to known processes from appropriate available lactams. For example, by reacting a suitable lactam with dimethyl sulfate in a solvent such as benzene, toluene, xylene or the like at the reflux temperature of the solvent the corresponding O-methyllactimether for 2-24 hours.

The amines to be used according to the invention - either as the free base or as the hydrochloride salt - can be obtained by various known processes. For example particularly suitable for this is the Leuckart reaction, in which the corresponding Naphthonderivat 2 to 12 hours with ammonium formate to about 180-200 ⁰ C is heated to form the desired amine. The naphthone derivative can be prepared by a standard Priedel-Crafts reaction of appropriately substituted naphthalene with a suitable acyl halide, or by the Grignard reaction of a suitable alkyl or aryl magnesium halide with a naphthalenonitrile. The resulting Grignard complex can also be reduced to the amine iri situ with LiAlH ₂ , whereby the I e'Jckart reaction is circumvented.

Likewise, the above reaction can be used using known thiolactim ethers, such as S-methylthiocapro-

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lactira (H. Behringer and H. Meier, Ann. 607, 67-91 *. 1957) or with the use of thiolactams, in which case it can be advantageous in the latter case, a catalyst such as mercury or silver oxide or -cyanide (J.A. Gautier and, J. Renault, CR. Acad, Sci. 2j [4, 2081, 1952).

The compounds according to the invention can also be prepared with the aid of a complex compound from a corresponding lactam and phosphorus oxychloride, phosgene, boron trifluoride etherate, dimethyl sulfate, hydrogen halide or a combination of two or more such reagents. The reaction is treated by H. Bredereck in a series of articles in Chem. Ber., 1953 ~ 1968, in particular in Volume 91, 2278 (1961) and Volume £ 7, 1 * 103 (1964). The complex formed is reacted with a corresponding primary amine described above in an aromatic hydrocarbon solvent such as benzene, toluene or xylene, or an alkyl polyhalide solvent such as carbon tetrachloride, chloroform, methylene chloride, tetrachlorethylene or the like. The reaction temperature is limited by the boiling point of the solvent; but it is in some cases advantageous, at room temperature or under cooling at 0 to -40 ⁰ C, depending on the reactants used to carry out the reaction.

Compounds according to the invention with a pentamethyleneimine radical can also by catalytic hydrogenation of a corresponding aminopyridine derivative according to T.B. Grave, J. Am. Chem. Soc. _46>, 1460 (1924), M. Freifelder and colleagues, J. Org. Chem. 2j), 3730 (1964) and L. Birkcfer, Ber. 75 429 (1942).

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The specific examples below are representative Compounds of the invention and their preparation explained.

example 1

Hexahydro-2-fl- (l-naphthyl) ethy] imino 3-azepine hydrochloride.

A mixture of 50.0 g of o- {1-naphthyl) ethylamine hydrochloride and 37.0 g of O-methylcaprolactim in 200 ml of anhydrous ethanol was stirred for three days at room temperature. The resulting precipitate was filtered off, recrystallized from anhydrous ethanol and dried. There were 33> OS ^it d desired product were obtained. Melting point 251.5-252.5 ° C.

The above compound was also obtained from the free base of the amine by adding one equivalent of hydrogen chloride to the reaction mixture, the hydrochloride salt being formed in situ .

Example 2
O-methylvalerolactime.

A refluxing solution of 100 g (1.01 moles) of vaierolactam in 350 ml of dry benzene was 125 pounds (0.99 mol) of dimethyl sulfate were added dropwise. The mixture was kept under reflux overnight and then treated with saturated potassium carbonate solution and dried and that Solvent was evaporated. The product was distilled at 20 im. Boiling point 55 - 57 C.

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Example 3

Was used in the procedure of Example 2 instead of the valerolactam the corresponding equimolar amount of butyrolactam (2-pyrrolidone), enantholactam or caprylolactam is used, so you got

O-methylbutyrolactim; Boiling point 65-67 ⁰ C (100 now), Ü-methylenantholactim; Boiling point 48-53 ° C (2.0 mm), Q-methylcaprylolactim; Boiling point 44 - 46 C (0.5 mm).

