DE1421000A1 - Bicyclic guanidines - Google Patents

Description

Patent attorneys. · -Η DlPL-ING. E. SPIANEMANN ^u

DIPt-ING-J-RICHTER. . blPL-lNG. R. SPLANEMANN

8000 monks 2 -ι /, o-innn

TheaflMmraee 33Ö4. IH ^ lUUU

33Ö4

CIBA AKTIENGESELLSCHAFT, BASEL (SWITZERLAND)

Case SU 248/1 + 2 / E New documents for

Disclosure

Patent registration in Germany

(G 22 641 IVd / i2p)

Bcyolic guanidines.

The invention relates to non-aromatic azabicycloalkyl- (N) -alkyi-guanidines of the general formula I.

A i ^An

\? m ^H 2 »

ι η 2n

BATH ORIGINAL 809805/0774 '

Documents (Art.711AlNk2Nr.l8 "U3dMÄn (tonina" w. "4.9.19e

and their .Salze, _ in which A is a 1-5-membered hydrocarbon chain which can also contain a double bond, m are the numbers 0-6, mV 2-7, η and n ^f 0-3, and R and R * stands for hydrogen or lower alkyl, with the proviso that CH separates the bridgehead atoms by a maximum of 2 carbon atoms, m + η + n '£ 2 if A forms a 3-5-golden isocyclic ring with the bridge members and m = 1 is when A forms a 5-membered isocyclic ring with the bridge members.

The azabicycloalkyl group is preferably replaced by the guanidino group by 2-3 carbon atoms of the alkylene radical separated. This means specifically 1,2-ethylene, 1,2-, 2,3- or 1> 3-propylene, also 1,3- * 2,3- or 1,4-butylene, 1,4- or 1,5-pentylene.

Azabicycloalkyl radicals. are preferably those of the general formula II or III. "

C Η " II or

BATH ORIGIfML 809805/0774

/ Vl-2R ₂ QJ Il D (C) _n . EN— III

^X (OH) ₂ ^ ₁ G- (CH _{2) 0} _ ₃

R ¹

where RR ¹ ″ stands for hydrogen or methyl, with the proviso that ring B has at least 6 ring members and ring E contains at least 5 ring members when ring D has 5 ring members.

Salts of the new compounds are primarily acid addition salts which can be used therapeutically.

The guanidines of the present invention reduce the norepinephrine content of the peripheral sympathetic nerves or interfere with their norepinephrine release and therefore cause a weakening of the sympathetic nerve stimuli hypertensive effect. These compounds can therefore be used as antihypertensive drugs to treat high blood pressure, especially neurogenic hypertension.

The bicyclic compounds according to the invention develop their physiological effectiveness on the basis of a new one Mechanism of action that is only found in compounds of the type < of 2-heptamethyleneimino-ethyl-guanidine can be found. These new mode of action can be achieved by relaxing the nictitating membrane

809805/0774

unanesthetized dog, abolition of the Carotid Abklemmungsrefle-Xes on the dog anesthetized with Nembutal and by antagonism to the pressure effect caused by amphetamine on the dog anesthetized with Nembutal. (See Maxwell et al., Journal of Pharmacology and Experimental Therapeutics, Vol. 128, p. 22, January 1960). ^- '

These new compounds with a novel chemical structure, e.g. 2- (3-isogranatamino) ethyl guanidine sulfate, 2- (4, 7, 8, 9-tetrahydro-isoindolino) ethyl guanidine sulfate, 2-hexahydro-isoindolino-ethyl-guanidine sulfate and 2-decahydro-isoquinolino-ethyl-guanidine sulfate show an equivalent in comparison to 2-heptamethyleneimino-ethyl-guanidine-sulfate The effect and the degree of effectiveness of these compounds is in the range of that of the comparison substance.

Particularly noteworthy are compounds in which the radicals of the general formulas IV and V

IV

CH --- (CH _{2) 0} _ ₂

I ^E I
cVo-i *.

^(CH 2 ^} 0-l ^0Η ~

BATH ORIGINAL 809805/0774 ■ ·

with the rest of the. Formula VI

NH

VI

are connected and their therapeutically applicable acid addition salts, with the proviso that ring B has at least 6 ring members and ring E contains at least 5 ring members if ring D has 5 atoms; namely 2- (hexahydro-indolino) -ethyl-guanidine, 2- (decahydro-isoquinolino) -ethyl-guanidine,
2- (3-Isogranatanino) ethyl guanidine or 2- (4, 7, 8, 9-tetrahydroisoindolino) ethyl guanidine, and their acid addition salts, especially the sulfate or the hydrochloride.

The new compounds are obtained by either in a manner known per se

a) an azabicycloalkyl- (N) -alkylamine of the general formula

GM-NH ₂ VII,

where G is the grouping

^C n ^H 2n

° · _η ^{Η 2η} ·

BATH ORIGINAL 809805/0 774

M denotes the radical -C, H, _, melts a compound

the general formula

NH

YC VIII ,

NH ₂

where Y is a removable radical, or reacts with cyanamide or salts thereof or

b) a reactive ester of a guanidino

alkanols of the formula

NH

HO-M-NH-C - IX

with an azabicycloalkane of the general formula G-H or reacting a reactive ester of an azabicycloalkyl- (N) -alkanol of the general formula G-M-OH with guanidine or

c) an azabicycloalkyl- (N) -alkyl ^ cyanamid of general formula

G-M-NH-CN X

or a functional derivative of a corresponding azabicycloalkyl (N) -alkyl-carbamic acid or azabicycloalkyl- (N) -alkyl-thiocarbamic acid reacted with ammonia or optionally hydrolyzed with aqueous mineral acid or

d) an azabicycloalkyl- (N) -alkyl-guanidine of the general Formula I, wherein a carbon atom of the alkyl group with the adjacent guanidino or imino nitrogen atom and / or a ring carbon atom with the neighboring one

809805/0774

Imino nitrogen is a carbamyl or thiocarbamyl group forms, reduces,

and optionally subsequently obtained salts are converted into the free bases in a manner known per se or treated free bases obtained with acids.

Cleavable radicals Y are, for example, alkyl mercapto, Alkoxy or 1-pyrazole radicals.

Compounds of the formula VIII shown in procedure a) are, for example, S- or O-substituted Isothioureas or isoureas, such as S-lower alkylisothioureas or O-lower alkyl isoureas or 1-guanyl pyrazoles. 1-guanyl-pyrazoles are mainly in the core, e.g. substituted by lower alkyl groups. The compounds mentioned can also be used in the form of acid addition salts, mainly mineral acid addition salts are present.

A particularly preferred compound of this group is S-methyl-isothiourea and its mineral acid addition salts, especially the S-methyl isothiourea sulfate. Further can also be preferred compounds O-methyl isourea sulfate, or 1-guanyl-J, 5-dimethylpyrazole nitrate will.

The reaction with S-lower alkyl-isothioureas isoureas or O-lower alkyl is preferably carried out in the presence of diluents, the selection _of:; with regard to the solubilities of the reaction components. ■ Water, for example, can be used as a diluent or solvent

BATH ORIGINAL

809805/077 / f

or water-miscible organic solvents, e.g. alkanols such as methanol, ethanol, propanol, i-propanol or tert. Butanol, ethers such as diethylene glycol diethyl ether, p-dioxane or tetrahydrofuran, ketones such as acetone or methyl ethyl ketone, Lower alkanecarboxylic acids, such as acetic acid, or formamides, such as formamide or dimethylformamide, or their aqueous mixtures. The reaction can be carried out at room temperature or, if necessary, at an elevated temperature, e.g. at the boiling point the solvent or diluent, at normal or elevated pressure or in the presence of an inert gas, e.g. Nitrogen.

