SI8912485A - New hypoglycaemic agents and process for their preparation - Google Patents

Abstract

New hypoglychemical preparations having the formula (I) and a process for their synthesis and the synthesis of their salts are described, where n = 0 or 1; R1 and R2 are aliphatic or cycloalkyl groups or NR1R2 represents, if needed, a substituted heterocyclic ring; R3 is an alkyl, cycloalkyl or, if needed, a substituted amino group; R5 is an alyphatic group; R6 is hydrogen, if needed, a substituted alyphatic group or a cycloalkyl group; or R3 and R5 making, if necessary, a substituted heterocyclic ring together with the carbon or nitrogen atom to which they are bonded; or R5 and R6 making a heterocyclic ring substituted, if needed, with an alkyl group, together with the atom of nitrogen to which they are bonded; and R7 is, if needed, a substituted alkyl, alkoxy, alkylthio, alkylsulfynyl, alkylsulfonyl, alkoxycarbonyl, trifluoromethyl or cyano group.

Description

THE BOOTS COMPANY PLC

Thane Road West

NOTTINGHAM

United Kingdom

NEW HYPOGLYCEMIC AGENTS AND PROCEDURE FOR THEIR PREPARATION

The present invention relates to novel therapeutic agents useful as antidiabetic agents, in particular as hypoglycemic agents, to a process for the preparation of these agents, and to pharmaceutical preparations containing them.

The present invention provides compounds of the formula:

and pharmaceutically acceptable salts thereof, in which n = 0 or 1; and R ₂ , which are the same or different, represent (a) an aliphatic group containing 1-3 carbon atoms which is optionally substituted by methoxy, (b) a cycloalkyl group of 3-7 carbon atoms, or (c) R and R ₂ together with the nitrogen atom to which they are attached form, if necessary, a substituted heterocyclic ring of the formula:

-N B

wherein R represents hydrogen or C ^ -3 alkyl group, B is C ₂ _4 alkylene group which is optionally interrupted by oxygen, sulfur, a sulphinyl group or a nitrogen atom which is

-2 optionally substituted with a C 1-6 alkyl group, said alkylene group being optionally substituted by one or more C 1-8 alkyl groups, or substituents on two adjacent carbon atoms in the alkylene group forming a benzene ring, or B being an alkenylene group with 3 carbon atoms;

Rg is a straight- or branched-chain alkyl group or a Cg_ ^, y cycloalkyl group or a group of the formula:

(III) where and R 4, which are the same or different, represent H or C 1-4 alkyl; Rg is H or a C _1-4 aliphatic straight or branched chain aliphatic group optionally substituted by methoxy; Rg is (a) H, (b) a C 1-8 straight or branched chain aliphatic group optionally substituted by an OH group or its acylated derivative, a C 1-6 alkoxy group, a C 1-6 alkylthio group, an amino group, which is, if necessary, alkylated with Cg_ ₇ carbocyclic group or CN, or (c) Cg_-y cycloalkyl ring; provided that when NR ^ Rg represents dialkylamino and Rg represents a group of formula (III), at least one of R4, R4Rg or Rg must be other than H; or the Rg group and the Rg group together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula;

(IV)

N -

I ^R 6 where Rg, as defined above, Rg and ^R 10 ', which are the same or different, represent hydrogen or a C 1-4 alkyl group, ο

-Jki is if necessary substituted by methoxy and D is the oxyethylene group, in which the oxygen atom is bonded to a carbon atom which bears the substituents R and R ^ O '^ 2-5 ^a lkil ^ens to ^a group, which is optionally substituted by one or more C1-3 alkyl groups; or the groups R3 and Rg together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of the formula:

wherein R is as defined above, R ^ is hydrogen or C ^ _2 alkyl group, E is ^a C2-4 lkil ^ens X is ^a group, which is optionally substituted by one or more C ^ _3 alkyl groups; or Rg and Rg, together with the nitrogen atom to which they are attached, form a heterocyclic ring of the formula:

wherein G represents a C 1-8 alkylene group, optionally terminated by an oxygen, sulfur or nitrogen atom, optionally substituted by a C 1-3 alkyl group, said alkylene group being optionally substituted by one or more C 3-3 alkyl groups. alkyl groups; and R7 represents hydrogen or one or more of the necessary presence of substituents selected from halogen, ^C i-4 alkyl groups which are, where appropriate, be substituted by methylthio, C ^ _3 alkoxy groups, alkylthio groups, C ^ _3 alkylsulfinyl groups, alkylsulfonyl groups, alkoxycarbonyl groups with a total of 2 or 3 carbon atoms, trifluoromethyl or cyano.

-4 In preferred compounds of formula (I) in which n = 0, and R ₂ , which may be the same or different, are selected from (a) alkyl groups optionally substituted by methoxy, (b) allyl groups and (c) cyclohexyl groups. In particularly preferred compounds of formula (I) in which n = 0, R 1 and R ₂ are both alkyl, allyl or 2-methoxyethyl or R ₂ is methyl and R ₂ is 2-methoxyethyl or cyclohexyl. In especially preferred compounds of formula (I) in which n = 0, represents the group NR ₂ R is dimethylamino, diethylamino, dialilamino, (2-methoxyethyl) methylamino, cyclohexylmethylamino or bis (2-methoxyethyl) amino.

In preferred compounds of formula (I) in which n = 0 and the group NR ^ R ₂ represents a heterocyclic ring of formula (II), R 8 is hydrogen or methyl, and B is a group selected from the following: - (CH ₂ ) ₂ ~, -CHMeCH ₂ -, o-phenylene, - (CH ₂ ) ₃ -, -CH ₂ CHMeCH ₂ -, - (CH ₂ ) ₄ -, -CH ₂ OCH ₂ -, -CHMeOCHMe-, -CH ₂ -SCH ₂ -, -CH ₂ S (O) CH ₂ -. -CH ₂ NMeCH ₂ - or -CH = CHCH ₂ -. In particularly preferred compounds of formula (I) in which n = 0 and the group NR ₂ R _{2 has the} formula (II) represents the group NR ₂ R ₂

1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl 1- (1,2,5,6-tetrahydro) pyridyl. In preferred compounds of formula (I) in which n = 1, the group NR 1 R _{2 is} morpholino or thiamorpholino.

In preferred compounds of formula (I) in which R ₃ represents an alkyl group, this group consists of 1 to 5 carbon atoms (for example methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl). In preferred compounds of formula (I) in which the group R _{3 is} cycloalkyl, such group is cyclohexyl.

In preferred compounds of formula (I) in which R ₃ represents a group of formula (III), R ₄ and R _{14 are} hydrogen, methyl or ethyl

-5 (for example Rg is amino, methylamino, dimethylamino or ethylamino).

In preferred compounds of formula (I) in which the Rg group does not form part of a heterocyclic ring, it is H or a C 1-6 alkyl group (for example methyl or ethyl) which is optionally substituted by methoxy (for example Rg is methoxyethyl) or allyl.

In preferred compounds of formula (I), R8 is hydrogen or a straight or branched chain C1-6 alkyl group (for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl) which is optionally substituted by hydroxy (for example, Rg is 2-hydroxyethyl, 3-hydroxypropyl,

2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl or 2,3-dihydroxypropyl), with an acylated derivative of a hydroxyl group, such as acetyloxy or benzoyloxy (for example, Rg is 2-acetyloxyethyl or 2-benzoyloxyethyl), with methoxy (for example, Rg is 2-methoxyethyl), with methylthio (for example, Rg is

2-methylthioethyl), with dimethylamine (for example, Rg is

2-dimethylaminoethyl), with phenyl (for example, Rg is benzyl or

2-phenethyl) or with cyano (for example, Rg is 2-cyanoethyl), or Rg represents a straight or branched chain Cg_g alkenyl group (for example, Rg is allyl or 2-methylallyl).

In preferred compounds of formula (I) in which Rg is a cycloalkyl group, these have 5 or 6 carbon atoms (for example Rg is cyclopentyl or cyclohexyl).

In particularly preferred compounds of formula (I) in which the groups Rg and Rg together with the carbon and nitrogen atoms to which they are attached do not form a heterocyclic ring, the group -N = C (Rg) NRgRg:

acetamidino,

N-methylacetamidino,

N, N-dimethylacetamidino,

-6N, N-diethylacetamidino,

N- (2-acetoxyethyl) acetamidino, N-butylacetamidino, N-pentylacetamidino,

N-methylpropionamidino, N, N-dimethylpropionamidino, N-ethylpropionamidino, butyramidino,

N-methylbutyramidino,

N, N-dimethylbutyramidino, N-ethylbutyramidino, isobutyramidino, N-methylisobutyramidino,

N, N-dimethylisobutyramidine, valeramidine,

N-methylvaleramidino,

N, N-dimethylvaleramidine pivalamidine,

N-methylpivalamidino,

N, N-dimethylpivalamidino, N-methylpropamidino, N-methylcyclohexanecarboxamidino, diaminomethyleneamino,

N-methylguanidino,

N, N'-dimethylguanidino, N-ethylguanidino,

N-butylguanidino, N-ethyl-N-methylguanidino, N, N-diethylguanidino,

N, N'-diethylguanidino,

N, N ', N'-trimethylguanidino,

1,1,3,3-tetramethylguanidino, N-ethyl-N'-methylguanidino,

1-ethyl-1,3,3-trimethylguanidino, 1-butyl-1,3,3-trimethylguanidino,

-7N-methyl-N-propylguanidino,

N-butyl-N-methylguanidino,

N-sec-butyl-N ¹ -methylguanidino,

N-tert-butyl-N'-methylguanidino,

N-isobutyl-N ¹ -methylguanidino,

N-butyl-N'-methylguanidino,

N-butyl-N'-ethylguanidino,

N-methyl-N'-pentylguanidino,

N-cyclopentyl-N'-methylguanidino,

N- (2-methoxyethyl) guanidino,

N- (2-methoxyethyl) -N-methylguanidino,

N- (2-methoxyethyl) -N'-methylguanidino,

N-ethyl-N- (2-methoxyethyl) guanidino,

Ν, Ν-bis (2-methoxyethyl) guanidino,

N-methyl-N- (2-methylthioethyl) guanidino,

N-allyl-N-methylguanidino,

N-allyl-N'-methylguanidino,

1- allyl-1,3,3-trimethylguanidino and

N, N-diallylguanidino.

In one group of preferred compounds of formula (I) in which R ₃ and Rg together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula (IV), Rg and R0O 'may be the same or different represent is hydrogen or C ^ _ ₃ alkyl groups (e.g. methyl, ethyl or isopropyl), which are, where appropriate, be substituted by methoxy (for example R and / or R q are methoxyethyl), D is selected from - (CH ₂₎ -, ~ (CH ₂ ) ₃ -, - (CH ₂ ) ₄ -, - (CH ₂ ) ₅ -, -CH ₂ CMe ₂ - or

-O (CH ₂ ) ₂ -, while the Rg group is preferably hydrogen, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or

2- methoxyethyl. In particularly preferred compounds of formula (I), formula (IV) represents:

2- pyrrolidinylidene, 1-methyl-2-pyrrolidinylidene,

3- methyl-2-pyrrolidinylidene,

-8l-ethyl-2-pyrrolidinylidene,

1-isopropyl 1-2 pyrrolidinylidene,

1-cyclohexyl-2-pyrrolidinylidene,

1- (2-methoxyethyl) -2-pyrrolidinylidene,

1,3- dimethyl-2-pyrrolidinylidene,

5.5- dimethyl-2-pyrrolidinylidene,

1.3.3- trimethyl-2-pyrrolidinylidene,

1.5.5- trimethyl-2-pyrrolidinylidene,

3-isopropyl-1-methyl-2-pyrrolidinylidene,

1- ethyl-3,3-dimethyl-2-pyrrolidinylidene,

3.3-diethyl-1-methyl-2-pyrrolidinylidene,

2- piperidinylidene, 1-methyl-2-piperidinylidene,

1,3-dimethylpiperidinylidene, 1-ethyl-2-piperidinylidene, 1-isopropyl-2-piperidinylidene,

1- (2-cyanoethyl) -2-piperidinylidene,

1- (2-acetoxyethyl) -2-piperidinylidene,

3- (2-methoxyethyl) -1-methyl-2-piperidinylidene,

2- hexahydroazepinylidene,

1- methyl-2-hexahydroazepinylidene,

2- octahydroazocinylidene or

3- morpholinylidene.

In another group of preferred compounds of formula (I), in which the group R ₃ , together with the carbon and nitrogen atoms to which they are attached, form a heterocyclic ring of formula (V), represents E -CH 2 CH 2 -, -CMe 2 CH 2 -, -CHMeCHMe-,

CHMeCH2- or - (01 ^) 4-, R ^ -j. 3 ^s ° dichlorobenzene, methyl or ethyl and R is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoiloksietil, 2-methoxyethyl, cyclohexyl , benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl. In particularly preferred compounds of formula (I)

-9 represents 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,

1- (n-butyl) -2-imidazolidinylidene,

1-Isobutyl-2-imidazolidinylidene, 1-pentyl-2-imidazolidinylidene,

1-allyl-2-imidazolidinylidene,

1- (2-methylallyl) -2-imidazolidinylidene,

1- (2-hydroxyethyl) -2-imidazolidinylidene,

1- (2-hydroxyethyl) -3-methyl-2-imidazolidinylidene,

1- (2-acetoxyethyl) -2-imidazolidinylidene,

1- (2-benzoyloxyethyl) -2-imidazolidinylidene,

1- (2-benzoyloxyethyl) -3-methyl-2-imidazolidinylidene,

4,5-dimethyl-1- (2-hydroxyethyl) -2-imidazolidinylidene, 1- (2-methoxyethyl) -3-methyl-2-imidazolidinylidene,

1- (2-methoxyethyl) -2-imidazolidinylidene,

1-cyclohexyl-2-imidazolidinylidene,

1-benzyl-2-imidazolidinylidene,

1- (2-phenethyl) -2-imidazolidinylidene,

1- (2-dimethylaminoethyl) -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.

- ΙΟΙ-butyl-3-methyl 1-2-imidazolidinylidene, 1-isopropyl-4,4-dimethyl-2-imidazolidinylidene, 1-methyl-2-perhydropyrimidinylidene, or

1,3-diazacycloheptan-2-ylidene,

In preferred compounds of formula (I) in which Rg and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI) represents a G group selected from - (ch ₂ ) ₄ -; - (ch ₂ ) ₅ -, - (ch ₂ ) ₂ o (ch ₂ ) ₂ -, - (ch ₂ ) ₂ s (ch ₂ ) ₂ -, - (CH ₂ ) ₂ NMe (CH ₂ ) ₂ -, - (CH ₂ ) ₂ CHMe (CH ₂ ) ₂ - or -CH ₂ CHMeOCHMeCH ₂ -.

In particularly preferred compounds, the NRgRg group is 1-pyrrolidinyl, piperidino, 4-methylpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholino or 4-methyl-1-piperazinyl. In particularly preferred compounds of formula (I) in which Rg and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI), the group -N = C (Rg) NRgRg:

N, N- (3-oxapentamethylene) guanidino,

1,1-dimethyl-3,3- (3-oxapentamethylene) guanidino,

N, N- (2,4-dimethyl-3-oxapentamethylene) guanidino,

N, N- (3-thiapentamethylene) guanidino,

N, N- (3-methylpentamethylene) guanidino,

N, N- (N-methyl-3-azapentamethylene) guanidino,

N-methyl-N ', N'-tetramethyleneguanidino,

Ν, Ν-pentamethyleneguanidino and

1,1-dimethyl-3,3-pentamethyleneguanidino.

In preferred compounds of formula (I), Ry represents hydrogen or one or more substituents (preferably one or two substituents) selected from the following: fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, methoxycarbonyl, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl or cyano.

