HU184746B - Process for producing heterocyclic amidine derivatives bonded in spiro-position and stereo- and optical isomeres thereof - Google Patents

Abstract

Field of the Invention The present invention relates to an anti-depressive, heterocyclic spiro-coupled amidine compound of formula (I) and physiologically acceptable salts and optically active forms of these compounds, wherein n is 1 or 2, R1 is hydrogen, optionally substituted with hydroxy or morpholino 1 C-C alkyl, C *-C alkyl, C *6 alkyl, Cil-C, alkyl, Cített-C alkyl, Camin-C alkyl, C8-C alkyl, C8-Cild alkyl or R 'and R jelentése together with adjacent nitrogen atom 5.6 or 7-membered saturated ring substituted with phenyl, hydroxy, benzoylamino, benzimidazoln-4-on-2-yl, and six-membered rings with an additional heteroatom as oxygen, sulfur or nitrate. they may contain an oxygen atom, the nitrogen atom being hydrogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 2-5 alkoxycarbonyl, benzyl, benzoyl, fluorobenzyl (C 1-4) alkyl, optionally C 1-4 alkyl. or substituted with halogen substituted phenyl, or R 1 and R 5 together with the adjacent nitrogen atom form thiomorpholine-1-oxide-4-yl. R 4 is phenyl optionally substituted with 1 or 2 C 1-4 alkyl, C 1-4 alkoxy, halogen, trifluoromethyl or amino. -1-

Description

This invention relates to a novel heterocyclic spiro amide of formula (I). These compounds have antidepressant effects.

The present invention provides novel heterocyclic spiro amidines of formula (I) and physiologically acceptable salts thereof, wherein n is 1 or 2,

R ¹ is hydrogen, C 14 alkyl optionally substituted with hydroxy or morpholino,

R ^{1 is C} 2 -C 6 alkyl optionally substituted by hydroxy, phenyl, C 1 -C 14 alkoxy, substituted phenyl, C 14 alkyl, diethylamino or hydroxybenzylamido, C 5 -C 8 cycloalkyl, or

R ¹ and R ² together with the adjacent nitrogen atom represent a 5-6 or 7 membered saturated group optionally substituted with phenyl, hydroxy, benzoylamino, benzimidazolin-2-one-1-yl or 1-phenylimidazolidin4-one-2-yl the six-membered rings may contain additional heteroatoms instead of one carbon atom such as oxygen, sulfur or nitrogen, wherein the nitrogen atom is hydrogen, C14 alkyl, C14 hydroxyalkyl, C2-5 alkoxycarbonyl, benzyl, benzoyl, C 1 -C 4 alkyl, optionally C 14 alkyl or halogen substituted phenyl, or R ¹ and R ² together with the adjacent nitrogen atom form a thiomorpholin-1-oxide4-yl group,

R ⁴ is phenyl optionally substituted with 1 or 2 C 14 alkyl, C 14 alkoxy, halogen, trifluoromethyl or amino.

The compounds of formula II can be used as intermediates in the process of the invention. In the general formula (II)

R ⁴ is as defined for formula (I),

Z is -halogen or -SH, -SR ^s , or -OR ⁵ , wherein

R ⁵ is C 1 -C 6 alkyl, benzyl, phenylalkyl or phenylsulfonyl.

Compounds of formula I of the invention (I) are prepared in a way that optionally, (III), the compound obtained in a compound of formula XVI - where n and R ⁴ are as ^stated above - with phosphorus oxychloride or phosphorus pentoxide and reacting an amine of formula IV wherein R ² is as defined above, or

b) a (II) - wherein n and R are as defined above and Z is a halogen, SH, SR ^s - or OR group - ^R5 is C1-6 alkyl, benzyloxycarbonyl-, alkyl or phenyl, phenylsulfonyl, with an amine of formula IV wherein R ² is as defined above, or

c) treating a compound of formula V wherein n and R ⁴ are as defined above with an alkylating agent; or

d) optionally reacting a compound of formula III prepared from a compound of formula XVI, wherein n and R ⁴ are as defined above, with an arylsulfochloride in anhydrous pyridine at -30 ° C to room temperature, preferably at -10 ° C; reacting the imino ester obtained as an intermediate with an amino compound of formula IV wherein R ² is as defined above, or

(II) with an intermediate of formula - a ') wherein Z is a halogen atom - is prepared by reacting a compound (III) of formula - wherein n and R ⁴ are as defined above - is reacted with an inorganic acid halide, b') in the in the case where Z is SR ⁵ - is prepared by reacting a compound of formula (VI) wherein n and R ⁴ are as defined above with an egv alkylating agent, c ') in the case where Z is OR ⁵ - by reacting a compound of formula (III) with a trialkyloxonium fluoroborate of formula R3OBF4, or d ') in the case where Z is ORr, by preparing a compound of formula (III), reacting with an acid halide and subsequently treating it in situ with an alkali alcoholate, e ') in the case where Z is SH - prepared by The compound of formula (III) is reacted with phosphorus pentasulfide or phosphorus pentasulfide pridine coniplex.

Preparation of compounds of formula (I)

0-120 ^° C, is preferably carried out at 50 ° C in an inert solvent, preferably benzene, toluene, chloroform, carbon tetrachloride, trichlorethylene, or dioxane.

In process (b), the compounds of formula (II) are dissolved in an inert solvent, preferably diphenylene glycol dimethyl ether, dioxane, dimethylformamide or tetrahydrofuran, and the gas or liquid or dissolved amine is introduced into this solution. Depending on the nature of the starting material used, the operation is carried out under refrigeration at room temperature or at a moderately elevated temperature.

Compounds of formula (II) wherein Z is a togen atom, preferably chlorine or bromine, are directly reacted directly with the amine compound in the reaction solution containing the imidohalide without prior isolation.

Compounds of formula (II) wherein Z is alkyl ^and SR, a protic solvent, preferably an alcohol, methanol, isopropanol is reacted with (IV) wherein the amine compounds. The use of dimethylformamide may also be advantageous. When a high boiling amine derivative of formula (IV) is used, the reaction is carried out in the absence of a solvent at the boiling point of the amine, but preferably below 140 ° C.

In process (c), a compound of formula (V) is treated in a known and conventional manner with an alkylating carbon, such as an alkyl halide, or an alkyl or dialkyl sulfate, or is otherwise alkylated, such as by Leuckart-Wallch.

Process d) is conveniently carried out in anhydrous pyridine at a temperature of -30 to 2 ° C, preferably at -10 ° C (H. Henecka, P. Kurtz, Houben-Weyl: Methoden dérorganchen Chemie, III / 8, 704/1952). /).

Intermediate compounds of formula (II) are prepared according to the following procedure a'-e ':

In process a '), phosphorus pentahalides are suitably in an anhydrous organic solvent such as dioxane, chloroform carbon tetrachloride or trichlorethylene at a temperature of -40 ° C to 50 ° C, preferably at -10 ° C with a compound of formula III with.

The alkylating agent used in process Ab ') is alkyl halides, preferably methyl iodide or ethyl bromide, as well as diesters of sulfuric acid or toluenesulfonic acid. Suitable solvents are alcohol, methanol, tetrahydrofuran or dioxane, especially acetone. The temperature of the operation is between 0 ° C and the boiling point of the solvent, preferably between 30 ° C and 60 ° C.

The triethyloxonium fluoroborate used in process c ') can be prepared from boron trifluoride etherate and epichlorohydrin. (H. Meervein et al., J. pr. Chem. (2), 147, 257 (1937), 154 83 (1939)).