Example 4

Were used in the procedure of Example 1 instead of the o- (l-naphthyl) -äthylamina the corresponding equimolar amounts of 1-naphthylmethylamine or 2-methyl-1-naphthylmethylamine used, one obtained

Hexahydro-2- (1-naphthylmethylimino) azepine hydrochloride; Melting point 214-214.5 ° C,

Hexahydro-2- [1- (2-methyl) -naphthylmethylimino 3-azepine hydrofluoride;

Melting point 223- "227.5 ° C

Example 5

Was used in the procedure of Example 1 instead of the Q-methylcaprolactim an equimolar amount of O-methylvalerolactime, 0 ~ methylbutyrolactim or O-methylenantholactim used, so c-rhit: It man

2- [i - (i-naphthyl) ethylimino J-piperidine hydrochloride; Melting point 258 - ■ 259 ° C,

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2- [1- (1-naphthyl) ethylimino J-pyrrolidine hydrochloride;

Melting point 300 - 300.5 ° C,
2- fl "(l" naphthyl) ethylimino D-octahydroazocin hydrochloride; Melting point 234 to 235.5 ⁰ C

Example 6 ■

2-fl- (1-naphthyl) -äthylimino J-azacyclotridecan-hydrochlorii.

A solution of 21.7 g of 2-azacyclotridecarr in 200 ml 15.3 ε phosphorus oxychloride were added dropwise to dry benzene. With the exclusion of atmospheric moisture, the mixture was stirred for four hours at room temperature and then treated with 17.1 g of a- (l-naphthyl) ethylamine. It stirring was continued for one hour at room temperature and then for four hours at reflux temperature. The mixture was parked overnight, then washed with 2N MaOH and then treated with 2N HCl, which leads to the formation of Methylene chloride led. The organic phase was dried over sodium sulfate and the solvent was evaporated. The obtained material was made from acetone and mixtures of methanol / acetone to give the desired one Recrystalline product with a melting point between 217 and 219 C. sated.

Example 7

2- Ll- (naphthyl) ethylimino 3-octahydroazonine hydrochloride.

The procedure of Example 1 was followed using the corresponding equimolar amount of O-methylcaprylolactime instead, dos O-methylcaprolactim carried out, s-> received

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- 15 - ■ ■ ■.

you get the product you want. That connection was too obtained by the procedure of Example 6 if one 2-Azacyclotridecancn by the corresponding equimolar Amount of 2-azacyclododecanone replaced.

Example 8 . _: ^; , "

Using the corresponding equimolar amount of jJ-Chiorcaeprolactam or l-methyl-2-piperidone instead of the 2-Azacyclotridecanone followed the procedure of the example to 3-chloro-2-11- (1-naphthyl) ethylimino 3-hexahydroazepine hydrochloride respectively. " .

l-methyl-2-ti- (l-naphthyl) ethylimino 3-piperidine hydrochloride.

Example 9

2- fl- (2-naphthyl) -äthylimino ^ -hexahydroazepine hydrochloride.

Using the corresponding equimolar Menn; e of c- (2-Wnphthyl) -äthylamine (AW Ingersoll and coworkers, .τ. Ära. Chem. Soc. 5jR, 18p8 - 18ll, 1936) instead of ο • (l-Naphthyi) ethylamine the procedure of example 1 led to the desired product, mp 251 - .252 ⁰ C.

Example Io . -. ·. .

Using the corresponding equimolar amount of ^ -Mitro-1-naphthalenemethylamine (P. Kristian and coworkers ^., Coll. Czech. Chem. ¹ Commun. JO, 3658-63, 1965) or 'l "Mc-» thoxy-- c-! nethylnaphthalene-methylamine (B. Day and S ..; «viofr'Palarr, Arch. Pharm. 277, 359-74 and 377-98, L'jj ^) .'.-. nstolle of c- (ll > Taphthyl) -äthy-lamin led the way

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Procedure of Example 1 too

Hexahydro-2-fl- (5-nitronaphthyl) -methylimino 3-azepine hydrochloride and

Hexahydro-2- [l - (*} - methoxy-l-naphthyl) ethylimino J-azepine hydrochloride.

Example 11

2- [2- (6-methoxy-1-naphthyl) ethylimino 3-piperidine hydrochloride.