The specific compounds of formula (I) are as follows:

-114- [2- (2-Piperidinylideneamino) phenylthorpholine,

4- [2- (1-methyl-2-piperidinylideneamino) phenylnorph oline,

4- [2- (1-ethyl-2-piperidinylideneamino) phenyltorpholine,

4- [2- (1-Isopropyl-2-piperidinylideneamino) phenylthorpholine,

4- [2- (2-Hexahydroazepinylideneamino) phenylthorpholine,

4- [2- (1-methyl-2-hexahydroazepinylideneamino) phenylthorpholine, 4- [2- (2-octahydroazocinylideneamino) phenylthorpholine,

4- [2- (2-Pyrrolidinylideneamino) phenyltorphinoline,

4- [2- (1-methyl-2-pyrrolidinylideneamino) phenyltorpholine,

4- [2- (1,3-dimethyl-2-pyrrolidinylideneamino) phenylthorpholine,

4- [2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) phenyltorpholine, 4- [2- (1-ethyl-2-pyrrolidinylideneamino) phenyltorpholine,

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

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

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

4- [2- (1,3-dimethyl-2-piperidinylideneamino) phenyltorpholine, 4- [3-methyl-2- (2-piperidinylidenamino) phenyltorpholine, 4- [3-methyl-2- (1-methyl-2- Piperidinylideneamino) phenyltorphinoline, 4- [4-methyl-2- (2-piperidinylideneamino) phenyltorpholine, 4- [4-methyl-2- (1-methyl-2-piperidinylideneamino) phenyltorpholine, 4- [5-methyl-2- ( 2-piperidinylideneamino) phenylthorpholine, 4- [6-methyl-2- (2-piperidinylideneamino) phenylthorpholine, 4- [4-ethyl-2- (2-piperidinylidenamino) phenylthorpholine, 4- [3-chloro-2- (2- Piperidinylideneamino) phenyltornorpholine, 4- [4-chloro-2- (2-piperidinylideneamino) phenylthorpholine, 4- [4-chloro-2- (1-methyl-2-piperidinylideneamino) phenylthorpholine, 4- [5-chloro-2- ( 2-piperidinylideneamino) phenylthorpholine, 4- [6-chloro-2- (2-piperidinylideneamino) phenylthorpholine,

4- [4-fluoro-2- (2-piperidinylideneamino) phenylthorpholine,

4- [4-fluoro-2- (1-methyl-2-piperidinylideneamino) phenylthorpholine,

-124- [4-Methoxy-2- (2-piperidinylideneamino) phenylthorpholine, 4- [4-methoxycarbonyl-2- (2-piperidinylideneamino) phenylthorpholine, 4- [4-methylsulfonyl-2- (2-piperidinylideneamino) phenylnorpholine, 4 - {2- [1- (2-Acetoxyethyl) -2-piperidinylideneaminophenylmorpholine, 4- {2- [1-methyl-3- (2-methoxyethyl) -2-piperidinylideneaminophenylmorpholine,

4- [2- (3-methyl-2-pyrrolidinylideneamino) phenyltorpholine, N-methyl-N '- (2-morpholinophenyl) acetamidine,

N- (2-morpholinophenyl) -N'-propylacetamidine,

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) propionamidine,

N-ethyl-N '- (2-morpholinophenyl) propionamidine,

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

N-methyl-N '- (2-morpholinophenyl) butyramidine,

N-ethyl-N '- (2-morpholinophenyl) butyramidine,

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

N-methyl-N '- (2-morpholinophenyl) -2-methylpropionamidine, N, N-dimethyl-N' - (2-morpholinophenyl) -2-methylpropionamidine, N-methyl-N '- (2-morpholinophenyl) valeramidine,

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

N-methyl-N '- (2-morpholinophenyl) pivalamidine,

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

N-methyl-N '- (2-morpholinophenyl) hexanamidine,

N-methyl-N '- [2- (1-pyrrolidinyl) phenylbutyramidine,

N-methyl-n '- [2- (1-pyrrolidinyl) phenylpivalamidine,

N-methyl-N '- (2-morpholinophenyl) cyclohexanecarboxamidine, N-methyl-N' - (2-piperidinophenyl) pivalamidine,

1- [2- (2-piperidinylideneamino) phenylpyrrolidine, 1- [2- (1-methyl-2-piperidinylidenamino) phenylpyrrolidine,

1- [2- (1-ethyl-2-piperidinylideneamino) phenylpyrrolidine, 1- [4-chloro-2- (1-methyl-2-piperidinylideneamino) phenylpyrrolidine,

-13l- [3-methyl-2- (1-methyl-2-piperidinylidenamino) phenylpyrrolidine, 1- [2- (1-methyl-2-pyrrolidinylideneamino) phenylpyrrolidine,

1- [2- (1,3-dimethyl-2-pyrrolidinylideneamino) phenylpyrrolidine,

1- [2- (1-methyl-2-hexahydroazepinylideneamino) phenylpyrrolidine, 1- [4-methyl-2- (2-piperidinylidenamino) phenylpyrrolidine, 1- [4-chloro-2- (2-piperidinylideneamino) phenylpyrrolidine] , 1- [3-methyl-2- (2-piperidinylideneamino) phenylpyrrolidine, 1- [6-methyl-2- (2-piperidinylideneamino) phenylpyrrolidine,

4- [2- (2-piperidinylideneamino) phenylthiamorpholine,

1- [2- (2-piperidinylideneamino) phenylpiperidine,

1- [2- (1-methyl-2-piperidinylideneamino) phenylpiperidine, 1- [2- (2-piperidinylidenamino) phenylhexahydroazepine,

2,6-dimethyl-4- [2- (2-piperidinylideneamino) phenylmorpholine, 4-methyl-1- [2- (2-piperidinylideneamino) phenylpiperidine,

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

2-methyl-1- [2- (2-piperidinylideneamino) phenylpyrrolidine, - [2- (2-piperidinylideneamino) phenylisoindoline,

4- [2- (1-methyl-2-piperidinylideneamino) phenylthiamorpholine, 4- [4-methyl-2- (2-piperidinylideneamino) phenylthiamorpholine,

N- (2-methoxyethyl) -N- [2- (2-piperidinylideneamino) phenylmethylamine,

N- [2- (2-piperidinylideneamino) phenyl dimethyl lamin,

N- [2- (2-piperidinylideneamino) phenylldiamine lamin,

N-cyclohexyl-N- [2- (2-piperidinylideneamino) phenyl lime lamin, N- [2- (2-piperidinylidenamino) phenyl-bis- (2-methoxyethyl) amine, 4- [2 - (1,3,3 -trimethyl-2-pyrrolidinylideneamino) phenylthiamorpholine, 1- [2- (1,3,3-trimethyl-2-pyrrolidinylidenamino) phenylpiperidine, 1- [2- (1,3,3-trimethyl-2-pyrrolidinylidenamino) phenyl] - 4-methylpiperazine, 1- [2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) phenylpyrrolidine, 4- [4-methyl-2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) phenylmorpholine, 1- [2- (1-methyl-2-pyrrolidinylideneamino) phenylpiperidine, 1- [2- (1,3-dimethyl-2-pyrrolidinylideneamino) phenylpiperidine, 4- [2- (5,5-dimethyl-2-pyrrolidinylideneamino) phenylmorpholine,

-144- [1,5,5-Trimethyl-2-pyrrolidinylideneamino) phenylmorpholine, N- [2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) phenyl] -bis- (2methoxyethyl) amine,

N- (2-morpholinophenyl) acetamidine,

N- (5-methyl-2-morpholinophenyl) acetamidine,

N- (2-morpholinophenyl) propionamidine,

N- (2-morpholinophenyl) butyramidine,

N- (2-morpholinophenyl) isobutyramidine,

N- (5-methylthio-2-morpholinophenyl) isobutyramidine,

N- (5-fluoro-2-morpholinophenyl) isobutyramidine,

N- (2-morpholinophenyl) valeramidine,

N- (2-morpholinophenyl) pivalamidine,

4- (2- [1- (cyanoethyl) -2-piperidinylideneamino] phenyl} morpholine, - [2- (3-morpholinylideneamino) phenyl] morpholine,

4- [2- (2-piperidinylideneamino) benzyltorphin oline, - [2- (1-methyl-2-pyrrolidinylideneamino) benzylmorpholine, 4- [4-chloro-2- (2-piperidinylideneamino) benzylmorpholine olin,

4- [2- (1,3, 3-trimethyl-2-pyrrolidinylideneamino) benzyl] morpholine, N-methyl-N '- (2-morpholinomethylphenyl) pivalamidine,

4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenylinorpholine, - [2- (1,3-dimethyl-2-imidazolidinylidenamino) -4-fluorophenyl} morpholine,

4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -3-methylphenylmorpholine,

4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -4-methylphenyl} morpholine,

4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -5-methylphenyl} morpholine,

4- [4-chloro-2- (1,3-dimethyl-2-imidazolidinylidenamino) phenyl] morpholine,

4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -4-methoxyphenyl} morpholine,

4- [4,5-dimethoxy-2- (1,3-dimethyl-2-imidazolidinylideneamino) phenylinorpholine, - [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenylpyrrolidine,

-151 - [2- (1,3-dimethyl-2-imidazolidinylidenamino) -3-methylphenylpyrrolidine,

1- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenylpiperidine, 4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenylthiamorpholine,

2,6-dimethyl-4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenylmorpholine,

N- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyldiethylamine, 1- [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenyl] -2-methylpyrrolidine,

4- [3-chloro-2- (1,3-dimethyl-2-imidazolidinylidenamino) phenylmorpholine,

1- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -4-methylphenylpyrrolidine,

N- [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenyl] -bis- (2methoxyethyl) amine,

4- [2- (1,3-diethyl-2-imidazolidinylidenamino) phenylmorpholine,

4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) -6-methylphenylpyrrolidine,

4- [2- (1-ethyl-3-methyl-2-imidazolidinylideneamino) phenylinorpholine, 4- [2- (1-n-butyl-3-methyl-2-imidazolidinylidenamino) phenylmorpholine, N ,,

4- (2- [1- (2-benzyloxyethyl) -3-methyl-2-imidazolinylideneamino] phenylmorpholine,

2- (2-morpholinophenyl) -1,1,3,3-tetramethylguanidine, 1-ethyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine, 1-allyl-2- (2-morpholinophenyl) - 1,3,3-trimethylguanidine, ln-butyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine, 1-pentyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine, 4- {2- [1-methyl-3- (2-methoxyethyl) -2-imidazolidinylidene aminolfol enylmorpholine,

4- {2- [1-methyl-3- (2-hydroxyethyl) -2-imidazolidinylidene aminophenyl enillmorpholine,

N, N-dimethyl-N '- (2-morpholinophenyl) morpholine-4-carboxamidine, N, N-dimethyl-N' - (2-morpholinophenyl) piperidine-1-carboxamidine, 4- [2- (1,3- dimethyl-2-imidazolidinylidenamino) phenylthiamorpholine-161-oxide,

4- [2- (2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-methyl-2-imidazolidinylideneino) phenylinorpholine,

4- [2- (1-ethyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-n-propyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-isopropyl-2-imidazolidinylideneamino) phenylinorpholine, 4- [2- (1-n-butyl-2-imidazolidinylidenamino) phenylinorpholine],

4- [2- (1-Isobutyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-pentyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-allyl-2-imidazolidinylideneamino) phenylinorpholine,

4- {2- [1- (2-hydroxyethyl) -2-imidazolidinylidenamino] phenyl} morpholine,

4- {2- [1- (2-hydroxyethyl) -2-imidazolidinylidenamino] -3-methylphenylmorpholine,

4- {2- [1- (2-methoxyethyl) -2-imidazolidinylidenamino] phenyl} morpholine,

4- [2- (1-cyclohexyl-2-imidazolidinylideneamino) phenylinorpholine, 4- [2- (1-benzyl-2-imidazolidinylideneamino) phenyltorpholine, 4- {2- [1- (2-phenylethyl) -2-imidazolidinylidenephenylphenolpholine]. 4- {2- [1- (2-dimethylaminoethyl) -2-imidazolidinylidenamino] phenyl} morpholine,

4- {2- [1- (2,3-dihydroxypropyl) -2-imidazolidinylidenamino] phenyl} morpholine,

4- {2- [1- (2-methylallyl) -2-imidazolidinylideneamino] phenyl} morpholine _/ N- [2- (1-methyl-2-imidazolidinylidenamino) phenylbis (2-methoxyethyl) amine,

N- (2- [1- (2-hydroxyethyl) -2-imidazolidinylidenaminolfenylbis (2methoxyethyl) amine,

4- [2- (1-methyl-2-imidazolidinylidenamino) phenylthiamorpholine,

1- [2- (1-methyl-2-imidazolidinylidenamino) phenylpyrrolidine,

4- [2- (1-n-butyl-2-imidazolidinylideneamino) phenylthiamorpholine, 4- [2- (1-methyl-2-imidazolidinylidenamino) -3-methylphenylmorpholine,

4- [2- (1-methyl-2-imidazolidinylideneamino) -4-methylphenylmorpholine,

-171- {2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl} pyrrolidine,

1- {2- [1- (2-hydroxyethyl) -2-imidazolidinylidenamino] phenyl} -2methylpyrrolidine,

4- [4-methyl-2- (1-n-butyl-2-imidazolidinylideneamino) phenyl] morpholine, - [2- (2-imidazolidinylidenamino) phenylpiperidine,

1- [2- (1-methyl-2-imidazolidinylideneamino) phenylpiperidine,

1- [2- (1-methyl-2-imidazolidinylideneamino) -3-methylphenyl] piperidine,

4- {2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenylthiamorpholine,

1- {2- [1- (2-hydroxyethyl) -2-imidazolidinylidenamino] phenyl} piperidine,

4- (2- [1- (3-hydroxypropyl) -2-imidazolidinylideneamino] phenyl} morpholine,

4- {2- [1- (2-hydroxypropyl) -2-imidazolidinylidenamino] phenyl) morpholine,

4- {2- [1- (2-hydroxybutyl) -2-imidazolidinylideneamino] phenylmorpholine,

4- {2- [1- (2-hydroxy-2-methylpropyl) -2-imidazolidinylideneamino] phenyl] morpholine oline,

4- [2- (4-methyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (4,5-dimethyl-2-imidazolidinylideneamino) phenylinorpholine,

4- {2- [4,5-dimethyl 1-1- (2-hydroxyethyl) -2-imidazolidinylideneaminophenyl] morpholine

4- [2- (1-isopropyl-4,4-dimethyl-2-imidazolidinylideneamino) phenylinorpholine,

4- [2- (1-methylperhydropyrimidin-2-ylidenamino) phenylinorpholine

2- (2-morpholinophenylimino) -1,3-diazacycloheptane,

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

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

1.3.3-trimethyl-2- (2-morpholinophenyl) guanidine, 1-ethyl-2- (2-morpholinophenyl) -3-methylguanidine,

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

-184- (2- [1- (2-acetyloxyethyl) -2-imidazolidinylideneamino] phenylnorpholine,

4- (2- [1- (2-benzoyloxyethyl) -2-imidazolidinylidenamino] phenyl] morpholine,

1- (n-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-morpholinophenyl) guanidine,

1- (n-propyl) -2- (2-morpholinophenyl) -3-methylguanidine,

1- (2-methoxyethyl) -3-methyl-2- (2-morpholinophenyl) guanidine, 1-cyclopentyl-2- (2-morpholinophenyl) -3-methylguanidine, N-methyl-N'-2- (2-morpholinophenyl) ) pyrrolidine-1-carboxamidine,

1- (n-butyl) -2- (2-morpholinophenyl) -3-ethylguanidine,

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

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

4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] -4methylphenyl) morpholine, 1-methyl-2- (2-morpholinophenyl) -3- (n-pentyl) guanidine,

1- (n-butyl) -2- (5-methyl-2-morpholinophenyl) -3-methylguanidine,

1- (n-butyl) -2- (6-methyl-2-morpholinophenyl) -3-methylguanidine,

1- (n-butyl) -2- (5-fluoro-2-morpholinophenyl) -3-methylguanidine, 1- (n-butyl) -2- (5-methylthio-2-morpholinophenyl) -3-methylguanidine, 1- isobutyl-2- (2-morpholinophenyl) -3-methylguanidine, 1-sec-butyl-2- (2-morpholinophenyl) -3-methylguanidine, 1-tert-butyl-2- (2-morpholinophenyl) -3-methylguanidine, 1-allyl-2- (2-morpholinophenyl) -3-methylguanidine,

1- (n-butyl) -2- (2-thiamorpholinophenyl) -3-methylguanidine,

1,1-dimethyl-2- (2-morpholino-5-trifluoromethylphenyl) guanidine,

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

1.3- di- (n-propyl) -2- (2-morpholinophenyl) guanidine,

2- (2-morpholinophenyl) guanidine,

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

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

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

-191.1- 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-2-morpholinophenyl) guanidine,

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

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

1- (n-butyl) -1-methyl-2- (2-morpholinophenyl) guanidine,

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

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

N- (2-morpholinophenyl) pyrrolidine-1-carboxamidine,

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

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

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

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

1,1-dimethyl-2- {2-tN- (2-methoxyethyl) -N-methylamino] phenyl} guanidine, 1,1-dimethyl-2- [2- (4-methyl-1-piperazinyl) phenylguanidine,

N- (2-piperidinophenyl) morpholine-4-carboxamidine N- (2-piperidinophenyl) piperidine-1-carboxamidine

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

1-ethyl-2- (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-methoxyethyl) -1-methyl-2- (2-morpholinophenyl) guanidine, 1-allyl-1-methyl-2- (2-morpholinophenyl) guanidine,

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

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

N- (2-morpholinophenyl) -4-methylpiperazine-1-carboxamidine,

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

N- (2-morpholinophenyl) thiamorpholine-4-carboxamidine,

N- (2-morpholinophenyl) -4-methylpiperidine-1-carboxamidine,

N- (2-morpholinophenyl) thiamorpholine-1-carboxamidine,

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

-ΙΟΙ, 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) benzyltorpholine, 4- [4-chloro-2- (1,3-dimethyl) -2-imidazolidinylideneamino) benzylmorpholine,

N, N-dimethyl-N '- (2-morpholinomethylphenyl) guanidine,

N- (2-morpholinomethylphenyl) morpholine-4-carboxamidine, and pharmaceutically acceptable salts thereof.