The reaction is carried out in situ with a compound of formula III. Particularly suitable solvents are diethyl ether or halogenated hydrocarbons such as carbon tetrachloride. The reaction temperature is from 0 ° C to the reflux temperature of the solvent, preferably from 30 ° C to 40 ° C.

In process d '), the imido halide of formula II obtained in process a'), wherein Z is halogen, is reacted in situ with an alkali alcoholate, preferably sodium methylate or ethylate, in an inert solvent. The reaction temperature is 0 to 60 ° C, preferably 30 to 40 ° C.

In process (e '), compounds of formula (III) are reacted with phosphorus pentasulfide. The reaction is carried out in a suitable solvent such as pyridine or toluene. Calcium oxide is used as the basic catalyst. The reaction is allowed to proceed at 20-120 ° C, preferably 50 ° C. In addition, the compounds of formula (III) may be reacted with a commercially available phosphorus pentasulfide-pyridine complex in an inert solvent such as benzene, chloroform, methylene chloride, tetrahydrofuran or dioxane, preferably in pyridine or toluene at a temperature of from 30 to 110 ° C. -80 ° C.

Starting compounds of formula IX wherein R ⁴ is phenyl, methoxyphenyl, hydroxyphenyl, chlorophenyl or aminophenyl are described in U.S. Patent No. 2,931,805. Compounds of formula (IX) containing other substituents at R ⁴ may be prepared according to Scheme A.

The nitro-block compounds of formula (VII), wherein R ⁴ is as defined for formula (I), can be prepared by the Diels-Alder reaction using a suitable ω-nitrostyrene in the presence of hot cyclopentadiene. See J. Org. Chem., 26, 4898 (1961), 8, 373 (1943), J. Amer. Chem.

Soc .: 73 5068 (1951))

Michael addition of nitro compounds of formula (VII) with methyl acrylic acid by the addition of a base, preferably benzyltrimethylammonium hydroxide, in alcohol, methanol, tetrahydrofuran, preferably butanol or dioxane at 0 to 120 ° C, preferably 10100 ° C. on.

The starting compounds of formula (XI) wherein R ⁴ is the same as that of formula (I) can be prepared from the bicyclic compounds of formula (X) wherein R ⁴ is as defined above in Scheme B.

Known 2-nitrobromocyclo (2,2,2) -oct-5-ene compounds known in the art can be prepared from ω-nitrostrilol and excess 1,3-cyclohexadiene. The starting compounds are used crude in the present invention without purification.

Among the compounds of the present invention, the following may be mentioned:

- 5 '- (4-phenyl-piperidino) -3-phenyl-spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrroline) - 3-phenyl-5'-thiamorpholin-spiro (bicyclo (2,2,1-heptane-2,2'-5-pyrroline), 3- (4-chlorophenyl) -5 '- (2-methylpiperidino) -spiro (bicyclo (2.2 1,1-heptane-2,2'-5-pyrroline), -3- (4-chlorophenyl) -5 '- (3-methylpiperidino) spiro (bclldo- (2,2,1) -heptene- 2,2'-5-pyrroline), 3- (4-chlorophenyl) -5 '- (4-methylpiperidino) spiro (bicyclo-2,2,1) heptane-2,2' -5- pyrroline), - 3- (4-chlorophenyl) -5 '- (2-methylmorpholino) spiro (bicyclo-2,2,1-heptane-2,2'-5-pyrroline), - 3- / 4- chlorophenyl-5 '- (3-methylmorpholino) -spiro (bicyclo (2,2,1) -heptane-2,2' -5-pyrroline), -3- (4-chlorophenyl) -5 '- / 2 6-dimethylmorpholino-spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrroline), 3- (4-chlorophenyl) -5 '- (2,5-dimethylmorpholino) -spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrroline), -3- (4-chlorophenyl) -5'-thiamorpholinopiro (bicyclo (2,1,1) -heptane-2 , 2 '-5-pyrroline), 3- (4-chlorophenyl) -5' - (2-ethylpiperidino) -spiro (bicyclo (2,2,1) -heptane-2,2 '-5- pyrroline), 3- (4-chlorophenyl) -5 '- (2-methylpiperidino) spiro (bicyclo (2,2,1) heptane-2,2' -5-pyrroline), - 3- (4-chlorophenyl-5 '- (3-methylpiperidino) -spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrroline), - 3/4-chlorophenyl / -5' - (4-methylpiperidino) -spiro (bicyclo (2,2,1) heptane -2,2'-5-pyrroline) - 3- (4-chlorophenyl) -5 '- (2,2), 6,6-tetramethylpiperidino-spiro [bicyclo (2,2,1) -heptone-2,2'-5-pyrroline), -3- (4-bromophenyl) -5'-pyrrolidino-spiro ( bicyclo _(2.2> l) heptane-2,2 '-5 pyrrolyl) - 3- / 4-bromophenyl / -5' - / 4-phenylpiperidino / -spno (bicyclo (2,2,1 ) -heptane-2,2'-5-pyrroline), 3- (4-bromophenyl) -5'-morpholino-spiro (bicyclo (2H, 1) -heptane-2,2'-5-pyrroline), - 3- (4-bromophenyl) -5 '- (2,6-dimethylmorpholino) -spiro (bicyclo (2,21) heptane-2,2'-5-pyrroline), - 5' -morpholino-4 - (4-trifluoromethylphenyl) -spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrroline), - 5 '- (4-phenylpiperidino) -3- (4-) trifluoromethylphenyl / -epiro ·

- (bicyclo (2,2,1) heptane-2,2'-5-pyrroline), 5'-piperidino-3- (4-trifluoromethylphenyl) spiro (bicyclo (2,2,1)) -heptane-2,2'-5-pyrroline), 5'-pyrrolidino-3- (4-trifluoromethylphenyl) -spiro (bicyclo (2,2,1) -heptane-2,2'-5-pyrrole) )

184,746

5'-piperazino-3- (4-trifluoromethylphenyl) -plro (bidclo [2,2,1] heptane -2,2'-5-pyrroline), 5 '- (2,6-dimethylmorpholino) (-3- (4-trifluoromethylphenyl) epiro (bidklo (22,11) -heptane-22'-5-pyrrolidone), 3- (4-methoxyphenyl) -5'-morpholinepiro (bicyclo (2 (2,1-heptane-2,2'-5-pyrroline),

3- (4-methoxyphenyl) -5 '- [2,6-methylmethyl-morpholino] spiro (bi-cyclo (2,2,1) -heptane-2 (2'-S-pyrroline), 3- (4-methoxyphenyl) -5'-piperidino-splro (bidklo (22-1) heptane-2,2'-5-pyrroline),

3- (4-tert-phenyl) -5 '-morphollno-splro (bldklo (2,2,1-heptane-2,2' -5-pyrroline),

3- (4-aminophenyl) -5 '-morpholino-spiro (bidklo (2 (2,1)) heptane-2,2' -5-pyrroline),

3- / 4-amino-phenyl / -5'-piperidino-spiro (bicine] p (2,2, l) heptane-2,2'-pyrroline-5 /

3- (4-methylaminophenyl) -5'-morpholino-spiro (dichloro- (2,2,1) -heptane-2,2'-5-pyrroline), 3- (4-methylaminophephil) - 5'-piperidino-spiro (biciklo15

J llvj / lul Father "D 1 X / Alil'P)

- 3- (2,3-di-dorophenyl) -5 '-morpholino-spiro (bidkio (2,2-l) -heptane-2,2'-S-pyrroline),

- 3- (2,4-dichlorophenyl) -5 '-pyrrolidino-spiro (bidklo (2,2,1) -heptane-2,2'-5-pyrroline),