Using the corresponding equimolar amounts of ß-methoxy-1-naphthalene ethylamine (SV Kessar and coworkers, Tetrahedron Letters 1965 »32 * 15) or O-methylvalerolactim instead of ü- (l-naphthyl) ethylamine and O-methylcaprolactim resulted Procedure of the example to the desired product.

Example 12

2- (6-Bromo-2-methoxy-1-naphthylmethylimino) -azacyclotridecane hydrochloride. ,

The process was carried out using the corresponding equimolar amount of 6-bromo-2-methoxy-1-naphthalenemethylamine (RD Haworth and coworkers, J. Chem. Soc. 1952 , 2857-8) instead of ct- (1-naphthyl) ethylamine of Example 6 to the desired product.

Example 13

2 ~ [l-Ci-chloro-l-naphthyD-ethylimino 3-hexahydroazepine hydrochloride.

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A. A mixture of 50.0 g of 4'-chloro-l'-acetonaphthon (prepared according to the method according to DT Mowry and coworkers, J. Am. Chem. Soc. 68> Ilo5, 1946) and 49.0 g of ammonium formate was used slowly with stirring to 150 - 155 ⁰ C heated. After the initial foaming had subsided, the temperature of the hot bath was increased to 180-195 ° C for five hours. After cooling, the mixture was treated with various portions of water and then with benzene. 31 ml of concentrated HCl were added to the residue. The mixture was refluxed for one hour, then cooled and neutralized with 40% sodium hydroxide solution. The product, 4-chloro-a-methyl-lnaphthylmethylamine, was extracted into ether, converted into the hydrochloride salt and recrystallized from acetonitrile / methanol; Melting point 293-294 ° C.

B. A mixture of 24.2 g of 4-chloro-G-methyl-1-naphthylmethylamine hydrochloride and 12.7 g of Q-methylcaprolactim in 50 ml of anhydrous ethanol was left for three days at room temperature touched. At first the mixture became homogeneous, then A precipitate formed which was recrystallized from acetonitrile / methanol to give the desired product; Melting point 263 - 265 *

-O

Example 14 _; ., ^:

Using the corresponding equimolar amounts of -fluoro-l'-acetanaphthon (S ^ Berkovic, Israel J \ Chem. J .., 1 - II »1963) or T'-fluoro-l'-acetanaphthon. (E. Jensen, Isfp.el J. Chen. 3, 79-82 * 1965) instead of U'-chlorine-! '- a ^ etonaphthon was obtained by the method of Example 13.

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- Ιοί? · - tl ~ (k -Fluor- l-naphthyl) "äthylimino 3-HeJcahydroazepin- hydrochloride and

2-Ll- (7-fluoro-1-naphthyl) ethylimino 3-hexahydroa2epine hydrochloride.

Example 15

2- II- (5,8-dimethyl-1-naphthyl) -ethylimino .T-piperidine hydrochloride.

A. With vigorous stirring, a suspension, cooled to 0-10 ° C., of 50.0 g of anhydrous aluminum chloride in 225 ml of carbon tetrachloride 29, ^{for example} acetyl chloride, and then 50.0 g of ^{1, 1-dimethylnaphthalene were added dropwise.} The mixture was stirred for four hours and then poured onto ice and dilute HCl. The organic phase was separated off, _{washed with 2N HCl and 10 μl Na 2} CO, solution and dried over sodium sulfate, and the solvent was evaporated. The oil obtained in this way was distilled _{at 0 t} b rr.ia; Boiling point 1 ^ 5 - lf> 5 C, 5 ¹ jS ^ -dimethyl-l'-acetonaphthon, which by Leuckart reaction according to Example 13 (Λ) in o, 5,8-trimethyl-l-naphthalenemethylamine-h;
was leading.

methylamine hydrochloride with a melting point of 270 - 271 C

B. Using the corresponding equimolar amounts of O-methylvalerolactime and 0,5,8-trimethyl-1-naphthalenemethylamine-HCl instead of O-methylcaprolactim and 1-Clilora-methyl-1-naphthylniethylamine-HCl, remäP was obtained . Process of example 1} (B) the desired product, with i>cliW> i-5ipunkt 205-2C> 7 ° C (below decomposition). · ' ■■. ■: ■

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-, 19 -

Example 16

2- ri ~ (5 ₃ 8-dimethyl-.l-naphthyi) .- ethylimino J-hexahydroazepine hydrochloride. . '■ "· ■

