HUT58693A - Process for preparation of substances having pharmaceutical effectivity - Google Patents

Abstract

Compounds of formula I <IMAGE> and their salts in which n = 0 or 1, R1 and R2 are each aliphatic or cyloallkyl or NR1R2 is an optionally substituted heterocyclic ring, R3 is alkyl, cycloalkyl or optionally substituted amino, R5 is H or an aliphatic group, R6 is H, an optionally substituted aliphatic group or a cycloalkyl group, or R3 and R5 together with the nitrogen and carbon atoms to which they are attached form an optionally substituted heterocyclic ring or R5 and R6 together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted by alkyl and R7 is hydrogen, halogen, optionally substituted alkyl, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl or cyano have utility as hypoglycaemic agents and may be incorporated into pharmaceutical compositions.

Description

FIELD OF THE INVENTION The present invention relates to novel anti-diabetic compounds of formula (I), in particular to blood glucose lowering agents, and pharmaceutically acceptable salts thereof, and to pharmaceutical compositions containing them.

• · «·

- 2 In the formula (1), R1 is 0 or 1;

R 1 and R 2 may be the same or different and may be C 1-3 alkyl optionally substituted by methoxy, C 3-7 cycloalkyl, or R 1; and R? together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic group of formula (11)

R 8 is hydrogen or C 1-3 alkyl; B-alkylene wherein the carbon atoms may be optionally substituted with oxygen, sulfur, sulfinyl or optionally substituted with C 1-3 -alkyl, said alkylene being optionally substituted with one or more C 1-3 -alkyl, or two adjacent carbon atoms may form part of a benzene ring;

R 1 is C 1 -C 7 linear or branched alkyl, C 3 -C 7 cycloalkyl, or a group of formula (III) wherein R 1 and R 4 may be the same or different and are hydrogen or C 1 -C 4 alkyl;

R 4 is hydrogen or a linear or C 1 -C 4 optionally substituted methoxy group.

- a group of 3 branched aliphatic hydrocarbons;

is a hydrogen atom, a C3-C7 cycloalkyl group, or a C1-C6 straight or branched aliphatic hydrocarbon group optionally having hydroxy or acyloxy, a C1-C3 alkoxy or alkylthio group, optionally alkylated amino, a C3-7 carbocyclic group or a cyano group as a substituent; obsession

R 1 and R 8 taken together with the carbon atom and the nitrogen atom to which they are attached form a heterocyclic group of formula (IV) wherein Rg in the heterocycle has the meaning given above,

R 8 and R 4 - g may be the same or different and represent hydrogen and C 1-4 alkyl optionally substituted by methoxy; and

D is oxyethylene, wherein the oxygen atom is attached to the carbon atom of R8 and ^R10 , or alkylene having from 2 to 5 carbon atoms, optionally substituted with one or more C1 to 3 alkyl groups; obsession

R 1 and R 8 taken together with the carbon atom and the nitrogen atom to which they are attached form a heterocyclic group of formula V

- 4 having the meaning given above,

R &lt; 3 &gt; is hydrogen or alkyl having 1 or 2 carbon atoms, and

E is alkylene having from 2 to 4 carbon atoms, optionally substituted with one or more C 1-3 alkyl groups; or and R 4 together with the nitrogen atom to which they are attached form a heterocyclic group of formula VI

G represents an alkylene chain containing from 4 to 5 carbon atoms, optionally substituted with oxygen, sulfur or nitrogen, which may be optionally substituted with C 1-3 alkyl, optionally substituted with one or more C 1-3 alkyl groups; and

Ry is hydrogen or halo, C 1-4 alkyl optionally substituted with C 1-3 methylthio, C 1-3 alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, total An alkoxycarbonyl group of 2 or 3 carbon atoms and a trifluoromethyl or cyano group which may be optionally substituted with one or more rings.

Of particular interest are compounds of formula (1) wherein n is 0 and R _{2 is the} same or · ··· ·····························

- 5 different alkyl groups having 1 to 3 carbon atoms, optionally substituted with methoxy, or allyl or cyclohexyl.

Of particular interest are those compounds of formula (I) wherein n is 0 and both R p and R ₂ are alkyl, allyl or 2-methoxyethyl, or R 2 is 2-methoxyethyl. - or cyclohexyl.

Of particular interest are those compounds of formula (I) wherein R 1 is 0 and the radical R 1 - (N 1) is dimethylamino, diethylamino, diallylamino, methyl (2-methoxy). ethyl) amino, cyclohexylmethylamino or bis (2-methoxyethyl) amino.

Of the compounds of formula (I) wherein n is 0 and the group R 1 -R 4 - represents a heterocyclic group (11), those in which R 8 is hydrogen or methyl, and B is of particular importance. is selected from the group consisting of ethylene, methyl 1-ethylene, o-phenylene, trimethylene, 2-methyltrimethylene, tetramethylene or propenylene, and -CH ₂ -O-CH ₂ -, -CH / CH ₂ - O. -CH (CH-j) -, -CH ₂ -S-CH ₂ -, -CH ₂ -S / O-CH ₂ -, or -CH ₂ -N / CH-j / -CH ₂ -. Thus, by virtue of their extreme importance, those compounds of formula (I) wherein n is 0 and the group ^ 1 ^ 2 ^ 'represents a heterocyclic group (11) are those in which the heterocyclic group in question is 1. -pyrrolidinyl, 2-methyl

- 6-pyrrolidin-1-yl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiomorpholino, thiomorpholin-1-oxide-4-yl- , 2-isoindolyl, 4-methylpiperazin-1-yl or 1,2,5,6-tetrahydropyridin-1-yl.

When β is 1 in the formula (1), the compounds in which morpholino or thiomorpholino is the equivalent are considered to be significant.

Of particular interest are compounds of formula I wherein R 1 is C 1 -C 5 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl, or cyclo. the alkyl group is cyclohexyl.

When referring to compounds of formula (I) in which R1 represents a group of formula (III), it is preferable that R1 and hydrogen are methyl and ethyl, that is to say, in the formula of particular importance, R1 is amino, methylamino, dimethylamino or ethylamino.

When in formula (1) it has a meaning different from that in which it is part of a heterocycle, then R 1 is preferably hydrogen, C 1-3 alkyl such as methyl or ethyl, or methoxy substituted alkyl such as methoxyethyl. , somehow represents an allyl group.

In the compounds of formula (I) of particular importance, Rg is hydrogen, straight or branched C1-C5 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. , tert-butyl or pentyl sweep; a hydroxyalkyl group such as 2-hydroxyethyl 1-,

3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, -2-hydroxy-2-methylpropyl or 2,3-dihydroxypropyl, or acylated, such as acetylated or benzoylated derivatives such as 2-acetoxyethyl or 2- (benzoyl-oxy) ethyl1; and methoxy substituted alkyl groups such as 2-methoxyethyl 1; methylthio-substituted alkyl, such as 2- (methylthio) ethyl; phenyl substituted alkyl such as benzyl or phenethyl; a cyano-substituted alkyl group such as 2-cyanoethyl; and straight or branched C 3 -C 6 alkenyl groups such as allyl or 2-methylallyl.

When Rg in formula (1) is cycloalkyl, those compounds wherein Rg is C5 or C6, such as cyclopentyl or cyclohexyl, are preferred.

A particular group of compounds of formula (I) are those in which R 1 and R 4 are different from those in which R 1 and R 6 taken together with the carbon atom and the nitrogen to which they are attached form a heterocycle, and are of particular importance here. which are derivatives of compounds of the formula R 1 -R 8 -NC / R 1 = N-, i.e.

With respect to α'-substituted amidines and 2-substituted guanidines, the free valence here is attached to a suitably substituted phenyl group as follows: acetamidine, N-methylacetamidine, NN-dimethylacetamidine, N, N-diethylacetamidine, N - (2-Acetoxyethyl) -acetamidine, N-butylacetamidine, N-pentylacetamidine, N-methylpropionic acid amidine, N, N-dimethylpropionic acid amidine, N-ethylpropionic acid amide, butanoic acid amidine, N-methyl -butanoic acid amidine, N, N-dimethylbutanoic acid amidine, N-ethylbutanoic acid amidine, 2-methylpropanoic acid amidine, N-methyl-2-methylpropanoic acid amidine, N, N-dimethyl-2-methylpropanoic acid amidine, pentanoic acid amidine, N-methyl pentanoic acid amidine, N, N-dimethylpentanoic acid amidine, 2,2-dimethylpropanoic acid amidine, N-methyl-2,2-dimethylpropanoic acid amidine, N, N-dimethyl-2,2-dimethylpropanoic acid amidine, N-methylhexanoic acid amidine , N-methylcyclohexanecarboxamidine, guanidine, 1-methylguanidine, 1,1-dimethylguanidine, 1,3-dimethylguanidine, 1-ethylguanidine, 1-butylguanidine, 1-ethyl-1-methyl -gu anidine, 1,1-diethyl-guanidine, 1,3-diethyl-guanidine, 1,1,3-trimethyl-guanidine, 1,1,3,3-tetramethyl-guanidine, 1-ethyl-3-methyl-guanidine, 1-ethyl-1,3,3-trimethyl-guanidine, 1-butyl-1,3,3-trimethyl-guanidine, 1-methyl-1-propyl-guanidine, 1-butyl-1-methyl-guanidine, (sec-butyl) -3-methyl-guanidine, 1- (tert-butyl) -3-methyl-guanidine, 1-isobutyl-3-methyl-guanidine, 1-butyl-3-methyl-guanidine, 1-methyl- 3-pentyl guanidine, 1-cyclopentyl-3-methyl guanidine, 1- (2-methoxyethyl) guanidine, 1-methyl-1- (2-methoxyethyl) guanidine, 1-methyl-3- (2-memoxyethyl) guanidine, 1-ethyl-1- (2-methoxyethyl) guanidine, 1,1-bis (2-methoxyethyl) guanidine, 1-methyl-1- [2- (methylthio) ethyl] guanidine, 1-allyl -1-methylguanidine, 1-allyl-3-methylguanidine, 1-allyl-1,3,3-trimethylguanidine and 1,1-diallyl- guanidine.

• ·

- 9 A particular class of compounds of formula (I) are those in which R 1 and R 4 together with the carbon atom and the nitrogen to which they are attached form a heterocyclic group of formula (IV), wherein R in the heterocycle ^ and R ^ q have the same or different meanings and are hydrogen or respectively

C1-C3 alkyl groups such as methyl, ethyl or isopropyl optionally substituted by methoxy groups, i.e., R4 and / or R4q are, for example, methoxyethyl, e.g. ethylene, trimethylene, tetramethylene -, pentamethylene, 1,1-dimethylethylene or oxyethylene, and Rg is preferably hydrogen, and is methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxy. you are ethyl

2-methoxyethyl. Of particular interest are those compounds of formula (1) wherein the group (IV) is 2-pyrrolidinylidene, 1-methyl-2-pyrrolidinylidene, 1-ethyl-2-pyrrolidinylidene, 1-isopropyl-2 pyrrolidinyl dene, 1-cyclohexy-2-pyrrolidinylidene, 1- (2-methoxyethyl) -2-pyrrolidinylidene, 1,3-dimethyl-2-pyrrolidinylidene, 5,5-dimethyl-2-pyrrolidinylidene, 1,1,3,3-trimethyl-2-pyrrolidinylidene, 1,5,5-trimethyl-2-pyrrolidinylidene, 3-isopropyl-1-methyl-2-pyrrolidinylidene, 1-ethyl-3,3-dimethyl -2-pyrrolodinylidene, 3,3-diethyl-1-methyl-2-pyrrolidinylidene, 2-piperidinylidene, 1-methyl-2-piperidinylidene, 1,3-dimethyl-2-piperidinylidene, 1-ethyl- 2-piperidinylidene, 1-isopropyl-2-piperidinylidene, 1- (2-cyanoethyl) -2-piperidinylidene,

1- (2-acetoxyethyl) -2-piperidinylidene, 1-methyl-3- (2-methoxyethyl) -2-piperidinylidene, 2-hexahydroazepinylidene, 1-methyl-2-hexahydroazepinylidene -, 2-octahydroazocinylidene or 3-morpholinylidene.

Another outstanding class of compounds of formula (I) are those in which R1 and R4 are taken together with the carbon atom to which they are attached to form a heterocyclic group of formula (V) wherein E is ethylene in the heterocycle. , 1,1-dimethylethylene, 1,2-dimethylethylene, trimethylene, propylene or tetramethylene, R1 is hydrogen or methyl or ethyl and R1 is hydrogen or methyl. ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl,

2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2- (benzoyloxy) ethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3- hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxypropyl or 2- (dimethylamino) ethyl. . Particularly important compounds of formula (1) are those represented by the formula (V): 2-imidazolidinylidene, 1-methyl-2-imidazolidinylidene, 4-methyl-2-imidazolidinylidene,

4,4-dimethyl-2-imidazolidinylidene, 4,5-dimethyl-2-imidazolidinylidene, 1-ethyl-2-imidazolidinylidene, 1-propyl-2-imidazolidinylidene, 1-isopropyl-2-imidazolidinylidene, -butyl-2-imidazolidinylidene, 1-isobutyl-2-imidazolidinylidene, 1-pentyl-2-imidazolidinylidene, 1-allyl-2-imidazolidinylidene, 1- (2-methylallyl) -2-imidazolidinylidene •: : ···, · • · · * ·· ··· · · · ♦

- 11- (2-hydroxyethyl) -2-imidazolidinylidene, 1- (2-hydroxyethyl) -3-methyl-2-imidazolidinylidene, 1- (2-acetoxyethyl) -2-imidazolidinylidene; , 1- [2- (benzoyloxy) ethyl] -2-imidazolidinylidene, 1- (2-benzoyloxy) ethyl] -3-methyl-2-imidazolidinylidene, 1- (2-hydroxy) ethyl) -4,5-dimethyl-2-imidazolidinylidene, 1- (2-methoxyethyl) imidazolidinylidene, 3-methyl-1- (2-methoxyethyl) -2-imidazolidinylidene, 1-cyclohexyl- 2-imidazolidinylidene, 1-benzyl-2-imidazolidinylidene, 1-phenethyl-2-imidazolidinylidene, 1-Q2- (dimethylamino) ethyl] -2-imidazolidinylidene, 1- (3-hydroxypropyl) - 2-imidazolidinylidene, 1- (2-hydroxypropyl) -2-imidazolidinylidene, 1- (2-hydroxy-2-methylpropyl) -2-imidazolidinylidene, 1- (2-hydroxybutyl) -2- imidazolidinylidene, 1- (2,3-dihydroxypropyl) -2-imidazolidinylidene, 1,3-dimethyl-2-imidazolidinylidene, 1,3-diethyl-2-imidazolidinylidene, 1-ethyl-3-methyl- 2-imidazolidinylidene, 1-butyl-3-methyl-2-imidazolidinylidene, 1-isopropyl-4,4-dimethyl-2-imidazolidinylidene, 1-methyl -2- perhydropyrimidinylidene or 1,3-diaza-cycloheptylidene.

Another particularly important group of compounds of formula (I) are those in which Rg and the nitrogen atom to which they are attached form a heterocyclic group of formula (VI) wherein G in the formula (VI) is tetramethylene, pentamethylene -

3-oxa-pentamethylene, 3-thia-pentamethylene, 3-methyl-3-aza-pentamethylene, 3-methyl-pentamethylene or 2,4-dimethyl-3-oxa-pentamethylene. In the compounds of particular interest, the group R 1 R 9 N is replaced by 1-pyrrolidinyl, piperidino,

It consists of 4-methyl-piperidino, morpholino, 2,6-dimethylmorpholino, thiomorpholino or 4-methylpiperazin-1-yl.

In the case of the compounds of the formula (I) in which R 1 and R ₆ together with the nitrate atom to which they are attached form a heterocyclic group of the formula (VI), the compounds are represented by R 1 - the guanidine derivative of the general formula in the 2-position, this position of the free valence, which is substituted with a phenyl group bearing appropriate substituents, namely the following, which are of particular importance:

1,1- (3-oxapentamethylene) guanidine, 1,1-dimethyl-3,3- (3-oxapentamethylene) guanidine, 1,1- (2,4-dimethyl-3-oxapentamethylene) ) -guanidine, 1,1- (3-thia-pentamethylene) -guanidine, 1,1- (3-methyl-pentamethylene) -guanidine, 1,1- (3-methyl-3-aza-pentamethylene) -guanidine, 1-methyl-3,3-tetramethylene-guanidine, 1,1-pentamethylene-guanidine and 1,1-dimethyl-3,3-pentamethylene-guanidine.

In the significant compounds of formula I, Ry is hydrogen or R? one or more, preferably one or two substituents selected from the group consisting of fluoro and chloro, and methyl, ethyl, isobutyl, (methylthio) methyl, methoxy, dimethoxy, methoxycarbonyl, methylthio; , methylsulfinyl, methylsulfonyl, trifluoromethyl or cyano.

Representative compounds of formula (1), including pharmaceutically acceptable salts thereof, include:

4- £ 2- (2-piperidinylidene-amino) -phenyl-morpholine,

4- ^ £ 2- (l-methyl-2-piperidinylidene) amino | ^ -phenyl-methanone,

4- [2- (1-Ethyl-2-piperidin-1-ylamino) -phenyl} -morpholine,

4- [2- (1-Isopropyl-2-piperidinyleneamino) -phenyl] -morpholine,

4- [2- (2-Hexahydroazepnidine amino) phenyl] morpholine,

4- [2- (l-methyl-2-hexahidroazepiniÜdén) phenyl] morpholine,

4- [2- (2-octahydroazocinylidene-amino) -phenyl] -N-morpholine,

4 - [^ 2- (2-pyrrolidinyl-amino) -phenyl-morpholine,

4- [2- (1-methyl-2-pyrrolidinylenediamino) phenyl] morpholine,

4- [2- (1,3-Dimethyl-2-pyrrolidinylidene-amino) -phenyl] -morpholine, 4- [2- (1,3,3-trimethyl-2-pyrroidinylidene-amino) -phenyl] -morpholine

4- [2- (1-ethyl-2-pyrrolidinylideneamino) phenyl] morpholine, 4- (2- {1- (2-methoxyethyl) -2-pyrrolidinylideneamino-phenyl) morpholine,

- [2- (1-cyclohexyl-2-pyrrolidinylideneamino) phenyl] morpholine, 4- [2- (3,3-dimethyl-1-ethyl-2-pyrrolidinylideneamino) phenyl] morpholine,

4- [2- (3,3-Diethyl-1-methyl-2-pyrrolidinylideneamino) phenyl] morpholine,

4- [2- (3-isopropyl-1-methyl-2-pyrrolidinylideneamino) phenyl] morpholine,

- [2- (1,3-dimethyl-1-piperidin-2-ylideneamino) phenyl] morpholine,

- [3-methyl-2- (2-piperidinylidene) amino] phenyl] morpholine,

4- [3-methyl-1-2- (1-methyl-2-piperidinylamino) -phenyl] -morpholine,

4- [4-methyl-2- (2-piperidinylideneamino) phenyl] morpholine,

4-β-methyl-2- (1-methyl-2-piperidinylideneamino) phenyl] morpholine,

4- [5-methyl-2- (2-piperidinylideneamino) phenyl] morpholine,

- 1, 6-methyl-1-2- (2-piperidinylideneamino) phenyl-1-morpholine,

4- [4-Ethyl-1-2- (2-pieridinylidene-amino) -phenyl] -morpholine

4- [3-chloro-2- (2-piperidinylidene-amino) -phenyl-morpholine,

4- [4-chloro-2- (2-piperidinylideneamino) phenyl] morpholine,

- [4-chloro-2- (l-methyl-2-piperidinylideneamino) phenyl] morpholine,

-? 5-chloro-2- (2-piperidinylideneamino) phenyl] morpholine,

4- [6-chloro-2- (2-piperidinylideneamino) phenyl] morpholine,

- [4-fluoro-2- (2-piperidin-1-ylamino) -phenyl] -morpholine,

4- [4-fluoro-2- (1-methyl-2-piperidinylideneamino) phenyl] morpholine,

4- [4-methoxy-2- (2-piperidinylidene-amino) -phenyl] -morpholine,

- [4-methoxycarbonyl-2- (2-piperidinylideneamino) phenyl] morpholine,

4- [4-methylsulfonyl-1-2- (2-piperidinylideneamino) phenyl] morpholine,

4- [2- [1- (2-Acetoxyethyl) -2-piperidinylidene] amino] phenyl] -morpholine.

morpholine,

- [2- (3-methyl-2-pyrrolidinylideneamino) phenyl] morpholine,

N-methyl-N '- (2-morpholinophenyl) acetamidine

N- (2-morpholinophenyl) -N'-propilacetamidin

N- (n-butyl) -N '- (2-morpholinophenyl) acetamidine

N- (n-pentyl) -N '- (2-morpholinophenyl) acetamidine

N- (2-acetoxyethyl) -N '- (2-morpholinophenyl) acetamidine

N, N-dimethyl-N '- (2-morpholinophenyl) acetamidine

N, N-diethyl-N '- (2-morpholinophenyl) acetamidine

N-methyl-N '- (2-morpholinophenyl) -propionsavamidin

N-ethyl-N '- (2-morpholinophenyl) -propionsavamidin

N, N-dimethyl-N '- (2-morpholinophenyl) -propionsavamidin

N-methyl-N '- (2-morpholinophenyl) -butánsavamidin

N-ethyl-N '- (2-morpholinophenyl) butanoic acid amide ·:: ···. .