3- (3,4-Dichlorophenyl) -5'-morpholinyl-splro (bidldo (2,2-1) -heptane-2,2'-5-pyrroline), 3- (3,4-dichloro) rphenyl / -5'piperidino-spiro (bicyclo (2,2 • l) heptane-2,2'-5-plrrolÍn)

3- (3,5-dichlorophenyl) -5 '-morpholino-splro (bi-dichloro (2,2-j-heptane-2,2'-5-pyrroline),

morpholino-3-phenyl-spiro (bicyclo (2,2, l) hept-5-en-2,2-pyrroline-5);

3-phenyl-5 '-piperidino-splro (bicyclo (2,2,1) -hept-5-ene, 2,2'-5-pyrroline),

3-phenyl-5'-piperazinna-spiro (bidklo (2,2,1) 'hept-5-ene-2,2'-5-pyrroline),

3-phenyl-5- (4-phenyl-piperidino) -spro (bicyclo (22.1) -hept-5-ene-2,2'-S-pyrroline), 3- / 3-chloro-phenyl-S ' morpholino-spiro (bioílíÍ0 (2.2 »l) ·

-hept-5-en--2,2'-5-pinolin),

- 3- (4-dorophenyl) -5'-piperidine-aplro (Wcldldo (3,2,1)) -hept-5-en-22'-5-indole;

- 3- (4-k) h -phenyl-5'-pperaziroyl-spiro (bicyclo (2,2,1) -hept-5-ene-2,2'-5-pyrroHn),

- 3- (4-chlorophenyl) -5'-thiamorpholino-spiro (bicildo (22-1) hept-5-ene-2,2 '- $ - pyrroline),

- 3- (4-methylphenyl) -5 '-morpholino-splro (biclldo (22,1) -hept-5-ene-2,2'-5-pyrroline),

- 3- (4-amino-phenyl) -5'-morpholine-spiro (bidklo (2,3, -1) -hept-5-ene, 2,2'-5-pyrroline),

- 3- / 2,4-dichlorophenyl / 5 '-morpholino-splro (bidklo (2 (2, -1) -hept-5-ene-2,2' -5-pyrroline),

- 3- (3,4-dichlorophenyl) -5 ^, -morpholine-spiro (bicyclo (2,2,40)

-1) -hept-5-en-2,2 '-5-pyrrole),

- 3- (4-Chloro-phenyl) -5'-morpholino-spiro (bicyclo (2,2,2) 50

octane-2,2'-pyrroline-5);

- 3- (4-chlorophenyl) -5'-piperidino-spiro (bidldo (2,2,2) -octane-2,2 '-5-pyrroline),

- 3- (4-chlorophenyl) -5 '-thia morpholino-spiro (bidklo (2,2-2) octane-2' -5-pyrroline),

- 3- (4-chlorophenyl) -5 'morpholino-spiro (bicyclo (2,2,2) -octane-2,2'-5-pinoline),

- 3- (4-bromophenyl) -5'-piperidinepiro (bidklo (2,2,2) -octane-2,2 '-5-pyrroline),

- 3- (4-bromophenyl) -5'-thiamorpholinopyrrolo (bidklo (2,2,2,2) -octane -2,2 '-5-pyrroline),

- 3- (4-fluorophenyl) -5 '-morpholino-spiro (bicyclo (222) -octane-2,2' -5-pyrroline),

- 3- (4-fluorophenyl) -5 '-piperidine-spiro (bidklo (2 2 2) -octane-2,2' -5-pyrroline),

- 3- (4-fluorophenyl) -5 '-thiamorpholinepiro (bidklo (222) -octane-2 2' -5-pyrroline),

- 5 '-morpholino-3- (4-trifluoromethylphenyl) -spiro (bicyclo (2,2,2) -octane-22' -5-pyrroline),

- 5 '-piperidino-3- (4-trifluoromethyl-phenyl) -epiro (bidklo ·

- (2,2,2) -octane-2,2 '-5-pyrroline),

- ^5, -tiamqrfolino-3- / 4-trifluoromethyl-phenyl / spiro (bicyclo (2,2,2) s maybe -2,2 '-5-pyrroline),

- 3- (2,4-dichlorophenyl) -5 '-morpholino-spiro (bicyclo (2,2,2) -octane-2 2' -5-pyrroline),

- 3- / 2,4-dichlorophenyl / -5 '-piperidine-spiro (bidklo (2,2-2) octane-2,2' -5-pyrroline),

- 3- (3,4-dichlorophenyl) -5'-morpholino-spiro (bicyclo (22 >) -2-octane-2,2 '-5-pyrroline),

- 3- (3,4-Dichlorophenyl) -5 '-piperidino-spiro (bidklo (2 2, ·

-2) -octane-2,2 '-5-pyrrolone),

- 5 '-morpholino-3-phenyl-spiro (bicyclo (2,2,2) -oct-5-en-22'-5-pyrroline),

- 3/4-chlorophenyl / -5'-morpholino-spiro- (bicyclo ₍₁ 22 2) oct -5 -en-2,2 '-5 pyrrolyl);

- 3- (4-Bromo-phenyl) -5'-morpholino-9-spiro (bicyclo (222) -oct-5-en-2 2 '-S-pyrroline),

- 3- / 4-fluoro-phenyl / -5'-morpholine-spiro (bidklo (222) -oct-5-ene-2'-S-pyrroline),

- 5 '-morpholino-3- (4-trifluoromethyl-phenyl) -spiro (bicyclo (2,2,2) -oct-5-ene-2,2' -S-pyrroline),

- 3- (2,4-dichlorophenyl) -5 '-orpholinol-spiro (bidklo (22-2) -oct-5-ene-2,2' -5-pyrrole),

- 3- (3,4-dichlorophenyl) -5 '-morpholino-spiro (bidklo (22-2) -oct-5-ene-2,2' -5-pyrroline),

The compounds of formula (I) may exist in four stereoisomeric forms, each stereoisomer having two ethyl ether forms. It has been found that the main product for the preparation of the compounds of formula (I) according to the invention is the exoaryl-endo-sploprolrolone stereoisomeric form of formula (XII). In the formula (XII), R, R, and R ⁴ are as defined in formula (I). The configuration of the compounds of formula (I) is determined by the spatial structure of the nitrobenzyclic compounds of formula (XIII) and (XIV) as starting materials.

The preparation of these nitro-cyclocyclic compounds generally results in a mixture of the stereoisomers of the formula (XIII) and the formula (XIV), the main product being the oxo-endo-endolyl derivative of the formula (XIII) (as determined by 1 H-MMR). In the further steps of the synthesis, where the mixture of nitro-diblock compounds is subjected to Michael addition, the exo-arylenedio-nitro esters of formula (XV) are formed in the crystalline state, while the endo-aryl-exo-nitro compounds of formula (XV1) they stay in the mother liquor.

Synthesis of the compounds of the invention may also be carried out on the mother liquor of the exo-aryl-endo-nitro ester of formula (XV) by column chromatography on the isomeric endo-aryl-exo-nitroester of formula (XV1). Synthesis affords compounds of formula I; having a three-dimensional structure represented by the general formula (XVII). In the enaoaryl exo-pyrroline compounds of formula (XVII), n, R ¹ , R ³ , and R * are as defined for formula (I).

Surprisingly, it has been found that the heterocyclic spiroamidines XII and XVII show an unexpected difference in biological activity. For example, the anti-depressant effect of the left rotating isomer is significantly greater than that of the right rotating isomer. The latter shows less activity than the racemate. ¹

SUMMARY OF THE INVENTION The present invention relates to the preparation of optically active stereoisomers of compounds of formula (XII) and (XVII): wherein R ² , R ¹ and R ⁴ are as defined for formula (I). The invention also relates to the preparation of acid addition salts thereof and to pharmaceutical compositions containing these compounds.