One of the groups of preferred compounds of formula (I) includes compounds of formula (I) in which n = O, -N, N is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, Rg is -NH2, R5 is an aliphatic group of 1 -4 carbon atoms (for example methyl, ethyl or allyl), Rg is an aliphatic group of 1-4 carbon atoms which is optionally substituted by methoxy or methylthio (for example methyl, ethyl, allyl, methoxyethyl or methylthioethyl) or Rg and R _g together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI) (for example, morpholino or thiamorpholine) and R 4 is hydrogen, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.

Specific compounds belonging to this group of preferred compounds include:

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

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

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

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

1,1-dimethyl-2- (6-methyl-2-morpholinophen, yl) guanidine,

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

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

-211.1-dimethyl-2- (5-methylthio-2-morpholinophenyl) guanidine, 1-ethyl-1-methyl-2- (2-morpholinophenyl) guanidine,

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

1- (2-methoxyethyl) -1-methyl-2- (2-morpholinophenyl) guanidine, 1-methyl-1- (2-methylthioethyl) -2- (2-morpholinophenyl) guanidine,

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

1.1- dimethyl-2- (piperidinophenyl) guanidine,

1,1-dimethyl-2- [2- (1-pyrrolidinyl) phenylguanidine,

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

N- (2-morpholinophenyl) thiamorpholine-4-carboxamidine, and pharmaceutically acceptable salts thereof.

The following group of preferred compounds of formula (I) includes compounds of formula (I) in which n = 0, NR ^ R ₂ 3 ^is morpholino or thiamorpholino, Rg is a group of formula (III) in which R _{4 is a} C 1-4 alkyl group (for example methyl) and R ' ₄ is hydrogen, Rg is hydrogen, Rg is an aliphatic group of 1-4 carbon atoms (for example methyl, butyl or t-butyl) which is optionally substituted by methoxy (e.g. methoxyethyl) and is hydrogen, fluoro, methyl, methylthio or methylthiomethyl.

Specific compounds belonging to this second preferred group include:

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

1-methyl-3-tert-butyl-2- (2-morpholinophenyl) guanidine, 1-methyl-3-tert-butyl-2- (4-fluoro-2-morpholinophenyl) guanidine, 1-methyl-3-tert- butyl-2- (4-methyl-2-morpholinophenyl) guanidine,

1-methyl-3-tert-butyl-2- (4-methylthio-2-morpholinophenyl) guanidine, 1-methyl-3-tert-butyl-2- (4-methylthiomethyl-2-morpholinophenyl) guanidine,

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

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

1-methyl-3-tert-butyl-2- (2-thiamorpholinophenyl) guanidine,

-22and their pharmaceutically acceptable salts.

A further group of preferred compounds of formula (I) includes compounds of formula (I) in which n = O, -NR - ^^ ίθ is morpholino, thiamorpholino, morpholinomethyl or thiamorpholinomethyl, R ₃ is a C 1-4 alkyl group (for example methyl and t -butyl), Rg and Rg are hydrogen and R7 is hydrogen, fluoro, methyl, methylthio or methylthiomethyl.

Specific compounds belonging to this further group of preferred compounds include:

N- (2-morpholinophenyl) acetamidine,

N- (4-fluoro-2-morpholinophenyl) acetamidine,

N- (4-methyl-2-morpholinophenyl) acetamidine,

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

N- (4-methylthiomethyl-2-morpholinophenyl) acetamidine,

N- (2-thiamorpholinophenyl) acetamidine,

N- (2-morpholinomethylphenyl) acetamidine,

N- (2-morpholinophenyl) pivalamidine,

N- (2-morpholinomethylphenyl) pivalamidine, and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may exist as salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, hydrogens (in the Serbian text: chlorhydrates, bromhydrates, iodhydrates; in the text: (hydrochlorides, hydrobromides, hydroiodides), sulfates, nitrates, maleates, acetates, citrates, fumarates, tartrates, succinate, benzoates, pamoates and salts with acidic amino acids such as glutamic acid Compounds of formula (I) and their salts may also exist in the form of solvates (for example hydrates).

-23Certain compounds of formula (I) contain one or more asymmetric carbon atoms and therefore exist in different optically active forms. When the compounds of formula (I) contain one chiral center, there are compounds in two enantiomeric forms and the present invention encompasses both enantiomeric forms and mixtures thereof. When the compounds of formula (I) contain more than one chiral center, they may exist in diastereoisomeric forms. The present invention encompasses each of such diastereoisomeric forms and mixtures thereof.

The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) together with a pharmaceutically acceptable diluent or carrier.

In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. The therapeutic compositions of the present invention may therefore take the form of any known pharmaceutical preparation for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such preparations are well known in the art of pharmacy. The compositions of the invention contain from 0.1 to 90 wt. % of active compound. The compositions of the invention are in principle prepared in unit dosage form.

Oral administration preparations are preferred compositions of the present invention and have pharmaceutical forms which are customary for such administration, such as tablets, capsules, syrups, and aqueous or oily suspensions. The excipients used in the preparation of such preparations are known pharmaceutical excipients. The tablets may be formulated by mixing the active compound with an inert diluent, such as calcium phosphate, in the presence of disintegrating agents, such as maize starch and a lubricant,

-24in the case of magnesium stearate and then tabletting the mixture using known methods. The tablets may be formulated in a manner known per se and may be made in such a way as to ensure a prolonged elimination of the compounds of the present invention. The tablets may, if necessary, be coated with an enterological coating (= gastric juice-resistant) in a conventional manner, for example using cellulose acetate phthalate. Similarly, capsules, for example hard and soft gelatin capsules containing the active compound with or without excipient, may be prepared in known manner. The capsules can also be coated with an enterological coating. Preferably, the tablets and capsules contain 50 to 500 mg of the active compound. Other oral administration preparations include, for example, aqueous solutions with the active compound, aqueous suspensions containing the active compound in aqueous medium in the presence of non-toxic suspending agents, such as sodium carboxymethylcellulose, as well as oily suspensions containing the compound of the present invention in a suitable embodiment. vegetable oil, such as arachis oil.

In some preparations, it may be advantageous to use the compounds of the present invention in the form of very fine particles, such as particles obtained by grinding with the energy of a liquid.

In the compositions of the present invention, the active compound may, if necessary, be combined with other compatible pharmacologically active ingredients.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) may be used to treat hyperglycemia in humans. In such treatment, the daily dose of the compound of formula (I) will be in the range of 50 to 3000 mg. The preferred route of administration is oral administration.

-25 We will now describe methods for the preparation of compounds of formula (I), which are an integral part of the invention.

The compounds of formula (I) can be prepared by reaction of an aminophenyl compound of formula:

with an amide or urea of the formula Rg.CO.NRgRg, in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulfonyl chloride.

Compounds of formula (I) in which the groups Rg and Rg together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula (IV) can be prepared by reacting an aminophenyl compound of formula (VII) with:

a) lactam of formula = C

R (VIII) in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, cyanuric chloride, phosgene, carbon tetrachloride / triphenyl phosphine, phosphorus pentachloride or benzenesulfonyl chloride.

b) with a compound of the formula:

in which R- ^ is chloro, -O-POCl, -O-SOCl or -SC ^ Ph, and Βθ is an anion, such as a halogen (for example Cl ^- ) or POCl ^ ^- ,

c) with a compound of the formula:

in which R 1 is an alkyl group and inθ is an anion, such as fluoroborate or metosulfate.

d) when Rg represents hydrogen, with a ketoxime of the formula:

in the presence of sulfonyl chloride (for example benzenesulfonyl chloride).

Compounds of formula (I) in which the groups Rg and Rg together with the carbon and nitrogen atoms to which they are attached form the ring represented by formula (V) can be prepared by

-27reaction of the aminophenyl compound of formula (VII) with the urea of the formula:

(XII) in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulfonyl chloride.

Compounds of formula (I) in which the group R ₃ and together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula (V) can be prepared by reaction of a compound of formula:

Ί4 (XIII)

T5 is optionally in the form of a salt (for example, a hydroiodide salt) wherein R 4 and R 4 are hydrogen, with a diamine of the formula:

r ₁₁ nhenhr ₆ (XIV)

The compounds of formula (I) in which R is an alkyl group with straight or branched chain alkyl or C ₃ _ ^ cycloalkyl group, a group NRgRg is 1¾, can be prepared by reacting a compound of formula (VII), if appropriate in the form of salts (e.g. hydrochloride salts) with a cyano compound of formula R4 CN, optionally in the presence of aluminum chloride.

Compounds of formula (I) in which the group R ₃ represents NH 2 is

-28 can be prepared by reacting compounds of formula (VII), optionally in the form of a salt (for example, a hydrochloride salt), with a cyanamide compound of formula RgRgNCN. The reaction may be carried out in a liquid reaction medium (for example m-cresol) or by heating the reactants in the absence of a liquid carrier.

Compounds of formula (I) in which Rg represents NH ₂ can be prepared by reaction of compounds of formula:

(CH.) NRR 2. n 12 (XV)

NHCN with amines of the formula NHRgRg, optionally in a liquid reaction medium (for example ethanol).

Compounds of formula (I) in which Rg represents a group of formula (III) wherein R _{4 is} alkyl and R ₁₄ is hydrogen or alkyl can be prepared by reaction of a compound of formula (XIII) in which R ₄₄ represents group R ₄ , R ₄₅ is the group R ₁₄ , with an amine of the formula HNRgRg. The reaction may be carried out in an alcoholic medium (for example ethanol or n-butanol), optionally in the presence of a base such as pyridine or triethylamine or in the presence of potassium hydroxide and lead acetate. When NHRgRg represents ammonia, the ammonia may be dissolved in an alcoholic medium and the reaction may be carried out under elevated pressure in a sealed reaction vessel.

Compounds of formula (I) in which R 8 represents a group of formula (III) wherein R _{4 is} alkyl and R ₁₄ is hydrogen or alkyl may be prepared by the reaction of a thiourea of the formula:

(CH-) NR.R2 n 12

R (xvi)

NH.CS.N

-29 where R4 represents the group R4 and Rgg represents the group R14, with an amine of the formula HNRgRg. The reaction may be carried out in the presence of a base (such as potassium hydroxide or potassium carbonate) and lead acetate. When HNRgRg represents ammonia, the ammonia may be dissolved in an alcoholic medium (such as ethanol) and the reaction may be carried out under elevated pressure in a sealed reaction vessel.

Compounds of formula (I) in which Rg is a group of formula (III) wherein R4 is alkyl and R14 is hydrogen and where Rg is hydrogen may be prepared by the reaction of a carbodiimide of formula:

R

NR.R-, n 1 4 (XVII) with an amine of the formula HgNRg.

Compounds of formula (I) in which n = 0 and NR 4 R 8 represents a morpholino, thiamorpholino, i-pyrrolidinyl or piperidino group can be prepared by reaction of a compound of formula:

(XVIII) with a disubstituted compound of the formula:

K (CH ₂ ) ₂ ^l (CH ₂ ) ₂ ^K (XIX) where K represents a prominent group such as halogen (for example bromo or chloro) or tosyloxy and L is -O-. -S-,

-30a simple bond or -CHg-.

Compounds of formula (I) in which Rg represents a group of formula (III) wherein R4 is propyl and R'4 is hydrogen and in which Rg is hydrogen and Rg is propyl may be prepared by the reaction of an amine of formula HgNRg wherein Rg is propyl , with a thiourea of formula (XVI) in which R1 and R4 represent methyl groups, in the presence of potassium hydroxide and lead acetate. In this reaction, the amino group -NHRg replaces both the thioxo group and the dimethylamino group.

Compounds of formula (I) in which Rg is a group of formula (III) wherein R4 is methyl and R14 is hydrogen, Rg is hydrogen and Rg is methyl can be prepared by the reaction of an amine of formula H ₂ NRg wherein R8 is methyl, with a compound of formula (XIII) in which NR24R2.5 represents butylamino. In this reaction, the amino group -NHRg replaces both the methylthio group and the amino group ^-NR i4 ^R i5 ·

Compounds of formula (I) in which NR ^ Rg represents a thiamorpholino-l-oxide group can be prepared by oxidizing (for example, using sodium metaperiodate) a compound of formula (I) in which -NR- ^ Rg is thiamorpholino.

Compounds of formula (I) in which Rg is substituted with an acyloxy group can be prepared by acylating (for example acetylation or benzoylation) the corresponding compound of formula (I) in which Rg is substituted by hydroxy.

Compounds of formula (I) in which R-y is an alkylsulfinyl group may be prepared by oxidizing (for example, using sodium metaperiodate) compounds of formula (I) in which R7 is an alkylthio group.

The compounds of formula (VII) can be prepared by nitro reduction

(XX) groups in the compound of the formula:

NO for example (a) using hydrogen and a Raney nickel catalyst, (b) hydrogen and a palladium-on-carbon catalyst, (c) sodium sulfide, (d) stannous chloride dihydrate or (e) iron in the presence of acid.

Compounds of formula (IX) in which R4 represents a group of formula OPOCI2, OSOCl, OCOCl and OSO2Ph may be prepared by reaction of compounds of formula (VIII) with phosphorus oxychloride, thionyl chloride, phosgene or benzenesulfonyl chloride.

The compounds of formula (X) may be prepared by reaction of compounds of formula (VIII) with an alkylating agent such as dialkyl sulfate, trialkyloxonium fluoroborate or boron trifluoride ether / diazoalkanes, followed by alkalisation with sodium carbonate or sodium hydroxide solution.

The compounds of formula (XIII) can be prepared by reaction of methyl iodide with thioureas of formula (XVI).

The compounds of formula (XV) may be prepared by reaction of potassium hydroxide with compounds of formula (XIII) wherein R1 and R5 are both hydrogen or R4 is benzoyl and R4 is hydrogen in the presence of lead. acetate.

The compounds of formula (XV) can be prepared by the reaction of a thiourea of formula (XVI) wherein R 3 and R 2 are hydrogen, with sodium chlorite in the presence of a base, such as sodium carbonate and a copper catalyst, such as a mixture of cupro and chlorides of chloride.

-32Tioureas of formula (XVI) in which R1 and g are hydrogen may be prepared by reaction of ammonia with an isothiocyanate of the formula:

(CH) NR.R _n zn Iz

NCS (XXI)

Compounds of formula (XVI), wherein R ^ ₄ alkyl and R g is hydrogen, can be prepared by reacting an aminophenyl of formula (VII) with alkilizotiocianatom formula R NCS.

Carbodiimides of the formula (XVII) may be prepared by the reaction of thioureas of formula (XVI) in which R ₄ represents R ^, R ^ g is hydrogen, with sodium chlorite.

The compounds of formula (XVIII) can be prepared by reduction of, for example, hydrogen and Raney nickel compounds of formula:

(XXII)

Compounds of formula (XX) in which n = 0 and NR- [Rg] represents a morpholino, thiamorpholino, 1-pyrrolidinyl or piperine group can be prepared by reaction of 2-nitroaniline with compounds of formula (XIX). Compounds of formula (XX) in which n = 0 and -NR 1 -R 8 and ^{e is} morpholino, thiamorpholino, 1-pyrrolidinyl, piperidino,

1-Hexahydroazepinyl or 4-methyl-1-piperazinyl may be prepared by reaction of morpholine, thiamorpholine, pyrrolidine, piperidine, 1-hexahydroazepine or 4-methyl-1-piperazine with halonitrobenzene (for example, 2-fluoronitrobenzene or

2- chloronitrobenzene) in the absence or presence of a solvent such as benzene, ethanol or acetonitrile.

-33 Compounds of formula (XXI) can be prepared by reacting a compound of formula (VII) with thiophosgene in a liquid reaction medium, such as in dioxane.

Compounds of formula (XXII) may be prepared by reaction of an amide or urea of formula I, N, CO.NRgRg with 2-nitroaniline in the presence of a condensing agent (such as phosphorus oxychloride or thionyl chloride). The compounds of formula (XXII) can be prepared by reaction of amidine or guanidine of formula R 1 .CNH.NR 4 R 8 with halonitrobenzene (for example 2-fluoronitrobenzene or 2-chloronitrobenzene).

The hypoglycemic effect of the compounds of formula (I) given in the Examples that follow was demonstrated by the following test. Rats weighing between 150 and 200 g fasted for 18 hours and were then subcutaneously injected with glucose (800 mg / 4ml / kg) followed by an oral dose of the test compound (x mg in 4 or 5 ml of 0.2% agar) / kg). After 2 to 4 hours, blood was obtained by orbital hemorrhage and plasma glucose was determined on a Beckman glucose analyzer using a specific glucose oxidase method (Kadish, A H, Little R L and Sternberg J C, Ciin chem 14 116, [1968]). The plasma glucose reduction percentage was then calculated by reference to control animals not given the test compound but 0.2% agar homogenate. The compounds were considered to have a hypoglycaemic effect in this assay, insofar as a decrease in plasma glucose of up to 15% or greater was observed at any x value less than 200, both within 2 hours and over 4 hours.