Using the appropriate equimolar amount of Q-Fiethyloaprolaetlm received instead of O-methylvalerolactir follow the procedure of Example 15 (B) to obtain the correct finish .Product with melting point 265 - 267 C (with decomposition). ·

■ Example 17

2 - [! - (^ - Dodecyl-1-naphthyl) ethylimino 3-hexahydroazepine hydrochloride. ■

Using the appropriate equimolar amount of 3- (l-naphthyl) dodecane (D. G. Anderson and co-workers, J. Ghem. Soc. 1953, 413 -, 45O) - instead of 1,4-dimethylnaphthalene obtained according to the procedure of Example 15 (Λ) ^ -dodecyl-o-methylnaphthalenemethylamine hydrochloride.

Use the corresponding equimolar amount of 'l-dodecyl-c-methylnaphthalenemethylamine hydrochloride anstolle.von 4-chloro-o-methyl-1-naphthylmethylamine hydrochloride Following the procedure of Example 13 (B), the desired product was obtained.

Example 1 8. '

? - te-f-tethy 1 -1- (1-naphthyl) -propy 1 imino .T-hexahydroavsepine hydrochloride.

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A Grignard reagent was prepared from J> 1 ₃ 8 g of magnesium turnings and 161.0 ρ isopropyl bromide in 250 ml of anhydrous ether. To this reagent, 50.0 g of 1-cyanonaphthalene in 800 ml of dry toluene were added dropwise.
When the exothermic reaction had subsided, the mixture was boiled until it reached the boiling point
Toluene heated, and all the ether evaporated xirar. The mixture was refluxed overnight, then
cooled and carefully mixed with 600 ml of 6N HCl. This mixture was refluxed for 6 hours and the organic phase was separated. The crude product obtained from the organic phase was distilled at 0.6 mm, boiling point 160-170 ° C., yielding 56.2 g of 2-methyl-

25th
l'-propionaphthon, N ^ = 1.5925 This was in ct-Iso-

propyl-1-naphthalenemethylfinine hydrochloride, melting point
Transferred to 289 ⁰ C according to the procedure of Example 13 (A) - 288th

Using the corresponding equimolar amount of o-isopropyl-1-naphthalenemethylamine hydrochloride instead of U- chloro-o-methyl-1-naphthylmethylamine hydrochloride
Following the procedure of Example 13 (B), the
desired
setting).

desired product, melting point 290 - 291 ° C (under dec

Example 19

Hexahydro-2-fl- (2-trifluoromethyl-1-naphthyl) -ethylimino D-p.zepine hydrochloride.

Using the procedure of Example 18, 2'-trifluoromethyl-1'-acetonaphthone was obtained from 2-trifluoromethyl-lnaphthonitrile (L. Yagupol'skii and Yu Fialkov, Zhur,

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Obsehei Khim 2_9, 3082, 1959) and according to the example 13 (Λ) in a-methyl-2-trifluoromethyl-l-naphthalenemethylamine hydrochloride convicted. If you put rips into the process Example 13 (B) instead of 4-chloro-α-methyl-1-naphthylmethylamine hydrochloride the corresponding equimolar amount of arMethyl-2-trifluoromethyl-1-naphthalenemethylamine hydrochloride a, the desired product was obtained.

Example 2o

Hexahydro-2- [1- (1-naphthyl) pentylimino 3-azepine hydrochloride.

Using the procedure of Example 18 was prepared ketone using butylmagnesium n-butyl-1-naphthy! (Boiling point 185 -'189 ⁰ C, 0.5 mm), and then according to Example 13 (A), but using a higher Temperature (200 G) converted into cr-n-butyl-1-naphthylmethylamine hydrochloride, melting point 246-247 ° C.

According to Example a 3 (B) using the corresponding equimolar amount of a-n-butyl-1-naphthylmethylamine hydrochloride instead of 4-chloro-o-methyl-1-naphthylmethylamine hydrochloride the desired product, melting point 200 - 201 ° C.

Example 21

Hexahydro-2- [1- (6-n-hexyl-2-naphthyl) -hexylimino 3-azepine hydrochloride.