Particularly favorable optically active stereoisomers include:

- (-) - 3-exo- (4-chlorophenyl) -5'-morpholino-spio (bicyclo, lO (2,2,1) -heptane-2,2'-5-ene-pyrroline) ), - N - (3-endo-4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -heptane-2,2'-5-exo-pyrroline), - N - [3- (4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -hept-5-ene-2,2'-5-endo-pyrroline), - (-) - 3-endo- (4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -he pt-5-en-2,2 '-5-exo) pyrroline), N - [3- (4-fluorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -cyano-2,2'-5-endo-) pyrroline), - N - (3-endo- (4-fluorophenyl) -5 '-morpholino-spiro (bicyclo (2,2,1) -hexane-2,2' -5-exo) pyrroline), N - (- 3-exo- (4-fluorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -hept-5-ene-2,2 '-5- endo-pyrroline), N - (3-endo- (4-fluorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) -hept-5-en-2,2, - 5-exo-pyrroline), 3-exo (4-bromophenyl) -5 '-morpholino-spiro (bicyclo (2,2,1) -heptane -2,2' -5-endo-pyrroline) ), - 3-endo- (4-bromophenyl) -5'-morpholino-spiro (bicyclic) clo- (2,2,1) -heptane -2,2 '-5-exo-pyrroline), 5'-morpholino-3-exo- (4-trifluoromethyl-phenyl) -spiro- (2, ·

2,1) -hexane-2,2'-5-endo-pyrroline), 5'-morpholino-3-endo- (4-trifluoromethylphenyl) -spiro- (bicyclo (2,2,1) ) -heptane-2,2'-5-exo-pyrroline),

The optical isomers of the present invention may be prepared by known racemic compounds of formula (XII) and (XVII), wherein n, R ^2, R ¹ and R ⁴ are as defined in formula (I), or racemic intermediates thereof. Thus, it is separated into optical isomers and converted to the isomers XII and XVII.

It is desirable to separate the above-mentioned compounds of formula (XII) and (XVII) into optical isomers by known methods.

The racemic mixture may also be resolved by separating the intermediate of formula (V) to obtain two optical isomers, followed by one or both of the resulting isomers.

Most commonly, however, the racemic mixture of the compounds of formula (XII) or (XVII) is resolved into isomers using an optically active acid as described in the literature. For example, the racemate mixture is dissolved in a suitable solvent such as alcohol and treated with a solution of an optically active acid. During the crystallization of the salt, one enantiomer can be isolated, and the other enantiomer can be separated from the mother liquor, if necessary, after treatment with a base, followed by treatment with another optically active acid. The racemate solution can also be treated with the optically active acid salt of the other enantiomer. It is not possible to determine in advance which solvent and optically active acid is to be used in each case, and the choice of solvent and acid is made simply by experiment. The most advantageous combination is that which produces the salt in high purity (i.e., free of the other enantiomer) and in crystalline form.

It has now been found that D (-) - and L (+) - tartaric acid, D (-) - and Lü) -dibenzoyl tartaric acid and D (-) - and L (+) - tartaric acid can be successfully used to separate isomers of the compounds of formulas XII and XVII. ) - and L ( ⁺ ) -di-p-tolyl tartaric acid.

When the pure salt of one of the isomers is separated, it is treated with a strong base, such as ammonium hydroxide, sodium hydroxide or sodium carbonate solution to liberate the free base of the optically active amidines.

The compounds of formula (I) or the stereoisomeric forms of these compounds (XII) and (XVII) may be isolated as such or in the form of an acid addition salt. Acid addition salts include pharmaceutically acceptable non-toxic addition salts which may be prepared with suitable acids such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, organic acids such as formic acid, propionic acid, tartaric acid, succinic acid, glycolic acid, lactic acid, malonic acid, hydroxy maleic acid, fumaric acid, oxalic acid, citric acid, malic acid, mucosal acid, benzoic acid, salicylic acid, naphthalene-1, 5-disulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, or synthetic resins containing acidic groups, such as ion exchange resins.

The acid addition salts thus obtained are converted into basic compounds in a known manner, for example by treatment with a base such as metal hydroxide, metal alcoholate, metal carbonate, ammonia or hydroxyl ion exchanger or other suitable reagent. The acid addition salts can be converted into other salts in a known manner, for example by treating a salt formed with an inorganic acid with a metal salt such as sodium, barium or silver salt in a suitable solvent (in which the resulting inorganic salt is insoluble). separated. An acid addition salt can be converted to another acid addition salt using an anion exchange composition. The free base can be treated with an alkyl halide to give a quaternary ammonium salt.

U.S. Patent No. 2 931 805 discloses spiro-norbomanic compounds which have antihypertensive, vasodilatory, local anesthetic activity and activity in the central nervous system. The spiro compounds of the present invention were not expected to exhibit strong antidepressant activity.

The compounds of the present invention and their pharmacologically acceptable salts have an ED ₅ q of from 0.1 to 10 mg / kg: see Tables 1 and 2, when administered intraperitoneally or orally to mice, antagonize tertabenazine ptosis. five 22-g diluted mice are dosed with 1% solution (prepared with carboxylmethylcellulose). The solution administered has a sodium chloride content of 0.9% (in distilled water). The ptosis produced by the previously administered tetrabenazine is eliminated after administration of the compounds of the invention. Evaluation of the antidepressant effect of the compounds of the present invention and their potential for use in the treatment of various depressive disorders in mammals, as well as in the study of murine brain synaptosomes (inhibition of noradrenaline and dopamine reuptake).

The compounds show little toxicity. '

LD50 values are generally in the range of 100 to 500 mg / kg oral (mouse).

The compounds of the present invention and pharmaceutically acceptable salts thereof may be administered over a wide dosage range, and the dosage employed will depend upon various factors, such as the compound employed, the condition, species, size, etc. of the mammal being treated. In human therapy, the daily dose is generally between 10 and 60 mg.

Single dose values of 0.1 to 5 mg pro kg are used in test animals such as mice and rats. The compounds of the invention and their salts are generally administered orally or by injection. For this purpose, the compounds of the present invention and their salts are prepared in the form of a pharmaceutical composition. The pharmaceutical compositions are prepared in a known manner and comprise at least one compound of the invention or a salt thereof, and a suitable pharmaceutically acceptable carrier. The pharmaceutical composition of the present invention is prepared by admixing or diluting the active ingredient with the excipient or enclosing it in an excipient such as a capsule or other wrapper. Diluents include solid, semi-solid, or liquid materials which can serve not only as diluents, but also as vehicle or excipient. Carriers include lactose, dectrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, syrup, methylcellulose, methyl and propylhydroxybenzoate, magnesium hydroxide, and the like.

The pharmaceutical compositions of the present invention are formulated so as to release the active ingredient rapidly, continuously, or delayed upon administration.

The formulation will depend on the administration. For oral use, a tablet, capsule or suspension may be formulated for parenteral injection.