We then examined the results obtained for each x value in the assays listed and classified the hypoglycemic activity of each compound on the scale that follows. When more than one result group is available for a given x value, the mean% reduction% is used to classify the activity of the compound.

-34A reduction greater than 25% after 2 and 4 hours.

B reduction greater than 25% after 2 hours but less than 25% after hours.

C reduction between 15 and 25% after 2 hours but greater than 25% after 4 hours.

D reduction in the range of 15 to 25% after 2 hours as well as after 4 hours.

E reduction between 15 and 25% after 2 hours but less than 15% after 4 hours.

F reduction less than 15% after 2 hours but greater than 15% after 4 hours.

The activities of the compounds described in the Examples that follow are given in Table A.

TABLE A

Example X Activity Example X Activity 1 25 A 2 25 B 3 25 B 4 25 B 5 25 A 6 25 E 7 25 B 8 36 B 9 200 E 10 25 B 11 25 A 12 25 A 13 50 D 14 200 A 15 100 E 16 25 D 17 50 B 18 25 E

-35TABLE A - continued

X Activity Example X Activity 40 A 20 25 A 25 C 22 25 B . 50 A 24 25 B 25 D 26 25 B 25 A 28 25 A 25 E 30 25 D 50 D · 32 · 25 D 25 B 34 25 B 25 D 36 200 F 200 E 38 200 D 200 A 40 200 A 200 A 42 36 D 25 B 44 200 A 200 D 4 6 36 B 37 B 48 200 A 38 E 50 36 A 200 D 52 36 B 36 B 54 37 B 36 A 56 35 A 25 A 58 25 B 35 A 60 37 E 36 D 62 25 C 100 A 64 25 B 25 A 66 36 D 200 A 68 25 C 43 D 7.0 36 A 36 A 72 25 B 25 A 74 25 A 50 F 76 25 D 25 E 78 25 F 200 A 80 25 D 200 D 82 50 E 25 A 84 25 E 25 D 86 25 F 200 D 88 200 F

-36TABLE A - continued

X Activity Example X Activity e

200 C 90 25 E 200 A 92 25 B 25 C 94 200 Č 25 E 96 25 F 50 D 98 50 A 25 A 100 25 '' - B 25 B 102 200 • A 25 B 104 27 A 37 E 106 37 E 25 B 108 25 B 25 B 110 36 B 25 B 112 36 B 25 D 114 25 E 25 D 116 25 B 25 B 118 25 A 25 D 120 25 B 25 E 1 22 25 A 38 B 124 37 B 36 B 126 200 A 25 E 128 25 ' A 25 B- 130 1 00 B 50 B 132 200 A 25 B 134 25 A 25 A ' 136 25 B 25 B 1 38 25 B 25 B 140 100 A 25 E 142 25 A

-37 ·

TABLE A - continued

X Activity Example Activity X '. 25 B 144 25 B 25 C 146 200 A 36 D 148 25 D ” 36 D 150 68 F 25 C 152 25 D 25 B 154 39 ' 'D 133 B 156 25 D 25 A 158 25 A 50 D 160 26 D 34 A 162 35 B 25 B 164 25 D 200 B 166 25 D 25 B 168 25 B 25 A 170 .25 A 25 D 172 25 D 25 D 1 74 25 B 25 B 176 35 C 25 B 1 78 200 A 25 D 180 25 E 43 D 182 25 D 25 D - 184 34 F 200 D 186 25 A 25 A 188 25 B 25 A 1 90 25 A 36 D 192 25 B 25 A 194 200 C 12.5 A 196 25 A

-38TABLE A - continued

X Activity Example X Activity e 25 D 198 25 A 25 E 200 25 A 25 E 202 25 B 100 A 204 200 A 200 A 206 200 C 50 A 208 30 - 'D 25 B 210 30 • D 36 A 212 25 F 50 D 214 25 E 25 E 216 35 A 30 E 218 200 D 200 D 220 36 A 200 A 222 35 A 35 D 224 35 C 25 B 226 200 A 25 F 228 35 A 35 A 230 35 C 35 F 232 25 B 25 B 234 25 B 34 A 236 38 C 35 A 238 35 A 35 A 240 36 A 34 A 242 200 A 200 B ' 244 200 E 25 B 246 200 D 37 A 248 36 A 36 B 250 25 E 35 E 252 200 A 35 A 254 36 B

-39TABLE A - continued

Example

X

Activity Example

Activity

X

255 36 A 256 34 B 25 7 36 A 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 A 282 200 C 283 200 E 284 200 E 285 200 B 286 35 B 287 36 B 288 38 E 289 200 A 290 25 D 291 25 B 292 85 C 293 35 A 294 25 B 295 25 B 296 25 D 297 35 B · 298 35 E 299 34 e ' 300 200 A 301 25 B 302 38 A 303 39 B 304 40 B 305 28 A 306 29 A 307 30 B 308 NT 309 100 D 310 200 D 311 200 E 312 200 E

NT = not tested

-40The present invention will be illustrated by the following Examples which are given by way of illustration only. The characterization of the final product from each case was performed by elemental analysis.

Example 1

A solution of delta-valerolactam (24 g) in dry benzene (100 ml) was cooled to 10 ° C in an ice / water mixture and treated with freshly distilled phosphorus oxychloride (22.2 ml) under a nitrogen atmosphere for 10-15 minutes. The initially formed white solid was converted to a clear yellow oil over 3 hours. A solution of 4- (2-aminophenyl) morpholine (36 g) in dry benzene (150 ml) was added and the mixture was stirred at 65 ° C for 32 hours with stirring. The benzene layer was decanted, the oil was washed twice with benzene (2 x 40 ml), ether (100 ml) was added and the mixture was cooled in ice and treated with 10% aqueous sodium hydroxide solution to alkaline pH with stirring. The aqueous layer was extracted with ether (2 x 100 mL) and the combined ether extracts were washed with water and brine and dried. The solution was filtered and the solvent removed to produce a thick oil that solidified after trituration with hexane. The crude solid was recrystallized from hot hexane to give 4- [2- (2-piperidinylideneamino) phenylmorpholine (mp 89-90 ° C).

Example 2

A solution of the product of Example 1 (10.2 g) in dry methanol (30 ml) was treated with fumaric acid (4.6 g). The resulting solid was filtered and recrystallized from methanol to give 4- [2- (2-piperidinylideneamino) f enylinorph olin fumarate as a colorless crystalline solid [m.p. 210 ° C (decomposition)].

-41Examples 3 to 37

In a manner similar to that described in Example 1, the compounds listed in Table 1 were prepared by the reaction of an aminophenyl compound of formula (VII) in which NR 16 represents morpholino (A grams in B milliliters of benzene) with a compound of formula (VIII) (C grams in D milliliters of benzene) in the presence of phosphorus oxychloride (E milliliters) for F hours, at a temperature in the range of 60 to 70 ° C.

Notes to Table 1 (1) The product was recrystallized from hexane.

(2) The product was purified by column chromatography on alumina using a 1: 1 mixture of dichloromethane and hexane as eluent.

(3) The product was isolated in the form of a hydroiodide salt which was recrystallized from a 1: 1 mixture of methanol and ether.

(4) The coupling reaction was carried out at room temperature.

(5) The product was recrystallized from ether.

(6) The compound of formula (VIII) was dissolved in a mixture of benzene (60 ml) and acetonitrile (40 ml).

(7) The product was purified by column chromatography on aluminum oxide using the following eluent sequence: hexane, 1: 9 mixture of dichloromethane and hexane, 3: 7 mixture of dichloromethane and hexane, 1: 1 mixture of dichloromethane and hexane and dichloromethane.

-42 (8) The product was isolated as a monofumarate salt which was recrystallized from a 1: 1 mixture of methanol and ether.

(9) The product was isolated as a monohydroiodide salt which was recrystallized from a 2: 3 mixture of methanol and ether.

(10) The coupling reaction was carried out at room temperature for 24 hours and 8 hours at 70 ° C.

(11) The product was isolated as a fumarate salt which was recrystallized from propan-2-ol.

(12) The product was isolated as sesquifumarate salt, which was recrystallized from a 1: 1 mixture of methanol and ether.

(13) The compound of formula (VIII) was dissolved in acetonitrile (120 ml).

(14) The product was purified by column chromatography on alumina using a 99: 1 mixture of dichloromethane and methanol as eluent. The product was recrystallized from a 1: 1 mixture of dichloromethane and hexane.

• 43TABLE 1 χ-χ

CM

0 z * x Z— \ z ~ \ z-v Z- \ z ~ s a I— Γ ~ , - f · 1- CO., LTD and— and— o \ ~ s s-z m ^ z z \ -z s-z s ^ z in lo <M 0 o co '- co 1- 00 o CM o o \ 1 cn 00 1 σ \ • o 1 1 1 γ- CO., LTD 1 i — l m CM Oh \ Ό Cn ΓΟ <r cn (ΰ r— Os r— cn r- CM r— \ 00

U (V) (L) ZOL-ΟΙΟΙ;

KO &

Oh

Φ 4J

S W

P cu • «M <u

EC s

EC EC <u

S

ci EC EC EC EC EC EC EC EC EC cn Φ Oi EC EC EC EC EC EC EC EC S ci EC EC EC Ed EC f-J-4 EC EC EC B cn m cn <r <r m CM CM CM KO <r CM o kO kO Ό OO KO ft | cn Γ ““ , _ co m <r CM <r • ♦ • • • • • w cn <r <r co m σ \ CM r- ~ CM o o o uO o o Oh Oh Oh Q o <r m CM un un CM CM CM 1— 1— <7 r- cn m CM 00 • • • • • • ω KO U0 KO <r r ^. CM CM CM ' and— un Oh m IO o un Oh o Oh ec CM CM CM cn CM r— Ό co CO., LTD mt <r KO r- Ό < Γ · '- > Oh m LO un o cn o CO., LTD and— and— 1—

e-f cn <r io KO r>. oo cn Oh and— r— I—

-44TABLE 1 - continued

Ml

Oh CM CM co t— 0 and— kO and— m MO and— τ- <r r— O \ l ι 1 j 1 1 o o 1 o <r Γ- * Oh rH CM <r and— CM σ> Oh co vD , - (0 O- ΟΊ r— r— , - r- 1— r— 4J

σ \ o

i

CO CTs O r- 00 r— t— Cf \

MO (. O

p—

E σ \ cd

d)

From here

S

d) s

• L)

E

d) r— ( s • H o Λί CM C E 43 Oh Oh CM in rH E Ή U <u d) d) d) υ Mr E 2 2 2 E 2 d) in E E E E E K 2 E L E * d) in 1 d) E K 2 E • r4 s E E

K

E

OJ

2 E E 'E E E E E E

-Et H H H 204-205 (7) (8)

d) Φ d) <y d) d)

S S S S S S S i i i i i i i

E E E E E ►Ύ- » E E E co CO., LTD <r LO MO <r Mr Rücker CM CM CM CM CM CM CM co co CO., LTD co ro CO., LTD CO., LTD co LO oo <r lo LO oo LO CM co LO <r <r <r o o LO r ~ - r— r— r— E <r LO -C * <r <r <r ro CM CO., LTD CM OO • CM co CM LO CM CM CM M CM r- CM UO CM co Oh LO CO., LTD co CO., LTD LO LO o o LO o LO o Oh o Q co CM LO <r co CM MO LO CM oo CM LO CM rO Oh CM lo co <7 00 CO., LTD CO., LTD r- co • • • co • • • • co co <7 co · CO., LTD co r- oo CM 00 CM MO co <7 « co o LO o o o LO Oh o LO o LO Oh o o CM co r “- co ^k CO., LTD ro CM co CM co 1— CM < MO CIO M0 - LO MO <r LO 00 <- co 00 iO CO., LTD cO ro CO., LTD co CM MO CO., LTD MO ro LO CM P Ph CM co <r LO ' MO oo co o CM CO., LTD MT LO MO r— r— H— r— r— r- r— 1— CM CM CM CM CM CM CM

• 45

TABLE 1 - Continued (U <r

Q z ~ s r— g Ό

About z-x

d z ~ \ s ~~ \ ζ “χ Z> / —M. z ~ s z ~ s co z-s o m r— r * ~ 1— J— and— «- , - r— 1— and— S-Z \ ^ z V-Z S-Z \ -z s-z s-z s ^ z f- o CTi VO r— <r <r CM in kO Γ-- Oh <r t— r— o m 0 r— · r * ~ r ~ * «- J— co and— t— «- 1— r- 1 1 I i 1 co 1 I I 1 vO VO cn co o m 1 o co CM r * " 1 • vO o o <r r ~ CM I- o and— m VO r— ( | - r— and— r— r— 00 , - Γ “ r— r— vD fO • U Oh < Oh CM X o CM VO G) d) X era x X 2 X X X s X X X o o r— X X X X X X X: X X X X X σ \ X X X X X X X X X X X X (U ω 2 2 0) Oh CM r— ( r — i • —4 r — 4 r — 1 2 o Oh in o o in in X Pp o in 00 1 1 i I l | 1 1 1 1 X cg <r that vO <· <r *? <r X E co co co eh CO., LTD cO CO., LTD co co co CO., LTD LO m CO., LTD <r <r <r m <r m <r co Pp CM m 00 vo CM vO CM <r w CM CO., LTD CM m that and CM CM CO., LTD CM CO., LTD Oh o m o o o m Oh Oh o o Cl CM CO., LTD CM LQ <r co CM co <r vO <r m CM r- A- 00 υ • • ♦ <o VO CM VO VO VO CM CO., LTD <r 00 vo o Oh tn m Oh o m o Oh M <r CM CM CM LA CM CM CO., LTD CM co CO., LTD »- vO r— CO., LTD < • • • • » • co m <r vO VO m co co <r m vo P 00 O-v O · r ~ CM CO., LTD <r m vO o- CM CM CM co CO., LTD co CO., LTD co CO., LTD CO., LTD CO., LTD

-46Example 38

In a manner similar to that described in Examples 1 and 2, 1-methyl-3- (2-methoxyethyl) -2-piperidone (2.56 g) in benzene (30 ml) was reacted with 4- (2-aminophenyl) of morpholine (2.49 g) in benzene (30 ml) in the presence of phosphorus oxychloride (1.37 ml) for 12 hours at 70 ° C. The product obtained was 4- {2- [1-methyl-3- (2-methoxyethyl) -2-piperidinylidenamino] phenyl) morpholine sesquifumarate (mp 174 ° C), which was recrystallized from a 1: 1 mixture of methanol and ether .

Example 39

In a manner similar to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) was reacted with 4- (2-aminophenyl) morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70 ° C to give 4- [2- (1-benzyl-3-methyl-2-pyrrolidinylideneamino) phenylnorpholine (m.p. 96-97 ° C) which was recrystallized from hexane.

The recrystallized product from the previous paragraph (2 g) was refluxed with cyclohexane (6 ml), 10% Pd / C (1.5 g) and methanol (100 ml) for 4 hours to give 4- [2- (3- methyl-2-pyrrolidinylideneamino) f eniltnorpholine as an oil. This oil (1 g) was dissolved in methanol (20 ml) and a solution of fumaric acid (0.47 g) in methanol was added to give 4- [2- (3-methyl-2-pyrrolidinylideneamino) phenylmorpholine fumarate (m.p. 185 °. C) recrystallized from a 1: 1 mixture of methanol and ether.

Examples 40 - 62

In a manner similar to that described in Example 1, the compounds listed in Table 2 were prepared by reaction of an aminofe-47nyl compound of formula (VII) (A grams in B milliliters of benzene) with an amide of formula R4 .CO.NRgRg ( C grams in D milliliters of benzene) in the presence of phosphorus oxychloride (E milliliters) for F hours at a temperature of 60 to 70 ° C.

Notes to Table 2

Notes (1) and (8) have the same meaning as those given in Table 1.

(15) The product was isolated as a monofumarate salt which was recrystallized from methanol.

(16) The coupling reaction was carried out at 80 ° C.

(17) The coupling reaction was carried out at 75 ° C.

(18) The product was obtained in the form of monohydrate.

(19) The product was recrystallized twice from n-pentane.

(20) The product was obtained as an oil whose boiling point was not determined. The oil was purified by chromatography on an alumina column using the following eluent sequence: hexane, a 1: 1 mixture of dichloromethane and hexane and dichloromethane.