'·· ··· «·» ·

-15N, N-dimethyl-N '- (2-morpholinophenyl) -butánsavamidin

N-methyl-N '- (2-morpholinophenyl) -2-methyl-propionsavamidin

N, N-Di Methyl-N '- (2-morpholinophenyl) -2-methylpropionic acid anhydride

Meti1-N-N '- (2-morpholinophenyl) -pentánsavamidin

N, N-dimethyl-N '- (2-morpholinophenyl) -pentánsavamidin

N-methyl-N '- (2-morpholinophenyl) -2,2-dimethyl-propanoic acid amidine

N, N-dimethyl-N '- (2-morpholinophenyl) -2,2-dimethyl-propanoic acid amidine

N-methyl-N '- (2-morpholinophenyl) -hexánsavamidin

N-methyl-N '- [J2 (l-pyrrolidinyl) phenyl-butiramidin

N-Methyl-N '- [2- (1-pyrrolidinyl) phenyl] -1,2,2-dimethyl-propanoic acid amidine

N-methyl-N '- (2-morpholinophenyl) -ciklohexánkarboxamidin

N-methyl-N '- (2-piperidino-phenyl) -2,2-dimethyl-propanoic acid amidine

1- [2- (2-piperidinylidene-amino) -phenyl] -pyrrolidine

1- [2- (1-Methyl-2-piperidinylidene-amino) -phenyl] -pyrrolidine

1- [2- (1-Ethyl-2-piperidinylidene-amino) -phenyl] -pyrrolidine

1- [4-Chloro-2- (1-methyl-2-piperidinylideneamino) phenyl] pyrrolidine

1- £ 3-methyl-2- (l-methyl-2-piperidinylidene) amino-pyrrolidin -feni1J

1- [2- (1-Methyl-2-pyrrolidinylideneamino) phenyl] -1H-pyrrolidine

1- [2- (1,3-Dimethyl-2-pyrrolidinylideneamino) phenyl] pyrrolidine

1- [2- (1-Methyl-2-hexahydroazepinylideneamino) phenyl] -J-pyrrolidine

1- [4-Methyl-2- (2-pieridinylidene-amino) -phenyl] -pyrrolidine

1- [4-Chloro-2- (2-piperidinylideneamino) phenyl] pyrrolidine

1- [3-Methyl-2- (2-piperidinylidene-amino) -phenyl] -pyrrolidine 1- [6- (methyl-2- (2-piperidinylidene-amino) -phenyl] -pyrrolidine ··· '' · · ·. ί ··· ··:. ·: · ··· *. · ...... ... ·

4 - [[2- (2-piperidinylidene-amino) phenyl-thiamorpholin

1- [2- (2-Piperidinylideneamino) phenyl] piperidine

1- [2- (1-Methyl-2-piperidinylideneamino) phenyl] piperidine 1- [2- (2-piperidinylideneamino) phenyl] hexahydroazepine

2,6-Dimethyl-4- [2- (2-piperidinylideneamino) phenyl] morpholine 4-methyl-1- [2- (2-piperidinylideneamino) phenyl] piperidine

1- [2- (2-Piperidinylideneamino) phenyl] -1,2,5,6-tetrahydropyridine

2-Methyl-1- [2- (2-piperidinylideneamino) phenyl] pyrrolidine

2- [2- (2-piperidinylidene-amino) phenyl-isoindolin

4- [2- (l-methyl-2-piperidinylideneamino) phenyl] thiomorpholine

4- [4-methyl-2- (2-piperidinylideneamino) phenyl] thiomorpholine

N- (2-methoxyethyl) -N- [2- (2-piperidinylideneamino) phenyl] methylamine

N- [2- (2-piperidinylideneamino) phenyl] dimethylamine

N- £ 2- (2-piperidinylidene) amino -fenijJ-diallylamine '

N-cyclohexyl-N- [2- (2-piperidinylideneamino) phenyl] methylamine

N- [2- (2-piperidinylidene-aminophenyl)] - bis (2-methoxyethyl) -amine

4- [2- (l, 3,3-trimethyl-2-pyrrolidinylideneamino) phenyl] thiomorpholine

1- [2- (1,3,3-Trimethyl-2-pyrrolidinylideneamino) phenyl] piperidine

1- (2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) phenyl] -4-methylpyridin-piperazine

1- [2- (1,3,3-Trimethyl-2-pyrrolidinylideneamino) -phenyl] -pyrrolidine 4- [4-methyl-2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) - phenyl-morpholine

1- [2- (l-methyl-2-pyrrolidinylideneamino) phenyl] piperidine

1 - [_ 2- (l, 3-dimethyl-2-pyrrolidinylideneamino) phenyl] piperidine

4- (2- (5,5-Dimethyl-2-pyrrolidinylideneamino) phenyl] -morpholine

- [1,5-Trimethyl-2-pyrrolidinylidene-amino] -phenyl] -morpholine

N-2- (l, 3,3 ~ trimethyl-2-pyrrolidinylidene amino) phenyl-bis (methoxyethyl) amine

N- (2-morpholinophenyl) acetamidine

N- (5-methyl-2-morphenylphenyl) acetamidine

N- (2-morpholinophenyl) -prop ion savamidine

N- (2-morpholinophenyl) butanoic acid amidine

N- (2-morpholinophenyl) -2-methyl-propánsavamidin

N- (5-methylthio-2-morpholinophenyl) -2-methyl-propánsavamidin

N- (5-fluoro-2-morpholinophenyl) -2-methyl-propánsavamidin

N- (2-morph over-phenyl) pentane wait din

N- (2-morpholinophenyl) -2,2-dimethyl-propanoic acid amidine

4- {2- [1- (Cyanoethyl) -2-piperidinyl] -enediamine} -phenyl} -morpholine

4- £ 2- (3-morfolinildién) phenyl] morpholine

4-Q2- (2-piperidinylideneamino) benzyl] morpholine

- [2- (1-Methyl-2-pyrrolidinylideneamino) -benzyl] -morpholine

4- [4-Chloro-2- (2-piperidinylideneamino) -benzyl] -morpholine

4- [2- (1,3,3-Trimethyl-2-pyrrolidinylideneamino) -benzyl] -morpholine N-methyl-N '- (2-morpholinomethyl-phenyl) -2,2-dimethyl-propanoic acid amidine

4- [2- (1,3-Dimethyl-2-imidazo [i] lidinyleneamino) -phenyl] -morpholine

4- £ 2- (l, 3-dimethyl-2-imidazolidinyl) -4-fluoro-phenyl-morpholine

4- [2- (1,3-Dimethyl-2-imidazolidinylideneamino) -3-methylphenyl] -morpholine

4- [2- (1,3-Dimethyl-2-imidazolidinylene-amino) -4-methyl-phenyl] -morpholine

4- (2- (l, 3-dimethyl-2-imidazolidinyl) -5-methylphenyl] morpholine

4- (4-Chloro-2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl) morpholine

4- (2- (1,3-Dimethyl-2-imidazolidinylene-amino) -4-methoxyphenyl] -morpholine

4- (4,5-dimethoxy-2- (l, 3-dimethyl-2-imidazolidinyl) phenyl]

morpholine

1- (2- (1,3-Dimethyl-2-imidazolidinylideneamino) phenyl] pyrrolidine

1- (2- (1,3-Dimethyl-2-imidazolidinylene-amino) -3-methyl-phenyl] -pyrrolidine

1- (2- (l, 3-dimethyl-2-imidazolidinylideneamino) phenyl] piperidine

4- (2- (l, 3-dimethyl-2-imidazolidinylideneamino) phenyl] thiomorpholine

2,6-dimethyl-4- (2- (l, 3-dimethyl-2-imidazolidinylideneamino) phenyl] morpholine

N- (2- (1,3-Dimethyl-2-imidazolidinylideneamino) phenyl) diethylamine 1- (2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl) -2-methyl-

pyrrolidine

4- (3-chloro-2- (l, 3-dimethyl-2-imidazolidinylideneamino) -phenyl-morpholine

1- (2- (1,3-Dimethyl-2-imidazolidinylideneamino) -4-methyl-1 H -pyrrolidine

N- (2- (1,3-Dimethyl-2-imidazolidinylideneamino) phenyl] bis (2-methoxyethyl) amine

4- (2- (1,3-Diethyl-2-imidazolidinylideneamino) phenyl] morpholine

4- (2- (l, 3-dimethyl-2-imidazolidinylideneamino) -6-pyrrolidin-meti1-feni1J

4- [2- (1-Ethyl-3-methyl-2-imidazolidinylidene-amino) -phenyl] -morpholine

4- [2- (1-Butyl-3-methyl-2-imidazolidinylideneamino) phenyl] -N-morpholine (2-benzyloxyethyl) -3-methyl-2-imidazolinylidene

-amino! -feni1 <-moor fel in

2- (2-morpholinophenyl) -1,1,3,3-tetramethyl-guamdin-

-1-ethyl-2- (2-morpholinophenyl) -1,3,3-trimethyl guanidine 1-allyl-2- (2-morpholinophenyl) -1,3,3-trimethyl guanidine

1-Butyl-2- (2-morpholinophenyl) -1,3,3-trimethyl guanidine 1-pentyl-2- (2-morpholinophenyl) -1,3,3-trimethyl guanidine 4- - [l-methyl-3- (2-methoxyethyl) -2-imidazolidinylidene

amino-phenyl ^ -morpholin

2- ^ 4- [l-methyl-3- (2-hydroxyethyl) -2-imidazolidinylideneamino -propionic phenyl ^ -morpholin

N, N-Dimethyl-N '- (2-morpholine-phenyl) -morpholine-4-carboxamidine N, N-dimethyl-N' - (2-morpholin-phenyl) -piperidine-1-carboxamidine 4 - £ 2- ( 1,3-Dimethyl-2-imidazolidinyl-dichloro-amino) -phenyl] -N-thiomorpholine-1-oxide

4- [2- (2-Imidazolidinylidene-amino) -phenyl] -morpholine

- [2- (1-Methyl-2-imidazolidinylidene-amino) -phenyl] -morpholine 4- [2- (1-ethyl-2-imidazolidinylidene-amino) -phenyl] -morpholine 4- [2- (1-propyl-2-) imidazolidinylidene-amino) -phenyl] -morpholine 4- [2- (1-isopropyl-2-imidazolidinylidene-amino) -phenyl] -morpholine

4- £ 2- (1-butyl-2-imidazolidinylideneamino) -phenyl-morpholine

- [2- (1-Isobutyl-1-imidazolidinylamino) phenyl] morpholine

4- [2- (1-Pentyl-2-imidazolidinylamino) phenyl] 1 H -morpholine

4- [2- (1-Allyl-2-imidazolidinylideneamino) phenyl] -4- [2- (1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl] -morpholine ✓

4- (2- [l- (2-hydroxyethyl) -2-imidazolidinylideneamino-3 -propionic acid methyl

phenyl ^ -morpholin

4 - (- 2- [l- (2-methoxyethyl) -2-imidazolidinylideneamino] morpholine -fenily

4- (2- (l-cyclohexyl-2-imidazolidinylideneamino) -phenyl-morpholine

4- [2- (1-Benzyl-2-imidazolidinylideneamino) phenyl] morpholine

4 - (- [i ^- (2-phenylethyl) -2-imidazolidinylideneamino -propionic-phenyl) -morpholine

4- (2- (1- (2-dimethylamino-ethyl) -2-imidazolidinylideneamino -propionic-phenyl) -morpholine

4- (2- £ l- (2,3-dihydroxypropyl) -2-imidazolidinylideneamino -propionic phenyl ^ -morpholin

4- (2- [l- (2-methylallyl) -2-imidazolidinylideneamino -propionic-phenyl) -morpholine

N- [2- (l-methyl-2-imidazolidinylideneamino) phenyl] bis (2-methoxyethyl) amine

N- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl] -bis (2-methoxyethyl) amine

4- [2- (1-Methyl-2-imidazolidinylideneamino) phenyl] -thiomorpholine

1- (2- (1-Methyl-2-imidazolidinylideneamino) phenyl] pyrrolidine

4- [2- (1-Butyl-2-imidazolidinylideneamino) phenyl] -thiomorpholine

- [2- (l-methyl-2-imidazolidinylideneamino) -3-methylphenyl] morpholine

4- [2- (1-Methyl-2-imidazolidinylideneamino) -4-methylphenyl] -morpholine

pyrrolidine

-2-methyl-pyrrolidine

4- [4- (4-Methyl) -2- (1-butyl-2-imidazolidinylidene) phenyl] morpholin-1- [2- (2-imidazolidinylideneamino) phenyl] piperidine 1- [2- ( 1-Methyl-2-imidazolidinylidene-amino) -phenyl] -piperidine 1- [2- (1-methyl-2-imidazolidinylidene-amino) -3-methylphenyl] -N-piperidine

4- (2- {1- (2-Hydroxyethyl) -2-imidazolidinylideneamino-phenyl) -thiomorpholine 1- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) -piperidine-4- (2- [1- (3-hydroxypropyl) -2-imidazolidinylideneamino] phenyl-morpholine

4- (2- [1- (2-Hydroxypropyl) -2-imidazolidinylideneamino] phenyl] morpholine

4- (2- [1- (2-Hydroxybutyl) -2-imidazolidinylideneamino] phenyl) morpholine

4- (2- [1- (2-Hydroxy-2-methylpropyl) -2-imidazolidinylideneamino] phenyl] morpholine

4- [2- (4-Methyl-2-imidazolidinylideneamino) phenyl] morpholine

4- [2- (4,5-Dimethyl-2-imidazolidinylideneamino) phenyl] morpholine 4- (2- {4,5-dimethyl-1- (2-hydroxyethyl) -2-imidazolidinylideneamino) amino phenyl ^ -morpholin

4- {2- (l-isopropyl-4,4-dimethyl-2-imidazolidinylideneamino) phenyl] morpholine

4- [2- (1-Methyl-perhydropyrimidin-2-ylideneamino) -phenyl] -morpholine

2- (2-morpholino-phenylimino) -l, 3-diazacilloheptán

1,1-dimethyl-2- (2-morpholinophenyl) guanidine

1,3-dimethyl-2- (2-morpholophenyl) guanidine

1.3.3-Trimethyl-2- (2-morpholinophenyl) guanidine

1 éti1-2- (2-morpholinophenyl) -3-methyl-guanidine

1,3-diethyl-2- (2-morpholinophenyl) guanidine

4- (2- [1- (2-Acetoxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine

4- (2- [1- (2-Benzoyloxyethyl) -2-imidazolidinylideneamino] phenyl-morpholine 1- (butyl) -2- (2-morpholinophenyl) -3-methylguanidine 1- (2) -methoxyethyl) -2- (2-piperidinophenyl) guanidine 1- (2-methylthioethyl) -2- (2-morpholinophenyl) guanidine 1- (2-methoxyethyl) -2- (2-Morpholin-phenyl) -guanidine 1- (propyl) -2- (2-morpholin-phenyl) -3-methyl-guanidine 1- (2-methoxy-ethyl) -3-methyl-2- (morpholin-phenyl) ) -Guanidine 1-Cyclopentyl-2- (2-morpholinophenyl) -3-methyl guanidine N-methyl-N '- (2-morpholinophenyl) pyrrolidine-1-carboxamidine 1- (butyl) -2 - (2-morpholinophenyl) -3-ethyl-guanidine

1,3-Dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine 1-allyl-2- [2- (1-pyrrolidinyl) phenyl] -3-methyl guanidine

1,3-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine

4- {2- [1- (2-Hydroxyethyl) -2-imidazolidinylideneamino] -4-methylphenyl} morpholine • · ·

- 23 1-Methyl-2- (2-morpholinophenyl) -3- (pentyl) guanidine 1- (butyl) -2- (5-methyl -2-morpholinophenyl) -3-methyl guanidine

1- (Butyl) -2- (6-methyl-2-morpholinophenyl) -3-methyl-guanidine 1- (butyl) -2- (5-fluoro-2-morpholinophenyl) -3-methyl -guanidine 1- (butyl) -2- (5-methylthio-2-morpholinophenyl) -3-methylguanidine

1 izobuti1-2- (2-morpholinophenyl) -3-meti1 guanidine

1-sec-Buty-2- (2-morpholinophenyl) -3-methyl-guanidine 1-tert-butyl-2- (2-morpholinophenyl) -3-methyl guanidine

1 alli1-2- (2-morpholinophenyl) -3-methyl-guanidine

1- (butyl) -2- (2-thiomorpholin-phenyl) -3-methyl-guanidine

1,1-dimethyl-2- (2-morpholine-5-trifluoromethyl-phenyl) -guanidine

1,1-dimethyl-1-2- (5-cyano-2-morpholinophenyl) guanidine 1,3-dipropyl-2- (2-morpholinophenyl) guanidine

2- (2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-methyl-2-morpholine-phenyl) -guanidine

1,1-dimethyl-2- (6-methyl-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (4-chloro-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (3-chloro-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-methoxy-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-methylthio-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (4-methyl-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-ethyl-1-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-methylthiomethyl-2-morpholinophenyl) guanidine

1,1-diethyl-1-2- (2-morpholinophenyl) guanidine

1- (butyl) -l-methyl-2- (2-morpholinophenyl) guanidine

1,1-bis (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine

N- (2-morpholinophenyl) -morflin-4-carboxamidine

Ν- (2-morpholinophenyl) pyrrolidine-l-carboxamidine

1,1-dimethyl-2- (2-piperidin-phenyl) -guanidine

1,1-dimethyl-2- (2- (1-pyrrolidinyl) phenyl) guanidine

1.1-dimer ti1-2-2-1 lomorpholin (phenyl) guanidine

1,1-dimethyl-1-2- (2-dimethylaminophenyl) guanidine

1,1-dimethyl-2- (2- [N- (2-methoxyethyl) -N-methylamino] phenyl] guanidine

1,1-Dimethyl-2- [2- (4-methyl-1-piperazinyl) phenyl] guanidine

N- (2-piperidin-phenyl) -morpholin-4-carboxamidine

N- (2-piperidin-phenyl) -piperidin-l-carboxamidine

1,1-dimethyl-2- (5-methoxycarbonyl-2-morpholinophenyl) guanidine

1-Methyl-2- (2-morpholinophenyl) guanidine 1-ethyl-2- (morpholinophenyl) guanidine 1-butyl-2- (2-morpholinophenyl) guanidine

1-Ethyl-1-methyl-2- (2-morpholinophenyl) guanidine 1-methyl-1- (2-methylthioethyl) -2- (2-morpholinophenyl) guanidine 1- (2-methoxy) ethyl) -1-methyl-2- (2-morpholinophenyl) guanidine 1-allyl-1-methyl-2- (2-morpholinophenyl) guanidine

1 eti1-1- (2-methoxyethyl) -2 - (- morpholinophenyl) guanidine

1,1-diallyl-2- (2-morpholinophenyl) guanidine

N- (2-morpholinophenyl) -4-methyl-piperazine-l-carboxamidine

N- (2-morpholinophenyl) -2,6-dimethylmorpholine-4-carboxamidine

N- (2-morpholinophenyl) thiomorpholine-4-carboxamidine

N- (2-morpholinophenyl) -4-methylpiperidine-l-carboxamidine

N- (2-morpholinophenyl) -tiamorfolin-l-carboxamidine

1,1-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-fluoro-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (3-methyl-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (4-methoxy-2-morpholinophenyl) guanidine

1,1-dimethyl-2- (5-isobutyl-2-morpholinophenyl) guanidine

1,1-Dimethyl-2- (5-methylsulfinyl-2-morpholinophenyl) guanidine 4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) benzyl] morpholine 4- [4-chloro-2 - (1,3-dimethyl-2-imidazolidinylideneamino) benzene 1J -

morpholine

N, N-dimethyl-N '- (2-morpholin-methylphenyl) guanidine

N- (2-morpholinomethylphenyl) -morpholine-4-carboxamidine is thus summarized as one of the group of compounds of the general formula (I), wherein n is 0 and R _{1 is} R _2. The equivalent of N is morpholino, thiomorpholino, piperidino, or 1-pyrrolidinyl, R 1 is amino, a C 1-4 aliphatic hydrocarbon group such as methyl, ethyl, or allyl, and R ₆ is also a C 1-4 aliphatic hydrocarbon group optionally substituted with a methoxy or methylthio group such as methyl, ethyl, allyl, methoxyethyl, or (methylthio) -. ethyl, or R 4 and R 6 together with the nitrogen atom to which they are attached form a heterocyclic group of formula VI, such as morpholino or thiomorpholino, and R 6 '; is hydrogen, fluorine craving for chlorine or methyl, ethyl, (methylthio) methyl or methylthio.

♦ «

Typical representatives of this group of compounds are:

1,1-dimethyl-2- (2-morpholinophenyl) guanidine,

2- (5-fluoro-2-morpholinophenyl) -l, 1-dimethyl-guanidine,

2- (5-chloro-2-morpholinophenyl) -l, 1-dimethyl-guanidine,

1,1-dimethyl-1-2- (5-methyl-2-morpholinophenyl) guanidine,

1,1-dimethyl-2- (6-methyl-2-morpholinophenyl) guanidine,

2- (5-ethyl-2-morpholinophenyl) -1,1-dimethyl-guanidine,

1,1-Dimethyl-2- (5- (methylthio) methyl] -2-morpholinophenyl) guanidine

1,1-dimethyl-2- [5- (methylthio) -2-morpholinophenyl] guanidine,

1-I-1-methyl-2- (2-morpholinophenyl) guanidine,

1,1-diethyl-2- (2-morpholinophenyl) guanidine, 1-methyl-1- (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine, 1-methyl-1- [2 - (methylthio) ethyl] -2- (morpholinophenyl) guanidine,

1.1-dimethyl-1-2- (2-thiomorpholinophenyl) guanidine,

1,1-dimethyl-2- (2-piperidinophenyl) guanidine,

1,1-dimethyl-2- [2- (1-pyrrolidinyl) phenyl] guanidine,

N- (2-morpholinophenyl) morpholine-4-carboxamidine and

N- (2-morpholinophenyl) -thiomorpholine-4-carboxamidine and pharmaceutically acceptable salts of all of these compounds

Another group of compounds of outstanding importance are those compounds of formula (I) wherein n is 0, R 1, R _{2 are} N or morpholino or thiomorpholino, R 1 is a compound of formula (111) wherein R 1 is C 1 -C 4 alkyl, such as methyl,

and R 4 is hydrogen, R 4 is also hydrogen, and R 4 is a C 1-4 aliphatic hydrocarbon group such as methyl, butyl or tert-butyl optionally substituted with methoxy such as methoxy. ethyl, and Ry is hydrogen or fluoro, or methylthio or (methylthio) methyl.