The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

Table 1

Compound Name of compound

First /-/-exo-3-/4- chlorophenyl/-5'-morpholino-spiro (bicyclo (2.2.1.1)) - heptane-2,2 '-5-pyrrole / -D- -hydrogentartarate Second [3- (4-Fluoro-phenyl) -5-morpholino-spiro (bicyclo (2.2.1) -heptane-2,2-5-pyrroline) -D- [-] -hydro- géntartarát Third [-] - 3- / 3,4-dichloro-phenyl / bicyclo (2.2.1) HEP tan-spiro-2.2-5-morpholino-5-morpholino-5- of red in -D-hydrogen tartrate 4th 3-endo (4-chlorophenyl) -5-morpholino-spiro (bicyclo (2.2.1) heptane -2,2, -5-exo-pyrroline-hydro- hydroiodic 5th 3- (4-Dichlorophenyl) -5-morpholinopiro [bicyclo (2.2.1) hept-5-ene-2,2-5-pyrroline] hydrogen iodide 6th 3- (4-Chloro-phenyl) -5-piperidino-pyro [b] cyclo - - (2.2.1) hept-5-ene-2,2-5-pyrroline / hydroiodide 3- (4-chlorophenyl) -5- (1,2,5,6-tetrahydropyridyl) - -s piro | cyclo (2.2.1) heptane -2,2 -5-pyrroline / hydrogen fumarate Table 2 Compound Tetrabenazine Ptosis Antagonismus ED _cn (mg / kg ip) First 0.2 ^U Second 0.35 Third 0.4 4th 0.2 5th 0.4 6th 0.5 7th desmethyl 0.3 imipramine 1.0

Example 1

3- (2-Methoxyphenyl) -5'-pyrrolidino-spiro (bicyclo (2.2.1) heptane-2,2 '-5-pyrroline) hydrogen iodide

a) Methyl c- (3- / 2-methoxyphenyl / -2-nitrobicyclo (2.2.1) -hept-5-en-2-yl) propionic acid

1.) 0.1 mol of 3- (2-methoxyphenyl) -2-nitrobicyclo (2.2.1) hept-5-ene is dissolved in 600 ml of dioxane, 12 ml of triton B and 0.1 mol of acrylic acid methyl After the addition of the ester, the solution was heated to reflux (TLC). After distilling off the solvent, the residue is recrystallized from ethanol by the addition of activated carbon. Colorless crystals, m.p. 72-26 ° C.

2.) 0.4 mol of 3- (2-methoxyphenyl) -2-nitrobicyclo (2.2.1) -hept-5-ene, 40 ml of tert-butanol and 6 ml of triton B solution (40%). of methanol) (0.4 moles of methyl acrylic acid) was added with stirring at 5 ° C. The reaction mixture was stirred at room temperature for 3 hours while the temperature rose briefly to 40 ° C. The mixture was diluted with ethanol, neutralized with a little dilute hydrochloric acid and evaporated. Recrystallization from ethanol gave colorless crystals, m.p. 72-76 ^U

b) 3- (2-Methoxyphenyl) -spiro (bicyclo (2.2.1) heptane-2,2'-pyrroline) -5 '-one

Dissolve 0.2 mole of c- (3- (2-methoxyphenyl) -2-nitrobicyclo (2,2,1-l) hept-5-en-2-yl) propionic acid in 800 ml of ethanol. for that, 2 spatulányi Raney-nik-61

184,746 g were added, hydrogenated at 50 ° C and 70 bar. The catalyst is filtered off, the solvent is distilled off and the residue is recrystallized from isopropanol. The colorless crystal obtained has a melting point of 260 ° C.

c) 3- (2-methoxyphenyl) spiro (cyclohexyl (2.2.1) heptane-2,2'-pyrrolidine) -5'-thione 'mole 3- (2-methoxyphenyl) spiro (bicyclo) 2.2.1) -heptane-2,2'-pyrrolidin-5'-one, 10 g of phosphorus penta sulfide and 9 g of calcium oxide were dispersed in 260 ml of toluene and stirred for 2 hours in a water bath heated to 50 ° C. Filter into saturated sodium carbonate solution, · Boil the residue three times with toluene, dissolve in concentrated hydrochloric acid, dilute with water, transfer to a separatory funnel with the basic filtrate and the toluene extract. The phases were dried over sodium sulfate and concentrated in vacuo to give colorless crystals, which were recrystallized from ethyl acetate, m.p. 194 ° C.

d) 3- (2-Methoxyphenyl) -5'-methylthiopyro-spiro (bicyclo (2,2,1) heptane-2,2'-pyrroline) hydroiodide mole 3- / 2-methoxy- A mixture of phenyl-spiro (bicyclo (2.2.1) -heptane-2'-pyrrolidine) -5'-thione and 7 ml of methyl iodide was heated in 200 ml of acetone under reflux for 10 minutes. After cooling, the residue is filtered off to give a pale yellow compound, m.p. 228 ° C (dec.)

e) 3- (2-Methoxyphenyl) -5 '-pyrrolidino-spiro (bicyclo (2,

... 2, l) heptane-2,2'-5-pyrroline) -hydrogen iodide ^γ, 12 mmol of 3- (2-methoxyphenyl) -5'-methylthiopyropo (bicyclo (2,2, l) heptane-2,2'-5-pyrroline) hydrogen iodide and 2 g of pyrrolidine in 50 ml of ethanol are refluxed. The solvent was evaporated and the residue was recrystallized from isopropanol to give colorless crystals, m.p. 228 ° C.

The compound thus prepared is an exoarylendospiropyrroline derivative. Compounds with analogous structures can be prepared as described above, and are summarized in Table 1 below.

Unless otherwise indicated in the table, heterocyclic spiro-linked mi din derivatives and their intermediates each have an exoaryl endopyrroline structure.

The processes a) to d) of the present invention provide a yield of 60-85%.

Table 3

XVIII. Compounds of general formula IIa

Example number Y ¹ Y ² JR ¹ 'V Salt melting point decomposition point oC Second H H NH-n-butyl HJ 165-167 3 H H > 2 ^H 5 .νηκη ₂ ) ₂ -ν ^ h hydrogen 1,5-naphthalene disulphonate 266-267 4th H H NH-benzyl HJ 203-205 5th H H A group of formula (1) HJ 153-155 6th H H A group of formula (2) , 1 hydrogen 1,5-naphthalene dlszulfonát 144-150 7th H H A group of formula (3) - 114 8th H H A group of formula (4)  hydrogen fumarate A. Preparation 177 9 H H -ΝΗ- (0Η ₉ ) _? -Ο-0 ₉ Η ^ -N- (CH - CH _o OH) _o . HJ 190 10th H H hydrogen oxalate 130 11th H H ^HH 3 ′ ^N CH, -CH (OH) -CH ₃ (5) hydrogen naphthalene-1,5-disulfonate 140-142 12th H H HJ 227-228 13th H H A group of formula (6) hydrogen oxalate 217 14th H H (7) - 127 15th H H A group of formula (8) hydrogen oxalate 96 16th H H A group of the formula (0) DL-bitartrate 238 17th H H Is a group of formula (10) hydrogen maleate 173 18th H H A group of formula (11) hydrogen maleinate hydroiodide 201 19th H H Is a group of formula (12) hydrogen maleate 190 20th H H Is a group of formula (13) dihydrogen maleate 198-200 21st H H A group of formula (14) HJ 245 22nd H H Is a group of formula (15) dihydrogen maleate 215 23rd H H A group of formula (16) HJ 160 24th H 2-C1 A group of formula (8) hydrogen fumarate A. Preparation 230 25th H 2-C1 A group of formula (9) hydrogen naphthalene 1,5diszulfonát 278 26th H 2 Cl- Is a group of formula (10) DL-bitartrate 225