TABLE 2 (P

0 ft o Ul m . — S ul : - '-. f Z-S 00 S-Z zx Z— \ 00 K-z in co cn <r KO αθ co r ~ kO 00 who 0 σ \ , - t— r— o r-— 1 CM Γ- 1 1 00 1 co 1 Ul N 1 1 who r — 1 co 00 N KO 00 CO., LTD KO Oh (ΰ 4J r ~ f- ~ > - f- , - KO · '.R- , r> r ^ · E Cd X E E E Oh E E E r— < and— o E CM 0 Ul z—. CQ o CM who G) U 1 1 E ω 4J OJ 4) E S E C C Oh 2 ω 2 C / ^ z (V m <u 4J E X E E e E 2 ω E

/ o ω G) Φ <D Φ Φ in co s cd 2 2 2 2 2 s ω

cč

0 o Oh O · o 0 0 Oh d c c C c C C C • H • H • rl • rl 'Rl • P • P • P rP t-H P P P T ”1 P P CM Oh 0 Oh Oh Oh Oh o o E P M-l P P p P uu M-t P P P P P P P M E S o Oh Oh o o Oh o 0 e Mr Rücker s s e e s Mr Rücker o CD 00 00 o CM E - <r Γ “ Ul CO., LTD co co cn W CTt co <r <r AO CM CM KO Oh ui m go Oh Oh Oh o a UO CM CM CM GO CM CM

3.7 5 morpholino Et H Et H 105-1 07 (1) (1 6)

CO., LTD m ul CM co U ~ 1 kD υ <r GO o o oo go Ul o Oh o Oh « co co co cO <7 CM CM co r- co CM CM 00 Ul ui CTK C kO r-. o- o Γ-— C0 cO 00 P o _t _ CM co <r GO kO ru <7 <r <r <7 <7 <r <7 <7

<r o

m m

m co

-r

-49TABLE 2 - continued

CO <D

CTK n

ft o s ^ z 00 co Z — K. lO t— 00 Z— \ 00 <-z > - ' CO., LTD V_ ' X “S 1 ^. z-s 00 z ~ \ o. Oh CM Χ-Ζ 00 K ^ z — s oo x— \ 00 z — s M-Z in r ~ - Oh σκ CM σ \ m Α- <r 0 co kO KO CM CM CO., LTD ΓΑ OK a ^ r— I— and— , - , - 1— r— I— <r _φ a » 1 1 1 1 1 1 1 1 ca. rH o o 1 that o kO 00 1— CO., LTD <r LA co 1 <d n 00 LA 00 CM m Ό CM CM co cA Okay CA p - r— * a - CM - " * " - ..ca n & EC EC X EC £ EC a K EC b- < p- < EC K

KO ω Φ P d) d) d) d) d) d) G) d) dl d) GJ ec S S w s S S Σ S S S S Z S S LO d) d) G) G) d) cC S EC EC X EC 2 EC S; EC S EC EC EC EC co oo i — t co 1 P P d) d / • H d) o P P P P EP EP z S P P S r — 1 k> CO., LTD ω EP EP (P 1 1 C d o o C EP Oh f-M • rl ec • P 'Rl CQ EQ 1 1 d) 1 U

CP

o o 0 o Oh o Oh o 0 o Oh 1 1 o c c c c c c C C c c c • r4 • rl c • rl • rl • P • rl • rl • rl • rl • rl Ή • rl • rl r — 1 r-4 • rl r4 rH r ^- 4 and — 1 r4 r — 1 t — 4 t — 4 t-4 rH i — l Oh o rH o o o o o o o o o o o P P P r-4 o fo m 44 44 4-4 > 4-1 4-4 4-4 4-1 4-1 4-1 • rl 'rl • rl * r4 44 r— P P P P P P P P P P P cx c CK C. P fo o o o o o o Oh Oh o Oh o 1 -H 1 p 0 ES S e E e e B E B B B E P Ό pH Ie B CM lO CO., LTD m CM CM Ό CK) 00 <r o 00 00 O \ fo > - <r <r r— r— <- r- Okay Okay n OK OK σκ OK r— σκ <r r- KO ω KO KO co KO KO κΟ kO <r <r κθ KO CA CM Oh LO o m Oh o that Oh o o o o o m Q a- A · » CKI r- r- a- CA co <r CM o co CA CM a ^ \ O kO LO KO KO KO 1— • CKJ lo A- Okay co o • • • • • o a • * T CO., LTD 'a- CO., LTD lO r— LA LO OK A- co <T

Oh Oh o o Oh Oh Oh o o o o o Oh o CQ CO., LTD CA CO., LTD CA CA CA CA CO., LTD co CP u) LA CM CO., LTD

OK σκ CO., LTD σκ σκ σκ CM σκ co er » • η A C OO co UO 00 co 00 A CO., LTD LA m 00 co CA iO

P p, CA o Γ- CM CA - <r IO Oh Α- 00 σκ o f— CKI -a · IO) ΙΑ LA LA LA LO LA ΙΑ UO ιθ KO KO

-50Example 63

A mixture of N-methylpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) was stirred at room temperature for 3 days. A solution of 1- (2-aminophenyl) piperidine (14 g) in benzene (80 ml) was added and the mixture was heated at 65-70 ° C for four days to produce N-methyl-N '- (2-piperidinophenyl) pivalamidine ( mp 78 ° C) which was recrystallized from hexane. The product was obtained as 0.25 hydrate.

Examples 64-75

In a manner similar to that described in Example 1, the compounds listed in Table 3 were prepared by reaction of an aminophenyl compound of formula (VII) in which NR- ^ Rg represents 1-pyrrolidinyl (A grams in B milliliters of benzene). with a compound of formula (VIII) (C grams in D ml of benzene) in the presence of phosphorus oxychloride (E milliliters) for F hours at a temperature in the range of 60 to 70 ° C.

Notes to Table 3

Notes (1), (4) and (8) have the same meaning as in Table 1.

(21) The product was isolated as its monofumarate salt which was recrystallized from a 1: 2 mixture of methanol and ether.

(22) The product was isolated as its monofumarate salt which was recrystallized from a 1: 3 mixture of methanol and ether.

TABLE 3 ft i-f (ΰ

4->

O /

OZ sr cZ 0

Z - <z pi o

Pi

Pi

'—Z' r- '· pi

S

3-1 r03

H

z- * s Z ~ \ CM z-s Z ** \ oo CN CN r " CM <r 03 <r Oh p- <r un un 30 <r o , - 00 cn «- «- co _r _ 1 Γ 03 j 1 t 1 1 03 1 1 c- CM 03 CM 03 < θ ' CM 03 m 1/3 co 03 r " 03 <3 JJ <3 (3 (3 (3 <3 33 S w 2 2 2 2 2_ 33 X 33 33 33 33 33 33 <3 33 33 33 33 33 2 33 i — l (3 o 2 33 33 33 <r cn 33 33 CO., LTD cn cn cn 03 CM CM <r \ D 03 θ ' 30 <r 00 03 CO., LTD « CO., LTD CM r— CM cn c- cn CM CM <r CN cn CM cn <r o U3 o U3 1/3 03 o o CM CM 03 CN CM CM cn cn r \ r ^. 03 'CM 03 CN <r 03 <r U3 Oh 03 Oh 03 03 U3 tn Oh CM CN CN CM CM CM CM CM CM 03 un 03 CO., LTD cn 03 <r cn <r <r <r U3 30 00 03 o 30 30 30 30 30 30 r- r-

, 33

33

X

a) r-l υ

I I <r -o03 03 oo <r cn cn oo i—

O O 30 CN

O r— CN

O O 03 03

CO r—

CN 03 033 33

33

33 φ O

S 2 i i

30

03 and <r

CN CN <r o co

KO 03 o

r- <r o o Ό 03 oo <r co <r 03 Γ θ '

-52Examples 76-91

In a manner similar to that described in Example 1, the compounds listed in Table 4 were prepared by reaction of an aminophenyl compound of formula (VII) (A grams in B milliliters of benzene) with 2-piperidone (C grams in D ml of benzene) in the presence of phosphorus oxychloride (E ml), during F hours, at a temperature in the range of 60 to 70 ° C.

Notes to Table 4

Notes (1), (8), (11) and (21) have the same meanings as those given in Tables 1 and 3.

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

(24) The product was isolated as a monofumarate salt which was recrystallized from methanol.

(25) The product was recrystallized from a 1: 2 mixture of dimethoxyethane and hexane.

(26) The product was recrystallized from hexane and then from a mixture of dimethoxyethane and hexane.

(27) The product was purified by column chromatography on alumina using a 49: 1 mixture of dichloromethane and methanol as eluent. The product was isolated in the form of its dihydroiodide salt, which was recrystallized from a 1: 1 mixture of ethanol and ether.

(28) The coupling reaction was carried out at 90-100 ° C.

-53TABLE 4

l—

<D r— cn CM z z- ^ 1— z — S 00 z — S s-✓ z— \ • <r OJ S - ** Z “\ S-Z 0 ft Oh z — S 00 in 0 ο- CO., LTD m <o π- and co <r οί CM en 1- 1- r— 1 r- ~ co 1 1 1 1—1 m 1 1 CM CM LO (0 1— o m m <r OJ 4J OJ co 1— r- CO., LTD o Pi K ft S ft 1-4 • -ft « K r ^. Pi K ft ft ft ft 1 ed μ 4J CM 1 <y Pi o c o P 1 r — 1 in i r— Pi • H 0 o T3 ♦ rl Oh kO rj c c • rl 4J o c s Oh • H • | “l X! rH Φ c 1 -H LO M-l Ό -o 0 »H 6 • H rJ TJ P 'H • H W C • rl H • rl »rl OJ 0 P K4 -H Ί3 Oh In P Λ 6 Oh Oh 0) IX I M-l <U Φ 1- ^ d X (X Φ \ O μ £ (X s-z • H • H ♦ rl l N * o 1 -rl | U (X (X »—And ed CJ B <r ix rd m OJ co m <r P- ft * " <r Axles OJ o- co m ♦ • • • » • w Axles LO OJ CmJ o- θ ' m r— <r o Oh lo o o o o Q Oh OJ OJ CO., LTD lo vO m ¹ <r • I \ CJ OJ NO • co. that 00 cD r— OJ CQ Oh Oh LO oo LO o m ¹ <r OJ OJ OJ <r CM m <r co in £> < • • ♦ co <T co OJ LO θ ' m n kO r \ co er. o CM Pm o- θ ' o- co 00 00

hydro) pyridyl

54TABLE 4 - continued

CO., LTD

Φ cm

• Mr z-s z-s s »z z-s Z-s o Z “S IT) Z — S MO Z — S ZS and— r— t— CM and— CM CM 00 r— »- CM Oh U Q s ^ z sz s »z sz s »z MZ SZ LO m r— lO LO m o CM CM m m 00 cn r— r— 1— · r— T ~ cn r— r— ί 1 f t r MO 1 J <r <r o m m 1 cn (d 4J 1— CM CM m cn CM 00 CM r- T— r— MO r- and— MO 0) 0) & E E s H-M HM E E E E 2 OJ £ 1 E E E E <r E E E E E '·· r — l • rl Φ « CM s J4 CM E rH o 0 o 0) Z — s r — 1 • rl P c CM z ω & Γ 1 -rl r-l • rl • rl EC o s -H C o r — l r — l CO., LTD Ή o z 1 -H Π3 o o CM CM 04 CM H Ί3 P M-l m-i EC z-s • rl z • H · Η • rl μ μ CJ ι — l U o 4-> rH Oh o Oh z — s, 'Rl z-s CM o o N B · B  1 » CM r-1 Φ z e μ • rl <0 CO., LTD s Φ E CJ 1 -H 1 • rl • rl S_Z E S_Z s_z CM P. CM U 4J Z z z Z z <r <r MO cn r- m <r <· OO E CM CM MO cn m m CM CM « lO CM CM m 1 ^ - r- <r <r CM Oh o LO o o o o Q cn CM CM <r <r <r <r CO., LTD m and CM LO • M0 m r- Oh MO cn CM <r 00 00 • • • <r CM m o and o o o o m m E r— <r CM lO cn cn CM CM CM < cn 00 r- CM CM <r CM r— CM IT) CM m *> T and <r lO <r P dl n <r m MO 00 CT> Oh 00 00 00 CO., LTD 00 00 00 CJL cr>

-55Examples 92-101

In a manner similar to that described in Example 1, the compounds listed in Table 5 were prepared by reacting an aminophenyl compound of formula (VII) (A grams in B milliliters of benzene) with methyl-substituted-2-pyrrolidinone (C grams in D ml of benzene) in the presence of phosphorus oxychloride (E ml) over F hours at a temperature in the range of 60 to 70 ° C.

Notes to Table 5

Notes (1) and (4) have the meaning given in Table 1.

(29) The product was isolated in the form of its dihydroiodide salt, which was recrystallized from a 1: 1 mixture of methanol and ether.

(30) The coupling reaction was carried out at room temperature for F hours.

(31) The product was isolated as its dihydroiodide salt which was recrystallized from a 1: 3 mixture of ethanol and ether.

-56TABLE 5 o o m cn

Φ -

ΓΝ ^, β.

f /

X k <£

V

0 z-s s_z \ wX Z ~ ^ d z * x cn / -. 1— z—. z — s and— o 1- t— CN I— l- 1— r— r— and— cn ^ z • o · \ ~ z ^ z Ν-Χ - ^ z in cN cn and— 0 CN 00 cn and— m NO , - NO kO l— <r 1 kO 00 1 NO r ^ 1 co , Oh 1 o 1 CN 1 1 o 1 co r “l CN CN 03 cn CO., LTD cn m cn cn n- (ΰ 1— kO CN 00 t— NO 1— NO Γ ~ jj <u r- '. 1 X X > - < > —4 X X <r X t-r * X X X NO «U ω cu OJ ω <U 0) (U cu X 2 S S S S 2 S X 2 2 CN CN ' cn CN CN CN. CN CN CN Φ CU CN X K K 32 ' 'K K X 2 2 X o o Oh o Oh U υ Oh o o Oh CN CN CN CN <N G) CN CU Oh (U (U (D CN Σ CN CN <U S Σ S 2 S lr ¹ (- * M S X X 2 < U Oh Oh Oh Oh Oh Oh o in U

r— { o c '—F • ri C CU • H o 1> rl • H Oh o 2 r ~ i c F-i C T Oh c c o 0 Oh o • H 1 -H • ri c • ri • H c C CN Tl H N rH • H Ό TJ • ri • H M M • ri • H o r-i • ri • ri f — 1 rH in CN Oh K W P P Oh i-i P o o H <u 0 Φ • H M-i Oh Φ m CN X 03 p. 6 P < CL a P. P. M (J X i— » • H Ή 1 -H 1 Oh • H • ri o o o X 4J P. <r p. and i B P. CL e B \ _z S 2 <r NO CO., LTD o m co <r o X CN Γ—. CN m <r 00 CN <r <r cn <r <r w - CN m CN cn CN m <r CN o o o co CO., LTD co o o cn Oh Q CN CN cn <r CN CN <T CN CN CN cn NO CN CN 00 00 r- U CN m cn <r ΓΌ <r CN Ό vO m CO., LTD o o o o o Oh CO., LTD Oh o « CN CN CN co f— CN -d · cn r— m CO., LTD r- oo m , _ , _ <T • • « « ♦ • ♦ • < CN cn <r <T 00 Ό cn Γ'- <r o I-i CN- m <r m co h-. 00 cn o o CM Cn cn cn cn cn cn cn cn J— r—

-57Example 102

A mixture of 4- (2-aminophenyl) morpholine (5.34 g), acetonitrile (4.52 ml) and anhydrous aluminum chloride (12 g) was heated at 160-170 ° C for 4 hours to produce N- (2-morpholinophenyl) acetamidine (mp 140-141 ° C) recrystallized from hexane.

Example 103

A mixture of 4- (2-amino-4-methylphenyl) morpholine (5.76 g), acetonitrile (3.5 g) and anhydrous aluminum chloride (12 g) was heated at 160-170 ° C for 5 hours to produce N- (5 -methyl-2-morpholinophenyl) acetamidine (m.p. 121 ° C) recrystallized from hexane.

Example 104

A mixture of 4- (2-aminophenyl) morpholine (5.34 g), propionitrile (4.7 g) and anhydrous aluminum chloride (12 g) was heated at 160-170 ° C for six hours to produce N- (2-morpholinophenyl) propionamidine (mp. 114 ° C) recrystallized from hexane.

Example 105

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) was heated at 170 ° C in a sealed pressure vessel made of stainless steel for 60 hours. The excess n-butyronitrile was removed and the residue dissolved in water, basified with 10% aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and then brine, dried and the solvent removed. The residue was purified by column chromatography on neutral alumina. By eluting with

-581: 1 a mixture of dichloromethane and hexane was removed the unreacted starting material and then eluting with a 1:99 mixture of methanol and dichloromethane produced a solid which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give produced N- (2-morpholinophenyl) butyramidine monofumarate (m.p. 168-170 ° C) which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 106

Powdered anhydrous aluminum chloride (12 g) was added in small portions to a mixed suspension of 4- (2-aminophenyl) morpholine (5.34 g) and n-butyronitrile (6 g) at 40-50 ° C. The mixture was then heated at 160-170 ° C for 6 hours, allowed to cool and then digested with 40% aqueous sodium hydroxide solution. The solution was extracted with water and the extract was washed with water and brine and dried. Removal of the solvent produced a residue which was recrystallized from a 1: 1 mixture of ethyl acetate and hexane to produce N- (2-morpholinophenyl) butyramidine (m.p. 131 ° C) which was converted to its monofumarate salt (m.p. 173 ° C) and this salt was recrystallized from propan-2-ol.