The reaction with cyanamide is carried out, for example, in such a way that a mixture of the azabicyeloalkyl- (N) -alkylamine of the kind mentioned above, especially a salt thereof, e.g. an addition salt with a mineral acid such as Hydrochloric acid, hydrobromic acid or sulfuric acid, and the cyanamide heated, the obtained melt in a solvent, E.g. a lower alkanecarboxylic acid, such as acetic acid, dissolves and the reaction product in a manner known per se isolated. The above reaction can also be carried out in the presence of a solvent or diluent, e.g. a lower alkanol, such as ethanol, or a concentrated aqueous acid such as hydrochloric acid, can be carried out, the acid addition salt of the starting product can also form an intermediate. The cyanamide can also be formed as an intermediate.

BATH ORIGINAL 809805/0774

The reaction can be exothermic, if necessary, heated one to temperatures between about 80 and 200, possibly in the presence of an inert gas, e.g. nitrogen.

The implementation of the azabicycloalkyl- (N) -alkylamines described above with a 1-guanyl-pyrazole takes place in Anoder Absence of a diluent, for example by heating the mixture to each melting point or in the presence a solvent, e.g. a lower alkanol such as ethanol, to its boiling point. It is advantageous to close them Presence of carbon dioxide by using an inert gas.

Examples of reactive, functional carbamic acid derivatives or thiocarbamic acid derivatives are Compounds mentioned in which as substituents of the azabicycloalkyl- (N) -alkyl group of the general formula G-M- given above, the following radicals are possible: ureido or thioureido groups, e.g. isoureido or isothioureido groups etherified by lower alkanols or aralkanols or e.g. by lower alkanols or aralkanols esterified carbamic acid or thiocarbamic acid groups or carbamic acid halide groups or cyanurea or cyanthiourea groups or their tautomeric groups To shape.

Such substituents are converted into the guanido group in the customary manner, mostly by ammonolysis or optionally hydrolysis.

BATH ORIGINAL

809805/077 / »

- ίο -

For the implementation of the azabicycloalkyl- (N) -alkylcyanamides of the general formula X with ammonia, one can use the Apply ammonia in liquid form under pressure and preferably at elevated temperature, if desired, in the presence an anion donor, such as ammonium acetate, sulfate or chloride, which forms a stable salt with the guanidine formed. Instead of ammonia, ammonia-releasing agents, such as secondary ammonium phosphate, can also be used or can be left Ammonium nitrate to an alkaline earth metal, such as calcium, or alkali metal, act like sodium or potassium compound of cyanamide in the presence of catalytic amounts of water.

If the azabicycloalkyl- (N) -alkyl group is substituted by the ureido group, the reaction with ammonia can be carried out for example, in the presence of a dehydrating agent such as phosphorus pentoxide. This reaction is mostly increased at Temperature carried out in closed vessel; The temperature and pressure can be lowered if they are non-aqueous Diluents and / or reaction accelerators, such as finely divided nickel, aluminum or aluminum oxide, can be used.

In the case of analogous compounds with a thioureido group, they are reacted with ammonia, for example in Presence of water and / or a non-hydrolytic "diluent, e.g. toluene, and the presence of a desulphurizing agent. The latter are e.g. basic oxides or carbonates of heavy metals such as tin, lead, zinc, cadmium or mercury

BATH ORIGINAL 809805 / 077A

- li -

silver; namely lead or mercury (II) oxide or basic lead (II) carbonate, but also mercury chloride can be used. The reaction is mainly carried out at an elevated temperature and, if necessary, in a closed Vessel carried out.

If corresponding isourea or isothiourea derivatives are used to produce the new guanidines, the ammonolysis is carried out in the manner indicated above, if necessary, in the presence of an ammonium salt or a dehydrating or desulfurizing agent. '

The implementation of the corresponding S-Niederalkylcyanisothioharnstoff.mit In the presence of an ammonia becomes the anion of a strong acid, such as hydrochloric acid, or nitric acid Compound containing sulfuric acid, e.g. its ammonium salt, carried out.

Contains the amino group of the azabicycloalkyl- (N) -alkylamines of formula VII a nitrogen-free, functionally modified carboxyl group, such as a halocarbonyl or thiocarbonyl group, e.g., a chlorocarbonyl group, or one by lower alkanols, such as methanol or ethanol, or lower alkyl mercaptans, such as methyl or ethyl mercaptan, esterified carboxyl group, the reaction with ammonia in the presence of a dehydrating or Desulfurizing agent of the type mentioned above carried out.

The hydrolysis of N- [azabicycloalkyl- (N) -alkyl] -N-cyano ureas or -cyanthiohrnstoffe or their tauto-

BATH ORIGINAL

meren forms, for example, with dilute aqueous Mineral acids, 'such as sulfuric acid, carried out at the same time corresponding biuret compounds can also arise as a by-product.

In procedure d) the reduction =, for example by the action of a Dileichtmetallhydride, especially an alkali metal aluminum hydride, such as lithium or sodium aluminum hydride, or an alkaline earth metal aluminum hydride, such as magnesium aluminum hydride or aluminum hydride itself. If necessary, the Reducing agents also together with activators, e.g. Aluminum chloride, can be used. The reduction with the hydrides mentioned is preferably in the presence of a Solvent, e.g. an aliphatic, araliphatic, aromatic or cyclic ether, such as diethyl or Dipropyl ether, anisole, diphenyl ether, tetrahydrofuran or p-dioxane, carried out and, if desired, at increased Temperature and / or in the presence of an inert gas, e.g. nitrogen.

The reduction of the carbonyl group can, however, also be carried out by the action of hydrogen in the presence of suitable catalysts, for example copper-chromium catalysts, in the presence of inert solvents and, if necessary, at elevated pressure. You can also use electrolytic cathodes with high overvoltage, such as mercury, lead amalgam

BAD ORIGINAL 80 980 5/0 7 7 / ".

or lead cathodes. As a catholyte, for example, a mixture of water, sulfuric acid and a Lower alkanoic acid, e.g. acetic or propionic acid, can be used. The anodes may be made of platinum, carbon, or lead and the anolyte used is preferably sulfuric acid.

The conversion of the thiocarbonyl group into the Methylene group can, for example, likewise by hydrogenation in the presence of freshly prepared hydrogenation catalysts, e.g. Raney nickel, and a diluent, e.g. a lower alkanol such as methanol or ethanol, or, as indicated above, by electrolytic reduction.

The reduction of the azabicycloalkyl- (N) -alkyl-

guanidines of the formula I, in which one or more ring carbon atoms Forming a carbamyl or thiocarbamyl grouping with an adjacent nitrogen atom is carried out, for example, by Reduction with an aluminum hydride, hydrogenation or electro-lytic Reduction. .

Reactive esters of guanidinoalkanols of the formula IX or of azabicycloalkyl- (N) -alkanols of the formula G-M-OH are, for example, those of strong inorganic acids, e.g. mineral acids such as hydrochloric acid, hydrobromic or hydriodic acid or sulfuric acid, or of strong organic acids, e.g., organic sulfonic acids such as p-toluenesulfonic acid.

The reaction is carried out in procedure b) e.g.