Examples of this second group of compounds of paramount importance include, by name:

1-Butyl-3-methyl-2- (2-morpholinophenyl) guanidine, 1- (tert-butyl) -3-methyl-2- (2-morpholinophenyl) guanidine, 1- (tert-butyl) ) -2- (4-fluoro-2-morpholino-phenyl) -3-methyl-guanidine, 1- (tert-butyl) -3-methyl-2- (4-methyl-2-morpholino-phenyl) -guanidine, 1- (tert-butyl) -3-methyl-2- [4- (methylthio) -2-morpholinophenyl] guanidine, 1- (tert-butyl) -3-methyl-2- (4 - [( methylthio) -methyl 1, 2-morpholinophenyl-4-guanidine, 1-methyl-3- (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine,

1,3-dimethyl-1-2- (2-thiomorpholinophenyl) guanidine and 1- (tert-butyl) -3-methyl-2- (2-thiomorpholinophenyl) guanidine, and pharmaceutically acceptable salts thereof.

A further class of outstanding compounds of formula (I) are those wherein R1 is 0, R1 is N is morpholino or thiomorpholino, R1 is C1-C4 alkyl, such as methyl or ·· »· · · β · · · · · · · · · · · · · · · · · · · · · ·

- 28-tert-butyl and hydrogen, and Ry is hydrogen or fluoro or methyl, methylthio or (methylthio) methyl.

Representative of this latter class of compounds are the following: N- (2-morpholinophenyl) acetamidine,

N- (4-fluoro-2-morpholinophenyl) acetamide, N- (4-methyl-2-morpholinophenyl) acetamide,

N- [4- (methylthio) -2-morpholinophenyl] -N-acetamidine,

N- (4- (methylthio) methyl] -2-morpholinophenyl) acetamide,

N- (2-thiamorpholinophenyl) acetamidine

N- [2- (morpholinomethyl) phenyl] acetamide, N- (2-morpholinophenyl) -2,2-dimethylpropanoic acid amidine and N- [2- (morpholinomethyl) phenyl] -2,2,2 -dimethylpropanoic acid amidine and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may also be prepared in the form of salts with pharmaceutically acceptable acids. Examples of such salts are hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, maleate, acetate, citrate, fumarate, tartrate, succinate, benzoate and pamoate, as well as salts of acidic amino acids such as glutamic acid. The compounds of formula (I) and their salts may also exist in solvated form, for example as their hydrates.

Some of the compounds of formula (I) contain one or more centers of asymmetry, and consequently different optically active forms are possible. If the compound has a single chiral center, two enantiomeric forms may exist and both enantiomers and mixtures thereof are encompassed within the scope of the invention. When multiple chiral centers are present in the molecule, the compound may exist in the form of diastereomers and all diastereomers, including mixtures thereof, are encompassed within the scope of the invention.

The invention further relates to a process for the preparation of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as active ingredient in combination with a pharmaceutically acceptable diluent or carrier.

For therapeutic use, the active compounds may be administered orally, that is, orally, clavically, i.e., rectally, and parenterally, i.e., bypassing the digestive tract, and may also be administered topically, however, oral administration is preferred.

Thus, as stated above, the pharmaceutical compositions may be prepared in any of the known dosage forms, i.e., oral, rectal, parenteral or topical formulations. Pharmaceutically acceptable carriers and other excipients suitable for the preparation of various dosage forms are well known to those skilled in the art, to mention, for example, magnesium stearate as a lubricant, and methods for preparing compositions such as tablets are well known. The skilled artisan also knows how to make a long-acting tablet.

30, from which the active compounds of the invention are released only over a prolonged period. If desired, such tablets may be coated with an enteric coating, such as cellulose acetate phthalate, according to known procedures. Similarly, hard or soft gelatin capsules containing the active ingredient with or without other excipients, which may also be prepared by conventional procedures well known in the art, may be formulated and enteric coated in a known manner. Tablets and capsules generally contain between 50 and 500 mg of the active ingredient.

However, other oral formulations may be prepared, such as aqueous solutions containing the active ingredient in dissolved form, aqueous suspensions in which the active ingredient is dispersed in an aqueous medium using a suitable non-toxic suspending agent, for example, sodium salt of carboxymethylcellulose, that is, oily suspensions containing the active compounds of the present invention suspended in a suitable vegetable oil such as arachidone oil.

For some dosage forms, it is preferable to use the active compounds of the invention in micronized form to cut into very small particles. Such a small particle size material can be prepared, for example, in a fluidization mill.

If desired, the pharmaceutical compositions of the invention may contain other pharmacologically active substances which are compatible with them in addition to the active substances of the invention. contain.

The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) may be used to treat people with hyperglycemia, i.e., a patient whose disease is manifested by a higher than normal blood sugar level. Such patients are generally treated with a daily dose of 50-3000 mg of the active ingredient of formula (I). Oral administration is preferred as a mode of administration.

The following describes the essence of the invention, i.e. the methods by which the compounds of formula (I) can be prepared.

In particular, the compounds of formula (I) may be prepared by reacting an aniline derivative of formula (VII) in the presence of a condensing agent such as phosphorus chloride oxide, sulfinyl chloride, phosgene, phosphorus N-chloride or benzenesulfonyl chloride. reacting _{C0-NR5 R6} acid amide or a urea of formula.

Compounds of formula (I) wherein R 1 and R 4 taken together with the nitrogen atom and the carbon to which they are attached form a heterocyclic group of formula (IV) may be prepared by reacting an aniline of formula (VII)

a) reacting with a lactam of formula VIII: a condensing agent such as phosphorus trichloride, sulfinyl chloride, cyanuric chloride, phosgene , in the presence of carbon tetrachloride triphenylphosphine, phosphorus N-chloride or benzenesulfonyl chloride;

b) a compound of formula IX: in the formula

R 2 represents a chlorine atom, dichlorophosphoryloxy, chlorosulfinyloxy, chloroformyloxy or phenylsulfonyloxy, and B 'represents an anion such as a halide, especially chloride, or POCl. reacting a - ion;

c) reacting a compound of formula X wherein R 1 is alkyl and B - is an anion such as tetra-fluoroborate or methylsulfate;

d) a sulfonyl chloride such as benzenesulfonyl-

in the presence of chloride is reacted with a ketoxime of formula XI, in which case R 1 is hydrogen.

Among the compounds of formula (I), those in which R 4 and R 6 together with the carbon atom and the nitrogen to which they are attached form a heterocyclic group of formula (V), an aniline of formula (VII) and a compound of formula (XII) The urea derivative of Formula I may be prepared by reacting a condensing agent such as phosphorus trichloride oxide, sulfinyl chloride, phosgene, phosphorus N-chloride or benzenesulfonyl chloride. The same compounds of formula (1) / (33) are compounds of the formula: wherein R 4 and R 4 are taken together with the carbon atom and the nitrogen atom, to which they are attached form a heterocyclic group of formula (V), they may also be prepared by reacting a compound of formula (XIII), optionally in the form of a salt such as a hydroiodide salt, wherein R 4 and R ₅ are hydrogen; Reaction with diamine XIV.

If the compound of formula (1) to be prepared, R 1 is C 1-7 straight or branched alkyl or C 3-7 cycloalkyl and R 1 R 1 N is replaced by an amino group, reacting the corresponding compound of formula (VII), or optionally a salt thereof, such as its hydrochloride, with a cyano compound of formula R 1 -CN, optionally in the presence of aluminum chloride.

All of the compounds of formula (I) wherein R 1 is an amino group may be prepared by reacting a compound of formula (VII), optionally in the form of a salt such as a hydrochloride, with a cyanamide of the formula R 1 -NCN. The reaction may be carried out by employing a liquid reaction medium such as cresol to react the starting compounds, or it may be possible to effect the reaction by heating the reactants in the absence of any reaction medium.

• · · ♦ ·· · • · «* · • · · · · · · · · ·

Compounds of formula (I) wherein R-j is amino may also be prepared from compounds of formula (XV) if the appropriate derivative is

The reaction is carried out with an amine of the formula R 1 -R 6 NH, optionally in a liquid reaction medium such as alcohol.

Compounds of formula (I) wherein R j is a group of formula (111) and in formula (111) R _{4 is} alkyl, R 4 alkyl or hydrogen may be prepared from a compound of formula (XIII) wherein R - ^ has the same meaning as R ^, and likewise, R ^ has the same meaning as R ^ by reacting it with an amine of formula R ^ R ^ NH. The reaction may be carried out in an alcohol such as ethanol or tuanole, optionally in the presence of a base such as pyridine or triethylamine or in the presence of potassium hydroxide and lead acetate. If the amine of formula R 1 -R 4 NH is ammonia itself, it is also possible to dissolve the ammonia in the reaction medium and carry out the reaction in a closed system at elevated temperatures.

If, in the compound of formula (I) to be prepared, R1 represents a group of formula (III) in which R1 represents an alkyl group and R1 represents a hydrogen atom or an alkyl group, then the procedure of formula XVI a thiourea derivative of the formula wherein R is R ^ and R ^ is a base such as potassium hydroxide.

- in the presence of 35 roxide or potassium carbonate and lead acetate, with an amine of formula R 1 -R 4 NH. If the amine of the formula R ₅ R ₆ NH is the ammonia itself, it can be dissolved in an alcohol such as ethanol and the alcohol will be the reaction medium and may be reacted at a higher temperature in a sealed reaction vessel.

Among the compounds of formula (I), wherein R 4 is a group of formula (III), and in formula (111), R 4 is alkyl and R 4 is hydrogen, and R ₅ is also hydrogen, by reacting a carbodiimide of formula XVII with an amine of formula R g -NHz.

Compounds of formula (1) wherein n is 0 and the equivalent of R 1 -N are morpholino, thiomorpholino, 1-pyrrolidinyl or piperidino, a compound of formula XVIII and a compound of formula XIX The bifunctional reagent of Formula I may be prepared by reaction of a leaving group such as a halogen atom such as a chlorine or bromine atom or a tosyloxy group, and L an oxygen or sulfur atom, a chemical bond or a methylene group.

If a compound of formula (I) is to be prepared wherein R1 represents a group of formula (III) and in formula (III) R1 represents a propyl group and R1 represents a hydrogen atom, and R1 represents a hydrogen atom, and R ^ is propyl, then it may be convenient to have a _R6 ~ -NH ₂ amine, wherein R ^ is propyl thiourea one / sixteenth / formula - is reacted with potassium hydroxide and lead: - wherein and are each methyl, in the presence of acetate, whereby both the dioxo group and the dimethylamino group are replaced by the group R 1 -NH-.

If, in the compound of formula (I) to be prepared, R1 represents a group of formula (111) wherein R1 is methyl and R1 is hydrogen, and also R1 is hydrogen and R1 is methyl, it is possible to do so. that an amine of formula R 1 -NH ₂ , wherein R 1 is methyl, can be reacted with a corresponding compound of formula XIII wherein R 1 - R 3 - N 'is replaced by a butylamino group as a result, both the methylthio group and the group R ₁₄ R ₁₅ N - are replaced by the group R 1 -NH.

Compounds of formula (1) wherein R 1 -R ₂ N- is the same as thiomorpholin-1-oxy-4-yl are the corresponding compound (I) instead of R 1 R ₂ n- thiomorpholino group, for example by oxidation with sodium metaperiodate.

• · · · ··· · · · * «· •« · · r · · ····· ·

When a compound of formula (I) represents a group substituted by an acyloxy group, these compounds may be prepared by acylation of the corresponding hydroxyl compound, for example, by acetylation or benzoylation of the corresponding compound of formula (1) wherein R 1 is a hydroxy group. represents a substituent

Compounds of formula (I) wherein R? is an alkylsulfinyl group, can be prepared by reacting the corresponding compound of formula (I) wherein R? alkylthio is oxidized, preferably with, for example, sodium metaperiodate.

Compounds of formula (VII) may be prepared by reduction of the corresponding nitro derivatives of formula (XX), e.g.

(a) hydrogen gas in the presence of a Raney nickel catalyst;

(b) hydrogen gas in the presence of a palladium on carbon catalyst;

c) sodium sulfide;

d) in a mixture of ethyl acetate or ethanol / hydrochloric acid, using a reducing agent tin-IV / chloride-water (1/2); obsession

(e) with iron in the presence of an acid.

Compounds of formula IX, wherein dichlorophosphoryloxy, chlorosulfinyloxy, chlorocarbonyloxy, or phenylsulfonyloxy, may be prepared from the corresponding compounds of formula VIII if they are in the above order or phosphorus trichloride «· ί · · 5 9 ·

9 · · ··· 9

9 9 9 99

oxide, or sulfinyl chloride, or phosgene, or benzenesulfonyl chloride.

For the preparation of compounds of formula (X), a compound of formula (VIII) may be prepared in the presence of an alkylating agent, such as dialkyl sulfate, trialkyl oxonium tetrafluoroborate or boron fluoride diethyl ether (1-1). reaction with a diazoalkane, and after alkylation, the reaction mixture is basified with, for example, sodium carbonate or sodium hydroxide.

Compounds of formula XIII may be prepared by reacting the corresponding thiourea of formula XVI with methyl iodide.

One way to prepare compounds of general formula (XV) is to provide a compound of general formula (XIII) wherein R 1 and R 4 are both hydrogen or R 1 is benzoyl and R 4 is hydrogen in the presence of potassium acetate. -hydroxide.

Compounds of formula XV may also be prepared by reacting the corresponding thioureas of formula XVI wherein both R1 and R1 are hydrogen, a base such as sodium carbonate, and a copper catalyst such as copper. in the presence of a mixture of chloride and copper (II) chloride with sodium chloride.

Thioureas of formula XVI, wherein R 1 and R 4 are both hydrogen, may be prepared by reaction of an isothiocyanate of formula XXI with ammonia ····

Compounds of formula (XVI) wherein R ₄ - ₄ is alkyl and R 4 - is hydrogen may be prepared by reacting an aniline (VII) with an alkyl isothiocyanate of formula R 4 -NCS.

To prepare the carbodiimides of formula XVII, a thiourea of formula XVI wherein R _{4 is} the same as R 4 and R 4 is hydrogen is reacted with sodium chlorite.

Compounds of formula XVIII may be prepared by reduction of the corresponding compound XXII, for example with hydrogen gas in the presence of Raney nickel.

All of the compounds of formula (XX) wherein n is 0 and the equivalent of R 1 -N is morpholino, thiomorpholino, 1-pyrrolidinyl or piperidino, are prepared by

2-Nitroaniline is reacted with a compound of formula XIX.

When n is 0 in the formula (XX) and the group R 1 -N is replaced by a morpholino, thiomorpholino, 1-pyrrolidinyl, piperidino, 1-hexahydroazepinyl or 4-methylpiperazin-1-yl group , these compounds may also be prepared by reacting either morpholine, or thiomorpholine, or pyrrolidine, or piperidine, or hexahydroazepine, or 1-methylpiperazine, in the above order. '· • · · ·· * · * ·· * ··· * ····

40 with the corresponding 2-halogenitrobenzene, for example 2-fluoronitrobenzene or 2-chloronitrobenzene. The reaction may be carried out in the absence of a solvent or in the presence of a solvent such as benzene, ethanol or acetonitrile.

Compounds of formula XXI can be prepared by reacting the corresponding compound of formula VII with thiophosgene in a liquid reaction medium such as dioxane.

The compounds of formula (XXII) may be prepared from the corresponding acid amide R 1 -CO-NR 1 R 4 R 2 by reaction with a 2-nitroaniline derivative in the presence of a condensing agent such as phosphorus trichloride oxide or sulfinyl chloride. to obtain the desired product. However, the compounds of formula (XXII) may also be prepared by reacting the appropriate 2-halonitrobenzene, for example 2-fluoronitrobenzene or 2-chloronitrobenzene having the desired substituents, with R With an acid amidine or guanidine of the formula NR 1 R 4.

The hypoglycemic, i.e. blood glucose lowering effect of the compounds of formula (I), described in more detail in the Examples below, was tested as follows:

Glucose was injected subcutaneously at a dose of 800 mg / kg in a volume of 4 ml to 150-200 g fasted rats for 18 hours. Subsequently, the animals r

The test substances were given orally in a volume of 4 or 5 ml / kg body weight, 0.2% agar suspension, as indicated in the column below x in Table 1.

and 4 hours later, blood was drawn from the ocular cavity and, using the specific glucose oxidase method, JVadish A.H., Little R.L., and Sternberg, J. C .: Clin. Chem. 14, 116 (1968) J, a Beckman glucose analyzer was used to determine the plasma glucose content. The control animals received the same amount of 0.2% agar suspension without active substance. Plasma glucose depletion was expressed as a percentage of the control group, and was attributed to those compounds tested as above at either 2 or 4 hours, up to 200 mg / kg, at any dose of 15%. has been reached or exceeded.

After evaluating the data from the series of assays performed above, the hypoglycemic potency of the active ingredients was classified according to the following criteria. If more than one dose was available for an active substance at a certain dose level, then the mean value was used as the basis for classification. A = a drop in blood sugar over 25% at 2 and 4 hours.

B = after 2 hours a decrease in sugar content of more than 25% can be measured, but after 4 hours the rate of loss is less than 25%.

C = reduction in the range from 15% to 25% after 2 hours but greater than 25% after 4 hours.

• · · ·

- 42 D = decrease after 2 and 4 hours in the range of 15 to 25%.

the drop in sugar is between 15% and 25% after 2 hours, but less than 15% after 4 hours.

F = the rate of decline is less than 15% after 2 hours but above it.

Table 1

Example

Activity Example x Activity

1 25 THE 2 25 B 3 25 B 4 25 B 5 25 THE 6 25 E 7 25 B 8 36 B 9 200 E 10 25 B 11 25 THE 12 25 THE 13 50 D 14 200 THE 15 100 E 16 25 D 17 50 B 18 25 E 19 40 THE 20 25 THE 21 25 C 22 25 B 23 50 THE 24 25 B 25 25 D 26 25 • B 27 25 THE 28 25 THE 29th 25 E 30 25 D 31 50 D 32 25 D

Table 1 (continued)

!the X Activity Pél ria X Nude 33 25 B 34 25 B 35 25 D 36 200 F 37 200 E 38 200 D 39 200 THE 40 200 THE 41 200 THE 42 36 D 43 25 B 44 200 THE 45 200 D 46 36 B 47 37 B 48 200 THE 49 38 E 50 36 THE 51 200 D 52 36 B 53 36 B 54 37 B 55 36 THE 56 35 THE 57 25 THE 58 25 B 59 35 THE 60 37 E 61 36 D 62 25 C 63 100 THE 64 25 B 65 25 THE 66 36 D 67 200 THE 68 25 C 69 43 D 70 36 THE 71 36 THE 72 25 B 73 25 THE 74 25 THE 75 50 F 76 25 D 77 25 E 78 25 F 79 200 THE 80 25 D 81 200 D 82 50 E 83 25 THE 84 25 É 85 25 D 86 25 F 87 200 D 88 200 F

Table 1 (continued)

Example x Activity Example x Activity

89 200 C 90 25 E 91 200 THE 92 25 B 93 25 C 94 200 C 95 25 E 96 25 F 97 50 D 98 50 THE 99 25 THE 100 25 B 101 25 B 102 200 THE 103 25 B 104 27 THE 105 37 E 106 37 E 107 25 B 108 ' 25 B 109 25 B 110 36 B 111 25 B 112 36 B 113 25 D 114 25 E 115 25 D 116 25 B 117 25 B 118 25 THE 119 25 D 120 25 B 121 25 E 122 25 THE 123 38 B 124 37 B 125 36 B 126 200 THE 127 25 E 128 25 THE 129 25 B 130 100 B 131 50 B 132 200 THE 133 25 B 134 25 THE 135 25 THE 136 25 B 137 25 B 138 25 B 139 25 B 140 100 ,THE 141 25 E 142 25 THE

• · · '

Table 1 (continued)

Example

Activity Example

Activity

143 25 B 144 25 B 145 25 C 146 200 THE 147 36 D 148 25 D 149 36 D 150 68 F 151 25 C 152 25 D 153 25 B 154 39 D 155 133 B 156 25 D 157 25 THE 158 25 THE 159 50 D 160 26 D 161 34 THE 162 35 B 163 25 B 164 25 D 165 200 B 166 25 D 167 25 B 168 25 B 169 25 THE 170 25 THE 171 25 D 172 25 D 173 25 D 174 25 B 175 25 B 176 35 C 177 25 B 178 200 THE 179 25 D 180 25 E 181 43 D 182 25 D 183 25 D 184 34 F 185 200 D 186 25 THE 187 25 THE 188 25 B 189 25 THE 190 25 THE ¹⁹¹ 36 D 192 25 B 193 25 THE 194 200 C 195 12.5 THE 196 25 THE

Example x

Activity

Table 1 (continued)

Activity Example ^:

197 25 D 198 25 THE 199 25 B 200 25 THE 201 25 E 202 25 B 203 100 THE 204 200 THE 205 200 THE 206 200 C 207 50 THE 208 30 D 209 25 B 210 30 D 211 36 THE 212 25 F 213 50 D 214 25 E 215 25 E 216 35 THE 217 30 E 218 200 D 219 200 D 220 36 THE 221 200 THE 222 35 THE 223 35 D 224 35 C 225 25 B 226 200 THE 227 25 F 228 35 THE 229 35 THE 230 35 G 231 35 F 232 25 B 233 25 B 234 25 B 235 34 THE 236 38 C 237 35 THE 238 35 THE 239 35 THE 240 36 THE 241 34 THE 242 200 THE 243 200 B 244 200 E 245 25 B 246 200 D 247 37 THE 248 36 THE 249 36 B 250 25 E 251 35 E 252 200 THE 253 35 THE 254 36 B

- 47.