Example 107

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated at 165 ° C for 2 hours in a sealed stainless steel pressure vessel to produce N- (2-morpholinophenyl) isobutyramidine (mp 140-141 ° C) recrystallized from hexane.

Example 108

A mixture of 4- (2-aminophenyl) morpholine (5.34 g), isobutyronitrile (6 g) and anhydrous aluminum chloride (12 g) was heated

-59 at 160-170 ° C for 6 hours to produce N- (2-morpholinophenyl) isobutyramidine (mp 138 ° C) which was recrystallized from a 1: 1 mixture of ethyl acetate and hexane.

Example 109

A mixture of 5-methylthio-2-morpholinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminum chloride (3.2 g) was heated at 140 ° C for 2 hours to produce N- (5-methylthio-2-morpholinophenyl) isobutyramidine (mp 155 ° C) recrystallized from hexane.

Example 110

A mixture of 5-fluoro-2-morpholinoaniline (1.96 g), isobutyronitrile (2 g) and anhydrous aluminum chloride was heated at 150 ° C for 4 hours to produce N- (5-fluoro-2-morpholinophenyl) isobutyramidine (m.p. 142 ° C) which was recrystallized from hexane and converted to its fumarate salt (m.p. 172 ° C), which was recrystallized from a 1: 1 mixture of methanol and ether.

Example 111

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (6.5 g) in valeronitrile (35 ml) was heated at 160-165 ° C under a nitrogen atmosphere for 25 hours and cooled. The mixture was treated with aqueous sodium hydroxide solution and the alkaline mixture extracted with dichloromethane. The solvent was removed by evaporation and the residue was distilled under a pressure of 50 mm Hg to remove half of the unreacted valeronitrile. During cooling, the solid was separated, which was separated by filtration, washed with hexane (50 ml) and recrystallized from hexane to give N- (2-morpholinophenyl) valeramidine (mp 135-136 ° C).

-60Example 112

A mixture of 4- (2-aminophenyl) morpholine (3.56 g), pivalonitrile (5 g) and anhydrous aluminum chloride (8 g) was heated at 160-170 ° C for 6 hours to produce N- (2-morpholinophenyl) pivalamidine (mp. 126 ° C) recrystallized from hexane and converted to its monofumarate salt (mp 211 ° C) recrystallized from methanol.

Examples 113 - 125 In a way similar to the one described in Example 2, we are compound ine. obtained listed below cases translated into nj ihove fumaratne the salts we have recrystallized from the solvents listed: Example Starting Pre-solvent m.p. fumaratne example crystallization salts (° C) 113 20 methanol 212 114 22 methanol 229-230 115 32 methanol 213 116 24 methanol 180 (breakup) 117 64 methanol 197 (breakup) 118 72 methanol 188 119 73 methanol: ether (1: 2) 208-210 120 99 methanol: ether (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

-61Example 126

The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallized from ethyl acetate to give 4- {2- [1- (2-cyanoethyl) -2-piperidinylideneamino] phenylmorpholine (m.p. 148 ° C).

Example 127

A mixture of 3-morpholinone (4 g) in dry acetonitrile (40 ml), 4- (2-aminophenyl) morpholine (3.6 g) in dry acetonitrile (20 ml) and phosphorus oxychloride (3.6 ml) was heated for 40 hours at 65- 70 ° C to produce an oil which was purified by column chromatography on neutral aluminum oxide (72 g) using (a) hexane, (b) dichloromethane: hexanes (1: 1) and (c) dichloromethane as eluent. 'The resulting oil was treated with a saturated solution of hydrogen chloride in methanol (25 ml) to produce a pale yellow solid, which was recrystallized from a 1: 1 mixture of methanol and ether to give 4- [2- (3-morpholinylidene) phenylinorpholine hydrochloride (mp 262-263 ° C).

Example 128

A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4- (2-aminobenzyl) morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70 ° C for 48 hours C to produce 4- [2- (2-piperidinylideneamino) benzyl] morpholine (mp 108-110 ° C) which was recrystallized from hexane.

Example 129

A mixture of 2-piperidone (6 g) in benzene (50 ml), 4- (2-amino-4-chlorobenzyl) morpholine (6.8 g) in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated over 5 hours at 60-65 ° C to produce 4- [4-chloro-2- (2-piperidinylideneamino) benzylnorpholine (m.p. 121-122 ° C) which was recrystallized from hexane.

Example 130

A mixture of 1-methyl-2-pyrrolidone (4.8 g) in benzene (20 ml), 4- (2-aminobenzyl) morpholine (7.6 g) in benzene (50 ml) and phosphorus oxychloride (4.8 ml) was heated for 18 hours at 65-70 ° C to produce an oil which was dissolved in methanol (30 ml). Treatment with 57% hydrochloric acid (10.1 ml) gave 4- [2- (1-methyl-2-pyrrolidinylideneamino) benzylnorpholine dihydroiodide (mp 230-232 ° C) which was recrystallized from ethanol.

Example 131

A mixture of 1,3,3-trimethyl-2-pyrrolidinone (3 g) in benzene (20 ml), 4- (2-aminobenzyl) morpholine (3.8 g) in benzene (10 ml) and phosphorus oxychloride (2.1 ml) was allowed at room temperature for 28 hours and then heated at 60-65 ° C for 14 hours to produce an oil (2.9 g) that was dissolved in methanol (15 ml). Treatment with 57% hydrochloric acid (2.8 ml) gave 4- [2- (1,3,3-trimethyl-2-pyrrolidinylideneamino) benzylnorpholine dihydroiodide (mp 256-258 ° C) recrystallized from 1: 1 mixtures of ethanol and ether.

Example 132

A mixture of N-methylpyrene amide (6.2 g) in benzene (50 ml), 4- (2-aminobenzyl) morpholine (9 g) in benzene (40 ml) and phosphorus oxychloride (5 ml) was heated at 80-85 ° C. over the course of 12 hours to produce the solid that we are

-63 dissolved in methanol (25 ml) and treated with fumaric acid (1.4 g) to produce N-methyl-N '- (2-morpholinomethylphenyl) pivalamidine monofumarate (m.p. 167-168 ° C) recrystallized from propan-2-ol.

Example 133

A mixture of 1,3-dimethyl-2-imidazolidinone (7 g) in benzene (45 ml), phosphorus oxychloride (6 ml) and 4- (2-aminophenyl) morpholine (8.5 g) in benzene (30 ml) was heated for 30 hours at 65-70 ° C. The product was recrystallized from hexane to give 4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl] -morph olin (mp 133-134 ° C).

Examples 134-154

In a manner similar to that described in Example 133, the compounds listed in Table 6 were obtained by reacting an aminophenyl compound of formula (VII) (A grams in B milliliters of benzene) with a compound of formula (VIII) (C grams in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range of 65 to 70 ° C.

Notes to Table 6 (32) The product was recrystallized from hexane.

(33) The coupling reaction was carried out at 90-95 ° C.

(34) The coupling reaction was carried out at 70-75 ° C.

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

(36) The product was isolated as its fumarate salt, which was recrystallized from a 2: 1 mixture

-64isopropanol and ether.

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

(38) The product was isolated as its monofumarate salt which was recrystallized from a 1: 2 mixture of methanol and ether.

(39) The product was isolated as its monofumarate salt, which was recrystallized from a 1: 3 mixture of methanol and ether.

(40) The coupling reaction was carried out at a temperature of 80-85 ° C.

(41) The product was purified by chromatography on an alumina column using dichloromethane as eluent.

(42) The coupling reaction was performed at 80-85 ° C for 48 hours and at 90-95 ° C for 14 hours. The product was purified by column chromatography on alumina using a 99: 1 mixture of dichloromethane and methanol as eluent.

(43) The product was isolated as its sesquifumarate salt, which was recrystallized from a 1: 2 mixture of methanol and ether.

-65 (1)

(d

4J

Ρί <r

CN t, i

W

CN

O o <r

CN-About CN

PQ LO CN

CO., LTD

C co. <r p co fP 1—

TABLE 6 z — N Z * S z-s co <r that CO., LTD CO., LTD co s-z s-z \ -z ZS With “N z—> z ~ \ rs z-s z ~ \ CN CN CN CN CN CN cO CN CN co CO., LTD CO., LTD CO., LTD CO., LTD co CO., LTD CO., LTD CO., LTD s-z \ z sz s ** s — z S — z s-z sz S »Z CO., LTD o <r 00 CO., LTD o Γ “ o 1- cO cO and— »- l— o r— , - CO., LTD CO., LTD 1 1 1 00 1 1 p-- 1 LO σ> CO., LTD 1 CN 1 tO Oh o o Cc r— · co - LO »- 00 r— r— - <- p · - ». . CO., LTD CN ZS Φ s o Φ Φ φ Φ i — f s - 1 Φ S o Oh LO co tO ~ <r < X CO., LTD X Φ D Φ Φ Φ Φ Φ Φ Φ Σ Σ s s s S s Σ Φ Φ Φ Φ 'Φ Φ Φ Φ Φ Σ 2 Ξ s 2 s S r — f • H • rf c c • rf • rf 0 0 0 o o o o T, c c c c c C c • rf • rf • H Ή • H • H • H • rf r — i r-f rH r — 1 Γ — 1 0 0 0 o o o o o P M μ 4 th M-l U4 U- ( <4-1 U-l o P P P P P J-l (X CU cu 0 Oh 0 o o Oh l i • rf e K e e s S 1 — i and —H (X o co tO co co CO., LTD 00 o o CO., LTD CN cO CN CN o- co r- 1 ^ co CN CO., LTD CN r- co CN co CN CN CN <r co o o IO o o Oh Oh o o Η ^- CO., LTD co CO., LTD co C0 CO., LTD CO., LTD that cO • CO., LTD CN r " tO J— that C \ i • CN <r CT \ CN CN CN LO co LO Oh IO o o Oh Oh o o CN CO., LTD CN <r C0 CN co CO., LTD 00 σ \ IO IO CN CN 00 Ct CN LO oo <r CO., LTD CO., LTD that co tO co 00 OC Oh Γ “ CN co CO., LTD CO., LTD CO., LTD CO., LTD C0 <r <r <r r— p— r— Γ “ r " p— Γ ““

66TABLE 6 - continued

z — s z-s z—> Ζ — Χ z — x z ~ x Z-X Z — M Z-X Φ c- o CO., LTD o 00 CM CM Λ he CO., LTD <r CO., LTD <r co co CO., LTD CO., LTD B \ Z s_z v ^ z x ^ Z X-z '—S x — z • Χ-Ζ x — z 0 z — χ z — s z ~ x Ζ-Χ Z-X z ~ x z— \ Z-X Z — s z — X Pl CM CM 00 OV CM 00 00 CM Oh o Oh m n CO., LTD co CO., LTD co co <r <r <r x »-z \ ^ z x-z • χ-ζ s.z x-z x_z K-Z o m > T C- vo m co o o oo VO Oh m o OO Ό r— r— co P— r— r— r— vo cr> 00 1 1 00 1 1 1 1 C- 1 1 <r co 1 m m <r vO 1 o Ό o 00 vO vo o m Oh m (0 σ> 00 l— r— 00 Γ— * Γ— r ~ I— C- P r-l OJ OJ o 2 2 c- 1 l 1 Pi X X X ►t »- · co <r X X VO X _t _ r— 0) OJ OJ OJ OJ ^: : qj OJ P 0) OJ Pi 2 S s S 2 2 2 W 2 2 vo 0) 0J 0) OJ 0) OJ OJ 4J OJ P Pi 2 S s S 2 2 2 ω 2 H rL CM Oh 1 • rl z — x c H l ~ I c Φ CM • rl • rl 1 -rl • rl S and — 1 «O o o Oh 0 Oh o OJ C 1 -rl c • rl CM c c c r ™ Ml r — 1 Ό • rl 1—1 a • rl • L • rl Pi p • rl and — 1 • rl »rl r-1 Oh o and — 1 i— | t — l Z o Ό O • In r-1 o p CM Oh 0 Oh e 1 M-l CM Φ 0 ML • rl cc ML Mp M-4 G3 kC M JJ E u p P. in JL μ p • rl * Oh w 1 -rl o 1 x ^ Z o Oh o 4J CM E a CM CL E rL a E = E vo <r CO., LTD o Oh CM 00 <r o CM r ^- CM en 00 CM r— • * T H <r <r > x <r 00 <r co m vo w <r m m CM CO., LTD <r m <r m m o o o o Oh m o o o o o vo <r <T <r CM <r m co co co r— 00 CO., LTD <r CO., LTD 00 <r co vo o • • • • and VO vo co <r m vo VO VO C- 00 o Oh Oh o m o o Oh o o m CO., LTD CO., LTD VO CM <r UO <r co VO co CM co VO CO., LTD 00 en CM vo • • • m co VO co m <r 00 LD C- C * <r m vO 00 σν o r— CM CO., LTD M <r <r <r <r <r <r m m m m PL • r— and— r— j— »- »- r— and— and— and—

154 4.4 20 5.9 50 4.4 60 morpholino Bu Me> H 135-136 (40) (41) (43)

-67Example 155

A mixture of N- (2-hydroxyethyl) ethylenediamine (31.2 g), urea (23.4 g) and water (3 ml) was heated at 130 ° C for 3 hours and at 210 ° C for 8 hours and then distilled directly from the reaction mixture. to produce 1- (2-hydroxyethyl) -2-imidazolidinone (30 g) as an oil [boiling point 150-160 ° C (0.2 mm)] which solidified to give a solid (m.p. 50-51 ° C).

A mixture of 1- (2-hydroxyethyl) -2-imidazolidinone (2.28 g), benzoic anhydride (4.5 g), triethylamine (2.4 g), 4-dimethylaminopyridine (0.1 g) and 1,2-dimethoxyethane (20 ml) was stirred at room temperature for 8 hours. Saturated aqueous sodium bicarbonate solution (15 ml) was added and the mixture was extracted with dichloromethane (100 ml). The extract was washed with water, brine and then dried and filtered. The solvent was removed to give 1- (2-benzoyloxyethyl) -2-imidazolidinone (mp 130-132 ° C), which was recrystallized from ethyl acetate.

A mixture of 1- (2-benzoyloxyethyl) -2-imidazolidinone (2.3 g) and methyl-4-toluenesulfonate (2 g) was heated at 90-95 ° C for 48 hours. The reaction mixture was then cooled to room temperature, treated with saturated aqueous sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (6 x 20 ml). The extract was washed with water and brine and dried and filtered. The solvent was removed to give an oily residue (2 g), which was purified by silica gel column chromatography (80 g, 100-200 mesh) using a 1: 1 mixture of ethyl acetate and hexane as eluent to give 1 - (2-Benzoyloxyethyl) -3-methyl-2-imidazolidinone as an oil.

In a manner similar to that described in Example 133, 1- (2-benzoyloxyethyl) -3-methyl-2-imidazolidinone (8.8 g) in benzene (30 ml) was reacted with 4- (2-aminophenyl) morpholine ( 5.2 g)

-68 in benzene (20 ml) in the presence of phosphorus oxychloride (3.3 ml) for 35 hours at 80-85 ° C to produce an oil. The oil was dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g). The solvent was removed by evaporation and the residue was washed with ether and then dissolved in water. The aqueous solution was basified to pH 9-10 with an aqueous solution of sodium carbonate and extracted with ether to produce an oil which was introduced onto an alumina column; dichloromethane was used as the eluent. The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4- (2- [1- (2-benzoyloxyethyl) -3-methyl-2-imidazolidinylidenamino] phenyl} morpholine monofumarate (mp 132-133 ° C) recrystallized from a 1: 2 mixture of methanol and ether.

Example 156

Reaction of tetramethylurea (10.4 g, 10.7 ml) in dry benzene (80 ml) with 4- (2-aminophenyl) morpholine (10.2 g) in dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65- 70 ° C gave an oil which was purified by column chromatography on neutral aluminum oxide (100 g) eluting with hexane to give an oil. A solution of this base (2.5 g) in methanol (10 ml) was treated with 57% hydrochloric acid (1.3 ml) to produce 2- (2-morpholinophenyl) -1,1,3,3-tetramethylguanidine hydroiodide as a pale a yellow crystalline solid (mp 215-216 ° C) recrystallized from a 2: 3 mixture of methanol and ether.

Example 157

Reaction of 3-ethyl-1,3,3-trimethylurea (6.57 g) in benzene (70 ml) with 4- (2-aminophenyl) morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) 45 hours at 65-70 ° C gave 1-ethyl-2- (2-morpholinophenyl) -1,3,3-tri-69methylguanidine (boiling point: 140 ° C at 0.2 mm Hg).

Example 158

Reaction of 3-allyl-1,3-trimethylurea (7.17 g) in benzene (50 ml) with 4- (2-aminophenyl) morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) 45 hours at 70 ° C gave 1-allyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine (boiling point: 148-150 ° C at 0.2 mm Hg).

Example 159

Reaction of 3-n-butyl-1,3,3-trimethylurea (7 g) in benzene (60 ml) with 4- (2-aminophenyl) morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml ) for 18 hours at 80-85 ° C gave n-butyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine (boiling point: 162-163 ° C at 0.7 mm Hg).