184,746

27th H 2-OCH ₃ A group of formula (9) hydrogen 1,5-naphthalene diszuifonát 255 28th H 2-OCH ₃ Is a group of formula (10) - 127 29th 3 OCHq 4-ocho Is a group of formula (10) - 114-116 30th H 4-Cl A group of formula (8) D, L-hydrogen tartrate 236 31st H 4-Cl A group of formula (9) D, L-hydrogen content was 218-220 32 H 4-Cl Is a group of formula (10) D, L-hydrogen tartrate 237 (decomposition) 33rd H 4-Cl A group of formula (17) D, L-hydrogen tartrate 205 34th H 4-Cl , A group of formula (11) D, L-hydrogen tartrate 211 35th H 4-Cl Is a group of formula (13) D, L-hydrogen tartrate 216-218 36th H 4-Cl 18 is ^CH 3 -N% 1'-CHOH-CH. Λ ^ 3 D, L-hydrogen tartrate hydrogen naphthalene 225-232 37th H 2-OCH ₃ 1,5-disulfonate 273-276 38th 39th H H 4-Cl 4-Cl DL-hydrogen tartrate DL-hydrogen tartrate 176-179 223 40th H 4-Cl A group of formula (9) DL-hi is a hydrogen tartrate 189-191 41st H 4-CH Is a group of formula (10) DL-bitartrate 235-236 42nd H 4-CH A group of formula (11) DL-bitartrate 195-197 43rd H 4-Cl * Is a group of formula (19) HJ 223-223 44th H 4-F A group of formula (9) DL-bitartrate 220-221 45th H 4-F Is a group of formula (10) DL-hydrogen tartrate 234 46th H 4-F A group of formula (11) DL-bitartrate 212-214 47th 3-C1 4-Cl A group of formula (9) HJ 224-226 48th 3-C1 4-Cl Is a group of formula (10) HJ 224-225 49th 2-C1 4-Cl • a group of formula (9) D, L-hi hydrogen tartrate 199-201 50th 2-C1 4-Cl Is a group of formula (10) D, L-hi hydrogen tartrate 202-205 51st H 4-NH-j A group of formula (9) - 151-155 52nd 4-Br H ² Is a group of formula (10) D, L-hydrogen tartrate 225-227 53rd 4-F H A group of formula (17) D, L-hi of hydrogen-tartrate 212 (decomposition) 54th 4-F H Is a group of formula (19) hydroiodic 220-224 55th 3-C1 H Is a group of formula (10) - 170 56th 4-Cl H Is a group of formula (20) hydroiodic 236-238 57th 4-Cl H Is a group of formula (21) D, L-hydrogen tartrate 233 58th 4-Cl H A group of formula (22) D, L-hydrogen tartrate 261-263 59th 4-Cl H Is a group of formula (23) hydroiodic 316 (decomposition)

Similarly to Example 1, the compounds described in Example 73 can be prepared:

EXAMPLE 73 '-Morpholino-3-exo-thienylpyro (bicyclo (2,2,1) -heptane-2,2'-5-endo-pyrroline) -hydrochloride, m.p. 137 -140 ° C.

Example 74

5'-Amino-2-phenyl-spiro (bicyclo] o (2,2,1) heptane-2,2'-5-pyrroline) -hydrofuramate mole 5'-methylthio-3-phenyl-spiro (bicyclo (2 2, 1) heptane-2,2'-5-pyrroline) -hydrogen iodide was treated with 250 ml of aqueous ammonia for 24 hours at 70 ° C and 80 bar of nitrogen. Evaporation of the solvent gave an oily product which solidified slowly. Fumaric acid is added to form the addition salt, m.p. 242 ° C (recrystallized from 1: 1 methanol: water).

Example 75

5 ^, -Morpholino-3-phenylspiro (from bicyclo (2,2,1) hept-5-en-2,2'-5-pyridine) -h eminaphthalene-1,5-disulfonate

a) 3-Phenyl-spiro (bicyclo (2,2,1) hept-5-ene-2,2 '-pyrroline) ·

-5'on

0.17 mole of methyl 2-nitro-3-phenyl-bidklo (2,2,1-l) hept-5-en40 -2-yl) -propionic acid (U.S. Patent No. 2,931,805) 100 tin powder (1.3 g) was added to 1.3 L of acetic acid and the mixture was stirred for 3 hours at 100-120 ° C. After cooling, it is neutralized with sodium carbonate solution and extracted twice with ether. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. Recrystallization from a little methanol gives colorless crystals. Mp 152-155 ° C.

b) 3-Phenyl-spiro (bicyclo (2,2,1) hept-5-ene-2,2, pyrroline) -5'-thione eq 20 mmol of 3-phenyl-spiro (bicyclo (2,2,1) a mixture of hept-5-en-2? -2-pyrrolidin) -5'-one, 4 g of phosphorus pentasulfide and 3 g of calcium oxide was stirred at 50 ° C for 2 hours and filtered into hot saturated sodium carbonate solution. The residue was quenched with concentrated hydrochloric acid, diluted with water, and the solutions combined.

The mixture is shaken several times with toluene, the organic phase is distilled off, dried and evaporated in vacuo. The residue was recrystallized from ethyl ester to give colorless crystals. Melting point: 204 DEG C. (dec.).

c) 5'-Methylthio-3-phenyl-spiro (bicyclo (2,2,1-hept-5-en60 -2,2'-5-pyrroline) -hydrogen iodide

3-Phenyl-spiro (bicyclo (2,2,1-l) hept-5-ene-2,2'-pyrrolidine) -5'-thione (184,746 mmol) was dissolved in acetone (30 mL) and treated with methyl iodide (1 mL) and refluxed for 10 min. heat under refrigeration. After cooling, the precipitate was collected by filtration. The TLC crystalline compound was used immediately for the next step.

d) 5'-Morpholino-3-phenyl-spiro (bicyclo (2,2,1-hept-5-ene-2,2'-5-pyrroline) -heminaphthalene-1,5-disulfonate mole 5'-methylthio-3- Phenyl-spiro (bicyclo (2,2,1) -hept-5-ene-2,2'-5-pyrroline) -hydrogen iodide and 2 ml of morpholine were dissolved in 30 ml of ethanol, and the solution was refluxed for one hour. heat the solution, then evaporate the solvent. The residue was extracted with ether saturated with sodium carbonate solution, the organic phase was separated, dried and evaporated. The residue was converted to the acid addition salt with 1,5-naphthalene disulfonic acid to give colorless crystals, m.p. 261 ° C (recrystallized from methanol).

Example 76

Example 75 was repeated using 3-phenyl-5 '-piperidine-spiro (bicyclo (2,2,1) hept-5-ene-2'-5-pyrroline) -heminaphthalene-1,5 of the disulfonate as colorless crystals, m.p. 176 ° C.

Similarly to Example 75, Examples 77 and 77 were prepared

Example 78 also takes its seats.

Example 77

3-Exo- (4-chlorophenyl) -5 '-morpholino-spiro (bicyclo (2 (2,1) hept-5-ene-2,2' -5-eno-dopyrroline) -hydrogen Todd

Colorless crystals, m.p. 253 ° C (dec.).

Example 78

3-Exo- (4-chlorophenyl) -5'-piperidino-spiro (bi-cyclo (2,2,1) hept-5-en-2,2'-5-endo-pyrroline) -hydrogen iodide

Colorless crystals, m.p. 198 ° C

Example 79

5'-Morpholino-3-phenyl-spiro (bicyclo (2,2,2) octane2,2 '-5-pyrroline) hemaphthalene-1,5-disulfonate

a) 2-Nitro-3-phenylbicyclo (2,2,2) oct-5-ene

A mixture of 45.1 g of 1,3-cyclohexadiene (EMKA), 41.9 g of ω-nitrostyrene, 60 g of o-xylene and 1 spatulan of hydroquinone was treated in an autoclave for 24 hours at 200 ° C and 60 bar of nitrogen. The solvent was distilled off and the residue was distilled under high vacuum. Boiling point 0.05-120-160 ° C.

b) (3- / 2-Nitro-3-phenyl-bidklo (2,2,2) oct-5-ene-2-yty-propionic acid methyl ester)

The version:

Dissolve 0.14 mol of 2-nitro-3-phenylbicyclo (2,2,2) oct-5-ene in 50 ml of dioxane, add 27 ml of triton B and 0.14 mol of acrylic acid methyl ester and add to the reaction mixture. is heated to reflux (4 hours). The solvent was distilled off and the residue crystallized. The residue is recrystallized from isopropanol, m.p. 127-132 ° C.