BAD ORiGlNAL

809805/077 4

carried out so that the azabicycloalkane of the formula G-H or an alkali metal, e.g., sodium or potassium, compound thereof with the reactive guanidinoalkanol ester or a Salt thereof, preferably in the presence of a diluent, is reacted. The starting materials mentioned can also be found under the Reaction conditions are formed, e.g. the alkali metal compound of the azabicycloalkane when reacting the components in liquid ammonia in the presence of alkali metals such as sodium or potassium, or their carbonates. If a salt of guanidine © - If alkanol ester is used, the free base can be set free in an alkaline reaction medium. That The diluent is thus chosen with regard to the reaction components, e.g. if the free ester base is used Ether, such as p-dioxane, or a hydrocarbon, such as benzene or toluene, or, if a salt is used, a lower alkanol, like methanol or ethanol. The reaction can be carried out with cooling, but preferably at elevated temperature, if desired be carried out in a closed vessel, under pressure or in an inert gas atmosphere. The implementation of the azabicycloalkyl- (N) -alkanol ester takes place in an analogous manner.

The starting materials are known or, if they are new, can be prepared by methods known per se will. For example, S-lower alkyl isothioureas or O-lower alkyl-isureas by alkylation of Thiourea or urea with lower alkyl halides,

BATH ORIGINAL 809805/077 / »

such as methyl or ethyl chloride, bromide or iodide, or di-lower alkyl sulfates, such as dimethyl or diethyl sulfate.

The azabicycloalkyl- (N) -alkylamines of the formula VII are obtained, for example, by reacting a corresponding one Azabicycloalkans with a cyano lower alkyl halide or with a lower alkenyl cyanide, in which the double bond through the Cyano group is activated. In the substituted lower alkyl cyanides obtained, the cyano group is then reduced to the Methylenamino group converted, for example by treatment with lithium aluminum hydride.

The azabicycloalkyl- (N) -alkyl-cyanamides of the formula X can be obtained, for example, by equivalent amounts of a corresponding azabicycloalkyl- (N) -alkylamine and a cyanogen halide.

The azabicycloalkyl- (N) -alkyl ureas used as starting materials Upper thioureas or their salts can be obtained, for example, by a corresponding azabicycloalkyl- (N) -alkylamine with a metal cyanate or thiocyanate or an ammonium cyanate or -thiocyanate converts.

The preparation of the azabicycloalkyl- (N) -alkylisourea- and isothichurea derivatives takes place, for example by reaction of azabicycloalkyl- (N) -alkylureas or thioureas or their metal compounds with lower alkyl or aralkyl halides or di-lower alkyl sulfates.

BATH ORIGINAL

8U9805 / 0 7 7Λ

The S-lower alkyl-cyano-asothioureas are obtained for example by azabicycloalkyl- (N) -alkyl-isothiocyanates Reacts with an alkali metal cyanamide and the resulting cyano-thiourea compound with a halo-lower alkane or a di-lower alkyl sulfate alkylated.

The carbamine or thiocarbamic acid halides or esters used as starting materials can, for example obtained by using corresponding azabicycloalkyl- (N) -alkylamines or salts thereof with phosgene or thiophosgene and, if desired, compounds obtained by treatment with alcohols in the esters or converted into the thiolester with mercaptans.

The N- [azabicycloalkyl- (N) -alkyl] -N-cyanoureas or -cyanthioureas are obtained, for example, when corresponding azabicycloalkyl- (N) -alkyl-cyanamides with an ammonium or alkali metal cyanate or thiocyanate in a neutral medium, e.g. in the presence of water.

The guanides or amides or the corresponding thio compounds used as starting materials in procedure d) are obtained, for example, by reacting halides of azabicycloalkyl- (N) -alkanecarboxylic acids with guanidine or those of guanidinoalkanecarboxylic acids with a corresponding azabicycloalkane ¹ .

The thio compounds used as starting products

BATH ORIGINAL 809805/077 / *

genes can, for example, from the corresponding, aforementioned guanides or amides by treatment with sulfurizing agents, like phosphorus trisulphide or phosphorus pentasulphide, getting produced.

The azabicycloalkyl- (N) -alkyl-guanidines used as starting materials, in which one or more ring coolant atoms with an adjacent nitrogen atom Form carbamyl or thiocarbamyl groups, for example can be obtained by converting into corresponding azabicycloalkanes, one or two adjacent to the nitrogen atom Containing carbonyl or thiocarbonyl groups, introduces an aminoalkyl group, e.g., by reacting the foregoing Azabicycloalkane with an alkene cyanide, e.g. acrylonitrile, or especially an alkali metal, such as lithium or sodium compound, of the azabicycloalkane with a haloalkyl cyanide, e.g. chloroacetonitrile, whereupon the azabicycloalkyl- (N) -alkyl cyanide the cyano group reduced to the methyleneamino group and amimes obtained in the guanidines, e.g. by treatment with a salt of an S-lower alkyl isothiourea, such as S-methyl isothiourea sulfate, convicted.

The reactive esters of guanidino-lower aikanole or their salts can be obtained, for example, by reacting a guanidino-lower alkanol with a thionyl halide implements.

The reactive azabicycloalkyl (N) alkanol esters used as starting materials can by implementing a

803X0 * 1

1421OCO

corresponding azabicycloalkane with a halohydrin or an epoxide and subsequent esterification of the azabicycloalkyl- (N) -alkanols _i as mentioned above.

The new guanidine compounds are obtained either as free compounds or in the form of their salts. A Salt can in a manner known per se, for example by Treatment with a strongly alkaline agent such as aqueous alkali metal hydroxide, e.g. lithium, sodium or potassium hydroxyd, or with strong anion exchange resins, such as quaternary ammonium exchange resins, into the free compound be transferred. Of the free bases, inorganic or organic acids can be used therapeutically Addition salts are produced, e.g. those of the hydrohalic acids, sulfuric acid, phosphoric acid, Nitric acid, acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, succinic acid, malic acid, tartaric acid, Ascorbic acid, methanesulfonic acid, ethanesulfonic acid, Oxyethanesulfonic acid, benzoic acid, salicylic acid, p-aminobenzoic acid or toluenesulfonic acid. Implementation with acids takes place preferably in suitable diluents, e.g. lower alkanols such as methanol, ethanol, n-propanol or i-propanol, Ethers such as diethyl ether or dioxane, esters such as ethyl acetate, halogenated hydrocarbons, such as methylene chloride, or mixtures of these. Basic, neutral, acidic or mixed salts can be obtained here.

809805/077 Λ ORIGINAL BATHROOM

In the process of the present invention, those starting materials are mainly used that the initially mentioned preferred end connections result.

The new guanidines and their salts are said to be used as remedies in the form of pharmaceutical preparations which these compounds together with pharmaceutical, organic or inorganic, solid or liquid Carriers that are used for enteral, e.g. oral, or parenteral Gift are suitable included. For the formation of the same such substances come into question that with the new compounds do not react, such as water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, Gum, polyalkylene glycols, petrolatum, cholesterol, and other known excipients. The pharmaceutical Preparations can be e.g. as tablets, coated tablets, capsules or in liquid form as solutions, suspensions or emulsions are present.

If necessary, these pharmaceutical preparations are sterilized and / or contain auxiliaries, such as Preservatives, stabilizers, wetting agents or emulsifiers, salts to change the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.

The invention is described in more detail in the following examples. The temperatures are in degrees Celsius specified.

ORJGiNAl.