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Using the corresponding equimolar amount of n-pentyl-6-n-hexyl-2-naphthyl ketone (B. Bannister and B. Eisner, J. CIe ^- I. Soc. 1951 , Io61) instead of V-chloro'-acetonaphthon according to Example 13 (Λ) 6-n-hexyl-an-pentyl-2-naphthylmethylamine hydrochloride.

Using the corresponding equimolar amount of 6-n-hexyl-o-n-pentyl-2-nap \; hylmethylamine hydrochloride instead of a- (l-naphthyl) ethylamine hydrochloride, according to Example 1, the desired product was obtained.

Example 22

Using the corresponding equimolar amounts of ß-isopropyl-1-naphthaleneethylamine (H. Pacheco and R. Gaige, Bull. Soc. Chim. France 1965 , 86l - 868) and of 1-naphthalene-pentylamine (C. Skinner and co-workers, J. Am. Chem. Soc. £ 9, 2843-6, 1957) instead of a- (1-naphthyl) ethylamine, the procedure of Example 1 was followed

Hexahydro-2- i2-isopropyl-2- (1-naphthyl) ethylimino "} - azepine hydrochloride and

Hexahydro-2-15- (1-naphthyl) pentylimino 3-azepine hydrochloride.

Example 23

5-tert-butylhexahydro-2-ri- (l-napthyl) -ethylimino] -azepine hydrochloride.

Using the appropriate equimolar amount of 5-tert-butylcaprolactam instead of 2-azacyclotridecanone led to the procedure of Example 6 to the desired one Product with melting point> 300 ° C.

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Example 24

2- [(α- ( ¹ I-PIuOr-1-naphthyl) -benzyl) -imino 3-hexahydroazepine hydrochloride.

A. 4-Fluoro-1-naphthylmagnesium bromide, prepared from 2.7 g of magnesium turnings and 25 jO g of 1-bromo-4-fluoronaphthalene in 100 ml of anhydrous ether, was added dropwise with 9 _{seconds of} 6 g of benzonitrile. The mixture was refluxed for one hour and turned off via na cit. The resulting heterogeneous mixture of ketimine salt was added portionwise to a slurry of 4.2 g of lithium aluminum hydride under 500 ml of anhydrous ether, and the mixture was stirred and refluxed overnight. The mixture was then decomposed by carefully adding 4.2 ml of water, 4.2 ml of 3N NaOH and 12.6 ml of water over a period of four hours. The resulting precipitate of inorganic material was filtered off and washed with ether. The Piltrat was acidified with 2N HCl and the resulting precipitate was collected and recrystallized twice from isopropanol / water to give 14.0 g of α- [l- (4-Pluornaphthyl)] -benzylamine hydrochloride with melting point 290-292 ⁰ C (under Decomposition) recrystallized.

B. Using the appropriate equimolar amount of c- [1- (4-fluoronaphthyl) 3-benzylamine hydrochloride instead of a- (2-naphthyl) ethylamine hydrochloride, the process according to Example 1 led to the desired product, Melting point 278-279 ° C (with decomposition).

Example 25

2- [(c- [4-Fluoro-1-naphthyl 3-bensyl) -imino3-piperidine hydrochloride.

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Using the corresponding equimolar amounts of c-fi (4-fluoronaphthyl)] benzylamine hydrochloride and O-methylvalerolactim instead of ct- (l-naphthyl) ethylamine hydrochloride and O-methylcaprolactim, the procedure of Example 1 led to the desired _product's melting point ^197-0

Example 26

Hexahydro-2- ("(e-methyl-ct-fl-naphthyl 3-benzyl) -imine 3-asepine hydrochloride.

A. Using an appropriate amount of 3-naphthyl magnesium bromide, made from 1-bromonaphthalene and magnesia turnings instead of 4-fluoro-l-naphthyl magnesium bremide and using an appropriate amount of o-methylbenzonitrile instead of benzonitrile the procedure of Example 24 (A) to o-methyl-Cr- (I-naphthyD-benzylamine hydrochloride.

B. With occasional stirring, a slurry of 14.2 g of o-methyl-o- (1-naphthyl) benzylamine hydrochloride in 27 ml of O-methylcaprolactim was allowed to stand at room temperature for three days. A small amount of anhydrous ethanol was added to keep the slurry stirrable. After cooling, the pesticide obtained was collected, washed with ether and recrystallized from methanol / acetone to obtain the desired product, melting point 290-292 ° C. (with decomposition).