Version B:

0.18 mol of 2-nitro-3-phenylbicyclo (2,2,2) oct-5-ene, 0.18 mol of acrylic acid methyl ester and 3.8 ml of triton B are mixed with 50 ml of tert-butanthole for 24 hours. After stirring, an additional 0.18 mol of acrylic acid methyl ester and 70 ml of dioxane were added. The mixture was heated at reflux for 24 hours.

Upon cooling, the reaction mixture crystallizes. After adding a little ethanol, the mixture was neutralized with 2N hydrochloric acid and filtered off with suction. The resulting crystals were recrystallized from isopropanol. 127-131 ° C.

_1- (c) 3-Phenyl-spiro (bicyclo (2,2,2) octane-2,2'-pyrroline) -5 ', 1-mmole O-2-nitro-3-phenyl-bicyclo (2, 2.2) Oct-5-en-2-yl-propionic acid methyl ester is dissolved in 100 ml of ethanol, to which is added 3 g of Raney nickel, and the solution is brought to hydrogen at 50 [deg.] C. and 70 bar. The catalyst is filtered off, the solvent is evaporated off and the residue is recrystallized from isopropanol.

d) 3-phenylspiro (bicyclo (2,2,2) octane-2,2'-pyrrolidine) -5'-thione, 3-phenylspiro (bicyclo (2,2,2) octane-2), 2'20-Pyrrolidin-5'-one is added to 200 ml of toluene and 7.3 g of phosphorus pentasulphide and 7 g of calcium oxide are added and the mixture is stirred at 50 [deg.] C. for two and a half hours. the residue was dissolved in concentrated hydrochloric acid, diluted with water and carefully combined with toluene sodium carbonate 25. The aqueous phase was extracted several times with toluene, the extracts were combined, dried and the residue was crystallized in vacuo. , on e) 5'-methylthio-3-phenyl-spiro (bicyclo (2,2,2) octane-2,2 ''^5'- 5-pyrroline) hydrogen iodide mole 3-phenylspiro (bicyclo (2) , 2,2) ^{octane-2,2-pyrrolidine)} -5'-thione and methyl iodide in 3 ml of a mixture of 50 ml of acetone were heated for 10 minutes. After cooling, the mixture is filtered and the crystals obtained have a melting point of:

192-193 ° C.

f) 5'-Morpholino-3-phenyl-spiro (bicyclo (2,2,2) octane-2,2'-5-pyrroline) -heminaphthalene-1'-disulfonate 10 mmol 5'-methylthio-3-phenyl- spiro (bicyclo (2,2,2) -octane-2,2'-5-pyrroline) -hydrogen iodide and 2 g of morpholine in 80 ml of ethanol were refluxed for 9 hours, the solvent was distilled off and the residue was treated with 4 N potassium. -hydroxide and ethyl acetate. The organic layer was separated, dried and evaporated. The acid addition salt of naphthalene-1,1-disulfonic acid has a melting point of 299-300 ° C.

* 5 Similarly to Example 79, the compounds of Examples 80 and 81 were prepared.

Example 80 fc-3-exo / 4-chlorophenyl / -5'-morpholino-spiro (bicyclo (2,2,2) · octane-2,2 '-5-endo-pyrroline)

3-exo- (4-chlorophenyl) -5 '-morpholino-spiro (bicyclo (2,2,2) octane-2,2'-5-endo-pyrroline) oil product Rr 0.23. Thin layer chromatography on silica gel with chloroform and ethanol

9: 1.

Example 81

5'-piperidino-3-phenyl-spiro (bicyclo (2,2,2) oktán2,2'-5-pyrroline) -heminaftaIin-8,5-disulfonate

298-299 ° C.

Ί 84 746

Example 82

3-endo- (44-dorophenyl) -5'-morpholino-spiro (bicyclo- (2,2,2) heptane-2 2 '-5-exo-pyrrolin) -hydrogen iodide

O- (3-exo- (4-chlorophenyl) -2-endo-nitrobicyclo (2,2,1) hept-5-cn-2-yl) prepared according to Examples 32 and 1a (a). The ethanolic mother liquor of the propionic acid methyl ester was purified by column chromatography to give [3- (3-endo-4-k] h-phenyl) -2-exonitrobicyclo (2,2,2) hept-5- en-2-yl) -propionic acid methyl ester is obtained as a stereoisomer in the form of colorless crystals (chromatographed on silica, eluting with methylene chloride).

The procedure for the preparation of 3-exo- (4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) heptane-2,2'-5-endo-pyrroline) was followed by and aryl-exo-pyrroline amidine hydroiodide stereoisomer. Colorless crystals, m.p. 279 ° C (dec), recrystallized from ethanol.

Example 83 N- (3-exo-4-chlorophenyl) -5'-morpholinepiro (bicyclo (2,2,1) heptane-2,2'-5-endo-pyrroline) -D. hydrogen tartrate

According to Example 32, the (±) -3-exo- (4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) heptane-2,2'-5-endo- pyrroline) -hydrogen iodide is treated with 2N potassium hydroxide / methylene chloride to give the free base.

12.3 g of a light yellow free base (oily product) are dissolved in 400 µl of methanol and a solution of 5.8 g of D / - / tartaric acid in 200 ml of water is added with stirring.

After an hour, the fine precipitate was filtered off. The solid was recrystallized with 500 mL of aqueous methanol (1: 1). This gives colorless plates which decompose at 270 ° C. [α] D = -106 ° C (methanol / water = 3: 1)

Rotation of the free base (¾ to -126 ° C (methanol / water = 3: 1)).

The following compound is obtained: + + - 3-exo- (4-chlorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) heptane-2,2'-5-ene) doopyrroline) -L-hydrogen tartrate, colorless plates: 270 ° C, [α] D 20 = + 106 ° C (methanol / water = 3: 1).

Example 84 N- (3-exo-4-chlorophenyl) -5 '- (2,6-dimethylmorpholino) spiro (bi-cyclo (2,2,1) heptane -2,2' -). 5-en dopyrroline) -D-hydrogen tartrate

The hydrogen iodide salt described in Example 65 is treated with 2N potassium hydroxide and methylene chloride, and the organic phase is dried over sodium sulfate, filtered and evaporated. Dissolve 2.5 g of oily product in 100 ml of methanol and then slowly add a solution of 1 g of D / - / - tartaric acid in 10 ml of water. The mixture was allowed to stand overnight and then filtered, the resulting material was recrystallized from aqueous methanol (1: 1).

Example 85 N- (3-exo-4-fluorophenyl) -5'-morpholino-spiro (bicyclo (2,2,1) heptane-2,2'-5-endo-pyrroline) -D- bitartrate

Following the procedure of Example 45, D, L-3-exo- (4-fluorophenyl) -5 '-morpholino-spiro (bicycle, 10 lo (2,2,1) beptane-2,2') precipitated from ethanol. -5-Endo-pyrroline) -hydrogen iodide was partitioned between 2N potassium hydroxide and methylene chloride to give a salt-free compound. After drying, filtration and evaporation of the organic phase, the oily product (10.7 g) was dissolved in methanol (185 ml) and a solution of D / - / tartaric acid (4.9 g) in water (60 ml) was added slowly. After stirring for 2 hours, the mixture was filtered and the solid was recrystallized from aqueous methanol (1: 1). Colorless crystals are obtained. Melting point: 256 ^υ 0 (dec.) [Α] D ³⁰ -76 ° (methanol / water = 3: 1)

In the same manner as above, the compound + / - 3-exo- (4-fluorophenyl) -5 '-morpholino-spiro (bicyclo- (2,2,1) -heptane -2,2'-5 pyrroline) -L-hi hydrogen tartrate. Colorless plates: 255 ° C, [α] D 20 = 69 ° C (methanol / water = 3: 1).