809805/077 h

Example 1 :

A mixture of 6.3 g of 2-hexahydroindoiinoäthylamine and 7 cnr of water is mixed with 5 * 38 g of S-methyl isothiourea. -sulfate added «heated to boiling for 5 hours on the reflux condenser and then cooled. The precipitated Precipitate, consisting of 2-kexahydroindoline-sthylguanidine-sulfate the formula

CH ₂ -CH ₂ -NH-C

NH ₂

is crystallized from ethanol, .F. 236-238 °. Yield 3 * 2 g.

_m ι

The starting material is obtained as follows: A mixture of 24 g of indoline, 4.4 g of potassium oxide and 75 cm "^ tetrahydrofuran is hydrogenated in the presence of Raney nickel in a closed vessel at 190-200 ° and atmospheres. The mixture obtained is filtered , the solvent is removed and the kexahydrölndoline obtained is distilled; b.p. _1K . 62-64 °. Yield 12.5 8

A mixture of 18.5% of the hexahydro indole obtained in this way, 12.2 g of chloroacetonitrile, 17 s of anhydrous Sodium carbonate, 100 cnr toluene and 0.5 cm water heated to boiling with stirring on the reflux condenser for 8 hours.

809805/077

BATH

The dark precipitate which has separated out is filtered off, washed with toluene, the toluene solution is combined and the solvent is evaporated off. The residue is distilled in a water jet vacuum and the hexahydro-indolinoacetonitrile is obtained in this way; Kp. _27mm 138-146 °. Yield 11.7g.

A solution of 11.7 g of hexahydro-yneolino-aeotonitrile in 150 cm of diethyl ether is added dropwise to an ice-cooled and nitrogen-kept mixture of 6 g of Li fcMuro-aluminum hydride in 200 cm of diethyl ether over a period of 2 1/2 hours while stirring. 'To the cold Reaktxonsgaßiiscb to f 18 cm of ethyl acetate, 6 he only water 12 1 sodium hydroxide solution and again water and 18 cm fi'itrisrt. vsn solid residue is vTässfot with ether, which approached concentrated and distilled the "/ 2 of Remaining-Hsxah ^ dro-indQlino-ethylamine in Vakuumj ^K P" i5 _ram 112-120 °. Yield 6.5g

BATH ORIGINAL

8098.05 / 0774

Example 2;

A solution of 7.8 g of 2-Haxahydro-Isoindolinoethylamine, 6.4 g of 3-methyl isothiourea sulfate and 10 cm V / ater is heated to the boil for 6 hours. The one while standing precipitating white precipitate, consisting of 2-hexahydro isoindolino-ethylguanidln-3ulfate of the formula

• r

JNH

N-GH ₀ CH ₀ -NK-G ' 2 2 ν

· ■ "ι

is crystallized from anhydrous ethanol; P. 238-240 °, yield 6.3 g.

The starting material can be obtained as follows:

50 g of 4,7,8,9-tetrahydrophthalimide are reduced in a Soxhlet apparatus with 20 g of lithium aluminum hydride in 800 cm of diethyl ether. After 22 hours of reflux, the reduction is stopped, the solution is concentrated and the residue is distilled under reduced pressure. The 4,7 * 8,9-Tetrahydroisoindolinj ^K P »i4_i5 _mji , 82-92 ° is obtained. Yield 16.5g.

A methanolic solution of 10 g of 4,7.8,9-ietrahydroisoindoline is then hydrogenated in the presence of 0.25 g of platinum oxide under a pressure of 3 atmospheres. The catalyst is removed, the piltrate is concentrated and the hexahydro-isoindoline obtained can be used for the next reaction stage without further purification. Yield 9 * 7 g *

80 980 5/07 74

A mixture of 11.8 g of hexahydro-isoindoline, 6.6 g of chloroacetonitrile, 20 g of sodium carbonate, 100 cnr toluene and 0.5 cnr water is allowed to boil on the reflux condenser with stirring for 12 hours. The solid material is filtered off, the filtrate is concentrated under reduced pressure and the remaining hexahydro-isolindolino-acetonitrile is distilled in vacuo, bp 110-140 °. Yield 10.7 6 · If 10.7 g of it is reduced with 4.9 g of lithium aluminum hydride in 200 cnr of diethyl ether, as described in Example 1, the desired 2 <-hexa-

hydro-isoindolino-ethylarain of bp ^ _- (yield 7.8 g).

120 - 125 °.

Example 3 «

A mixture of 11.2 g of 2- (4.7 * 8 * 9-tetrahydroisoindollno) ethylamine, 9.3 g of S-methyl iso thiourea sulfate and 15 cor of water are allowed to boil on the reflux condenser for 6 hours. The precipitated after standing for one week at room temperature Precipitate is filtered off and recrystallized in anhydrous ethanol. The 2- (4,7,8,9-tetrahydrop-isoindolino) ethyl guanidine sulfate is obtained in this way the formula

from the F. 222 - 224 °. Yield 8.5g.

BATH ORIGINAL

ι

A yellow oil separates from the aqueous filtrate of the reaction mixture and crystallizes from hot ethanol. After recrystallization in methanol-acetone, 2- (4,7,8,9-tetrahydroisoindolino) ethyl guanide sulfate of the formula is obtained

N-CK ₂ CH ₂ -NH-C

vS /

from P. 255-258 °.

The starting product is obtained as follows:

A mixture of 6.5 g of 4,7> 8,9-tetrahydro-isoindo ~

Lin, 4.4 g of chloro-eetonitrile, 20 g of sodium carbonate, 100 cnr toluene and 0.5 cnr water are allowed to boil for 12 hours on the reflux condenser with stirring. The cold reaction mixture is filtered, the solid residue is washed with benzene, the combined filtrates are concentrated under reduced pressure and the remaining 4,7 »8,9-tetrahydroisoindolino-aoetonitrile is distilled in vacuo * bp _15mm 140-148 °. Yield 6.5g.

13 * 4 g of the nitrile obtained, after reduction with 6.3 g of lithium aluminum hydride in 325 cnr diethyl ether, analogously to the method described in Example 1, give the desired 2- (4,7,8,9-tetrahydro-isoindolino) -ethyl. amin vonr ^{Kp #} l4-15mm ¹² S- ¹ Se ⁰ . Yield 11.2 g.

8098 0 5/07 74 BAP

Be laplel 4:

A solution of 3.3 g of 2- (Dekahydr0-3-benzazepino) ethylarain, 2.4 g of 8-methyl-iSQthiourea-sulfate and 4 cur Water is allowed to boil for 5 hours, acetone is added to the cooled reaction mixture, the precipitate is filtered off and The 2- (decahydro-3-benzazepino) ethyl guanitol sulfate thus obtained crystallizes the formula

. 2 H _g O

from ethanol-acetone * P. 197-200 °. Yield 1.9 so

The sulfate obtained can be converted into the hydrochloride as follows be transformed:

The aqueous suspension of the sulfate is treated with an excess of sodium hydroxide solution while cooling, the free base is extracted with chloroform, the extract is dried, filtered and concentrated; The residue is taken up in ethanol and ethanolic hydrochloric acid is added to the solution. The dihydrochloride precipitates on addition of diethyl ether. After recrystallization from isopropanol, it melts at 177 ° (decomposition).