Example 160

Reaction of 3-pentyl-1,3-trimethylurea (7.5 g) in benzene (80 ml) with 4- (2-aminophenyl) morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) 45 hours at 70 ° C gave 1-pentyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine (boiling point: 98 ° C at 1.5 mm Hg).

Example 161

The reaction of 1- (2-hydroxyethyl) -2-imidazolidinone (13 g) in dry dimethylformamide (125 ml) with sodium hydride (50% suspension in paraffin oil, 12 g) at 10 ° C was continued for 3 hours. by treatment with methyl iodide (35.5 g) over a period of 1 hour. The mixture was stirred at room temperature for 18 hours to produce 1-methyl-3- (2-methoxyethyl) -2-imidazolidinone (boiling point: 110-114 ° C at 0.4 mm).

-70Reaction of 1-methyl-3- (2-methoxyethyl) -2-imidazolidinone (11.4 g) in benzene (60 ml) with 4- (2-aminophenyl) morpholine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 30 hours at 80-85 ° C gave an oil whose portion (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to give 4- {2- [1-Methyl-3- (2-methoxyethyl) -2-imidazolidinylidenamino] phenyl} -morpholine monofumarate (mp 127-129 ° C) recrystallized from propan-2-ol.

Example 162

Reaction of 1-methyl-3- (2-hydroxyethyl) -2-imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) 1-methyl-3- (2-acetoxyethyl) -2-imidazolidinone was obtained in the form of an oil for 18 hours at room temperature.

Reaction of 1-methyl-3- (2-acetoxyethyl) -2-imidazolidinone (13.4 g) in benzene (80 ml) with 4- (2-aminophenyl) morpholine (10.6 g) in benzene (80 ml), in the presence of phosphorus oxychloride (7 ml) gave 4- {2- [1-methyl-3- (2-acetoxyethyl) -2-imidazolidinylidenamino] phenyl} morpholine for 30 hours at 80-85 ° C.

Reaction of 4- (2- [1-methyl-3- (2-acetoxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (2.7 g) in dimethylformamide (10 ml) with sodium hydroxide (0.4 g) in water (10 ml) under reduced pressure 1 hour at 10 ° C gave an oil which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give 4- {2- [1-methyl-3- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl} morpholine (mp 129-131 ° C) recrystallized from a 1: 2 mixture of methanol and ether.

-71Example 163

Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzene (25 ml) with 4- (2-aminophenyl) morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80-85 ° C gave N, N- dimethyl-N '- (2-morpholinophenyl) morpholine-4-carboxamidine (mp 126-128 ° C) recrystallized from hexane.

Example 164

Reaction of 1-dimethylcarbamoylpiperidine (3.7 g) in benzene (25 ml) with 4- (2-morpholinophenyl) morpholine (3.5 g) in the presence of phosphorus oxychloride for 35 hours at 80-85 ° C gave N, N-dimethyl-N '- (2-morpholinophenyl) piperidine-1-carboxamidine (mp 88-90 ° C) recrystallized from petroleum ether (boiling point: 40-60 ° C).

Example 165

Reaction of 4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenyl] thiamorpholine (1.5 g, prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10 ° C gave 4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) phenyl] thiamorpholine-1-oxide monohydrate (mp 103-105 ° C), which was recrystallized from 1: 1 mixtures of 1,2-dimethoxyethane and hexane.

Example 166

A solution of 2-morpholinophenyl isothiocyanate (2.3 g) was treated with a saturated solution of ammonia in ethanol (20 ml) and the reaction mixture was stirred at room temperature for 3 hours. The resulting solid was filtered, washed with ethanol and dried to produce 1- [2- (4-morpholino) phenyl] thiourea.

-72 (mp: 194-195 ° C).

A solution of 1- (2-morpholinophenyl) thiourea (7.2 g) in dry methanol (30 ml) was refluxed with methyliodide (4.2 g) for 2 hours. The solvent was removed under reduced pressure and dry ether (15 ml) was added. When rubbed with a glass rod, 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide precipitated (mp 151-152 ° C).

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (5 g) and ethylenediamine (2.4 g) in dry ethanol (50 ml) was heated under reflux for 6 hours, the solvent was removed under reduced pressure and the oil was dissolved in dichloromethane (50 ml), cooled, basified with 20% sodium hydroxide and the organic layer was washed first with water and then with brine and dried (Na ₂ SO ₄ ) and filtered. Filtration and removal of the solvent gave a solid which, after recrystallization from ethyl acetate, gave 4- [2- (2-imidazolidinylidenamino) phenylinorpholine (mp 185-186 ° C).

Example 167

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (3 g, prepared as described in Example 166), N-methylethylenediamine (2 ml) and absolute ethanol (35 ml) was heated under reflux under reflux. 8 hours to produce a solid which was recrystallized from ethyl acetate to produce 4- [2- (1-methyl-2-imidazolidinylidenamino) phenyl] morpholine (m.p. 156 ° C).

Examples 168 to 202

In a manner similar to that described in Example 167, the compounds listed in Table 7 were prepared by heating a mixture of a compound of formula (XIII) in which R ₄ and R _{4 are} hydrogen (G

-73 grams) and N-substituted ethylenediamine of formula H2N (CH2) 2 ⁿ H ^r 6 (H grams) in dry ethanol (I milliliters) under reflux for J hours.

Notes to Table 7

Notes (32), (38), (39) and (41) have the meaning given in the preceding tables.

(44) The product was recrystallized from ethyl acetate.

(45) The product was isolated in the form of its monofumarate salt, which was recrystallized from methanol.

(46) The preparation of the compound of formula (XIV) is given as Preparation Procedure A.

(47) The product was isolated as its fumarate salt, which was recrystallized from a 1: 2 mixture of methanol and propan-2-ol.

(48)

The product was recrystallized from a 1: 4 mixture of 1,2-dimethoxyethane and petroleum ether (boiling point 40-60 ° C).

(49) Preparation of Compound of Formula (XIV) Preparation Procedure B.

(50) Preparation of Compound of Formula (XIV) Preparation Procedure C.

(51)

Preparation of Compound of Formula (XIV) Preparation Procedure D.

is given as given as given as (52) The product was recrystallized from a 1: 2 mixture of ethyl acetate and hexane.

-74 (53) Preparation of Compound of Formula (XIV) Preparation Procedure E.

(54) Preparation of Compound of Formula (XIV) Preparation Procedure F.

(55) Preparation of Compound of Formula (XIV) Preparation Procedure G.

is given as given as is given as (56) The product was purified by chromatography on an alumina column using the following batch of eluents: hexane, a 1: 1 mixture of dichloromethane and hexane and then dichloromethane.

(57) The preparation of the compound of formula (XIV) is given as Preparation Procedure H.

(58) The product was recrystallized from a 1: 1 mixture of ethyl acetate and hexane.

CM

CO., LTD

-75TABLE 7

CM

CO., LTD

CM

CO., LTD

CM cO

CM

CO., LTD

CM

CO., LTD

CM

CO., LTD

0 σ \ CM CM 00 00 o rO CM cO CM 1— r— r— ' CZ. r—- <r r— • 1 ί f 00 1 r ^ - 1 rd Γ · Γ- Γ- 1 1 vO ίΰ o η η co CO., LTD CM CM 4J r— τ— t— c0 r— IM- Γ—

M P • ri U X X VO o) 1 b i 0) rp X W X • ri X • ri X OJ 0 0 0 0 o o o h c c c c c c CM 'Rl • H Ή * H Ή X rP t — 4 rP · —4 rp rp 1— 0 o 0 0 0 Oh Oh P4 P M-i m M-4 P P P P P P ' P o 0 0 Oh Oh o Oh e ^Mr e e £ s oo o <J · CM <r X X r— I— r ~ tn tn LO A m o o H <r CO., LTD vO <r OV LA Ό CM tn X X CM CM co A CO., LTD Γ- X 00 co 00 X X co in co CM co LA co Γ- » co 00 OV o CM X <r P VO VO f ^ · r ^. r— 1— and— and— r— t— r ~

75 3.8 3.1 45 25 morpholino CH _q CH _o 0H H 131 -1 32 (44)

76TABLE 7 - continued

MO x Cb o J— o \ O CO., LTD <7 <7 <r vo V0 VO <r U0 s ^ z s-z sz MmZ SwZ sz S-Z Z — S z— \ z * \ z— \ Z-M Z-M Z — ν Z * - \ Z — M Z ~ S Z ~ S with "" M Z— * M z — M vo CM CM CM <r CO., LTD σ \ 00 CM CM CM CM CM <r co <r co co <r <r <r co co c0 CO., LTD C0 VO CO., LTD Χ-Ζ s-z • ^ Z -Z MZ -Z s_z s_z S— ' s-z '-z Χ-Ζ '-Z

7 X x V0 x co r- co o r— V0 <r J ” CO., LTD <r <r r— r— r ~ - ra r— 00 Oh CM and — 1 1 r *. 1 x 1 1 1 1 l 1 1 1 1 rO co I x 1 \ O «- <r and— o Oh V0 ra Oh 4J σ> <7 00 CO., LTD o VO <r <T <r r- J— and— o CM r— r- r— X r— t— r— r— r— ' t—- r— 1— 'Ϊ—

ra

CM

I

CM

CM

d) OJ GJ

S 2 s i i i

CO., LTD 33 X 'X X X X X X r - i X X X co < X CM o X and — 1 CM CM in OJ >, d) X II X 1 £ -i N X s υ X Oh o d) X 2 X d) o CM CM X CM CM o s CM X X Oh X X X X s_z X o in r — 1 X Oh U o o Oh CM CM o CM CM CM CM CM CM X X > -> X X X X d) X d) d) 3 d) d) Oh in o Oh o Oh o Oh s o s s X Σ S

CM

Csi

Cd

CM <M Ή

o c • H o c • H 0 C • H o c • rl 0 c • rl o c 'Rl o Mr • rl 0 c • H ω S o CM Z — M Oh Oh CM o G • rl »—1 0 UH • rl Mr • rl • rl rM o Mr • rl r-l 0 <4-1 Oh Mr • H o c 'Rl r — 1 t — 1 i — l and — 1 r — l r — t 1-1 r — l Oh o μ 0 μ r — l r — l 0 0 0 o Oh Oh o 0 CM CM o μ 0 Oh 0 «AJ U-l M-l U-l V — 1 cui U-l X ZG e • μ e H-i <AJ P μ μι μι μ Lj μ CJ Oh Mr Cu Mr μ μ 0 0 Oh Oh Oh o Oh o S_z • rl 1 • rl 0 0 ε 6 e e e e e £ X ! Z U I ^- t AJ £ £

• O

Oh

m X <r CM CM ra <r CM * c * CM ra ra Oh <r ra o ra V0 r- CM r—- o m o o o o ra o LO ra o o o ra o ra X <r <r X Γ— <7 <r co X r- <r X r— CM ra CM vo ra co <7 <7 CM <r co ra <7 X CO., LTD CO., LTD <7 ra X ra ra c0 CM CM <r ra CO., LTD <7 ra

<r

X ra ra ra • c- ra CM o X <7 cn ra ra • • • • • and— ra ra ra r ^ - ^r ” ra ra <r ra VO ra cn ra Γ-- ra X o r— CM co <7 ra ra ra X o

r ^ · r · '- r <' oo oo oo co ra oo oo co co co x

-ΊΊTABELA 7 - continued e

r— Z — N <T Z ~ N m m un Z * N CM d- un s-z Z \ CM Z— \ o Z — s m (U 03 m 03 03 03 03 03 * ^ _ z S-Z N — Z N_Z x »z N_Z E Z ~ S S— \ z ~ x. Z ~ X z * ^ Z ^ \ By “* s Z ~ X z “\ z ~ x 0 co CN CN 00 r— 30 CO., LTD CM <r <r KO <r a o m cn 03 cn <r tn 03 03 <r <r 03 <r S »Z X-z N_Z S- / N_Z N — Z '-S NZ n-z N_Z υ 0 d- 30 Oh 00 03 03 30 1— and— o <r <r l— cn J— 1- 30 Oh and— 1— , - 1— 1— 1 i r- 00 r— 1 1 1 1 1 flj Jj 30 <r cn I 1 1 03 03 CN CM 30 t— 1- 30 LTi 30 cn Oh 03 <r r— cn r— CO., LTD - Γ— " d » co cn r— n · r " r— <- Φ d) 2 2 Γ-χ 1 1 03 33 33 <r »-K • -M id 03 K 33 dd 33 I-K 33 OJ -U d • 2 w d) 33 33 33 33 33 With “X 2 Oh Oh Oh Oh Oh 33 33 Zx CN CM CN CN 03 Oh Oh 33 id 33 33 »-1 * 4 Z ~ N V — z Oh υ Oh Oh Q CN id 33 • x_Z CM CM CN CM 33 in Oh o 30 33 33 3 Φ d) 33 33 Oh CM CN d P3 Oh Oh CQ 33 2 2 Oh U X> -Z 33 33 3C Oh U U and — 1 Ή Oh c r — l c • H 1 -H Oh 0 0 • H o TJ · - “· c Oh c C d r — i d Oh Oh Oh Oh CN • H 1 -H d • r-i • H • H o • H d c £ d 03 r — i J-i TJ • H Oh TJ TJ TJ Ή • H • H • H Oh • i-J · Η t-i • H • H • H P 'H r — i r-i f ^- i r-i 03 o AJ rH Oh M μ μ o μ Oh 0 Oh Oh Ή ω o 4- < GJ Oh φ e <u M-i 4-4 4-1 mh S d e o μ d d d d cx P (-1 μ M 1 1 -H Oh • H • H 'H • H • H o o o Oh I— ( CM d e d cx (X 4J co fš e Mr Rücker H <r CM CM <r <r o <r co 03 o 03 <r * ") CM cn t— CM CM Γ— 03 r- CM l ~ o o 03 03 03 o o o m 03 o o 03 1—1 cn <T Γ ““ cn r- <r <r KO r- 03 <r and— CM 30 03 <r Axles r— 03 cn 33 30 m UT) cn 03 03 CM cn 03 cn CO., LTD 03 CN 03 03 03 03 00 30 03 KO co U 1 ^. 03 03 r ^ · 03 CM cn 03 03 03 CN m <r 03 30 00 03 Oh r · - CN μ σ \ 03 cn 03 03 σ> 03 cn 03 Oh o Oh Pu, r— r— T— 1— r— and— 1 ” Γ “ r— CM CN CN

-78Preparation Procedure A

Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxane (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0 ° C for 30 minutes and at room temperature for 3 hours gave 6-methyl- 2-morpholinophenyl isothiocyanate as an oil.

Reaction of 6-methyl-2-morpholinophenyl isothiocyanate (8.8 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 1- (6-methyl-2-morpholinophenyl) thiourea (9 g) as pale yellow solid, m.p. 199 ° C, which was recrystallized from a 1: 1 mixture of ethyl acetate and hexane.

A mixture of 1- (6-methyl-2-morpholinophenyl) thiourea (9 g) and methyl iodide (2.5 ml) in dry acetone (100 ml) was heated at reflux at 90-95 ° C for 2.5 hours to produce 2 -methyl-1- (6-methyl-2-morpholinophenyl) -2-thiopseudine hydroiodide.

Preparatory procedure B

A solution of Ν, Ν-bis (2-methoxyethyl) benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) cooled to 0 ° C. The temperature of the mixture was allowed to rise to room temperature and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture was extracted with ether (3 x 20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to produce a residue which was heated at 45 ° C under vacuum (100 mm Hg) to give 2- [bis (2 -methoxyethyl) amino] phenyl isothiocyanate in the form of an oil.

A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2- [bis (2-methoxyethyl) amino] phenyl isothiocyanate (7.5 g) and ethanol (10 ml) cooled to 10 ° C. Mixture

-79 was stirred at 0 ° C for 8 hours and then stirred without cooling for another 16 hours. The solvent was then removed by evaporation and the residue was purified by chromatography on a silica gel column eluted with a 1: 4 mixture of ethyl acetate and hexane and then with a 1: 1 mixture of ethyl acetate and hexane to produce

1- {2- [bis (2-methoxyethyl) aminolfenylthiourea (mp 118-119 ° C).

A mixture of 1- {2- [bis (2-methoxyethyl) aminolfenylthiourea (5 g), methyl iodide (1.4 ml) and acetone (25 ml) was heated at 40 ° C for 2 hours. Removal of the solvent gave a residue triturated with ether to produce 2-methyl-1- [2- [bis (2-methoxyethyl) amino] phenyl) -2-thiopseudine hydroiodide (mp 111-112 ° C) .

Preparatory procedure

A solution of 2-thiamorpholinoaniline (14.6 g) in dioxane (10 ml) was added over a 15 minute period to a mixture of thiophosgene (8.77 ml) and water (120 ml) cooled to 0 ° C. The mixture was stirred and allowed to rise to room temperature. The mixture was then stirred for 4 hours and the ice / water mixture (200 ml) was added. The mixture was extracted with ether (2 x 100 ml) and the extracts washed with water (50 ml) and brine (50 ml) and the solvent removed by evaporation to give a residue which was heated at 40-45 ° C under vacuum ( 100 mm Hg) over 2 hours to produce

2- Thiamorpholinophenyl isothiocyanate (mp 55-56 ° C).