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Example 27

Hexahydro-2- [(o-methyl-α- [2-naphthyl 3-benzyl) imino] azepine hydrochloride.

The procedure was carried out using an appropriate amount of 2-bromonaphthalene in place of: L-bromonaphthalene of Example 26 (A) to o-methyl-α- (2-naphthyl) benzylamine hydrochloride. This was instead of o-methyl- (l-naphthyl) -benzylamine hydrochloride used in the procedure of Example 26 (B). The desired product with a melting point of 308-3O9 ° C. was obtained

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Claims (13)

Claims R each represents a hydrogen atom, a halogen atom, a Trifluoromethyl radical, an alkyl radical with 1 to 12 carbon atoms, an alkoxy radical with 1 to 3 carbon atoms or a nitro residue, Y is an alkylene radical having 1 to 6 carbon atoms, which is replaced by a phenyl radical or by halogen or a lower alkyl radical having 1 to 3 carbon atoms substituted phenyl radical can be substituted, Ro represents a hydrogen atom or a lower alkyl radical 1 to 4 carbon atoms, R-, a hydrogen atom, a lower alkyl radical with 1 to i | Carbon atoms or a halogen atom, and η is an integer from 3 to 11
mean. 209848/1223 2.) Compound according to claim 1, wherein Y of the formula -CH- and X is a lower alkyl radical up to 5 carbon atoms, R _{0 is} a hydrogen atom, R is a hydrogen atom ₃ and η is an integer from 3 to 6. 3.) A compound according to claim 2, wherein X of the formula is a Means methyl radical. h.) A compound according to claim 3, in which R of the formula in each case denotes a hydrogen atom. 5.) Hexahydro-2-fl- (l-naphthyl) -äthylimino3-azepJn or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 4. 6.) 2- [1- (2-Naphthyl) ethylimino 3-hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 4. 7.) 2- [1- (1-Naphthy1) ethylimino 3-octahydroazocin or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 4. 8.) 2- ti- (iJ-chloro-1-riaphthyl) ethylimino 3-hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 3 209848/1228 9.) 2- [1- (5,8-Dimethyl-1-naphthyl) -ethylimine-3-hexahydroazepine oder.a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 3 Io.) 2- t2-methyl-1-. ("1-naphthyl) propylimino 3-hexahydroazepine or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 2. 11.) A compound according to claim 1, wherein Y of the formula -CH- and X is a phenyl radical or a substituted one Phenyl radical, where the substituents on the substituted phenyl ring are halogen or lower alkyl with 1 to Represent 3 carbon atoms, R _{2 is} a hydrogen atom, R, a hydrogen atom, and η is an integer from 3 to 6. 12.) Hexahydro-2- ("(o-methyl-o- {1-naphthyl-3-benzyl) -azepm or a pharmaceutically acceptable acid addition salt thereof as a compound according to claim 11. 13.) 2- [(σ- PJ-fluoro-1-naphthyl 3-benzyl) -imino.! - piperidine or a pharmaceutically acceptable acid addition salt the same as a compound according to claim 11. I ¹ J-) Process for the preparation of a compound A. in the form of the general formula 209848/1228 (CH ₂ ) _n or B. in the form of a pharmaceutically acceptable acid addition salt the same, R each represents a hydrogen atom, a halogen atom, a Trifluoromethyl radical, an alkyl radical with 1 to 12 Carbon atoms, an alcohol radical with 1 to 3 carbon atoms or a nitro radical, Y is an alkylene radical having 1 to 6 carbon atoms, substituted by phenyl or by halogen or lower alkyl phenyl substituted with 1 to 3 carbon atoms can be substituted, Rp is a hydrogen atom or a lower alkyl radical with 1 to k carbon atoms, R, a hydrogen atom, a lower alkyl radical with 1 to 4 carbon atoms or one halogen atom, and η is an integer from 3 to 11 mean, characterized in that one has an excess of a lactimether the formula N -...
lower alkyl-OC 209848/1228 - 3ο - where R- and η have the meaning given above, with a primary amine of the formula - Y-NH, or a salt of the same, where R and Y have the meaning given above, implements. For Richardson-Mefrrell Ine, Dr.H.J. \ 7olff (Lawyer) 209848/1220