■ '■' ■■; 'BAD ORIGINAL

.. ·. . 809805/0774. ■ "

The starting material is obtained as follows: To a mixture of 52.2 g of 2,3,4,5-tetrahydro-3-benzazepine, 23.4 g Triäthylamln and 10 cnr benzene are added with stirring and ice-cooling within 1 1/2 Hours a solution of 18 aryl acetylochloride in 100 cm benzene, heated to the boil and stirred for 45 minutes. 200 cnr ™ V / water are then added with stirring, the aqueous layer is separated off and extracted twice with benzene. The extract is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue, consisting of 3-acetyl-2,5,4,5-tetrahydro-3-benzazepine, crystallizes from benzene-pentane, mp 80-83 °. Yield 30.0g.

30 g of the aoetyl derivative obtained are hydrogenated in the presence of 20 g of Raney nickel, 4.4 g of calcium oxide and 50 cnr of tetrahydrofuran at 200 ° under 200 atmospheric pressure. The cold reaction mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is distilled in vacuo. Mail receives 4.8 g of decahydro-3-benzazepine; . Kp _{Q 0} ^ _mm 36 ° and 19 * 4 g of 3-acetyl-decahydro-3-benzazepini Kp _{Q O} c ₉₃ -. 97 ° · The latter is allowed to trated in Gemisoh with 100 cnr concentrated »· ■ hydrochloric acid 12 hours Boil on the reflux condenser, concentrate and obtain 11.0 g of decahydro-3-benzazepine hydrochloride; 222-225 ° F. It can be converted into the free base in the usual way. Yield 7 * 7 g

80 9805/07 7

A mixture of 7 * 7 g of decahydro-3-benzazepine, 4.2 g of chloroacetonitrile, 6 g of sodium carbonate, 60 cnr toluene and 0.5 cnr water is allowed to boil for 8 hours on the reflux condenser with stirring. After standing overnight, the reaction mixture is filtered, the residue is washed three times with hot benzene and the filtrate is concentrated. The residue is distilled in vacuo and the decahydro-3-benzazeplnoacetonitrile of boiling point * is obtained. _l4mm I6o162 °. Yield 4.5g. If one reduces 4.5 g of it with 1.7 S lithium aluminum hydride in 125 oar diethyl ether, as described in Example 1, the desired 2- (decahydro-2-benzazepino) -äthylamln of ^bp -0.025ram *> is obtained " ⁶⁵ ° - ^yield 5.3 β

Example 5s

A mixture of 10 g of 2-decahydro-isoohinollnoäthylamine, 7.6 grams of S-methyl isothiourea sulfate and 5 cm Water is allowed to boil on the reflux condenser for 5 hours. The one which precipitates when the reaction mixture is diluted with acetone Precipitate is filtered off and crystallized from ethanol « The resulting 2-decahydro-isoohlnollno-ethylguanidine sulfate the formula

N-CH ₂ CH ₂ -NH-C _x

H ₂ SO ₄

BATH ORIGINAL 809805/077 / »'

1421ODO

melts at 195-199 °. Yield 11.7 S

The starting material is prepared as follows :

The mixture of 69 g Dekahydrc-isoquinolines 41.5 S Chloraoetonitril, 206 g of sodium carbonate, 250 cnr of toluene and 0.5 enr water ⁵ is allowed to rüokflussieäen 12 hours under stirring.

The reaction vessel is filtered, the solid residue with Toluene washed, the filtrate concentrated under reduced pressure.

concentrated and the residue, consisting of decahydroisoquinolinoacetonitrile, distilled in vacuo; Kd. _or 164-170 ° » yield 69 pp. " * ^25rara

To an ice-cold one kept under nitrogen

Mixture of 15 g of lithium aluminum hydride and 250 cm of diethyl ether are added with stirring within 5 hours of a solution of 54.5 S of decahydro-isoquinolino-acetonitrile in 250 cm of diethyl ether and stirring is continued for a further hour. Then ground 45 cm of acetic acid aefchylestc-nv, 15 cm of water, 30 cm of 15% sodium bicarbonate], eyes and 45 cm of water, stirring for half an hour, the reaction was filtered and the residue was washed with diethyl ether. The piltrate is concentrated and the residue, consisting of 2-decahydroisoquinolinoethylamine, is distilled under reduced pressure.

150-158 °, νξ ⁵ »1.4974. Yield 1 ^ 5.0g.

809805/0774 «D OHWWL

Example 6 j

A mixture of> g 2- (3 - Sogranatanirio) ethylamine, 2.48 g S-methyl isothioureal sulfate and 20 cm water is allowed to boil for 6 hours on the reflux condenser. The deposited precipitate is filtered off and _{recrystallized in boiling water 5.} This gives 2- (3-Xsogranatanino) ethylguanidine sulfate of the formula

4 1

-CH ₂

N-C

-CH,

After drying, it melts under reduced pressure at 295-530 °. Yield 1.2g.

The starting material is obtained in the following ways:

-JL

A solution of 8.5 g of 3-xsogranatanine in 100 cm of toluene is added dropwise to a suspension of 5 × 15 chloroacetonitrile, 16 g of sodium carbonate and 50 cm of toluene, and the reaction mixture is allowed to reflux for β hours. The mixture is then filtered, concentrated under reduced pressure, the residue taken up in Äefc'ier, the ethereal solution dried over sodium sulfate and evaporated to give 3-Isogranatanino-acetonitrile from P. 7 ^ -77 (from acetone-water) "yield £ 10.5

809805./0774

I-V-!

A solution of 9 S 3-lGOgranatanlno-acetonitrile in 50 cm of diethyl ether is added to a mixture of 3 g of lithium aluminum> 1 nm hydride and 150% of dry diethyl ether, the reaction mixture is left to reflux for 10 hours and stirred overnight . 3 oar water, 5.9 cnr 20% aqueous sodium hydroxide solution and 5 cc water are then added to the reaction mixture, the mixture is filtered, the organic phase is dried and concentrated. The residue is distilled in vacuo and the desired 2- (2-isogranatanlno) ethylamine of KP »13 _aa ¹ OS · 114 ° is obtained. Yield 4.2g.

BATH ORIGINAL

809805/077/4

1421Q0Q

Example f t

A mixture of 6.5 β 2 ~ (3-Aza ~ 3-bicyölo [3 »2, ii: J-nonyl) ethylamine and 5.38 g of S ~ methyl isothiourate * sulfate in 25 ml of water is used for 4 hours Boiled under reflux. The precipitate obtained after cooling is filtered off. One obtains the 2- (3-aza-3-bicyclo [3 _i 2.2] nonyl) ethyl guanidine sulfate (or 3- (2-ouanidinoethyl) -3-aza-bicyclo [3.2 , 2] nonan-sülfät) of the formula

JSf-OH ₀ -OH ₀ -BH-CK p. 2 2

-ΜΗ

which after recrystallization from water, at 280 (decomposition) melts. Yield 8o #.

The starting material used is as foigl; \ manufactured:

A mixture of 12.52 g of 3-aza-bicyelo [3 _J 2i2] nohäii ^,! 7 * 55 g of chloroacetonitrile and 22 g of anhydrous sodium carbide: in 225 ml of toluene, the mixture is refluxed for 6 hours while stirring. After filtering, the filtrate is evaporated under reduced pressure and the desired 3-aza-3-bicyclo (| j2,2] nonyl-acetonitrile (or 3-cyanomethyl-3-aza-bicycio (| j2,2] -nonane) is obtained isolated by distillation. Boiling point 72 - f§ / 0.1 mm. The product crystallizes after standing and

809805/0774 ORIGINAL BATHROOM

melts at 54 - 57 °.