Table 1 (continued)

Example X Activity 'Example X active 255 36 THE 256 34 B 257 36 THE 258 35 E 259 34 D 260 35 B 261 36 C 262 37 B 263 38 B 264 36 B 265 200 E 266 200 E 267 200 E 268 35 B 269 35 B 270 25 B 271 25 B 272 25 B 273 200 C 274 128 D 275 25 E 276 36 B 277 34 B 278 35 B 279 25 B 280 35 B 281 35 THE 282 200 C 283 200 E 284 200 E 285 200 B 286 35 B 287 36 B 288 38 E 289 200 THE 290 25 D 291 25 B 292 85 C 293 35 THE 294 25 B 295 25 B 296 25 D 297 35 B 298 35 E 299 34 E 300 200 THE 301 25 B 302 38 THE 303 39 B 304 40 B 305 28 THE 306 29 THE 307 30 - B 308 NT • 309 100 D 310 200 D 311 200 E 312 200 E

NT = no data · · · · · · · · · · · · · ·

The following examples illustrate the process of the present invention, but are intended to be exemplary only. In all examples, the final products were identified by elemental analysis.

EXAMPLE 1 2-Piperidone (g) was dissolved in 100 ml of anhydrous benzene, cooled to 10 ° C with ice-water, and 22.2 ml of freshly distilled phosphorus trichloride were added over 10-15 minutes under nitrogen. A white precipitate first precipitates out of solution, which, however, is converted to a light yellow oil within 3 hours. A solution of 4- (2-aminophenyl) morpholine (36 g) in anhydrous benzene (150 mL) was added and the mixture was stirred at 65 ° C for 32 hours. At the end of the reaction time, the benzene is decanted from the oil, the oil is washed twice with 40 ml of benzene, 100 ml of diethyl ether are added and the mixture is made basic with 10% aqueous sodium hydroxide with stirring under ice-cooling. The aqueous layer was extracted with diethyl ether (2 x 100 mL), and the combined ethereal solution was washed with water and brine and dried. The solution was finally filtered and the solvent evaporated to leave a thick oil. The oil solidified by trituration with hexane and this solid was recrystallized from hot hexane. 4- [2- (2-piperidinylideneamino) phenyl] morpholine, m.p. 89-90 ° C.

Example 2

10.2 g of the product of Example 1 are dissolved in 30 ml of anhydrous methanol and 4.6 g of fumaric acid are added. The resulting • * ·························································•

The solid product was filtered and recrystallized from methanol to give 4- 2- (2-piperidinylideneamino) phenyl-morpholine fumarate as colorless crystals melting at 210 ° C.

3-37. examples

Following the procedure described in Example 1, the corresponding anilines of formula VII wherein R 1 is N are morpholino groups and the corresponding compounds of formula VIII in benzene in the presence of phosphorus trichloride Reaction at -70 ° C to prepare the compounds of formula (1) listed in Table 2 wherein n = 0; and

R 1 and R 4 together form a group of formula (V) wherein 0 is - (CH 2 -) -.

From the columns in the table, A is the mass of the compound of formula VII in g, B is the amount of benzene used to dissolve in ml, C is the mass of compound of formula VIII in g, D is the amount of benzene used in dissolution in ml, E is the amount of phosphorus trichloride in ml and F is the reaction time in hours.

- 50 • ·· · ·····················································•

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Paa ΧΣΰΧΧΧΧΧΧ pá χχχχχχχα

cn cn <n -3 · «τ m cm cm

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- 51 · * ·· * · · * ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

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-ethyl Η Η Η 20A-205 (7) (8)

II. TABLE (continued)

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«3 un <r <· <r co CN CO CN 00 lake · - »- · 9Γ · » · - · * CN CO., LTD CN m CN CN CN 1- CN CN un CN co

She m She She She m un She SHE un She m She She SHE Q co CN un m r- CN xO un CN un CN m CN CO

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She SHE un She She She m She She un She un She She She r- r- CN oo r " cn r- cn CO CN cn CN cn r- CN

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Ο53

V ···? ·· ·····································································································································································································•

Notes to Table 2:

The product is crystallized from hexane.

The product is purified by chromatography on alumina, eluting with a 1: 1 mixture of dichloromethane and hexane.

The product is isolated as a salt with hydrogen iodide and recrystallized from a 1: 1 mixture of methanol and diethyl ether.

/ 4 / The coupling reaction proceeds at room temperature.

The product is recrystallized from diethyl ether.

Compound (6) is dissolved in a mixture of benzene (60 ml) and acetonitrile (60 ml).

The product is purified by chromatography on alumina successively using the following eluents: hexane; methylene chloride / hexane 1: 1; methylene chloride / hexane 3: 7; methylene chloride / hexane 1: 1; and methylene chloride.

The product is recovered as the monofumarate salt and recrystallized from a 1: 1 mixture of methanol and diethyl ether.

The product was isolated as a monohydroiodide and recrystallized from methanol: diethyl ether (2: 3).

The coupling mixture is allowed to react for 24 hours at room temperature and for 8 hours at 70 ° C.

The product is isolated as the fumarate salt and recrystallized from isopropyl alcohol.

The product is isolated as the sesquifumarate salt and recrystallized from a 1: 1 mixture of methanol and diethyl ether.

• · * • »» »*» »» »» »» »»

The compound of formula VII is dissolved in 120 ml of acetonitrile.

The product is purified by chromatography on alumina eluting with a 99: 1 mixture of dichloromethane and methanol and recrystallized from a 1: 1 mixture of ethylene glycol dimethyl ether and hexane.

Example 38

Similarly as described in Examples 1 and 2, 2.56 g of l-methyl-3- (2-methoxyethyl) -2-piperidone was dissolved in 30 ml of benzene and 2.49 g of 4- (2- aminophenyl) morpholine, followed by reaction of the two compounds in the presence of 1.37 ml of phosphorus trichloride oxide for 12 hours at 70 ° C. The resulting 4- [2- (1-methyl-3- (2-methoxyethyl) -2-pyridinylidene) aminophenyl] -morpholine sesquifumarate was recrystallized from methanol: diethyl ether (1: 1). 174 ° C.

Example 39

As in Example 1, dissolved in 80 ml of benzene, 14.17 g of 1-benzyl-3-methyl-2-pyrrolidone in the presence of 6.86 ml of phosphorus trichloride were dissolved in 8.9 g of 30 ml of benzene. reaction with aminophenyl) morpholine at 70 ° C for 24 hours, resulting in recrystallization from hexane, m.p. 96-97 ° C. -phenylmorpholine is obtained.

The above recrystallized product was dissolved in 100 ml of methanol, ml of cyclohexene and 1.5 g of 10% palladium on charcoal were added and the reaction mixture was refluxed for 4 hours. The oil thus obtained was 4- [2- (2-methyl-2-pyrrolidinylidene) -amino] -phenyl] -morpholine oil, containing 20 ml. Dissolve in methanol and add 0.47 g of a solution of fumaric acid in methanol. Recrystallization from a 1: 1 mixture of methanol and diethyl ether gave the resulting 4,3-methyl-2-pyrrolidinylidene-amino] -phenyl] -morpholine fumarate, m.p. 185 ° C. 40-62. example

Compounds of formula (I) listed in Table IH with n = 0 were prepared according to the same procedure as in Example 1, whereby a compound of formula (VII) was dissolved in benzene, measured in g or solvent. in ml of columns A and B of the table and reacting it with an acid amide R 1 -CO-NR 1 R 4 R 2, also dissolved in benzene, in the presence of phosphorus trichloride at -0-70 ° C. The amount of acid amide in g is given in Table C, the amount of benzene in ml is given in D and the hourly reaction time is shown in column F.

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- 5 «Notes to Annex III. table:

References in Sections (1) and (8) are given in Annex II. are identical to those given in Table.

(15) The product was isolated as the monofurarate salt and recrystallized from methanol.

(16) The coupling reaction proceeds at 80 ° C.

(17) The coupling reaction proceeds at 75 ° C.

(18) The product is obtained as a monohydrate.

(19) The product was recrystallized twice from pentane.

(20) The product is obtained in the form of an oil, the boiling point of which is not determined. The oil was purified by column chromatography on alumina, eluting with a column of hexane / dichloromethane / hexane 1: 1 and dichloromethane.

63.példa

A mixture of 11.5 g of N-methylpivalinsaamide, 120 ml of benzene and 9.2 ml of phosphorus trichloride is stirred at room temperature for 3 days, and then a solution of 14 g of 1- (2-aminophenyl) piperidine in 80 ml of benzene is added. and stirring at 65-70 ° C for four more days.

The thus obtained N-methyl-N '- (2-piperidinophenyl) -plvalic acid amidine was melted at 78 ° C. The product

0 _f contains 25 moles of water of crystallization.

6V75. examples

Following the procedure set forth in Example 1, the compounds of the general formula (I) listed in Table TV, where n = 0;

2

R and R together with the nitrogen atom form a pyrrolidinyl moiety; and ο κ and R ³ together form a group of Formula V wherein D is - (CHg) ^ - wherein an aniline of Formula VII is represented by the formula: pyrrolidinyl, in a benzene solution, in the presence of phosphorus trichloride oxide, is reacted with a compound of formula (VIII) at a temperature of from 0 to 70 ° C. The TV. the amount of compound of formula (VII) in g, the amount of compound of formula (VIII) in C, the amount of benzene in ml in B and D, the amount of phosphorus trichloride in ml in E, and finally the reaction time in Hours is shown in the F column.

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Notes on the TV. table:

References (1), (4) and (8) refer to Table H under the same number.

(21) The product is recovered as the monofumarate salt and recrystallized from methanol: diethyl ether (1: 2).

(22) The product is recovered as the monofumarate salt and recrystallized from methanol: diethyl ether (1: 3).

76-91. examples

Compounds of formula (I) listed in Table V, wherein n = 0; and R 4 together with carbon and nitrogen form a group of formula IV wherein

R and R are hydrogen; and

D is a trimethylene group prepared in the same manner as described in Example 1. According to this, an aniline of formula VII is dissolved in benzene - column A of the table gives the amount of aniline in g and B the amount of benzene in ml - with 2-piperidone at 60-70 ° C, phosphorus. 4 · 4 «

4 ······· · · · · · · ····

-63 '~

in the presence of trichloride oxide. The measurement in g is C, the amount of benzene required to dissolve in ml is D, the amount of condensing agent in E is E, the reaction time in hours is shown in the figures in column V in Table V.

• · · · · ···

SPREADSHEET

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- 66 -

Notes to Table V:

In the note section, numbers (1), (8), (11) and (21) refer to those given in tables 2 and 4.

(23) The coupling is carried out at 75-80 ° C.

(24) The product is recovered as the monofumarate salt and recrystallized from methanol.

(25) The product is ethylene glycol dimethyl ether and hexane

Recrystallize from a 1: 2 mixture.

(26) The product is crystallized first from hexane and then from a mixture of ethylene glycol dimethyl ether and hexane.

(27) The product was purified by chromatography on a column of alumina eluting with a 49/1 dichloromethane / methanol mixture. After purification, the dihydroiodide of the product is recovered and the salt is recrystallized from ethanol / diethyl ether (1: 1).

(28) The coupling is performed at 9θ "1θθ ° θ" οη.

92-101.példák

The VT. Compounds of formula (I) listed in Table I wherein n = 0;

• ·· ». · * «· · · · · · · · · · · · · · ···

5

R and R together with the carbon atom and the nitrogen atom form a group of formula IV

Wherein R and R together with the carbon atom form the group given in Table A are primary

D is a -CH8 -CG-C group attached to the carbon atom via the methylene group by the procedure of Example 1, i.e., reacting an aniline (VII) in a benzene solution with 2-pyrrolidinone substituted with a methyl group in the presence of phosphorus trichloride. C ~ C.

The amount of aniline and 2-pyrrolidinone in g is shown in Table A and C, the amount of benzene in B and D, the amount of condensation ester in m1 in E and the reaction time in hours are shown in column F.

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-69.Notes to Table VI:

In the comment box, the numbers (1) and (4) are a

Refer to Table II.

(29) The product was isolated as the dihydroiodide and recrystallized from a 1: 1 mixture of methanol and diethyl ether.

(30) The coupling reaction takes place at room temperature and the reaction time is shown in column F in hours.

(31) The product is isolated as the dihydroiodide and the salt is recrystallized from ethanol / diethyl ether (1: 3).

Example 102

A mixture of 5.34 g of 4 '(2-aminophenyl) morpholine, 4.52 ml of aoetonitrile and 12 g of anhydrous aluminum chloride is reacted for 4 hours at 1ό0-17θ ° 07θη to give N- (2-morpholinophenyl). -acetamidine is obtained. The product recrystallized from hexane had a melting point of from 14 ° to 141 ° C.

Example 103

5.7θg of 4- (2-amino-4-methylphenyl) morpholine,

A mixture of 3.5 g of acetonitrile and 12 g of anhydrous aluminum chloride was heated to 10-170 ° C and reacted at this temperature for 5 hours. The resulting N- (5 "methyl-2-morpholinophenyl) acetamidine was crystallized from hexane. over. The Product »4 ·· · 9 1 · 9» ·· * · · · · · 4 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · r

- 70-.

mp 121 ° C.

102 ·, Example

A mixture of 5 »3H g (2-phenophenyl) -morpholine, Lf., 7 g of propiononitrile and 12 g of anhydrous aluminum chloride was reacted at 160-170 ° C for 6 hours to give N- (2- morpholinophenyl) propionic acid amidine is obtained. The product recrystallized from hexane had a melting point of 112 ° C,

Example 105

A mixture of 7.5 g of 4- (2-aminophenyl) morpholine hydrochloride and 20 ml of butyronitrile was reacted in a sealed stainless steel vessel for 60 hours at 170 ° C.

The excess of butyronitrile was evaporated, the residue dissolved in water, read with 10% sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and brine, dried and evaporated, and the residue was chromatographed on a column of neutral alumina. First, the unreacted starting compound was eluted with a 1: 1 mixture of methylene chloride and hexane, followed by elution with a 1:99 mixture of methanol and dichloromethane to give a solid. The solution was dissolved in methanol and 0.4 g of fumaric acid was added. The resulting N- (2-morpholinophenyl) butanoic acid amidine fumarate was recrystallized from a 1: 2 mixture of methanol and diethyl ether, m.p. 168-17 ° C.

Example 106

To a mixture of 5.34 g of 4- (2-aminophenyl) morpholine and 6 g of butyronitrile was added 12 g of powdered anhydrous aluminum chloride in small portions at 40-50 ° C. The reaction mixture was heated at 160-170 ° C. for 1 hour and then allowed to cool and quenched with 4N aqueous sodium hydroxide.

five

The solution / extract is extracted with dagger, and the aqueous extract is washed with water and brine, then dried and finally concentrated. The residue was crystallized from ethyl acetate-hexane (1: 1) to give N- (2-morpholinophenyl) butanoic acid amidine, m.p. 13 ° C, which was subsequently converted to the monofumarate. The salt recrystallized from isopropyl alcohol melts at 173 ° θ ~ οη.

Example 107

In a sealed, stainless steel reaction vessel, a mixture of 10 g of 4 '(2-aminophenyl) morpholine hydrochloride and 60 ml of isobutyronitrile was reacted at 150C for 26 hours. The N- (2-morpholinophenyl) -2-propanoic acid amidine thus formed is recrystallized from hexane. Melting point: 14 DEG-141 DEG C .;

9999 99 ····· * · · · · · · 9 9 9 9999

9 · 9 · 9

999 9 99 9999999

^ -7 -

Example 108

A mixture of 5.34 g of 4 '(2-aminophenyl) morpholine, 6 g of isobutyronitrile and 12 g of anhydrous alumina was heated to 10-170 ° C for 6 hours. 2-Morpholinophenyl) -2-methylpropanoic acid amidine was recrystallized from ethyl acetate / hexane (1: 1). M.p. 138 ° C.

Example 109

1.8 g of 4R, 2-amino-4 '(methylthio) phenyl-morpholine,

A mixture of 1.66 g of isobutyronitrile and 3.2 g of anhydrous aluminum chloride was heated at 140 ° C for 2 hours to give N- [5 '(methylthio) -2-morpholinophenyl) -2-methyl- propanoic acid amidine is formed. The product recrystallized from hexane had a melting point of 155 ° 0.

Example 110

1.96 g of 4- (2-amino-4-fluorophenyl) morpholine,

A mixture of 1.96 g of isobutyronitrile and 2 g of anhydrous aluminum chloride was heated at 150 ° C for 4 hours to give N- (5-fluoro-2-morpholinophenyl) -2-methylpropanoic acid amidine. m.p. 142 DEG C., formed with a salt of fumaric acid and recrystallized from a 1: 1 mixture of methanol and diethyl ether, m.p. · · · · · · · ··· * ·· ··· ···>

73 fumarates melt at 172 ° C.

Example 111

A mixture of 6.5 g of 4 "(2-aminophenyl) -norpholine hydrochloride and 35 ml of valeronitrile was reacted under nitrogen gas at 160-15 ° C for 25 hours, and the reaction mixture was cooled, basified with aqueous sodium hydroxide solution. and extracted with dichloromethane. The extract was evaporated and the residue was distilled under vacuum at 5θ mm Hg to remove half of the unreacted valeronitrile. A solid precipitates from the residue to cool, which is washed with hexane (5 mL) and recrystallized from hexane. The N- (2-morpholino-phenyl) -pentanoic acid amidine thus obtained had a melting point of 135-13 ° C.

Example 112

A mixture of 3.56 g of 4 '(2-aminophenyl) morpholine, 5 g of pivalonitrile and 8 g of anhydrous aluminum chloride was heated at 110-170 ° C for 6 hours. The product was obtained as N- (2-morpholinophenyl). ) -pivalic acid amidine, m.p. 122 ° C recrystallized from hexane. The product is converted to a fumarate salt, m.p. 211 ° C, when the salt is recrystallized from methanol.

113-125. examples

By a procedure similar to that described in Example 2

fumarate salts of the compounds listed in the following table, which are then recrystallized from the solvent or solvent mixture indicated in the table.

VII. SPREADSHEET

EXAMPLE A Example number which, according to the recrystallization-furate salt number A, m.p.

113 20 methanol 212 114 22 methanol 229-230 115 32 methanol 213 116 34 methanol 180 (decomposes) 117 6b methanol 197 (decomposes) 118 72 methanol 188 119 73 methanol: deti-ether (1: 2) 208-210 120 99 methanol: diethylether (1: 2) 204-205 121 100 methanol 117-118 122 74 methanol: ether (1: 2) 179-180 123 102 methanol: ether (1: 1) 189 124 107 methanol: ether (1: 1) 162-163 125 111 isopropanol 156-158

• · · ·

Example 126

2.6 g of the product obtained in Example 1 are treated with 5 ml of acrylonitrile at room temperature. The resulting product was recrystallized from ethyl acetate 1Zj.8 ^o C melting point I2 ^ 1- (2-cyanoethyl) -2-amino ^ piperidinilidéni phenyl) -aorfolint obtained.

Example 127 Dissolved in 1.0 ml of anhydrous acetonitrile

2-morpholinone, 3.6 g of N - (2-aminophenyl) morpholine dissolved in 20 ml of anhydrous acetonitrile are added, and 3.6 ml of phosphorus trichloride are added and the reaction mixture is stirred at 65-70 ° C for 1 hour. we. The oil thus obtained was purified by chromatography on neutral alumina (72 g), eluting the column with hexane and then with dichloromethane / hexane (1: 1) to give ethylene dichloride. The pure oil is converted into 25 ml of methanol saturated with hydrogen chloride gas which is a pale yellow crystalline material which is recrystallized from a 1: 1 mixture of methanol and diethyl ether. M.p. 262-263 ° C, <128, mp 262-263 ° C. Example 2 Dissolve 3.6 g of 2-piperidone in 1 ml of benzene,

- 7 unk Add 5.7 g of 4 ′ (2-aminobenzyl) morpholine dissolved in 20 benz of benzene and 3.6 ml of phosphorus trichloride and keep the reaction mixture at 65 70 70 ° C for 48 hours. The thus obtained 4- [2- (2-piperidinylidene] arino) -benzyl] -phenorpholine is crystallized from hexane. Mp 108-110 ° C,

Example 129 A solution of 2-piperidone in 5θ ml of benzene, and

A solution of 6.8 g of 4 '(2-amino-4-chlorobenzyl) morpholine in 50 ml of benzene was added, 5.5 µl of phosphorus trichloride was added and the reaction mixture was heated at 6 6-65 ° ° for 5 hours. οη heat. The resulting p-p-chloro-2- (2-piperidinylideneamino) benzyl] morpholine is crystallized from hexane. M.p. 121-122 ° C.

Example 130

A solution of 4.8 g of 1-nethyl-2-pyrrolidone in 20 ml of benzene and 7.6 g of 4- (2-aminobenzyl) -morpholine in 50 ml of benzene are combined and 4.8 ml of phosphorus trichloride are added. and for 18 hours at 65-70 ° C. We. The resulting oil was dissolved in methanol (30 mL)

Hydrogen iodide (10.1 mL, $ 57) was added and the resulting 4 ', 2 - [(1-methyl-2-pyrrolidinylidene) amino] benzyl] -morpholine dihydroiodide was recrystallized from ethanol. Melting point: 230-232 ° C.