Example 86 N- (3-exo- (3,4-dichlorophenyl) -5'-morpholino-spiro- (bicyclo (2,2,1) heptane -2,2'-5-endo-pyrroline) D-hydrogen tartrate

In the same manner as in Example 48, the (±) -exo (3,4-dichlorophenyl) -5 '-morpholino-spiro (bicyclo (2,2)) heptane -2,2'-5 endo-pyrroline) -hydrogen iodide was first prepared in the salt-free form according to Example 83, followed by decomposition of the racemate with D-tartaric acid. Colorless crystals melting point: 236 DEG C. (dec.) [Α] D = -101 DEG (methanol / water = 3: 1).

Example 87

-phenyl-5 'morpholino-spiro (bicyclo (2 2 3) heptane-2,2'-5-pyrrolone / maleic acid salt

3.1 g of POCl 3 are dissolved in chloroform and this solution is added dropwise with stirring to a solution of 9.6 g of 3-phenyl-spiro- / bicyclo (2,2,1) heptane-2,2-pyridine in idin-5-one chloroform. . The reaction temperature should be kept below 25 ° C, and after stirring for 2 hours, the reaction mixture is kept at room temperature overnight. 1.7 g of morpholine solution are then added to the above reaction mixture with stirring at room temperature. The mixture was then heated to 60-75 ° C for several hours and the reaction mixture was added to aqueous 2N sodium hydroxide solution with stirring. The organic layer was separated, washed with ice water and dried. After evaporation of the solvent, maleic acid is added to the residue to give a maleic salt. Mp 173 ° C.

Proceeding as described above, the following compounds can be prepared: 2, 4, 5, 12, 13, 15,16, 24, 25, 26, 30, 31,32,40,41,44,45,47,48,50, 55,65,71,72,

Example 88 (Procedure c)

3-Phenyl-5-'-n-butylamino-spiro / bicyclo (2,2,1-heptane) -2,2' -pyrroline / Hydrogen Iodide

2.4 g (0.01 mol) of 5-amino-3-phenyl-spiro / bicyclo (2,2,1-heptane-2,2'-5-pyrroline) and an equimolar amount of n-butyl iodide. For 3 to 4 hours at a temperature of 0 ° C. The completion of the reaction is monitored by thin layer chromatography.

The resulting mixture was extracted with hot isopropanol. After cooling and recrystallization, using the same solvent, the title compound is obtained as the hydrogen iodide. 165-167 ° C.

The preparation of the starting compound for the alkylation reaction described above is described in Example 74.

Proceeding as above, compounds of the following Examples can be prepared: 4,5,9,12,13,32 and 66.

-101

184,746

Example 89 Process (d)

3-Phenyl-5'-pyrrolidino-spiro / bicyclo (2,2,1-l) heptane-23'-5-pyrrole / oxalic acid salt (1.1 mol) benzenesulfonyl chloride - 10 ° C 24 g (1 mol) 3 dropwise to a solution of phenyl-spiro (bicyclo * (2,2,1) heptane-2,2'-pyrrolidin) -5-one.

The latter compound was prepared with anhydrous pyridine (25 mL, 3 mol). After stirring for an additional 40 minutes at -10 ° C, 8.5 g (1.2 mol) of pyrrolidone are added in small portions. Cooling was then stopped and the mixture was heated on a steam bath for half an hour. The reaction mixture was poured into aqueous ammonia solution and extracted with chloroform. The organic layer was washed with water, dried over sodium sulfate, and the excess solvent and pyridine was distilled off under reduced pressure. The oily residue is taken up in ethanol, followed by the addition of an alcoholic solution of oxalic acid. The oxalic acid salt is recrystallized from ethanol. Mp 96 ° C.

By following the above procedures, the following compounds of Examples 12, 13, 96, 17, 18, 21, 24, 25, 26, 30, 31, 32, 36, 40, 41.42, 43, 44, 46, 47, 48, 49, 50,52,55,71.

Claims (3)

PATENT CLAIMS A process for the preparation of the heterocyclic spiro-linked amidine compounds of the formula I and their physiologically acceptable salts and optically active forms, wherein n is 1 or 2, R ^! C 1 -C 4 alkyl optionally substituted with hydroxy or morpholino, is hydrogen, R ^{2 is C 2} -C 6 alkyl optionally substituted with hydroxy, phenyl, C 1 -C 1, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, diethylamine or hydroxybenzylamino, or C 5 -C 8 cycloalkyl, or R ¹ and R ² together with the adjacent nitrogen atom represent a 5-6 or 7 membered saturated ring optionally substituted with phenyl, hydroxy, benoylamino, benzimidazolin-2-one-1-yl or 1-phenylimidazolidin-4-one-2-yl the six-membered rings may contain additional heteroatoms instead of one carbon atom such as oxygen, sulfur or nitrogen, where the nitrogen atom is hydrogen, C 1-4 alkyl, C 14 hydroxyalkyl, C 2-5 alkoxycarbonyl, benzyl, benzoyl (C14) -alkyl, optionally substituted C1-4 alkyl, or substituted halogénatofnmal substituted with phenyl, or ^R8 and ^R2 together with the nitrogen form a thiomorpholine-l-oxide-4-yl; 5 ^R4 optionally one or two C14 alkyl, C14 alkoxy, halogen, trifluoromethyl or amino-substituted phenyl, characterized in that. "Λ obtained in a (XVI) ^υ compound of formula a) optionally (III ) compound of formula - wherein n and R ⁴ are as ^stated above - with phosphorus oxychloride or phosphorus pentoxide, and (IV) with an amine of formula - wherein R * is as defined above - is reacted with · 15 us or you b) a compound of formula II wherein n and R ⁴ are as defined above and Z is a halogen, SH, SR ⁵ or OR ^S group have the meanings of C 1-6 alkyl, benzyl, phenyl, alkyl or phenylsulfonyl, with an amine of general formula (IV): wherein R ² is as defined above, or c) treating a compound of formula V wherein n and R ⁴ are as defined above with an alkylating agent; or d) optionally treating a compound of formula III prepared from a compound of formula XVI with n and R ⁴ is reacted with an aryl sulfochloride in anhydrous pyridine at -30 ° C to room temperature, preferably -10 ° C pn, followed by the imino ester obtained as intermediate θ with an amino compound of the formula IV wherein R ² is above - react. A process according to claim 1 for the preparation of compounds of formula XVI of formula 0) according to claim 1, characterized in that: 35 as the starting material (XV () exo-aryl-endo-nitro-ester of formula - in column isolated the mother liquor of preparation of (XVI) with a compound of formula (III): - wherein n and R ⁴ are as defined in claim 1; wherein n and R ⁴ are as defined above. 3. A process according to claim 1 or 2, wherein the left rotor isomer of the compound of formula I wherein n and R ^r are as defined in claim 1 is isolated. 4. Process for the preparation of pharmaceutical preparations, 45 wherein the optical isomer of a compound of formula (I) as defined in claim 1, wherein R ² , R ⁴ , n and the dashed line are as defined in claim 1, is a pharmaceutically acceptable excipient en a pharmaceutical composition, preferably for oral or parenteral administration.