A solution of 10.0 g of 3-aza-3-bicyclo [5.2.2] -nonyl-acetonitrile in 150 ml of tetrahydrofuran is slowly cooled to a solution of 3.48 g of lithium aluminum hydride added in 175 ml of tetrahydrofuran. The reaction mixture is refluxed for 21 hours and after cooling, 3.5 ml of water, 4.5 ml of a 20 # strength aqueous Sodium hydroxide solution and 12 ml of water were added. The solid The material is filtered off, the solvent is evaporated and the residue is distilled. The desired 2- (3-aza-3-bicyclo [3.2.2] nonyl) ethylamine is obtained (or 3- (2-aminomethyl) -3-aza-bieyclo [3.2.2] nonane); Boiling point 70 - 72 ° / 0.35 mm.

Example 8:

6.4 g of S-methyl-isothiourine are added to a solution of 7.1 g of 2- (2-isoquinuclidyl) ethylamine in 5 ml of water sulfate added. The solution is refluxed for 3 hours, left to stand at room temperature and diluted with acetone. The solid material is filtered off, triturated with isopropanol and recrystallized from aqueous acetone. Man receives 2- (2-isoquinuclidyl) ethyl guanidine sulfate (or 2- (guanidinoethyl) -isoohinuclidine sulfate) of the formula

809805/077 / »

OTL.

which contains 1 mol of water and at 258 - 26l ° (decomposition) melts. Yield 5.5 g

The starting materials are prepared according to the method described in Example 7, i.e. by converting 13 * 7 g of Isc- quinuclidine with 10.0 g of chloroacetonitrile in the presence of 38.2 g of sodium carbonate, 2.0 ml of water and 200 ml of toluene were obtained. The result is 2-IsochinuGlidyl-acetonitrile (or 2-cyanoniethyl-isoquinuclidine), boiling point 125 - 1JO ° / 17 mm, which after reaction with 5 * 7 g of lithium aluminum hydride desired 2- (2-isoquinuclidyl) -ethylamine (or 2- (2-amino ~ ethyl) -isoquinuclidine) results. The product boils at 110 Il4 ° / 15-20 mk.

Example 9:

A mixture of 9.8 g of 2- (3-methyl-l, 2,3,4,5 _J 6.7, -8,9,10-decahydro-isoquinolyl) -ethylamine and 7.0 g of S-MethyI- isothiourea sulfate in 10 ml of a 1: 1 mixture of ethanol and water is heated for 3 hours and left to stand over Naqht at room temperature. The solvent is distilled off, the residue is treated with acetone and the precipitate is filtered off. You get what you want

809805 / 077Λ

BATH ORIGINAL

2- (3-methyl- _{1,2,3,4,5,6,7 i} 8,9,10-decahydro-isoehinolyl) -ethyl-guanidine-sulfate (or 2- (2-guanidinoethyl) -3-methyl -1 * 2,3,4,5,6,7,8,9,10-decahydroisoquinoline sulfate) of the formula

ΠΎ "'

OH _n OH ₂ -NHH

^Χ ΝΗ

² ^ 2

which, after recrystallization from a little water containing Ethanol, melts at 253-257 °. Yield 7.8g.

The starting material is prepared as follows: A mixture of 44 g of 3-methyl-isoquinoline and

2.5 g of platinum oxide in 120 ml of ethanol and 30 ml of 4-n. Ethanolic hydrogen chloride is 4 hours at a pressure of 3 atmospheres treated with hydrogen. The reaction mixture is boiled to dissolve the precipitate, filter hot and cool. The precipitate is taken up in water and a 50 # aqueous sodium hydroxide solution is added. The 3-methyl-1,2,3,4-tetrahydroisoquinoline is treated with methylene chloride extracted, and used after evaporation of the solvent without further purification.

To a solution of 3-methyl-1,2,3j4-tetrahydroisoquinoline and 33 * 1 ml of triethylamine in benzene are slowly while cooling, add 26.0 ml of acetylchlorld in 150 ml of benzene * The reaction mixture is heated on a steam bath for 45 minutes, then cooled and diluted with ^ 25 ml of water. The watery

.809805 / 0774 BAD OWOINAL

14210C0

Layer is extracted three times with benzene, the B # n2oiixtr * kte

are combined, dried over magnesium sulfate and eini-; steams. To yield the 2-acetyl-3-methyl-l _<2,3,4-tetr & hYdi ^{i ö-:} isoquinoline. Boiling point 130-136 ° / O, 45 mm.

A mixture of 4δ, 5 S S-acetyl-J-methyl-1,!, ^, * ^ Tetrahydroisoquinoline, two tablespoons of Raney Niokel and 13 * 4 pounds of calcium oxide in 250 ml of tetrahydrofuran is hydrogenated at 200 atmospheres and 200 ° for 24 hours » the reaction mixtures virile fii *% trated, the Piltrat evaporated and the residue 'obtained Seifcilllerti the · 2-acetyl-3-methyl-l, 2,5,4,5,6,7,8,9ilÖ-dek * - hydro -isoquinoline, which is then heated for 12 hours in 225 ml of ion-cured hydrochloric acid. The mixture is allowed Heaftfcions- the ^f mixture overnight standing at room temperature, the precipitate is filtered off and evaporated, the Piltrat and the residue is dissolved in water. The aqueous solution is basified with 2 ni aqueous sodium sulfate and the organic material extracted with methylene chloride. After evaporation of the solvent oil and distillation of the residue, the desired product is obtained.

The desired 2- (> methyl-1,2,3,4,5,6,7 * 8,9, 10-decahydro-isoquinolyl) -ethylamine (or 2- (2-aminomethyl) -3-. methyl-1,2,3,4,5,6,7,8,9,10-decahydro-isoquinoline) liirdl water. obtained the procedure described in Example 7? 17.0 g of ^ methyl-l ^^^ S ^^ S ^ lO-dekahyäro quinoline and 9.1 S chloroacetonitrile in the presence of 35 g Sodium carbonate in 225 ml of toluene and 2 ml of water react.

BATH ORIGINAL

809805/077 / *

15.8 g of the 3-methyl-4,2,3,4,5,6,?, 8,9,1O-decahydro-2-isoquinolyl-acetonitrile obtained (or 2-cyanomethyl-3-diethyl-I * 2,3,4,5,6,7,8,9,10-decahydro-ispc4ainoline) i Boiling point 146-162 ° / 20 mm is then mixed with 6.2 g of lithium aluminum hydride treated to obtain the desired starting material. Boiling point 80 - 90 ° / Oj35 mm.

Example 10: '

A mixture of 3.5 g of 3- ^{(3-i-methyl-l,} 2,3,4,5,6,7 * - 8.9 * 10-decahydro-2-isoquinolyl) propylamine and .2,4 g 3-methylisothiourea sulfate in 5 nsl of a 1: 1 mixture of ethanol and water is refluxed for 3 hours and left to stand overnight at room temperature. Acetone is added and the precipitate is filtered off and air-dried. The desired 3- (3-methyl-1,2,3,4,5,6,7,8,9, lQ * decahydro-2-isoquinolyl) -propylguanidine-sulfafc (or 2- (3-guanidinopropyl) -3 -methyl-1,2,3,4,5,6,7,8 _J 9,10-decahydrpisoquinoline sulfate) of the formula

rrr-

' ^H 2 ^S0 4

809805 / 077A

BATH ORIGINAL

is recrystallized from aqueous ethanol. P. 2J5O-235 Yield 2.7g.