Example 131 3 g 1,3,3 ″ trimethyl-2-pyrrolidone was dissolved in 1 ml benzene, 3.8 g 4 ′ (2-aminobenzyl) morpholine dissolved in 10 ml benzene and 2.1 ml phosphorus trichloride were added. oxide, and the reaction mixture was allowed to stand at room temperature for 28 hours, then heated to 60-65 ° C and held at this temperature for 14 hours. The resulting oil was dissolved in methanol (15 mL), hydrogen iodide (57 mL, 2.8 mL) was added, and the resulting 4 'ζ 2 - [(1,3,3' - trimethyl-1-2-pyrrolidine-ude) amino] was added. The benzyl N -morpholine dihydroiodide is recrystallized from a 1: 1 mixture of ethanol and diethyl ether. 256-258 ° C.

Example 132 In benzene (6.2 ml), 6.2 g of N-methylpivalic acid amide were ground, 9 g of 4 '(2-aminobenzyl) morpholine dissolved in 4θ ml of benzene and 5 ml of phosphorus trichloride were added and the reaction mixture was stirred for 80-85 minutes. Keep at 12 ° C for 12 hours. The resulting solid product was dissolved in methanol (25 mL) and salt (1.4 g) was added to the solution. The resulting N-methyl-N * - [2- (morpholinomethyl) phenyl] -pivalic acid amidine monofumarate is recrystallized from isopropyl alcohol. The salt melts at 167-168 ° C.

Example 133

To a solution of 1,3-dimethylimidazolidinone in 45 ml of benzene was added 6 ml of phosphorus trichloride, a solution of 8.5 g of 4 '(2-aminophenyl) -morpholine in 30 ml of benzene was added and the reaction mixture was stirred at room temperature for 65 minutes. Keep at "7 ° C" for 3θ hours. The product was recrystallized from hexane to give crystals melting at 133-134 ° C.

4- [2- (1,3-dimethylimidazolidinylidene) amino] phenyl] -morpholine.

134-154. examples

By essentially following the procedure of Example 133, the compounds of formula (i) listed in Table VITT, wherein n = Of and

5

R and R together with the carbon atom and the nitrogen atom form a group of the formula V in which

Ξ represents an ethylene group.

According to this, an aniline of formula (VZI) is reacted in benzene with a compound of formula (VIH) in the presence of phosphorus trichloride in an amount of 65-7θ ° θ “θπ · The amount of aniline and of compound VIII in g is , columns C and C, respectively, are the amounts of benzene used for dissolution in B and D, the amount of condensing agent in ml is E, and the reaction time in hours is shown in column F.

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154 4.4 20 5.9 50 4.4 60 morpholino but 1 methyl II 135-136 (40) (41) (43) χφ PU un • ♦ ·

- 81 .Notes to the VZIZ. table:

(32) The product is recrystallized from hexane.

(33) The coupling reaction proceeds from 9θ to 95 ° 0-οη.

(34) The coupling reaction proceeds from 7θ to 75 ° 0-οη.

(35) The coupling was carried out at 60-65 ° C.

(36) The product is isolated as the fumarate salt and recrystallized from 2: 1 isopropyl alcohol: diethyl ether.

(37) The coupling was carried out at 75-80 ° C.

(38) The product was isolated as the monofumarate salt and recrystallized from methanol: diethyl ether (1: 2).

(39) The product was isolated as the monofumarate salt and then recrystallized from methanol / diethyl ether (1: 3).

(40) The coupling is carried out at 80-85 ° C.

(41) The product was purified by column chromatography over alumina eluting with dichloromethane.

(42) The coupling was carried out by holding the reaction mixture at 9θ 95 95 ° θ-οη for 48 hours, and then continuing the reaction for a further 14 hours at 9θ 95 95 ° θ ′ θη. The product is purified by chromatography on alumina. the eluent is a 99: 1 mixture of dichloromethane and methanol.

- $ 2 (43) The product was isolated as the sesquifumarate salt and recrystallized from a 1: 2 mixture of ether and diethyl ether.

Example 155

A mixture of 31.2 g of IT- (2-hydroxyethyl) ethylenediamine, 23.4 g of urea and 3 ml of water was heated for 3 hours at 130 ° C, then at 2 ° C to 10 ° C, and then directly distilled from the reaction mixture. 1- (2-hydroxyethyl) -2-imidazolidinone, weighing 3θ g, boiling at 15 0-160 ° C at 0.26 kPa. The product obtained as an oil solidifies, m.p. 50-51 ° C.

2.28 g of 1- (2-hydroxyethyl) -2-imidazolidinone,

A mixture of 4.5 g of benzoic anhydride, 2.4 g of triethylamine, 0.1 g of 4 '- (dimethylamino) pyridine and 20 ml of ethylene glycol dimethyl ether was stirred at room temperature for 8 hours, followed by 15 ml of saturated sodium hydrogen carbonate solution was added and the mixture was extracted with dichloromethane (100 ml). The extract was washed with water and brine, dried, filtered and evaporated. The residue was recrystallized from ethyl acetate to give 1- [2- (benzoyloxy) ethyl-2-imidazolidinone, m.p.

A mixture of 2.3 g of 1- [2- (benzoyloxy) ethyl] -2-imidazolidinone and 2 g of inethyl (4 "toluene sulfonate) was heated to 90-95 ° C and allowed to react at this temperature.

- 8L3 hours. The reaction mixture was then cooled to room temperature, saturated sodium bicarbonate solution (10 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 6). The extract was washed with water and brine, dried, filtered and the solvent was evaporated to give 2 g of an oily residue. This oil was purified by chromatography on 80 g of 100-200 mesh silica gel eluting the column with ethyl acetate: hexane (1: 1). The product is an oil, 1 '[2- (benzene 1-oxy) ethyl] -3-methyl-2-imidazolidinone.

Similarly to the procedure of Example 133, 8.8 g of 1- [2- (benzoyloxy) ethyl-3-methyl-2-imidazolidinone is dissolved in 30 ml of benzene, 5.2 g of 20 ml of benzene are added. (2-aminophenyl) morpholine, which is reacted with 3.3 ml of phosphorus trichloride oxide for 35 hours at 80-85 ° C. The product is obtained as an oil, which is dissolved in 10 ml of methanol and 1.8 g of fumarate are added. The solvent was evaporated, the residue was washed with diethyl ether, dissolved in water and the solution was adjusted to pH 9-10 with aqueous sodium carbonate solution and finally extracted with diethyl ether. After evaporation of the ethereal solution, the oil obtained is purified by chromatography on alumina, eluting with dichloromethane. The purified base (0.8 g) was dissolved in methanol (10 mL), 0.23 S fumaric acid was added and the resulting N- / 2- 1- [2- (benzene 1-oxy) SZ] was obtained. > -

-ethyl] -3 "-detyl-2-imidazolidinylidene] -amino] -phenyl'-morpholine monofumarate is recrystallized from methanol / diethyl ether 1: 2. 132-133 ° C.

Example 156

10 µg (10.7 µl) of 1,1,3,3-tetramethylurea are dissolved in 80 ml of anhydrous benzene and dissolved in 100 ml of anhydrous benzene, 10.2 g of 4- (2-aminophenyl) morpholine are added, with 8.3 ml of phosphorus trichloride at 65-70 ° C for 30 hours. The oil thus obtained is purified by chromatography on a column of 100 g of neutral alumina, eluting with hexane. The clear, oily base (2.5 g) was dissolved in methanol (10 mL) and treated with 57% hydrogen iodide (1.3 mL) to give 1,3,3,3-tetramethyl-2 as pale yellow crystals. - (2-morpholinophenyl) guanidine hydroiodide. The salt recrystallized from a 2: 3 mixture of methanol and diethyl ether had a melting point of 215-21 ° C.

Example 157

6.57 g of 1-ethyl-1,3,3 ″ trimethylurea are dissolved in 70 ml of benzene and dissolved in 30 ml of benzene, 6 g of 4- (2-aminophenyl) morpholine are added to give 4.71 ml of phosphorus trichloride. in the presence of oxide at 65-70 ° C for 45 hours. The product obtained is 1-ethyl-1,3,3 "

-trimethyl-2- (2-morpholinophenyl) -ghanidine, b.p. 140 ° C, 0.26 kPa (0.2 mm Hg).

Example 158

7.17 g of 1-allyl-1,3,3-trimethylurea are dissolved in 50 ml of benzene and dissolved in 30 ml of benzene, 6 g of 4- (2-aminophenyl) -morpholine are added to give 4.71 ml of phosphorus. in the presence of trichloride oxide at 70 ° C for 45 hours. The product was 1-allyl-1,3,3 ″ trimethyl-2- (2-morpholinophenyl) guanidine, boiling at 148-150 ° C at 0.26 kPa (0.2 mm Hg),

Example 159 · 1-Butyl-1 * 3,3-trimethylurea was dissolved in 60 ml benzene and 30 ml benzene 7.2 g

4- (2-Aminophenyl) morpholine was added, which was reacted with phosphorus trichloride (4 mL) at 8 ° to 85 ° C for 18 hours. The product was 1-butyl-1,3,3-trimethyl-2- (2-morpholinophenyl) guanidine, boiling at 0.91 kPa (0.7 mmHg) at 162-163 ° C.

16O. example

7.5 g of 1,1,3-trimethyl-3-phenyl-urea are dissolved in 80 ml of benzene and 30 ml of benzene are added 6.46 S 4- (2-aminophenyl) -morpholine, whereby 4.06 ml are obtained.

in the presence of phosphorus trichloride oxide at 70 ° C for 15 hours. The product obtained is 1.3 "trimethyl-2- (2-morpholinophenyl) -1-pentylguanidine, boiling at 1.98 kPa (1.5 Hgmrn) at 98 ° C.

Example 161

Dissolve 13 g of 1- (2-hydroxyethyl) -2-imidazolidinone, 12 g in 125 ml of anhydrous 1,1'-dimethylformamide.

Sodium hydride suspended in 50/3 paraffin oil was added and the mixture was stirred at 10 ° C for 3 hours. Methyl iodide (35.5 g) was added over 1 hour and stirring was continued at room temperature for a further 18 hours. The product thus obtained was 1-methyl-3 '- (2-methoxyethyl) -2-imidazolidinone having a boiling point of 0.52 kPa (0.1 µg Hgmta) at 110-11 ° C.

11 g of 1-methyl-3- (2-methoxyethyl) -2-imidazolidinone are dissolved in 60 ml of benzene and dissolved in 80 ml of benzene, 8.9 g of 4 '(2-aminophenyl) morpholine are added. , In the presence of 2 ml of phosphorus trichloride oxide at 80-85 ° C for 3θ hours. The reaction product oil, from which 1.8 g is dissolved in 10 ml of methanol, is treated with 0.9 g of fumaric acid to give 4- [2- (1H-methyl-3- (2-methoxyethyl) -2-imidazolidinylidene) ] -amino-4-phenyl-morpholine monofurarate is recrystallized from isopropanol. The melting point of the salt is 127 ~ 129 ° θ · • «

Example 162 162 g of 1- (2-hydroxyethyl) -3 "methyl-2-imidazolidinone in 9 ml of dichloromethane are treated with 9.2 g of acetic anhydride and 9 g of triethylamine and 0.1 g of 4" (dinjet 1-amino) - in the presence of pyridine at room temperature for 18 hours.

The product is 1- (2-acetoxyethyl) -3-methyl-2-imidazblidinone which is an oil.

13.4 g of 1- (2-acetoxyethyl) -3-raethyl-2-imidazolidinone are dissolved in 80 ml of benzene and dissolved in 80 ml of benzene to give 10.6 g of 4 '(2-aminophenyl) -morpholine with 7 ml of phosphorus trichloride at 80-85 ° C for 30 hours. The product was dissolved in 4 "- N - [[1- (2-aoethoxyethyl) -3" -methyl-2-imidazolidinylidene-1'-amino] -phenyl] -morpholine, ml Ν, Μ-dimethylformamide.

4- (2- (R 1 - (2-aoethoxyethyl) -3'-methyl-2-imidazolidinylidene] amino] phenyl) morpholine, 0.4 g of sodium hydroxide in 10 ml of aqueous solution was added and After 1 hour at C, the oil was dissolved in methanol (10 mL), fumaric acid (0.4 g) was added and the resulting 4 '[2- (1- (2-hydroxyethyl) -3') methyl was added. The 2-imidazolidinylidene-amino-4-phenyl] -morpholine fumarate was recrystallized from methanol: diethyl ether 1: 2 mp 129-131 ° C.

Example 163

3.8 g of N- (11, N-di-thiophenyl) -morpholine in ml of benzene, 2.1 ml of phosphorus in the presence of chloride oxide phenyl) -morpholine was reacted at 80-85 ° C for 40 h, the resulting N, N-dimatil lT ^~ - (2-morpholinophenyl) morpholine-4 "carboxamidine was crystallized from hexane, the product 126-128 ° C.

Example 164

3.7 g of 1- (IT, 1H-dimethylcarbamoyl) -piperidine in ml of benzene in the presence of phosphorus trichloride

3.5 g of 4 '(2-aminophenyl) -morpholine are reacted at 80-85 [deg.] C. for 1 hour. The resulting N, N-dimethyl-N' - (2-morpholinophenyl) piperidine is obtained. -1-Carboxamidine is recrystallized from a patrol ether of boiling point 40-60 ° C. M.p. 88-9 ° C.

Example 165 s- /

1.5 g of 4-ζ2 - [(1,3-dimethyl-2-imidazolidinylidene) amino] phenyl) thiomorpholine, prepared as described in Example 144, are dissolved in 20 µl of methanol, and 1.4 g of sodium metapariodate is added. A solution of water (4 ml) and stirred at 10 ° C for 4 hours. The resulting 4 '- [2- (1,3-dimethyl-2-imidazolidinylidene) -aza] phenyl] -thiomorpholine-1-oxide-water (1/1) ethylene glycol dimethyl "89"

recrystallized from a 1: 1 mixture of ether and hexane, m.p. 103-105 ° C.

Example 166 2.3 ml of ethanol saturated with ammonia

A solution of 2-morpholinophenyl isothiocyanate was added and the reaction mixture was stirred at room temperature for 3 hours. The precipitated solid product was filtered, washed with ethanol and dried to give a melting point of 194-195 ° C.

1- (2-morpholinophenyl) thiourea is obtained.

7.2 g of 1- (2-morpholinophenyl) thiourea are dissolved in 30 ml of anhydrous methanol, 4.2 ml of methyl iodide are added and the mixture is refluxed for 2 hours. The solvent was evaporated in vacuo and anhydrous diethyl ether (15 mL) was added to the residue. Scratching crystallizes 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, m.p. 151-152 ° C.

Dissolve in 5 ml of anhydrous ethanol

2-methyl-1- (2-morpholinophenyl) thiour6nium iodide; g of ethylenediamine and the mixture was refluxed for 6 hours and evaporated in vacuo.

The residual oil was dissolved in dichloromethane (50 mL), basified with sodium hydroxide solution (20 mL), and the organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The 4 S solid • - -

The residue was recrystallized from ethyl acetate to give 4 "[2- (2-imidazolidininylideneamino) phenyl] morpholine as crystals, m.p. 185-186 ° C.

Example 167 A solution of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide prepared in the same manner as in Example 166 and 2 ml of N-methylethylenediamine in 35 ml of anhydrous ethanol was heated under reflux. and the resulting 4- [2- (1-methyl-2-imidazolidinylidene) amino] phenyl] morpholine was recrystallized from ethyl acetate. Melting point of product

156 ° C.

168-202. examples

Following the procedure in Example 167 *, the a. Compounds of general formula (i) listed in Table I wherein n = 0; and

to form a group of formula V-

E is ethylene, · · · · ·.

• · · · ·· »• ♦ · · ·· ··« * ···

THE

- 91 ~

That is, a compound of formula (XIII) wherein R 1 and R 6 are both hydrogen are reacted with ethylenediamine R 8-1 in anhydrous ethanol, and the reaction mixture is refluxed. Column G of the table gives the amount of thiouronium salt in g and column H the amount of ethylenediamine in g, column I shows the amount of ethanol in ml, while column H shows the reaction time in hours.

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Notes to Table IX:

In the comment box, numbers (32), (3θ), (39) and (41) refer to the explanations given in the previous tables.

(44) The product is recrystallized from ethyl acetate.

(45) The product is obtained as the monofumarate salt and crystallized from methanol.

(46) The synthesis of the starting material of the general formula (HU) is described in the Preparation of Intermediates, then described under A / below.

(47) The fruits were isolated as the monofumarate salt and then recrystallized in a 2: 1 mixture of methanol and isopropyl alcohol.

(48) The product is recrystallized from a 1: 4 mixture of ethylene glycol dimethyl ether and petroleum ether boiling at 40-60 ° C.

(49) A. The preparation of the appropriate starting compound of the formula (XIII) is described below in Section B (Preparation of Intermediates).

(50) The preparation of the corresponding starting compound of formula (XIU) is described in section C / of the subsequent section "Preparation of Intermediates".

(51) (52) (53) (54) (55) (56) (57)

The preparation of the corresponding starting compound of formula (XXII) is described in Section D / of the following Preparation of Intermediates.

The product was 1: 2 ethyl acetate / thexane

It is crystallized from its mixture.

The preparation of the corresponding starting compound of formula XIH is described in Section E / Preparation of the following Intermediates.

The preparation of the corresponding starting compound of formula (XIII) is described in the following section F / Preparation of Intermediates.

The preparation of the corresponding starting compound of formula (XXH) is described in section G / G of the following section, Preparation of Lysis Products.

The product was purified by chromatography on alumina in hexanes, dichloromethane / hexane (1: 1) and dichloromethane, respectively.

The preparation of the corresponding starting compound of formula XIIT is carried out following

Manufacture of intermediate products section 11 / point-

1A.

(58)

The product was recrystallized from ethyl acetate / hexane (1: 1)

Manufacture of intermediates

THE/

9.6 g of 2j- (2-amino-3'-methylphenyl) -morpholine in a mixture of dioxane / ml and water (100 ml) were treated with thiophosgene (5.7 ml) at 0 ° C for 30 minutes and then at room temperature for 1 hour. The oil thus obtained is 6-ethyl-2-morpholinophenylisothiocyanate.

8.8 g of 6-methyl-2-chloropheninophenyl isothiocyanate was reacted with 35 ml of alcoholic ammonia solution at room temperature for 5 hours to give 9 g of 1- (6-methyl) as pale yellow melting crystals -2-morpholinophenyl) thiourea is obtained. The product is recrystallized from ethyl acetate / hexane (1: 1).

Dissolve 9 g in 100 ml of anhydrous acetone

1- (6-methyl-2-morpholinophenyl) thiourea and 2.5 ml of methyl iodide were added and the mixture was refluxed at 90-95 ° C for 2.5 hours. methyl-1- (old-ethyl-2-morpholinophenyl) -thiouronium iodide,

Dissolve 7.5 g of N, N-bis (2-methoxyethyl) -benzenediamine in 10 ml of dioxane and add 4 ml of thiophosgene in 0 ml of aqueous solution, which has been cooled to 0 ° C.

• · ····

At the end of the addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. Ice water (50 mL) was added to the reaction, extracted with diethyl ether (3 x 20 mL), washed with water (50 mL) and brine (50 mL), dried and evaporated and finally heated to 45 ° C under vacuum (100 mm Hg). the rest. The oil thus obtained is 2- (bis (2-methoxyethyl) amino] phenyl isothiocyanate.

7.5 g of 2-bis (2-methoxyethyl) amino] phenyl isothiocyanate is dissolved in 10 ml of ethanol, the solution is cooled to 10 ° C and 40 ml of a saturated aqueous solution of ammonia is added over 40 minutes. The mixture was then stirred for 8 hours

After stirring at 0 ° C, stirring was continued without cooling for an additional 16 hours. After evaporation of the solvent, the residue was purified by chromatography on silica gel, eluting with ethyl acetate / hexane 1: 4 and then ethyl acetate / hexane 1: 4. Elute column eluting with 1-4H-bis (2-methoxyethyl) amino] phenyl] thiourea, m.p. 118-119 ° C.

evaporated and the residue triturated with diethyl ether to give 1-; 2- (bis (2-methoxyethyl) amino] phenyl-2-methyl-benzhydrylthiouronium iodide obtained in • · · · · · · _e * ·: ·:

Mp 111-112 ° C.

Dissolve 8.77 ml of thiophosgene in C / 120 ml of water, cool to 0 ° C, and add a solution of 14.6 g of 4 '(2-aminophenyl) thymmiorphine in 10 ml of dioxane over 15 minutes. The reaction mixture was stirred and allowed to warm to room temperature, and after 4 hours 200 ml of ice water was added. The aqueous solution was extracted with diethyl ether (2 x 100 mL), washed with water (50 mL) and brine (100 mL), and concentrated in vacuo at 40-45 ° C under vacuum (100 mm Hg) for 2 hours. The thus obtained 2-thiomorpholinophenyl isothiocyanate, m.p. 55-56 ° C, is dissolved in 14 ml of 2-thioaorpholinophenyl isothiocyanate and 100 ml of 25% aqueous ammonium hydroxide solution are added at 10 The reaction mixture was stirred at 30 ° C for 24 hours and then cooled to 10 ° C, the precipitated 1- (2-thiomorpholinophenyl) thiourea was filtered, washed with water (100 mL) and dried.

12.6 g of 1- (2-morpholinophenyl) thiourea in ml of acetone are reacted with 7.1 g of methyl iodide at 9 to 95 ° C for 2.5 hours. The solvent is evaporated and the residue is vacuum dried at 6.66 kPa. (5 mmHg). The thus obtained 2-methyl-1- (2-thiomorpholinophenyl) thiouronium iodide has a melting point of 176-177 ° C.

í. ·:: ···. . · ··· · ·· ... ···.

Dissolve 10.6 g in 0/30 of methylene chloride

1- (2-arainophenyl) pyrrolidine and 10 ml of benzoyl isothioylate is added over 3 min. The reaction mixture was stirred at 30 ° C for 4 hours, then concentrated, the residue was dried in vacuo (5 mm Hg) and triturated with diethyl ether. The 1-benzoyl-3β- (1-pyrrolidinyl) phenyl] thiourea is filtered off, washed with diethyl ether and dried. Melting point: 172-173 ° C.

A mixture of 18 g of 1-benzene 1-3 [beta] -2- (1-pyrrolidinyl) phenyl] thiourea, 58 g of sodium hydroxide and 50 ml of water is heated to 995 ° C and maintained at this temperature for 4 hours. Ice and then concentrated aqueous hydrochloric acid (1: 1) were added, the resulting solution filtered and the filtrate adjusted to pH o with saturated sodium bicarbonate solution. The precipitated 1- (2- (1-pyrrolidinyl) phenylthiourea) was filtered off, washed with water and dried, m.p. 185-186 ° C.

In a mixture of 100 ml of acetone and 20 ml of methanol, 12.2 g of 1- [2- (1-pyrrolidinyl) phenyl] thiourea, 8.36 g of methyl iodide are dissolved in 9θ "95 ° θ" and under reflux. boil for 3 hours and then evaporate. The residue was dried under vacuum (6 mm Hg) to give 2-methyl-1- (2- (1-pyrrolidinyl) phenyl) thiouronium101 'iodide, m.p. 139-141 ° C.

E / 20 g of 4 "(2" amino-4-methyl "phenyl) morpholine in a mixture of 80 ml of dioxane and 100 ml of water are reacted with thiophosgene at 0 ° C for 3θ minutes and then at room temperature for 2 hours. The thus obtained 5 "deti 1-2-morpholinophenyl isotocyanate has a melting point of 91" to 92 ° C.

g of 5 "methyl-2-morpholinophenyl isothioyanate

Reaction with aqueous ethanolic ammonia solution at room temperature for 48 hours yields 1- (5 "methyl-2-morpholinophenyl) thiocarbanide · g 1- (5" η 1 -ethyl) as pale yellow crystals, m.p. 2-morpholinophenyl) thiourea,

A mixture of 7.9 g of methyl iodide and 50 ml of methanol is refluxed for 2 hours. The thus obtained 2 "methyl-1- (5-diethyl-2-morpholinophenyl) thiouronium iodide is a pale yellow solid, m.p. 157-159 ° C.

Dissolve 9.1 g in methylene chloride (F / 100 ml)

1- (2-Aminophenyl) -2-methylpyrrolidine and 9 x 2 g (7 x 7 mL) of benzene 1-isothiocyanate were stirred at room temperature for 8 hours and then left overnight after evaporation of the solvent. triturated with diethyl ether, 1 "benzene-3- [2- (2-methylpyrrolidin-1-yl) phenyl] thiocarb.

102 bajaid o t we get.

A mixture of 1-benzoyl-3 '- [2- (2-methyl-pyrrolidine-1-11) -phenyl] -thiourea, 1 g of sodium hydroxide in pellet and 10 ml of water was heated to 90-95 ° C. temperature for 4θ hours. The resulting 1- [2- (2-methylpyrrolidin-1-yl) phenyl] thiourea was purified by column chromatography eluting with ethyl acetate: hexane (1: 1), m.p.

3.4 g of 1- [2- (2-methylpyrrolidin-1-yl) -phenyl] thiourea in 60 ml of acetone _; 2.1 g of methyl iodide are reacted at 9 ° to 95 ° C for 3 hours. The mixture was concentrated to give 2-methyl-1- [2- (2-methylpyrrolidin-1-yl) phenyl] thiouronium iodide as a thick oil.

A solution of 17.6 g of 1- (2-aminophenyl) -piperidine in 100 ml of dioxane is added to a solution of thiophosgene (200 ml) in water (200 ml) cooled to 0 ° C, allowed to warm to room temperature and stirred for 4 hours. After adding 200 g of ice and 200 ml of water, the solution is extracted six times with 5 x 5 ml of diethyl ether, and the combined organic phases are washed with 100 ml of water and 100 ml of brine, dried and evaporated. , eluting the column with hexane, resulting in

The 2-piperidinophenyl isothiocyanate was obtained as an oil (103 ''), cooled to 10 ° C, treated with 60 ml of 25% aqueous ammonium hydroxide solution and stirred at 30 ° C for 24 hours, then cooled again to 10 ° C.

The resulting 1- (2-piperidinophenyl) thiourea was filtered, washed with water and dried. Melting point 143-145 ° C.

1- (2-piperidinophenyl) thiourea (10.01 g) in methanol (ml) was treated with methyl iodide (5.35 g) at 50-55 ° C for 2 hours. The solvent was evaporated and the residue was dried in vacuo at 5 mm Hg to yield 2-methyl-1- (2-piperidinophenyl) thiouronium iodide, m.p.

H / 6.4 g of 1- (2-amino-3-methylphenyl) piperidine in a mixture of 20 ml of dioxane and 60 ml of water were reacted with 5.7 g of thiophosgene for 3 ° at 0 ° C and for 2 hours at room temperature. The oil thus obtained is 6-methyl-2-piperidinophenyl isothiocyanate.

6.8 g of 6-methyl-2-piperidinophenyl isothiocyanate in 65 ml of ethanol are added, 65 ml of 25% aqueous ammonium hydroxide are added and the reaction mixture is stirred at room temperature for 8 hours. The resulting pale yellow solid, m.p. 197-198 ° C, is 1- (6-raethyl-2-piperidinophenyl) thiourea.

- 104 7E 1- (6-methyl-2-piperidinophenyl) thiourea was heated to reflux in 100 ml of anhydrous methanol and treated with 4.38 g of methyl iodide. This gave 2-methyl-1 as a pale yellow solid. - (6-methyl-2-piperidinophenyl) -thiouronium iodide, m.p. 204-205 ° C,

Example 203

3, θS, 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, prepared as described in Example 166, was refluxed in ethanol (45 g) for 2 hours, under reflux. The resulting solid A was recrystallized from ethyl acetate to give 4- [2- (4'-methyl-2-imidazolidinylidene) amino] phenyl] morpholine, m.p. 173-174 ° C.

Example 204

7.6 g of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, prepared according to the procedure of Example 166, is reacted with 1,2-dimethylethylenediamine at reflux in 9θ ml of ethanol. Recrystallization of the product gave 4- [2- ((4,5-dimethyl-2-imidazolidinylidene) amino] phenyl] -morpholine, m.p. 142-143 ° C.

Example 205 20 g of 2-chloroethanol 20 g of pasteurized potassium ··· *

105

ethylene oxide in 60 ml of methanol was reacted with 22.6 g of 1,2-dimethylethylenediamine in 50 ml of methanol at -15 ° C. The N- (2-hydroxyethyl) -1 2-dimethylethylene diene, colorless liquid, boiling point 89-91 ° C at 1 mmHg,

12.5 S 2-methyl 1-1- (2-morpholinophenyl) thiourea in 150 ml of anhydrous 90-95 ° θ-οη, refluxed, 8 g of N- (2-hydroxyethyl) Reaction with -1,2-dimethylethylenediamine for 6 days. The resulting dark oil was purified by chromatography on 250 g of neutral alumina, eluting with hexane, to give the solid 4 "f2- ([1- (2) -hydroxyethyl) -4,5 "-dimethyl-2-imidazolidinyl" diene] -amino} -phenyl] -morpholine. The product was crystallized from hexane, m.p.

Example 206

3.8 g of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, prepared according to the procedure of Example 166, are refluxed in 45 ml of ethanol.

3.95 g of Ν'-isopropyl-1,2-propylene diamine are reacted for 28 hours. The resulting oil was purified by column chromatography on neutral alumina, eluting with dichloromethane, from the appropriate fractions.

1.5 g of an oil are obtained which is dissolved in 10 ml of methanol.

106- and 0.5 g of fumaric acid were added to form the salt, A 2- {2 - ((1-isopropyl-Z, Z-dimethyl-2-imidazolidi Bilidene) -amino] -phenyl} -morpholine monofumarate, m.p. 206-208 ° C, crystallized from a 1: 3 mixture of methanol and diethyl ether.

Example 207

3.8 g of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide prepared according to the procedure of Example 166 are reacted with refluxing in 2.6 ml of anhydrous ethanol under reflux. tetramatilén diamine

Example 208

7.6 g of 2-methyl-1- (2-morpholinophenyl) -thiouronium iodide are refluxed in 150 ml of ethanol with 5.3 e of tetramethylenediamine for 60 hours. The white solid thus obtained, m.p. 135 DEG C., is recrystallized from ethyl acetate. 2.7 g of base are dissolved in 20 ml of methanol and salted with fumaric acid. [2- (2-morpholinophenyl) imino] -1,3-diaza-cycloheptane fumarate, m.p. 220-222 DEG C., recrystallized from 1: 1 methanol: diethyl ether, m.p. ·

107 -

Example 209 A mixture of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, 1 ml of a 33% solution of dimethylamine in ethanol (33 ml) and 2 ml of ethanol was allowed to react at room temperature for 48 hours. After cooling with an ice bath, the precipitate was filtered off and taken up in 5 plates of dilute aqueous sodium hydroxide solution and extracted with dichloromethane (2 x 50 ml). The extract was washed with brine, dried and evaporated to give 1,1-dimethyl-2- (2- Eiorpholinophenyl) guanidine is obtained. Recrystallization from hexane gave a melting point of 143-144 ° C.

Example 210

5.3 g of 4- (2-aminophenyl) morpholine are dissolved in dichloromethane, 3.2 g of methyl isothiocyanate are added, and the mixture is stirred at room temperature for 36 hours. morpholinophenyl) thiourea is recrystallized from a mixture of ethyl acetate and hexane (41), m.p. 115-111 ° C.

S 1 -methyl-3 (2-morpholinophenyl) -thiourea was refluxed in 30 ml of acetone,

Reaction with 2.8 g of methyl iodide for 4 hours

1,2-Dimethyl-3- (2-morpholinophenyl) -thiouronium iodide is recrystallized from a 1: 3 mixture of methanol and ethyl ether, m.p. 163164 ° C.

- 108 '-

3.9 g of 1,2-dimethyl-3- (2-norfolinophenyl) thiouronium iodide were reacted with 40 ml of 33% methanolic amine in 50-55 ° θ-οη for 28 hours. M.p. 137 DEG-138 DEG C., 3 "dimethyl-2- (2-morpholinophenyl)" guanidine is recrystallized from hexane.

Example 11

To 3.9 g of 1,2-dimethyl-3 '- (2-morpholinophenyl) thiouronium iodide prepared according to the procedure of Example 210 was added 25 ml of 33% ethanol in ethanol and allowed to react at room temperature for 25 days. . The solution is evaporated and the residue is purified by chromatography on alumina eluting with a 1:49 mixture of methanol and methylene chloride. The purified product is a solid which is dissolved in methanol and salted with fumaric acid. mp 192-194 ° C.

Example 12

Methyl sodium (3.5 g) was dissolved in 100 ml of methanol and 12.18 g of ethyl ammonium chloride were added to the sodium methanolate solution thus formed to liberate the ethylamine.

109 base, which is reacted with 3.3 g of 2-morpholinophenyl isothiocyanate. The 1-ethyl-3 '(2-morpholinophenyl) thiourea thus obtained was recrystallized from a 1: 1 mixture of ethyl acetate and hexane. M.p. 118-12 ° C,

3.2 g of 1-ethyl “3” (2-morpholinophenyl) thiourea are refluxed in 25 ml of acetone with 2 g of methyl iodide for b hours. 1-ethyl-2-methyl-3 '- (2-morpholinophenyl) -thiouronium iodide is obtained in the form of pale yellow crystals which is recrystallized from acetone ball, m.p. 170-172 ° C. To 3- (2-morpholinophenyl) thiouronium iodide was added 250 ml of a 33 ^C solution of methylamine _in anhydrous ethanol and the mixture was reacted at 45 ° C for 2b and allowed to stand at room temperature for 14 days. The 1-ethyl-3-methyl-2- (2-morpholinophenyl) guanidine thus obtained was a colorless crystalline solid, m.p. 118-119 ° C by recrystallization from hexane.

Example 13

300ul of ethanol were dissolved 23 g of sodium metal, a solution of ethyl acnaónium-chloride and methyl 1-ethyl-2 the thus liberated ethyl amine base at room temperature, produced 6 and _according to Example 212 with the procedure for 30 days 1- 3 '(2-morpholino-phenyl) - ti ouronium-j odiddal ·

1Τ0. The product was 1,3-diethyl-1-2- (2-morpholino-above) -guanidine, m.p. 101-102 ° C, recrystallized from hexane.

EXAMPLE 14 4 g of 4 '(2- [1,1' - (2-hydroxyethyl) -2-imidazolidinylidene] amino-phenyl)] rhodafoline prepared in Example 175 in 20 ml of methylene chloride with 0.86 g of acetic anhydride. The product thus obtained was crystallized from hexane to give 4 - [[2- [1- (2-aoethoxyethyl) -2-imidazolidinylidene] amino] -phenyl] -morpholine, m.p. 89-91 ° C.

215 * Example

2.9 g of 4- (2-hydroxyethyl) -2-imidazolidinylidene-aminophenyl, m.p. morpholine was reacted with 2.4 g of benzoic anhydride in 60 ml of methylene chloride in the presence of 2 ml of anhydrous triethylamine and 5θ mg of 4-dimethylamino-pyridine. The reaction product is an oil which is purified by chromatography on alumina, eluting with dichloromethane. The pure 4 '-2- [1- (2-benzoyloxy) ethyl] -2-imidazolidinylidene-4-amino] phenyl] -morpholine thus obtained was crystallized from ethyl acetate / hexane, m.p. 92-94. ° C.

• · »·« · · 4 · · ·· · ······ ·

-, 111 2 16, Example

5 θ g of 4 "(2-aninophenyl)" morpholine was dissolved in dichloromethane, 5 g of butyl isothioylate were added and the mixture was stirred at room temperature for 4 days. 3- (2-morpholinophenyl) thiourea, m.p. 105 ° C ·

5.8 g of 1-butyl-3 '- (2-morpholinophenyl) thiourea was refluxed in 25 ml of acetone

Reaction with 3.1 g of methyl iodide for 4 hours to yield 1-butyl-2-methyl-3- (2-morpholinophenyl) thionium iodide as colorless crystals melting at 154-156 ° C. .

To 200 ml of a 33-liter solution of methylamine in anhydrous ethanol was added 4.0 g of 1-butyl-2-methyl-3 '(2-morpholinophenyl) thiouronium iodide and the mixture was first heated at 45 ° C for 24 hours. οη and allow to stand at room temperature for 21 days. The 1-butyl-3-methyl-2- (2-morpholinophenyl) guanidine oil thus obtained was dissolved in 25 ml of methanol and 0.7 g of fumaric acid was formed, followed by 1: 1 methanol: diethyl ether. The resulting 1-butyl-3 &apos; -methyl-2- (2-morphinophenyl) -guanidine monofumarate had a melting point of 170-172 ° C.

Example 217

7.5 g, a 168-202. in the examples, the Intermediates • 999 · ·· ··· * ·· tt · · · · · · · · ·

··· * * · ··· ····

2-Methyl 1-1- (2-piperidinophenyl) -thiouronium iodide (40 g) in 40 ml of ethanol was reacted with 2 ml of (2-methoxyethyl) amine at room temperature. days. The solvent was evaporated and the residue was dissolved in methanol and a salt formed with fumaric acid. The thus obtained 1- (2 'methoxyethyl) -2- (2-piperidinophenyl) guanidine hemifumarate is crystallized from methanol: ethyl ether 1: 2 (1: 2). M.p. 218-220 ° C.

Example 18

1.7 6 of 2-methyl-1- (2-morpholinophenyl) thiouronium iodide, prepared according to the procedure of Example 166, was reacted with 1.8 g of 2- (methylthio) ethylamine in 25 ml of ethanol for 22 hours. The resulting 1- [2- (methylthio) ethyl] -2- (2-morpholinophenyl) guanidine was crystallized from hexane. M.p. 11511 ° C, Example 219

7.6 g of 2-methyl-1- (2-morpholino-phenyl) -thiouronium iodide in 45 ml of ethanol are treated with 2 ml of (2-methoxyethyl) amine at room temperature for 14 days. The resulting 1- (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine had a melting point through ethylene glycol dimethyl ether.

113 crystals ancient t 125-128 ° C. From the base, a fumarate salt is prepared which is crystallized from a 1: 2 mixture of methanol and diethyl ether, m.p. 136-18 ° C.

Example 220

7.8 g, obtained according to the procedure of Example 210

1,2-Dimethyl-3- (2-morpholinophenyl) -thiouronium iodide was treated with 5 g of ethanol in 1.3 g of propylamine at room temperature for 45 days. The product, which is an oil, is purified by chromatography on a neutral aluminum guard, eluting with a 1:99 mixture of methanol and dichloromethane / methylene chloride. The oil obtained in the purification was dissolved in methanol and reacted with fumaric acid to give 1-methyl- (2-morpholinophenyl) -3-propyl-guanidine-momofumarate, which was crystallized from a 1: 2 mixture of methanol / diacetyl ether / 1: 2. over. The product has a melting point of 1G7 to 188 ° C.

Example 221

Prepared according to the procedure of Example 210

3.9 g of 1,2-d ^r .matil-3- (2-morpholinophenyl) -tiourónium iodide dissolved in 25 ml otanolban, 0.82 g of (2-methoxyethyl) amine was added and stand at room temperature leave !: the rooster mix for 3 months. J. Tara formed: An oil which is dissolved in methanol and added to the hoasr salt by the addition of fumaric acid to give the 1-net thus obtained. l -'.- (2-metom <• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

114

-ethyl) -2- (2-morpholinophenyl) -guanldine monofumarate is recrystallized from a 1: 2 mixture of methanol and diethyl ether. Melting point: 158-110 ° C,

Example 222

Prepared according to the procedure of Example 210

7.86 g of 1,2-dinyl-9- (2-morpholinophenyl) -thiouronium iodide, 2.9 S-cyclopentyl-amine, 6.36 g of anhydrous sodium carbonate and 100 ml of ethanol in a pressure-resistant steel is placed in a vessel immersed in an 11 ° C oil bath and kept at this temperature for 2A hours. The reaction mixture is then cooled, filtered and a portion of T.Z. solvent evaporated.

The residue is poured onto ice, the mixture is extracted with dichloromethane, the extract is dried and evaporated.

The residue from the evaporation to form a salt with fumaric acid gives 1-cyclopentyl-3-methyl-2- (2-morpholinophenyl) guanidine monofurmarate which is methanol and diethyl ether. It is recrystallized from 1: 1 ether. The product has a melting point of 220 ° C.

Example 223

3.9 3 1,2-dimethyl-3 '- (2-fluorophenylphenyl) thiouronium iodide prepared according to the procedure of Example 210 in 40 ml of ethanol under reflux.

At reflux 115, 1 ml of pyrrolidine was reacted for 2 weeks.

The reaction product oil is purified by chromatography on neutral alumina, eluting with a 1: 1 mixture of methylene chloride and hexane and then a 1: 9 mixture of methanol and dichloromethane. The product thus obtained was N-methyl-N * - (2-morpholinophenyl) pyrrolidine-1-carboxamldine, which was converted to monofurwarate and recrystallized from isopropyl alcohol. The salt has a melting point of 1-3-171 ° C.

222 ». Example 1 g 1-Ethyl-2-πθ thi-3- (2-morpholinophenyl) thionium iodide obtained according to the procedure of Example 212 in 75 ml of tert-butyl alcohol with 2.7 g of butylamine reaction at 90-95 ° C for 172 hours. The 1-butyl-3-ethyl-2- (2-morpholinophenyl) guanidine thus obtained is converted to a monofumarate which is crystallized from a 1: 2 mixture of methanol and diethyl ether. The salt had a melting point of 15916 ° C.

Example 225

2.8 g of 7 - (2-Amino-'} - chlorophenyl) -1-tuorpholine are treated with 1.5 S butyl isotloanate in ethanol at room temperature for 60 days. The thus obtained 1-butyl-3- (5 ”chloro-2-fluorophenylphenyl) -thiourea, m.p.

116 ° C, 15 ° -152 ° C.

A mixture of 2,6-β-1-butyl-3- (5-chloro-2-niorophenylphenyl) -locarbamide, 1.4 g of methyl iodide and 20 t of aoetone is heated under reflux for 3 hours. The resulting 1-butyl-3- (5-chloro-2-morphollenophenyl) -2-methylthiouronium iodide has a melting point of 13 DEG-132 DEG C.

To 3,4 S 1-bi-ethyl-3 '- (5-chloro-2-nioropholtnophenyl) -2-methylthiouronium iodide was added 10 ml of a 33% solution of methylamine in ethanol and in a brazed vessel. The resulting product was 2- (5-chloro-2-morpholinophenyl) -1,3 "-dimethylguanidine, which was crystallized from hexane and had a melting point of 145-14 ° C. In reaction 2b, both the butyl arri.no and the net thio group were partitioned to the methyl amino group.

Example 226 g of 1- (2-aminophenyl) pyrrolidine in 45 ml of methyl. of methylene chloride in 6.3 g of dichloromethane at room temperature for h days to give 1-methyl-S [2- (1-pyrrolidinyl) phenyl] thiourea. The product has a melting point of 125-126 ° C.