The raw material is produced as follows:

Five drops of benzyltrimethylammonium hydroxide are added to a mixture of 11.6 g of 3-methyl-1,2,15,4,5i-6,7,8,9,10-decahydroisoquinoline and 4.0 g of acrylonitrile . The reaction mixture is heated over a steam bath and the β - ^ - is obtained by distillation
decahydro-2-isoquinolyl) propionitrile (or 2- (2-cyanoethyl) -3-methyl-1,2,3,4,5,6,7,8,9,10-decahydro-isoquinoline). Boiling point 122 - 134 ° / O, 4 mm.

A solution of 6.7 g of β- (5-methyl-1,2,5,4,5,6, -7 * 8,9,10-decahydro-2-isoquinolyl) propionitrile in 50 ml of diethyl ether is added dropwise 2.5 S lithium aluminum hydride was added. The reaction mixture is stirred for a further two hours and left to stand overnight. While cooling in an ice bath, 7 * 2 ml of ethyl acetate, 2.4 ml of water, 4.8 ml of a | 15 # aqueous sodium hydroxide solution and 7.2 ml of water are added and the reaction mixture is stirred for a further half an hour at room temperature. The inorganic 'precipitate is filtered off, washed three times with ether and the combined organic solutions are evaporated to dryness. The desired 3- (3-methyl-1 _i 2,5,4,5,6,7,8,9, 10- · decahydro-2-isoquinolyl) -prr> pylamine (or 2- (3-aminopropyl) - 3-methyl- _1,2,3,4> 5,6i7 * 8,9 _J 10-decahydroisoquinoline) is obtained by distillation. Boiling point 94-100 ° / 0.25 _ q., 15 _mm .

BATH

809805/0774

_ -zo _

Example 11:

A solution of 2.5 g of 2- (6-aza-6-bicyclo [5.2, l] octyl) ethylamine and 2.2 g of S-methyl isothiourea sulfate in 5 ml of water is refluxed for three hours. That Water is removed by repeated dilution with anhydrous ethanol and distillation. After all, the Ethanolic solution diluted with acetone and a white crystalline precipitate is obtained, which is filtered off and out aqueous ethanol-acetone is recrystallized. The 2- (6-aza-6-bicyclo [3.2, l] octyl) ethylguanidine sulfate dihydrate obtained the formula

_; NH

melts at 245 - 249 °. Yield 2.1g. '

The starting material is prepared as follows: A mixture of 15.0 g of 6-aza-bicyclo [^, 2, l] octane, 10.8 g of chloroacetonitrile, 4j5, 0 g of sodium carbonate, 1 ml of water and 200 ml of toluene is added Stir refluxed for 12 hours. The hot solution is filtered and the solvent of the piltrate is evaporated off in vacuo. The residue is distilled under reduced pressure, boiling point J / 30 - lj>'<£ / 24 mm. 80 980 5/0774 BADORfGiNAL

The 6-aza-6-bicyclo [3.2.1] octyl-acetonitrile obtained in 50 ml of tetrahydrofuran is added within two hours to a stirred suspension of 5 * 0 g lithium aluminum hydride added in 100 ml of tetrahydrofuran. The reaction mixture is stirred for three more hours, left to stand overnight at room temperature and then, with cooling and Stir with 15 ml of ethyl acetate, 5 ml of water, 10 ml of a 15 / ^ strength aqueous sodium hydroxide solution and. 15 ml of water treated. The inorganic material is filtered off and the piltrate is concentrated by distillation. The received 2- (6-Aza-6-bicyclo [3.2, 13octyl) ethylamine is distilled under reduced pressure. Boiling point 110-116 ° / 21 mm.

Example 12:

To a mixture of 8.4 g 2- (hexahydro-indolino) -

ethylamine in 80 ml of ethanol is 7.3 g of concentrated |

Sulfuric acid in 20 ml of ethanol was added and the mixture was refluxed with 3 * 15 g of cyanamide for 6 hours. Of the Ethanol is then evaporated off under reduced pressure, the residue is taken up in warm water and the solution with aqueous sodium hydroxide to approximately the p "value 9 'set. After cooling, the 2- (hexahydro-indoline) -ethyl-guanldine-hemisulphate falls from, which is recrystallized from ethanol. It melts at 236-238. Yield: 6.8 g.

■ The product is identical to that of Example 1.

BATH

809805/0774

Example Γ3:

A mixture of 2.8 g of decaftydroisoquinoline, 1.6 g of 2-guanidinoethyl chloride hydrochloride and J> 0 ml of ethanol is refluxed for 6 hours and then evaporated under reduced pressure. The residue is dissolved in water, the solution with aqueous sodium hydroxide approximately on the Ρττ-

Value Γ3 and afterwards with dilute sulfuric acid approximately

the p "value Q is set. The solution is reduced under ti

Evaporated pressure. After cooling, the 2- (decahydro-isocMnolino) ethyl guanidine hemisulfate precipitates from, which is recrystallized from ethanol. P. 195-197 ° · Yield 0.6g. That· Product is identical to that of Example 5.

The decahydro-isoquinoli can be converted into its sodium salt by reaction with sodium hydride in toluene. If this salt is made with freshly made 2-guanidino-ethyl chloride implemented, the above-mentioned product is obtained in a somewhat higher yield.

The starting material is prepared as follows: To a mixture of 10.5 g of 2-guanidino-ethanol hydrochloride 16.9 g of thionyl chloride are added in 500 ml of toluene with stirring. The reaction mixture is left stand overnight, then heat it up for 50 minutes and decant the toluene ,. The excess thionyl chloride and the

SAD ORIGINAL

809805/0774

- 4i -

existing toluene is evaporated. That obtained as a residue 2-guanidino-ethyl chloride hydrochloride is made from a mixture recrystallized from ethanol-ether.

Example 14:

A solution of 2.5 g of 2- (decahydro-isoquinolino) ethyl chloride hydrochloride and 2.2 g of guanidine sulfate in water is neutralized with aqueous sodium hydroxide and then made slightly basic. The reaction mixture is heated on a steam bath, a further amount of the sodium hydroxide solution being added dropwise to neutralize the acid formed. After cooling, the reaction mixture is acidified with sulfuric acid and concentrated under reduced pressure. The concentrate is adjusted to approximately the p "value 9. After cooling, the 2- (decahydroisoquinolino) -ethyl-guanidine-hemisulfate precipitates, which from λ

Ethanol is recrystallized. M.p. 195-198 · yield 1.6 g. The product is identical to that of Example 5.

The raw material used is produced as follows:

The suspension of 28.0 g of decahydroisoquinoline, 2.5 g of ethylene bromohydrin and 15 g of anhydrous sodium carbonate in 200 ml of benzene is refluxed with stirring overnight, then filtered and evaporated under reduced pressure.

8AD

809805 / 077A

The desired 2- (decahydro-isoquinolino) -ethanol is made by Obtained vacuum distillation of the residue.

There are 7.15 g of the distillate in 50 ml of benzene dissolved and a solution of 5 * 15 g of thionyl chloride in 150 ml Benzene is added dropwise with stirring. The reaction mixture is refluxed for 2 hours while stirring / then cooled, filtered and the solid material from methanol-ether recrystallized. The desired 2- (decahydroisoquinoline) ethyl chloride hydrochloride is obtained.

Example 15:

The mixture of 27.4 g of 2- (5-aza - ^ - bicyclo [3.2.2] nonyl) ethyl cyanamide hydrobromide and 150 ml of 15 # aqueous ammonium hydroxide solution is in an autoclave with stirring for 3 hours to 100 - Heated to 150 °. The reaction mixture is then concentrated under reduced pressure, acidified with sulfuric acid and further evaporated. The concentrate is adjusted with aqueous sodium hydroxide solution _m to about Pjt value. 9 After cooling, the 2- (3-aza-3-bicycloC ^^^ nonylJ-ethyl-guanidine hemisulfate crystallizes out. After recrystallization from water, the product melts at 285-290 (decomposition). Yield: 17.1 g. The product is identical to that of Example J.

BATH 809805/0774

14210C0

The starting material is made by reacting 16.8 g 2- (3-Aza-3-bicyelo [3.2.2] nonyl) ethylamine was obtained with 10.6 g of cyanogen bromide in 100 ml of ether and evaporation of the reaction mixture. . _--. ■■ '.-

Example 16:

3 * 5 g l- (2-isoquinuclidino-ethyl) -l-cyano urea

are with 50 ml 6-n. aqueous sulfuric acid for 3 hours on " heated about 50-80. After cooling, the p “value is set of the reaction mixture with aqueous sodium hydroxide solution to about 9 and evaporated it under reduced Pressure a. The 2-isoquinucidino-ethyl-guanidine hemisulfate obtained After recrystallization from aqueous acetone, it melts at 257-260 ° (decomposition). Yield 19 #. The product is identical to that of Example 8.

The starting material is prepared as follows: 15 * 4 g of 2-isoquinuclidino-ethylamine are in 100 ml Reacted ether with 10.6 g of cyanogen bromide. The reaction mixture is left to stand for 3 hours at room temperature and is shaken with 25 ml: four n. aqueous sodium hydroxide solution and evaporate the ether layer. 16.2 g of potassium cyanate are added to the residue. to dissolve the mixture in a minimal amount of water and leave the reaction mixture at room temperature for 24 hours stand. The excess gyanate is then destroyed with nitric acid and the reaction mixture is 1-n.

SAD ORIGINAL

809805/0774

aqueous silver nitrate solution added. The precipitated silver salt is filtered off, washed with water, suspended in warm water and treated with approximately equivalent amounts of hydrogen chloride acid decomposes. The mixture is filtered and the piltrate evaporated under reduced pressure. You get the desired l- (2-isoquinuclidino-ethyl) -1-cyano-urea.

Example 17:

To a mixture of 12.7 g of hexahydro-isoindoline. and 200 ml of benzene are 1 ^, 6 g of chloroacetyl guanidine with stirring added. The reaction mixture is refluxed for one hour, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue, which is essentially

borrowed from hexahydro-isoindolino-acetic acid guanide, is taken up in tetrahydrofuran. The solution slowly "" becomes a refluxing suspension of 6.0 g of lithium aluminum hydride added in tetrahydrofuran. The reaction mixture is refluxed for a further hour, destroy the excess hydride by carefully adding 1 ml Vass_er and 2 ml 1-n. aqueous sodium hydroxide solution. The solid material is filtered off, the filtrate acidified with sulfuric acid and evaporated under reduced pressure. "Man

gives 50 ml of water to the residue, represents the p ^ value of the Geil

mix in to approximately 9 and evaporate the mixture in vacuo

BATH ORIGINAL 8U9805 / Q77A

a. The 2- (hexahydro-isoindolino) -ethyl-guanidine hemisulfate obtained is recrystallized from anhydrous ethanol. P. 238-240 °. Yield 15.7g · The product is with that of example 2 identical.

BAD ORIGIN «. 809805/0774

Claims (1)

Patent claims: 1. Process for the preparation of non-aromatic azabicycloalkyl- (N) -alkyl-guanidines of the general formula ° · η ^{Η 2η} · R ¹ and their salts, in which A stands for a 1-5-membered hydrocarbon chain which can also contain a double bond, m denotes the numbers O- 6, m ^f 2-7, η and n 'O-3, and R and R ¹ stand for hydrogen or lower alkyl, with the proviso that CH separates the bridgehead atoms by a maximum of 2 carbon atoms, m + η + η = 2, if A forms a 3-5-membered isocyclic ring with the bridge members, and m = 1, if A forms a 5-membered isocyclic ring with the bridge members, characterized in that in a manner known per se either a) an azabicycloalkyl- (N) -alkylamine of the general formula GM-NH ₂ VII where G is the grouping BAD OR5GINM- 809805/077 Λ New UnierlanAn (Art. -> κ ι Λ * »- ο»>-><> - * - ~ ■■ · ■ « ^G n ' ^H 2n « and M is the radical -C _t H, - with a compound m 2m the general formula ^ NH Y-C "VIII, ^V NH ₂ where Y is a removable radical, or with cyanamide or converts their salts or b) a reactive ester of a guanidinoal kanols of the formula NH HO-M-NH-C IX NH ₀ with an azabicycloalkane of the general formula G-H or a reactive ester of an azabicycloalkyl- (N) -alkanol of general formula G-M-OH with guanidine or c) an azabicycloalkyl- (N) -alkyl-cyanamide of the general formula G-M-NH-CN X or a functional derivative of a corresponding aza-bicycloalkyl- (N) -alkyl-carbamic acid or azabicycloalkyl- (N) -alkyl- bath 809805 / 077Λ thiocarbamic acid is reacted with ammonia or, if appropriate, hydrolyzed with aqueous mineral acid or d) an azabicycloalkyl- (N) -alkyl-guanidine of the general formula J, in which one carbon atom of the alkyl group with the neighboring guanidino or imino nitrogen atom and.or. or one ring carbon atom with the neighboring one imino nitrogen atom forms a carbamyl or thiocarbamyl group, reduced, and optionally subsequently obtained salts are converted into the free bases in a manner known per se or treated free bases obtained with acids. 2. Azabicycloalkyl- (N) -alkyl-guanidines of the general formula Ό O _n H _2n HH ? m ^H 2m ° · η ^{Η 2η} · R ¹ where A stands for a 1-5-membered hydrocarbon chain which can also contain a double bond, m the numbers »0-6, m '2-7, η and n ¹ 0-3, and R and R' for hydrogen or Lower alkyl, with the proviso that C _m H _2m the bridgehead atoms through a maximum of 2 carbon atoms 80980.5 / 077 A "'. Bad original separates, m + η + η ¹ = 2 1st, if A forms a 3-5-membered isocyclic ring with the bridge members, and m έ ι if A forms a 5-membered isocyclic ring with the bridge members, and their salts. 5. Azabioyoloalkyl- (N) -alkyl-guanidines of the general formula Ψ —— <f2> Ol ° f2 ^l0H 2 ⁾ 0-2 Bra // f p (OHJ _0-1 -OH (OHJ _0- with the proviso that ring B has at least 6 ring members and ring E contains at least 5 ring members, if ring D has 5 atoms, and their therapeutically applicable acid addition salts. 4. The 2- (3-isogranatanino) ethyl «guanidine and its therapeutically applicable acid addition salts. 809805/0774 5. 2- (4,7,8,9-Tetrahydro-isoindolino) -ethylguanidine and its therapeutically applicable acid addition salts. 6. The 2-hexahydro-isoindolino-ethyl-guanidine and its therapeutically applicable acid addition salts. 8Ü9805 / 077A