18.5 S 1-Methyl-3- [2- (1-pyrrolidine) phenyl] -

Thiourea, a mixture of 12.3 g of methyl iodide and 100 ml of aoaton ·······························································································

The resulting 1,2-dimethyl-3- [2- (1-pyrrolidinyl) phenyl] -tlouronium iodide has a melting point of 161-162 ° C.

dissolve 4 to 45 g of allylamine in 1 ml of ethanol,

14.7 g of _1-f 2-dimatil Γ2- 3 · (1-pyrrolidinyl) phenyl] -tiourónium iodide at room temperature for 50 days was allowed before the reaction mixture to stand, and then heated for 20 hours under cooling visszaosepegő · The resulting The oil is converted to 1-allyl-3-methyl-2- [2- (1-pyrrolidinyl) -phenyl] -guanidine monofumarate with venous acid which is crystallized from a 1: 2 mixture of methanol and ethyl ether. Mp 162-163 ° C.

Example 227 4- (2-Amino-4-methylphenyl) morpholine (5.7 g) in methylene chloride (dichloromethane) and methyl isothiololanate (2.8 g) were added. The reaction was allowed to stand at room temperature for 6 days to give 1-methyl-3 '(5-methyl-2-morpholinophenyl) -l-urea as colorless crystals, mp 107 ° C.

A mixture of 6.4 l of 1-methyl-3 ^w (5-methyl-2-morpholinophenyl) thiourea, 3.3 g of methyl iodide and 60 ml of acetone was refluxed for 4 hours. Yes ···· • ·

1,2-dimethyl-3 '(3 (5' methyl-2-morpholino-phenyl) -tlourónium iodide pale yellow crystals was 118, the melting point amelynsk 1 (> 0 ~ 161 ⁰ C.

g 1,2-dimethyl-3 '(5' -ethyl-2-morpholinophenyl) i

Thiouronium iodidehop (250 ml) was added 33 µl of anhydrous ethanol in ethanol solution and allowed to react at room temperature for 21 days. The resulting 1,3-dimethyl-2- (5 "methyl-2-morpholinolinophenyl) guanidine oil was dissolved in methanol (60 mL) and treated with fumaric acid (1.7 g) to give 1.2 g of colorless crystals.

1,3-Dimethyl 1-2- (5 '') and 1-2-aorphinophenyl) guanidine fumarate is obtained. The salt was recrystallized from a 1: 1 mixture of methanol and diethyl ether to give a melting point of 201-202 ° C.

Example 228

Prepared according to the procedure of Example 227 ·

8.4 g of 1,2-dimethyl-3 '(5' '-yl-2-morpholinophenyl) -thiouronium iodide in 80 ml of ethanol are reacted with 6.8 ml of N- (2-hydroxyethyl) -ethylenediamine. boiled under refrigeration for 3 ^ sap. The oil thus obtained was dissolved in methanol by the addition of? 3 fumaric acid to give 4- [2- [1- (2-hydroxyethyl) -2-ididazolidinylidene] | -anjino-4-methylphenyl] -norpholine sesquifumarate. 135-136 ° C.

* ··· ·· ·· ««

- 119 "

EXAMPLE 229 g of the 1,2-dimethyl-3- (2-morpholinophenyl) -thiocarbamide and 1.7 g of tritium hydroxide and 5.3 S of lead are obtained from the gldrojodide salt of Example 210. ) -o-acetate-vlz (1/3) In the presence of 20 ml of ethanol, 2.1 g of ponti1-amine are reacted at 90-95 ° C for 40 cycles. The reaction product oil was extracted with hexane and the resulting 1-methyl-2- (2-morpholinophenyl) -3 'pentylguanidine was converted to the monofurarate and then recrystallized from methanol: diethyl ether (3: 5). Melting point 143-149 ° C.

Example 230 2.4 g of butylamine are dissolved in ml of ethanol,

12.2 g, prepared according to the procedure of Example 227

1,2-Dimethyl-3 '(5-methyl-2-morpholinophenyl) thiouronium iodide was added and the mixture was allowed to stand at room temperature for 4 months. After addition of 9 S 61om (IT) -aoacetate water (1/3), the reaction mixture was heated under reflux for 1 hour, and then the resulting 1-butyl-3-math 1-2- (5-iodine 1-2-) was added. morpholinophenyl) guanidine was converted to monofumarate and the salt was recrystallized from methanol: diethyl ether 1: 2. The product has a melting point of 150 ° C.

»· · · · · · * * T t t t t t t t t t t t t t t.

120 -

Example 231 θ, 75 g of 4 "(2-atnino-3-methylethylphenyl) -morpholine in 4 ml of methylene dichloride was reacted with 4.7 g of methyl 1-isothiolanate at room temperature for 4 days to give 1-methyl-3" (6- methyl 2-morpholinophenyl) thiourea is obtained. 182-183 ° C.

A mixture of 11.5 g of 1-methyl-3- (6-methyl-2-orpholinophenyl) thiocarbamide, 6.75 g of methyl iodide and 100 ml of aoetone

Reflux for 2.5 hours. The resulting 1,2-dimethyl-3- (6-methyl-2-morpholinophenyl) -thiouronium iodide, m.p. 187-188 ° C, was dissolved in 6.4 g of butylamine in ethanol.

17.8 g _1> 2-dim9til-3 '(6-methyl-2-morpholinophenyl) -tiouróniunj iodide are added and the reaction mixture was allowed to stand at room temperature for 60 days. Subsequently, after adding 2.2 g of potassium hydroxide and 7.6 g of 61 µm (TT) -aoacetate water (1/3), the mixture was refluxed for 5 hours, followed by the formation of 1-butyl-3 from methyl 2- (6-methyl-2-morpholinophenyl) guanidine to form a monofumarate which is recrystallized from a 1: 2 mixture of methanol and diatyl ether. The salt has a melting point of 2 ° C-204 ° C.

Example 232

Morpholinophenyl isothiololate S in 10 ml of ethanol was reacted with 15 ml of 33 J-03 dimethylamine in ethanol at 15 ° C for 4 hours to give 1,1-

121 dinje ti 1-3 (2-morpholinolenyl) thiocaranane · The product has a melting point of 150-152 ° C.

A solution of 7.5 seconds of 1,1-dimethyl-1- (2-morpholinophenyl) -thiourea and 1.7 ml of methyl iodide was heated under reflux for 2 hours, resulting in 1,1,2-trimethyl-3 ( 2-morpholinophenyl) thiouronium iodide is obtained. M.p.

2 g 1,1,2-trimethyl-3- (2-morpholinophenyl) thiouronium iodide, 10 ml saturated ethanolic ammonia solution and 10 ml pyridine were weighed into a pressure-resistant vessel made of stainless steel, and the mixture was heated at 9 ° to 95 °. Maintain at 0 and ΘΖ9Η for 19 hours. The pyridine is then removed in vacuo. The residue is resuspended in water. Insoluble 1,1-dimethyl-2- (2-morpholinophenyl) guanidine was filtered off, washed with water, dried and recrystallized from hexane. 142-143 ° C.

Example 233

3.3 5 2 uietll-1- (2-morpholinophenyl) -tiouróntutn iodide in 25 ml of pyridine in 5 ml of 33 ^f / - through ethanolic dimethylamine solution was reacted at 80 ° C for 6 hours. The pyridine is distilled off from the basin in vacuo and the residue is triturated with ice-water and the resulting

122

1,1-Dimethyl-2- (2-niorpholinophenyl) guanidine is recrystallized from hexane. M.p. 142-144 ° C.

Example 234

A mixture of 3.8 g of 2-methyl-1- (2-morphollenophenyl) thiouronium iodide, 5 ml of 33% solution of dimethylamine in ethanol and 25 ml of triethylamine was heated to 8 ° C. temperature for 8 hours. The triethylamine was evaporated in vacuo and the residue was triturated with ice water and the resulting 1,1-dimethyl-2- (2-morpholinophenyl) guanidine was recrystallized from hexane. 141-143 ° C.

235-241. examples

Vegyületek Compounds of formula (I) listed in Table X wherein:

Significant R is methyl anino

Significant R is hydrogen, such that A g (ZVT) is a thiourea of general formula wherein R 4 is methyl-washed and R 4 is hydrogen, B g potassium hydroxide, C 6 amine, 6 g (61 T) - a mixture of aetoacetate water (1/3) and t ml of ethanol - they refer to figures in the individual columns of the table - react at 9θ to 95 ° θ in Table I ^? column

123 over. The resulting oil is dissolved in methanol and added to fumaric acid to form the monofumarate of the compounds of formula (I). The melting points of the salts are given in the table and the solvents used for the recrystallization are mentioned in the notes to the table.

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• · · · · · · · · · · · ·

125

Notes to Table A:

(59) The salt is crystallized from methanol.

(60) The starting compound was prepared by reacting 4 g of (2-amino-4 'fluorophenyl) morpholine in 50 ml of methylene dichloride with 2.6 g of methyl isothioanate at room temperature for 25 days to give 1- ( Yield: 5 "Fluoro-2-morpholinophenyl] -N-ethylthiourea, m.p. 145-150 ° C.

(61) The base was purified by chromatography on neutral aluminium oxide, eluting with dichloromethane.

(62) The starting material is prepared by reacting 9.5 3 4 '[2-arino-4' (ethylthio) phenyl] morpholine in 100 N in dichloromethane with 3.1 g of methyl thiazothioanalate at room temperature for 30 days. over. 1-wetyl-3 '- [5' - (methylthio) -2-morpholinophenyl-thiourea, m.p. 132-133 ° C.

(63) The salt was recrystallized from a 1: 2 mixture of methanol and diethyl ether.

(64) The salt is crystallized from isopropanol.

Example 242 g 4- [2-α-α, α-α-α-trifluoro-4 ′ (trifluoromethyl) phenyl] rorpholine in a mixture of 30 ml of dioxane and 100 ml of water gave 3.6 g of tl · · · · · · · · Reaction with "126" phosgene at 0 ° C for 30 minutes and then at room temperature 2 hours. After evaporation of the reaction mixture, the residue was extracted with methylene chloride to give 2-morpholino-2- (5 "trifluorobutyl) -phenylisothioylate · g 2-morpholino-5" (trifluoro) as a yellow oil. Methyl phenyl phenyl isothioylate was dissolved in 2G ml ethanol and 5 ⁽¹ ml 33 ',' ethanolic ammonia solution) was added. The mixture was allowed to react at room temperature for 2 hours, resulting in 1 "- 2-morpholino-5" (trifluoro of methyl) -phenyl] thiocarbaride, m.p.

5.1 g of 1- [2-morpholino-5- (trifluoromethyl) phenyl] thiocarbarnate, 2.2 g of potassium hydroxide, 5.6 ml of 33% ethanolic dimethylamine solution, A mixture of 7.5 g of 61ora (IT) -aoacetate water (1/3) and 4θ ml of ethanol was heated to 9 ° to 95 ° C and maintained at this temperature for 2 hours. This gives 1,1-dimethyl-2- [2-morpholino-5 (trifluoroacetyl) -fanyl] -guanidine, m.p. Recrystallized from a 2 mixture of the salt, 223-23G. melted.

EXAMPLE 243 g of 4 (2-amino-4-cyanophenyl) -morpholine was eluted with 2 ml of dioxane and 25 ml of water with 1.15 ml of tlofosgene. · · · · · · · ·

- 127 was shaken at 0 ° C for 30 hours and then at room temperature for 2 hours. The residue obtained by evaporation of the reaction mixture was extracted with methylene chloride to give 5-cyano-2-morpholinophenyl isotloolanate, which was an oil.

2.5 S 5 "olano-2-morpholinophenyl isothioylate is dissolved in 10 ml of 3 Tan, 1 ml of 25 ml of aunionone hydroxide solution and allowed to react at room temperature for 3 hours. - (5-Cyano-2-morphollenophenyl) thiourea, m.p. 193-194 ° C.

5.2 g of 1- (5'-cyano-2-worfolinophenyl) thiocarbaride, 8.3 S potassium carbonate, 15 ml of 33 ', 4'-ethanolic diethylamine solution, lead (H) -acetate- (2/3) and 25 ml of ethanol are refluxed for 3 hours. The resulting 2- (5-cyano-2-morpholinophenyl) -1,1-dimethyl-guanidine, m.p. 125-127 ° C. is converted to the monofumarate and recrystallized from methanol. The salt melts at 223 "225 ° θ" θη with decomposition.

Example 2Z; 4 ·

2.65 g of 1,1-dimethyl-3- (2-morpholinophenyl) thiourea, prepared according to the procedure of Example 232,

A mixture of 1.6 ml of propylamine, 3.8 g of lead (XI) acetate acetate (1/3) and 25 ml of ethanol is heated at reflux for 5 h. Subsequently, 1.6 ml of propylamine were added to the reaction mixture and heated to reflux under reflux. · ····

The reaction was continued for an additional G hour. After evaporation, the residue was extracted with diethyl ether, the extract was clarified with ozone, filtered and evaporated to leave a sticky solid. The residue was dissolved in methanol (10 mL) and fumaric acid was added. The thus obtained 2- (2-narfolino-phenyl) _-1-f 3 "dipropll guanidine hemifumarate methanol-diethyl ether 1: 2 mixture of kristályoettjük. The salt has a melting point of 2 12-2 12 ° C.

Example 2 of j5 ·

2.55 g of 1,1-dinethyl-1,3- (2-morpholinophenyl) thiocarbamide obtained according to the procedure of Example 232,

3.3 A mixture of 3 olive oil (a. A. Aa) -atate water (1/3), 25 ml of a saturated solution of ammonia in ethanol, 1 12 l of potassium lithium oxide and 2 ml of ethanol in a pressure-resistant steel pressure vessel Reaction was carried out at 9 to 95 ° C for 5 hours. The reaction mixture was filtered and the filter cake was washed with ethanol and the ει 3 filtrate was combined with the washings and concentrated in vacuo. Ice is added to the residue, the precipitate is filtered off, washed with water and dried and filtered through hexane. The thus-obtained 1,1-climethyl-2- (2-morpholenophenyl) guanidine has a melting point of 12 ° -12 ° C-2 ° C.

21 / -2.69 · examples

RT. listed in the table (Σ) pseudonym.l public • ··································• ··· ····

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132 Notes to the LCC. table:

In the comment section, numbers (32), (jS), (44) and (45) refer to those reported in the previous tables.

(65) The reaction is carried out at 110 ° C.

(66) The product is isolated as the monofumarate salt and crystallized from a 1: 1 mixture of diethyl ether and diethyl ether (67). The reaction is first carried out at 90-95 ° C for 3 hours and then at 115-12 ° C. it will continue for 4 hours.

(63) The digestion was continued at 120-125 ° C.

(69) The alcoholic oil was heated for 9 hours at 90 to 95 ° C and then for 21 hours at 12 ° C.

(70) The reaction oil is extracted with hot hexane, the base thus obtained is converted to the monofumarate, and the salt is recrystallized from a 1: 3 mixture of methanol and diethyl ether.

(71) The reaction product is an oil which is extracted with hexane and the base thus obtained is purified by chromatography on neutral alumina using hexane, methylene chloride and a 1: 1 mixture of hexane, dichloromethane and methanol as the eluent. and methylene chloride (1:99). The purified base is then converted to the monofumarate and the salt

133 in a tan ol 63 diatyls 9r 2: 7 traverses his tanks.

Example 270

A mixture of 2.1 N - (2-amino-phenyl) -orpholine hydrochloride and 7 µL of N, ΖΓ-dimethyl-1-olanamide was stirred under nitrogen at 165-170 ° C for 12 hours, after which the reaction slurry was heated to The mixture is cooled to 0 ° C, the precipitate is sputtered, the thi 1 is sealed and the aqueous sodium hydroxide solution is discarded. The resulting residue was θ tracted with dichloromethane and the extract was washed with brine and then evaporated _. 5C.

Example 271

2.7 g of h- [2-amino-1H-matoxycarbonylphenyl] -morpholine in 15 ml of m-cresol are treated with 1 g of N, N, N-dimethylolamide at 90-95 ° C for 10 hours. The reaction mixture is then treated with yogh, acidified with 2N hydrochloric acid to the p1-j of h and extracted with dichloroethyl. The aqueous portion was cooled and the solution was <RTI ID = 0.0> 39g / l </RTI> until solid p.8 was added by addition of solid sodium bicarbonate and extracted with dichloromethane. The extract is dried

13U of Yidd, evaporated the crude solvent and the residue, which was purified by chromatography on oil in neutral alumina, eluting with 1:99 methanol: dichloromethane. The thus obtained 1,1-dimethyl-2 '- [5- (methoxycarbonyl) -2-taorophenolinophenyl] guanidine had a melting point of 152-154 ° C.

Example 272

10 g of 1- (2-morphollenophenyl) thiourea are suspended in 0 ml of hot water. 25 ml of potassium hydroxide are added to 70 ml of hot aqueous solution. The reakolóel9gyet 9 ° ^Ο 0 οη kept at 63 was added portionwise 17.5 3 ólo'i (T? C) -aoetát-water (1.3) ml of hot water was prepared. The mixture is refluxed for another 10 minutes, cooled to room temperature, filtered, and the filtrate is acidified to acetic acid. The precipitate formed is filtered off, washed with water and recrystallized from ethyl acetate.

.T- (2-m or f oll η o-f e ni 1) - m.p. 175-176 ° C.

15 µl for 3 T- (2-; aorphollenophenyl) -olanamide

A solution of -03 ethanol-methylmethylamine was added under refluxing for 4 hours. After cooling, the solvent is evaporated and the residue is suspended in 20% aqueous sodium hydroxide solution.

135 then the. azuszpans ¹ t .o hárouszor extracted with 25 of methylene chloride, washed with exbraktumot water and brine, dried and concentrated. Recrystallization from hexane gave the 1,1-dimethyl-2- (2-morpholtenophenyl) guanidine, m.p.

273-285. examples

Following the procedure described in Example 272, the compound of formula (II) is prepared. Compounds of formula (X) listed in Table I wherein n = 0;

/ morpholinoose with the nitrogen to which they are attached;

denotes amino; and / is hydrogen.

By that? g of IT- (2-morpholinophenyl) olanamide> g. of the amine in refluxing reflux condenser in R ml ethanol. Capital letters refer to the numbers in the table columns.

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In the comment section, numbers (32), (3θ), (44) and (45) refer to those reported in the previous tables.

(72) Reaction with 25 ml of 335 * ethanolic methylamine solution · (73) Reaction at 90-95 ° C (74) The product was isolated as monofumarate and the salt was dissolved in methanol and diethyl ether. (75) Recrystallize from product: hexane: ethyl acetate (1: 1). (76) Reaction at room temperature for 1 hour and then at 90-95 ° C for 20 minutes. (77) The product was recrystallized from ethyl acetate / hexane (3/7). (78) The reaction was carried out at room temperature for 4 hours and then refluxed for a further 4 hours,

Example 286

8.5 S 4- (2-Amino-4-chlorophenyl) morpholine was reacted with dioxane (25 mL) and thiophosgene (4 mL) at 0 ° C for 30 minutes and then at room temperature for 3 hours. The resulting pale yellow solid product is 5 "chlorine 139"

-2-Morpholinophenyl isothiocyanate, m.p. 86-87 ° C, was added to 5 g of 5-chloro-2-morpholinophenyl isothiocyanate in 33 ml of ethanolic ammonia solution and allowed to react at room temperature for 14 hours. 1- (5-Chloro-2-morpholinophenyl) thiourea, thus obtained as a yellow solid, m.p. 174-175 ° C.

5.97 S 1- (5 "Chloro-2-morpholinophenyl) thiourea is suspended in 4θ ml of water and 8.75 g of lead (II) -aoacetate water (1/3) in 4θ ml and 12.6 g aqueous solution of potassium hydroxide (35 ml) was added and the mixture was refluxed for 15 minutes. The white solid thus obtained was N- (5 "chloro-2-morpholinophenyl) cyanamide, m.p.

As described in Example 272, a mixture of 2.3 g of N- (5-chloro-2-morpholinophenyl) olamide, 10 ml of ethanol and 6 ml of 33 ml of ethanolic dimethylamine solution was heated under reflux for 4 hours. This gave 2- (5 "chloro-2-morpholinophenyl) -1,1-dimethyl-1-guanidine, m.p. The product thus obtained has a melting point of 223-225 ° C, · ··· “14ο -

Example 287 4 g of (2-anino-4 "fluorophenyl) morpholine was treated with 5.2 g of thiophosgene in 20 ml of dioxane and 40 ml of water for 15 minutes and then for 1 hour at room temperature. The residue obtained by evaporation of the mixture is extracted with dichloromethane, and the oil obtained from the extract is purified by chromatography on silica gel (100-200 mash) eluting with a column of hexane.

To 5.8 g of 5-fluoro-2-morpholinophenyl-1-isothiocyanate is added 30 ml of 33 N atanolic ananolic solution and the mixture is allowed to stand at room temperature for 3 hours. The resulting white solid product is 1- (5-fluoro-2-morpholinophenyl) thiourea, m.p. 195-19 ° C.

5.1 g of 1- (5 '-chloro-2-morpholinophenyl) thiourea, 7.95 g of lead (II) acetate water (1/3) in 36 ml and 11 ml of water are suspended in 6 ml of water. A solution of potassium hydroxide (45 g) in aqueous solution (32 ml) was added and the mixture was refluxed for up to 25 pairs. In this way, (5-fluoro-2-morpholinophenyl) cyanamide is obtained in the form of white crystals melting at 168-170 ° C.

Following the procedure described in Example 286

2.2 g of li- (5'-fluoro-2-morpholinophenyl) cyanamide, 10 ml

A mixture of ethanol and 6 ml of a 33'A solution of dimethylamine in ethanol was heated at reflux for 20 minutes to give 2- (5-fluoro-2-morpholinophenyl) -1,1-dimethylguanidine. . This product, recrystallized from hexane, melts at 137 "13θ ° 0-οη, and its fumarate is recrystallized from methanol. The salt had a melting point of 222-224 ° θ · 228

9.4 g of 4- (2-amino-6-methyl-phenyl) -morpholine in a mixture of dioxane and 200 ml of water were treated with 6 ml of thiophosene at 0 ° C for 30 minutes and then at room temperature for 2 hours. Extract with dichloromethane to give 3 * methyl-2-morpholinophenyl isothiocyanate as a red oil.

8 g of 3-methyl-2-morpholinophenyl isothioyanate are dissolved in ethanol, 60 ml of a saturated solution of ammonia in ethanol are added and the mixture is allowed to react at room temperature for 4 hours. The thus obtained 1- (3 '-nethyl-2-morpholinophenyl) thiourea, m.p. 178-179 ° C, was suspended in 1- (3-methyl-2-chlorophenylphenyl) thiourea in 9 ml of water. IIl) -acetate-water (1/3) A solution of 4θ ml and an aqueous solution of potassium hydroxide (13.5 €) (35 ml) was added and the reaction mixture was kept at 90-95 ° C for 1 hour. 3-methyl-2-morpholino ···

M.p. 137-138 DEG C., recrystallized from ethyl acetate.

Similar to Example 286, 2.5 g of N- (3-methyl-2-morpholinophenyl) olamide, 8 ml of ethanol and

A mixture of 3.5 ml of a 33% solution of dimethylamine in ethanol was refluxed for 1 hour. A further 3.5 mL of 33% ethanolic dimethyl-1-dimethylamine solution was added to the reaction mixture and refluxed for an additional hour, 1,1-dimethyl-2- (3 'methyl-2-morpholinophenyl) guanidine. recrystallize from hexane to form a monofumarate of the resulting melting point 100 DEG-0 DEG C. The melting point of the salt is 18 DEG C. recrystallized from a 1: 1 mixture of methanol and diethyl ether.

Example 289

4.7 S 4 '(2-amino-5 "methoxyphenyl) -morpholine in a mixture of dioxane and 75 ml of water was treated with 2.9 ml of thiophosgene at 0 ° C for 3θ minutes and then at room temperature for 3 hours. extraction of the residue with methylene dichloride to give 4-methoxy-2-morpholinophenyl isothioanate as an oil,

To 4 g of 4-methoxy-2-morpholinophenyl-isothioylate is added 3 m of a saturated solution of ammonia in ethanol and allowed to react at room temperature for 24 hours, resulting in 1- (4-methoxy-2-moxyphenylphenyl) thiourea · ··

143, mp 175 ° C,

3.8 g of 1- (4-methoxy-2-morpholinophenyl) thiourea are suspended in 26 ml of water and 5.7 g of 61 µmol (1T) -azoate water (1/3) in 26 ml, and 8.4 g of potassium aqueous solution of hydroxide (24 ml) was added. The reaction mixture was heated at 9 ° to 95 ° C for 3θ minutes to give l- (4-matoxy-2-chlorophenyl) olanamide,

To 1.9 g of K- (4-ethoxy-2-morpholinophenyl) olanamide was added 2.5 ml of a 33% solution of dimethylamine in ethanol and refluxed for 15 minutes. dimethyl 2- (4-methoxy-2-morpholinophenyl) guanidine was recrystallized from hexane, m.p. 135 ° C.

Example 290

4.1 g of 4- (2-amino-4-isobutyl-1-phenyl) -morpholine

hydrochloride in 15 ml of m-cresol was treated with 1.77 g of iT, H-dimethyl cyanamide 9θ-95 ° θ-οη for 6 hours. The product was extracted with hot hexane Purify the product by crystallization from a 1: 3 mixture of ethyl acetate-hexane. Initially precipitated, the residue was purified by column chromatography (EtOAc / dichloromethane, 2:98). The filtrate was evaporated to dryness and the residue was recrystallized from ethyl acetate: hexane (1: 3) to give 2- (5-isobutyl-2-morpholinophenyl) -1,1-dimethylguanidine.

Example 291

A solution of 3.75 g of sodium carbonate in 25 ml of water was added after addition of 5.6 g of sodium chloride, 0.2 copper (l) chloride and 0.34 S copper (ll) chloride water (1/2). After cooling to <RTI ID = 0.0> C, </RTI> a solution of 1- (2-morpholinophenyl) thiourea (6 g) in methylene chloride (45 ml) was added over 15 minutes. The mixture was then heated to 40 ° C and maintained at this temperature for 4.5 hours. Water (100 ml) and methylene chloride (200 ml) were added, the mixture was stirred for 10 minutes, then the organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried and evaporated. The residue was triturated with 100 ml of 20N sodium hydroxide solution on a steam bath with stirring, then filtered, the filtrate washed with diethyl ether, acetic acid pH 4i ^, acidified and extracted with dichloromethane. The extract was washed with brine, dried and evaporated and the residue 1 was purified by chromatography on silica gel eluting with hexane followed by continuous addition of ethyl acetate to increase the polarity of the eluent.

The ratio of 145 reaches 30 / Got. The N- (2-morpholinophenyl) olanamide thus obtained had a melting point of 175-176 ° C.

To a solution of 1.5 S H- (2-morpholinophenyl) olanamide was added 12 ml of a dimethylamine solution in ethanol (12 ml) and the mixture was refluxed for h. After evaporation of the solvent, the residue is taken up in a mixture of 100 ml of dichloromethane and 50 ml of sodium chloride solution, stirred for 5 minutes, the organic phase is separated off, dried and evaporated to give 1,1-dimethyl-2- (2-morpholino phenylguanidine is recrystallized from hexane, m.p.

Example 292

1,3 S, 1,1-dimethyl-2- [5- (methyl-1-thio) -2-morpholinophenyl] guanidine, prepared according to the procedure of Example 253, is reacted here as the free base with 1 g of sodium meta-pair iodate, 10 mL methanol and Zj. of water was allowed to stand at room temperature for 20 hours. Recrystallization from Styl acetate gave 1,1-dimethyl-2- (5-methylsulfinyl) -2-morpholinophenyl] guanidine, m.p.

Example 293

3.75 s sodium carbonate, 5.6 g sodium chlorite,

0.2 g copper (l) chloride, 0.34 2 copper (ll) chloride water (1/2) and ··· ♦

146

O _f 6 g benzyl-ammonium salt triiaetil chloride dissolved in 25 ml of water with stirring, was added over 15 pero

6.2 g of 1-methyl-2- (2-morpholinophenyl) thiourea were dissolved in 30 ml of dichloromethane and stirred for 2 hours.

2.4 g of sodium chlorite and 0.4 g of benzyltrimethylammonium chloride are added and stirring is continued.

After 1.5 hours, methylene chloride (20 ml) and water (50 ml) were added, and the aqueous phase was extracted with methylene chloride (2 x 100 ml), and the organic layer was combined, washed with brine, dried, filtered and evaporated. purify, first with hexane,. then eluting the column with ethyl acetate / hexane (1: 4). The resulting K-methyl-1 * - (2-morpholinophenyl) carbodiimide had a melting point of 67-68 ° C.

g IT-methyl-K * - (2-morpholinophenyl) carbodiimide,

A mixture of 0.5 g of butylamine and 5 ml of tert-butyl alcohol was heated to 90-95 ° C for 4 hours and then evaporated. The residue was dissolved in 100 ml of dichloromethane and the solution was quenched with water. wash, dry, finally filter and evaporate again. The residue was 1-butyl-3-methyl-2- (2-morpholinophenyl) guanidine which was converted to the monofumarate. Melting point 178-179 ° C,

147

294-300. examples

The fumarate salt of some of the compounds listed in the previous examples and listed in Table XHI is prepared according to the procedure in Example 2. The following table shows the solvent mixtures used for recrystallization.

TABLE XIII

The number of the example The number of the example according to which the output or excess is produced Atkris Tank Ancient Bag Solvent Fumarate salt melting point (° C) 294 133 methanol: ether 1: 2 173-175 295 134 methanol: ether 1: 2 183-184 296 167 methanol: diet 2: 1 192-193 297 175 metahol-étBr 1: 1 159-160 298 200 propan-2-ol 142-143 299 201 methanol-ether 1: 1 15 1- 152 300 204 methanol-ether 1: 2 170-171

Example 301

19.2 g of 4- (2-aminophenyl) -morpholine hydrochloride in ml m-cresol are treated with 9.45 g of Ν, ΙΤ-dimethyl cyanamide at 100 ° C for 5 hours, and the reaction mixture is cooled and 300 ml of 40 of sodium hydroxide solution and 300 g of ice. Add another 300 ml of water,

The precipitate was filtered off, washed with water and dissolved in dichloromethane. The solution was dried, evaporated, and the residue was recrystallized from hexane to give 12, 1-dimethyl-2- (2-morpholinophenyl) guanidine, m.p.

302-304. examples

The compounds of Examples 175 ·, 248 · and 3θθ · were prepared as a base in methanol and added with L - (-: -) - tartaric acid to give the following compounds in the above order. All three products were crystallized from methanol.

302.4 ”(2- {[1- (2-hydroxyethyl) -2-imidazolidinylidene] -

-amino-phenyl] -morpholine mono-tartrate, m.p. 147-14 ° C.

303. 1,1-Dimethyl-2 (5-methyl-2-morpholinophenyl) guanidine monotartarate, m.p. 183-182 ° C.

304. 1,1-Dimethyl-2- (2-morpholinophenyl) guanidine mono-tartrate, m.p. 184-185 ° C.

Examples 305 and 306

Acetyl chloride was added in methanol, the mixture was stirred for 30 minutes, and the hydrochloride formed was then salted from the compounds of Examples 248 and 301 to give the following products:

150

305, 1,1-Dimethyl-2- (5-methyl-2-morpholinophenyl) -

-guanidine monohydrochloride which is recrystallized from a 1: 1 mixture of isopropanol and diethyl ether, m.p. 161-162 ° C;

306, 1,1-Dimethyl-2- (2-morpholinophenyl) guanidine

-monohydrochloride, which is passed through a crystal of isopropanol and has a melting point of 2 ° C-201 ° C,

Example 307

Example 301 is reacted with sulfuric acid in acetone to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine hemisulfate which is crystallized from a 1: 1 mixture of methanol and diethyl ether. The salt has a melting point of 234 ~ 235 ° 0,

Example 308

The compound of Example 3θ1 is reacted in pyridine with pamoic acid to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine hesipamate, m.p. 158-160.

Example 309 4.6 g of 1,3-dimethyl-2-imidazolidinone are dissolved in ml of benzene, 3.8 g of 4 '(2-aminobenzyl) morpholine are dissolved in 20 ml of benzene, and 3.6 ml of phosphorus trichloride are added. oxide followed by the reaction at 65-7 ° C.

- Heat and keep at room temperature for 20 hours. The thus obtained 4- [2- (1,3-dimethyl-2-imidazolidinylidene) -amino] -1-benzyl] -morpholine is recrystallized from hexane, m.p. 56-58 ° C.

Example 310

10.95 S 1.3 "dimethyl-2-imidazolidinone is dissolved

In 100 ml of benzene, add a solution of 13.6 S 4 "(2-amino-4" chlorobenzyl) -morpholine-50 ml in benzene, then add 8.8 ml of phosphorus trichloride and add 60 "65 for 8 hours. The mixture is allowed to react at a temperature of about 0 ° C. The reaction product is an oil which is purified by chromatography on alrunium oxide, eluting with hexane / hexane / dichloromethane / dichloromethane (1: 1) followed by dichloromethane. The purified product (3.2 g) was dissolved in methanol (50 ml) and fumaric acid (1.2 g) was added to the solution, resulting in 4- [2 - ((1,3-dimethyl-2-imidazolidinidine) amino] -4 " The salt is recrystallized from a 1: 1 mixture of methanol and diethyl ether to give a melting point of from 19 ° to 17 ° C.

Example 311

A mixture of 10.6 g of 4 "(2" aminobenzyl) -morpholine "dihydrochloride, 4.2 g of H, H-dimethylolamide and 40 ml of cresol is heated to 9 ° -95 ° C and maintained at this temperature. ··

- 152 hours. From the resulting product, m.p. 120-121 ° C, g is dissolved in 15 ml of methanol and 0.9 g of fumaric acid is added to give [2- (morpholinomethyl) phenyl] guanidine monofumarate. crystallized from alcohol, m.p. 164-165 ° C ·

Example 12

6.8 g of 4- (2-aminobenzyl) -morpholine dihydrochloride,

A mixture of 4.3 g of 4-olormorpholine and m-cresol was reacted for 9 hours at 95 DEG-95 DEG C. for 12 hours, and the resulting 1 -119 ° C, recrystallized from hexane and converted to difumarate. The salt was recrystallized from isopropyl alcohol to give the product, mp 166-167 ° C.

Example 313

The use of the compounds of the present invention as active ingredients in pharmaceutical compositions is described below. In the following formulas, the active ingredient designation may refer to any compound obtainable by the process of the present invention, but is primarily intended to refer to the end products of the processes described in the preceding Examples.

·· «... ..

• · '': ”. . · * * * * ·· ··· ·· »·

- 153 -

a) Preparation of the capsule Lactose by weight is ground and mixed thoroughly. The mixture is then filled into hard zolatin capsules so that each capsule contains a unit dose or a proportion of the active ingredient,

b) Preparation of the tablet

The tablet consists of the following ingredients:

It is produced by the procedure of substitute 1 -

active ingredient: 10 parts Lactose 190 parts Corn starch 22 parts Poly (vinyl pyrrole) 10 parts Magnesium stearate 3 parts

The active ingredient, lactose and a portion of the corn starch are ground, mixed, and the mixture is granulated with ethanol solution of polyvinylpyrrolidone. The tabletting machine is configured so that each tablet contains a unit dose of the active ingredient or a predetermined proportion thereof.

• «« · β • · * · • ♦ ··· ····

- 154 -

c) Preparation of enteric coated tablet

The tablets are prepared by the process described in (b) and then coated in the usual manner well known in the art. we use a mixture of

d) Preparation of end □ yiUP

100 parts by weight of the active ingredient are processed well in 1300 parts by weight of a triglyceride-based suppository and the suppositories are formed into a suppository, each containing a therapeutically effective amount of the active ingredient.

Claims (11)

PATENT CLAIMS A process for the preparation of a compound of formula I wherein n is 0 or 1; R 1 and R 8 may be the same or different and may be C 1-3 alkyl optionally substituted by methoxy, C 3-7 oxoalkyl, or R 6 and R 8 taken together with the nitrogen atom to which they are attached, optionally substituted by the general formula (II). forms a heterocyclic group of the general formula: R ₈ is hydrogen or C 1-3 alkyl; B is C 3 -alkenylene or C 2 -C 4 -alkylene, where the carbon atoms may be optionally substituted with oxygen, sulfur, sulfinyl substituted or optionally substituted with C 1 -C 3 alkyl, and said alkylene may be substituted with one or more C 1 -C 3 alkyl groups. or two adjacent carbon atoms may form part of a benzene ring; R 1 is C 1 -C 7 straight or branched alkyl, C 3 -C 7 cycloalkyl, or a general formula (III) 156 where R 1 and R 6 are the same or different and are hydrogen or C 1-4 alkyl} Rg is hydrogen or a straight or branched aliphatic hydrocarbon group having from 1 to 4 carbon atoms optionally substituted by methoxy} R 8 is hydrogen, C 3 -C 7 cycloalkyl, or a C 1 -C 6 straight or branched aliphatic hydrocarbon group optionally having hydroxy or acyloxy, C 1 -C 3 alkoxy or alkylthio , an optionally alkylated amino group, a C 3 -C 7 carbocyclic group or a cyano group as a substituent} or R 4 and R 8 taken together with the carbon atom and the nitrogen atom to which they are attached form a heterocyclic group of formula IV wherein Rg has the meaning given above, R 4 and R ₁₀ are the same or different and are hydrogen and C 1-4 alkyl optionally substituted by methoxy; and D is the oxyethylene group where the oxygen atom is · · · « - 157 is attached to the carbon atom bearing the substituents R ₁₀ and R, or 2-5 carbon atoms, alkylene group optionally substituted by one or more C1-3 alkyl; obsession Rg and Rg taken together with the carbon atom and the nitrogen atom to which they are attached form a heterocyclic group of formula V wherein Rg has the meaning given above, R _X1 is hydrogen or alkyl having 1 or 2 carbon atoms, and E is alkylene having from 2 to 4 carbon atoms, optionally substituted with one or more C 1-3 alkyl groups; obsession Rg and Rg taken together with the nitrogen atom to which they are attached form a heterocyclic group of formula VI: G represents an alkylene chain containing from 4 to 5 carbon atoms, optionally oxygen, sulfur or nitrogen, which may be substituted by C 1 -C 3 alkyl, or optionally substituted by one or more C 1 -C 3 alkyl groups) and • ··· · ♦ · · - 158 Ry is hydrogen or halogen, C 1-4 alkyl optionally substituted with C 1-3 methylthio, C 1-3 alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, alkoxy having 2 or 3 carbon atoms in total. a carbonyl group and a trifluoromethyl or cyano group which may be optionally substituted with one or more ring substituents and pharmaceutically acceptable salts thereof, characterized in that an aniline of formula (VII) wherein n is Rp R ₂ and R are as defined above - an appropriate condensing agent such as phosphorus oxychloride, sulfinyl chloride, phosgene, phosphorus (V) chloride or benzenesulfonyl chloride in the presence of an acid amide or urea in an R-CO-NRejRg formula: - wherein R, _R5 and R ^ the above meanings, is reacted. Process according to claim 1, characterized in that the corresponding aniline derivative of formula (VII) is used a) a lactam of general formula (VIII): - wherein R, -. Rg, _R10 and D are as defined in claim 1 - is reacted with a condensing agent such as • · «« 159 in the presence of phosphorus trichloride oxide, sulfinyl chloride, cyanuric chloride, phosgene, carbon tetrachloride triphenylphosphine, phosphorus (V) chloride or benzenesulfonyl chloride; b) a compound of formula IX wherein R ₁₂ is chloro, dichlorophosphoryloxy, chlorosulfonyloxy, chloroformyloxy or phenylsulfonyloxy and B "is an anion such as a halide ion such as chloride or a BOCl 4 anion; c) reacting a compound of formula X wherein R 1 is alkyl and B 'is an anion, such as a tetrafluoroborate or methyl sulfate ion; d) a ketoxime of formula (XI): - wherein R, R ₁₀ and D are as defined in claim 1 and provides for Rg represents a hydrogen atom in the compound thus obtained (I) - is reacted with a sulfonyl chloride such as benzenesulfonyl chloride in the presence of; e) reacting with a urea of formula XII, wherein Rg and E are as defined in claim 1, a condensing agent such as phosphorus trichloride oxide, sulfinyl chloride, phosgene, phosphorus (V) chloride or benzenesulfonyl chloride presence. 160 3. A method according to claim 1, aiming to the preparation of formula (I) compounds wherein R ^ ® ^s ^ 5 together with the carbon and nitrogen to which they are attached form a (V), a heterocyclic radical, characterized in that one (XIII) with a compound of the formula: - wherein R _1Jt and R are hydrogen, and other symbols are as defined in claim 1 meanings optionally in the form of a salt with a diamine of formula (XIV): - wherein R, R _1X and E is as defined in claim 1. A process for the preparation of a compound of formula (I) according to claim 1 wherein R 1 is C 1-7 straight or branched alkyl or C 3-7 cycloalkyl and R g R g N is an unsubstituted amino group. characterized in that a compound of formula VII is reacted, optionally in the form of a salt, with a nitrile of the formula R1-CN, wherein R1 is as defined in claim 1, optionally in the presence of aluminum chloride. A process for the preparation of a compound of formula (I) according to claim 1 wherein R 1 represents an unsubstituted amino group, characterized in that a compound of formula (VII), optionally in the form of a salt, with a cyanamide of formula R 9 R 9 N-CN wherein Rg and Rg are as defined in claim 1. A process for the preparation of a compound of formula (I) according to claim 1 wherein Rg is an unsubstituted amino group, wherein a compound of formula (XV) is an amine of formula RgRgKH wherein the symbols have the same meanings as defined in claim 1. A process as claimed in claim 1. A process for the preparation of a compound of formula (I) according to claim 1 wherein R g is a group of formula (III) wherein R 1 is alkyl and R 6 is hydrogen or alkyl, characterized in that (XIII) wherein ^R 14 is R 1, R ₁ g is the same as R 6, optionally in the presence of a base or in the presence of potassium hydroxide and lead acetate, with an amine of formula ^R 9 ^R 9 KH. A process for the preparation of a compound of formula (I) according to claim 1 wherein Rg is a group of formula (III) wherein R6 is alkyl and R6 is hydrogen and Rg is hydrogen. Thiourea of formula (XVI) wherein R ^ is R ^ and R ^ is the same as R 6, the other symbols are as defined in claim 1, optionally in the presence of a base and lead acetate of the formula R g R g K H with an amine. A process for the preparation of a compound of formula (I) according to claim 1 wherein Rg is a group of formula (III) wherein Rg is alkyl and hydrogen is hydrogen and Rg is hydrogen. The carbodiimide of formula (II) is reacted with an amine of formula Rg-KHg, wherein the symbols are as defined in claim 1. A process for the preparation of a compound of formula I according to claim 1 wherein n is 0 and R 1 R 9 is morpholino, thiomorpholino, 1-pyrrolidinyl or piperidino, characterized in that a compound of formula (XVIII) ), wherein Rg, Rg, Rg and Ry are as defined in claim 1, with a bifunctional compound of formula XIX: wherein: 163 K represents a leaving group and L represents an oxygen or sulfur atom, a chemical bond or a methylene group. 11 · The pharmaceutical compositions containing compounds of the formula A process comprising (I) comprises reacting a compound of formula prepared according to claim 1 (I) wherein η A, B ^, & ₂ ^{»pL 3'R} 5> and represents the The enantiomer or pharmaceutically acceptable salt thereof, as defined in the preamble of claim 1, is admixed with carriers and / or other excipients customary in the pharmaceutical art, and the mixture is then converted into a pharmaceutical composition.