A mixture of aqueous ammonia (100 ml) was added to a mixture of 2-thiamorpholinophenyl isothiocyanate (14 g) and ethanol (40 ml) at 10 ° C. This mixture was stirred at 30 ° C for 24 hours and then cooled to 10 ° C. The 1- (2-thiamorpholinophenyl) thiourea was collected by filtration, washed with water (100 ml) and dried (mp 170-171 ° C).

-80A mixture of 1- (2-thiamorpholinophenyl) thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90-95 ° C for 2.5 hours. The solvent was removed by evaporation and the residue was dried in vacuo (5 mm Hg) to produce 2-methyl-1- (2-thiamorpholinophenyl) -2-thiopseudine hydroiodide (mp 176-177 ° C).

Preparation procedure

Benzoylisothiocyanate (10 ml) was added over 30 minutes to a mixture of 2- (1-pyrrolidinyl) aniline (10.6 g) and dichloromethane (30 ml). The mixture was then stirred for 4 hours at 30 ° C. The solvent was removed by evaporation and the residue was dried under vacuum (5 mm Hg) for 30 minutes and triturated with ether. 3-Benzoyl-1- [2- (1-pyrrolidinyl) phenylthiourea was collected by filtration, washed with ether and dried (mp 172-173 ° C).

A mixture of 3-benzoyl-1- [2- (1-pyrrolidinyl) phenyllithiourea (18.1 g), sodium hydroxide (5 g) and water (50 ml) was heated at 90-95 ° C for 4 hours. Ice was added followed by 50% aqueous hydrochloric acid. The mixture was filtered and the filtrate treated with saturated aqueous sodium bicarbonate solution to pH 8. 1- [2- (1-Pyrrolidinyl) phenyl] thiourea was collected by filtration, washed with water and dried (mp 185-186 ° C).

A mixture of 1- [2- (1-pyrrolidinyl) phenyl-urea (12.2 g), acetone (100 ml) and methanol (20 ml) was heated to 90-95 ° C. Methyl iodide (8.36 g) was added and the mixture was refluxed for 3 hours. The solvent was removed by evaporation to produce a residue, which was dried under vacuum (5 mm Hg) to give 2-methyl-1- [2- (1-pyrrolidinyl) phenyl] -2-thiopseudine hydroiodide (m.p. 139-141 ° C).

-81Preparation procedure E

The reaction of 5 ~ methyl-2-morpholinoaniline (20 g) in dioxane (80 ml) and water (200 ml) at 0 ° C for 30 minutes and for another 2 hours at room temperature gave 5-methyl-2-morpholinophenyl isothiocyanate (m.p. 91-92 ° C).

Reaction of 5-methyl-2-morpholinophenyl isothiocyanate (15 g) with 33% ethanol ammonia at room temperature for 48 hours gave 1- (5-methyl-2-morpholinophenyl) thiourea as a pale yellow solid (m.p. 181-182 ° C).

A mixture of 1- (5-methyl-2-morpholinophenyl) thiourea (14 g) and methyl iodide (7.9 g) in methanol (50 ml) was refluxed for 2 hours to produce 2-methyl-1- (5- methyl-2-morpholinophenyl) -2-thiopseudine hydroiodide as a pale yellow solid (mp 157-159 ° C).

Preparation procedure

A mixture of 2-methyl-1- (2-aminophenyl) pyrrolidine (9.1 g) and benzoyl isothiocyanate (9.2 g, 7.7 ml) in dichloromethane (100 ml) was stirred at room temperature for 8 hours and allowed to stand overnight. Removal of the solvent and trituration with ether gave 1-benzoyl-3- [2- (2-methyl-1-pyrrolidinyl) phenyl] thiourea (mp 105-106 ° C).

A mixture of 1-benzoyl-3- [2- (2-methyl-1-pyrrolidinyl) phenylthiourea (9 g), sodium hydroxide (1 g, as beads) and water (10 ml) was heated at 90-95 ° C during 48 hours to give 1- [2- (2-methyl-1-pyrrolidinyl) phenyl] thiourea (mp 145-148 ° C), which was purified by chromatography on a silica gel column using a 1: 1 mixture of ethyl acetate and hexane as eluent.

A mixture of 1- [2- (2-methyl-1-pyrrolidinyl) phenylthiourea (3.4 g) and

-82methyl iodide (2.1 g) in acetone (60 ml) was heated at 90-95 ° C for 3 hours and the solvent removed to give 2-methyl-1- [2- (2-methyl-1-pyrrolidinyl) phenyl] thiourea hydroiodide (3.7 g) as a thick oil.

Preparatory procedure

A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over a 25 minute period to a mixture of thiophosgene (10.2 ml) and water (200 ml), which was previously cooled to 0 ° C. The temperature of the mixture was allowed to rise to room temperature and the mixture was stirred for 4 hours. Ice (200 g) and water (200 ml) were added and the mixture was extracted with ether (6 x 50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to produce a residue which was purified by silica gel column chromatography eluting with hexane to give 2-piperidinophenyl isothiocyanate as an oil .

Aqueous ammonia solution (60 ml) was added to the mixture

2-piperidinophenyl isothiocyanate (12 g) and ethanol (25 ml), previously cooled to 10 ° C. The mixture was stirred 24 hours at 30 ° C and then cooled to 10 ° C. 1- (2-piperidinophenyl) thiourea was collected by filtration, washed with water and dried (mp 143-145 ° C).

A mixture of 1- (2-piperidinophenyl) thiourea (10.1 g), methyl iodide (5.35 g) and methanol (50 ml) was heated at 50-55 ° C for 2 hours. The solvent was removed by evaporation and the residue was dried in vacuo (5 mm Hg) to give 2-methyl-1- (2-piperidinophenyl) -2-thiopseudine hydroiodide (mp 160-162 ° C).

Preparation procedure H

Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxania (20

-83ml) and water (65 ml) with thiophosgene (5.7 g) at 0 ° C for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil.

Reaction of 6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) with a 25% aqueous solution of ammonia (65 ml) in ethanol (20 ml) gave 1- {6-methyl-2-piperidinophenyl) for 8 hours at room temperature. thiourea as a pale yellow solid (mp 197-198 ° C).

A mixture of 1- (6-methyl-2-piperidinophenyl) thiourea (7 g) and methyl iodide (4.38 g) in dry methanol (100 ml) was refluxed for 3 hours to produce 2-methyl-1- (6 -methyl-2-piperidinophenyl) -2-thiopseudine hydroiodide as a pale yellow solid (mp 204-205 ° C).

Example 203

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (3.8 g, prepared as described in Example 166), 2-methylethylenediamine (2.2 g) and ethanol (45 ml) was heated under reflux 8 hours to produce a solid which was recrystallized from ethyl acetate to give 4- [2- (4-methyl-2-imidazolidinylideneamino) phenylinorpholine (mp 173-174 ° C).

Example 204

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (7.6 g, prepared as described in Example 166), 1,2-dimethylethylenediamine (5.3 g) and ethanol (90 ml) was heated under reflux. over 70 hours to produce a solid which was recrystallized from ethyl acetate to produce 4- [2- (4,5-dimethyl-2-imidazolidinylideneamino) phenyl] morpholine (mp 142-143 ° C).

-84Example 205

Ethylene oxide prepared from 2-chloroethanol (36 g) and perl potassium hydroxide (20 g) in methanol (60 ml) was reacted with 1,2-dimethylethylenediamine (22.6 g) in methanol (50 ml) at -15 ° C. to give N- (2-hydroxyethyl) -1,2-dimethyl-ethylenediamine as a colorless liquid (boiling point: 89-91 ° C at 1 mm Hg).

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine (12.5 g) and N- (2-hydroxyethyl) -1,2-dimethylethylenediamine (8 g) in dry ethanol (150 ml) was heated under reflux at 90-95 ° C for 6 days to give a dark brown oil which was purified by column chromatography on neutral aluminum oxide (250 g) using a 1: 9 mixture of dichloromethane and hexane as eluent to give 4- {2 - [4,5-dimethyl-1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenylmorpholine (mp 108-109 ° C) recrystallized from hexane.

Example 206

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (3.8 g, prepared as described in Example 166), N'-isopropyl-2-methyl-1,2-propanediamine (3.95 g), and of ethanol (45 ml) was heated under reflux for 28 hours to produce an oil which was purified by column chromatography on neutral alumina using dichloromethane as eluent. The resulting oil (1.5 g) was dissolved in methanol (10 ml) and fumaric acid (0.5 g) was added to give 4- [2- (1-isopropyl-4,4-dimethyl-2-imidazolidinylidenamino) phenylinorpholine monofumarate (m.p. 206-208 ° C) which was recrystallized from a 1: 3 mixture of methanol and ether.

-85Example 207

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (3.8 g, prepared as described in Example 166),

3-methylaminopropylamine (2.6 g) and absolute ethanol (40 ml) were refluxed for 6 hours to produce a solid which was recrystallized from ether to give 4- [2- (l-methylperhydropyrimidin-2- ilidenamino) phenylmorpholine (mp 138-139 ° C).

Example 208

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (7.6 g) and 1,4-diaminobutane (5.3 g) in ethanol (150 ml) was refluxed for 60 hours to produce a white solid. (mp 135 ° C) recrystallized from ethyl acetate. The solid (2.7 g) was dissolved in methanol (20 ml) and treated with fumaric acid to produce 2- (2-morpholinophenylimino) -1,3-diazacycloheptane fumarate (mp 220-222 ° C), which recrystallized from a 1: 1 mixture of methanol and ether.

Example 209

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (1 g), dimethylamine (1 ml of a 33% solution in ethanol) and ethanol (2 ml) was maintained at room temperature for 48 hours. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute aqueous sodium hydroxide solution (5 ml) and the resulting mixture extracted with dichloromethane (2 x 50 ml). The extract was washed with brine, dried and the solvent was evaporated to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (mp 143-144 ° C), which was recrystallized from hexane.

-86Example 210

A solution of 4- (2-aminophenyl) morpholine (5.3 g) in dichloromethane (25 ml) was treated with methyl isothiocyanate (3.2 g) and the mixture was stirred at room temperature for 36 hours to produce 1- (2-morpholinophenyl) -3 -methylthiourea (mp 115-116 ° C) recrystallized from a 4: 1 mixture of ethyl acetate and hexane.

A mixture of 1- (2-morpholinophenyl) -3-methylthiourea (5 g) and methyl iodide (2.8 g) in acetone (30 ml) was refluxed for 4 hours to produce 2-methyl-1- (2-morpholinophenyl). ) -3-methyl-2-thiopseudine hydroiodide (mp 163-164 ° C) recrystallized from a 1: 3 mixture of methanol and ether.

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiophene hydroiodide (3.9 g) and a 33% solution of methylamine in absolute ethanol (40 ml) was heated at 50-55 ° C for 28 hours. to produce 1,3-dimethyl-2- (2-morpholinophenyl) guanidine, which was recrystallized from hexane (mp 137-138 ° C).

Example 211

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (3.9 g, prepared as described in Example 210) and dimethylamine (25 ml of 33% ethanol solution) stood at room temperature for 25 days. Removal of the solvent gave a residue which was purified by chromatography on an alumina column using a 1:49 mixture of methanol and dichloromethane as eluent. The resulting solid was dissolved in methanol and treated with fumaric acid to produce 1,3,3-trimethyl-2- (2-morpholinophenyl) guanidine monofumarate (mp 192-194 ° C), which was recrystallized from 1: 2 mixtures of methanol and ether.

-87Example 212

Reaction of 2-morpholinophenyl isothiocyanate (3.3 g) with ethylamine obtained from ethylamine hydrochloride (12.18 g) and sodium methoxide [obtained from sodium (3.5 g) and methanol (100 ml)] gave l-ethyl-3- (2 -morpholinophenyl) thiourea (mp 118-120 ° C) recrystallized from a 1: 1 mixture of ethyl acetate and hexane.

A mixture of 1-ethyl-3- (2-morpholinophenyl) thiourea (3.2 g) and methyl iodide (2 g) in acetone (25 ml) was refluxed for 4 hours to produce 2-methyl-3-ethyl-1 - (2-morpholinophenyl) -2-thiopseudine hydroiodide as a pale yellow solid (mp 170-172 ° C) recrystallized from acetone.

A mixture of 2-methyl-3-ethyl-1- (2-morpholinophenyl) -2-thiophene hydroiodide (6 g) and 33% methylamine in absolute ethanol (250 ml) was first heated at 45 ° C for 24 hours and then left at room temperature. 14 days to produce 1-ethyl-2- (2-morpholinophenyl) -3-methylguanidine as a colorless solid (mp 118-119 ° C) recrystallized from hexane.

Example 213

Sodium (23 g) was added to ethanol (300 ml) and the resulting sodium ethoxide solution was reacted with ethylamine hydrochloride to obtain an ethylamine solution which was stirred for 30 days at room temperature with 2-methyl-3-ethyl-1- ( 2-morpholinophenyl) -2-thiopse urea by hydroiodide (6 g, prepared as described in Example 212) to give 1,3-diethyl-2- (2-morpholinophenyl) guanidine (m.p. 101-102 ° C). which was recrystallized from hexane.

-88Example 214

Reaction of 4- {2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenylnnorpholine (3 g, prepared as described in Example 175) in dichloromethane (20 ml) with acetic anhydride (0.86 g) gave 4 - {2- [1- (2-Acetoxyethyl) -2-imidazolidinylidenamino] phenyl} morpholine (mp 89-91 ° C) recrystallized from hexane.

Example 215

Reaction of 4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (2.9 g, prepared as described in Example 175) in dichloromethane (60 ml) with benzoic anhydride (2.4 g), in the presence of dry triethylamine (2 ml) and

Of 4-dimethylaminopyridine (50 mg) gave an oil which was purified by chromatography on an alumina column using dichloromethane as eluent to give 4- (2- [1- (2-benzoyloxyethyl) -2-imidazolidinylideneamino] phenylmorpholine (mp 92-94 ° C) recrystallized from a 1: 1 mixture of ethyl acetate and hexane.

Example 216

A solution of 4- (2-aminophenyl) morpholine (5.8 g) in dichloromethane (60 ml) was treated with n-butyl isothiocyanate (5 g) and the mixture was stirred for 4 days at room temperature to give 1- (n-butyl) - 3- (2-morpholinophenyl) thiourea as a pale yellow solid (mp 105 ° C).

A mixture of 1- (n-butyl) -2- (2-morpholinophenyl) thiourea (5.8 g) and methyl iodide (3.1 g) in acetone (25 ml) was refluxed for 4 hours to produce 2-methyl-3 - (n-butyl) -1- (2-morpholinophenyl) -2-thiopseudine hydroiodide as a colorless solid, m.p. Mp 154-156 ° C.

-89A mixture of 2-methyl-3- (n-butyl) -1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (4.0 g) and a 33% solution of methylamine in absolute ethanol (200 ml) was heated first for 24 hours at 45 ° C and then allowed to stand at room temperature for 21 days to give 1- (n-butyl) -2- (2-morpholinophenyl) -3-methylguanidine as an oil; a solution of this oil in methanol (25 ml), after treatment with fumaric acid, gave a colorless solid which was recrystallized from a 1: 1 mixture of methanol and ether to give 1- (n-butyl) -2- (2 -morpholinophenyl) -3-methylguanidine monofumarate (mp 170-172 ° C).

Example 217

A mixture of 2-methyl-1- (2-piperidinophenyl) -2-thiopseudine hydroiodide (7.5 g, prepared as described in Preparation G), 2-methoxyethylamine (2 ml) and ethanol (40 ml) was stirred at room temperature. temperature for 20 days. Removal of the solvent gave a residue which was dissolved in methanol and treated with fumaric acid to give 1- (2-methoxyethyl) -2- (2-piperidinophenyl) guanidine hemifumarate (mp 218-220 ° C) it was recrystallized from a 1: 2 mixture of methanol and ether.

Example 218

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydroiodide (1.7 g, prepared as described in Example 166), 2-methylthioethylamine (1.8 g) and ethanol (25 ml) was heated at 90- 95 ° C for 22 hours to give 1- (2-methylthioethyl) -2- (2-morpholinophenyl) guanidine (mp 115-116 ° C), which was recrystallized from hexane.

Example 219

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiopseudine hydro-90 iodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was stirred at room temperature for 14 days to give 1- (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine (mp 125-128 ° C), which was recrystallized from 1,2-dimethoxyethane and converted to its fumarate salt (mp 136-138 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 220

A mixture of 2-methyl-1- (2-morpholinonophenyl) -3-methyl-2-thiopseudine hydroiodide (7.8 g, prepared as described in Example 210), n-propylamine (1.3 g) and ethanol (50 ml) was stirred. at room temperature for 45 days to produce an oil which was purified by column chromatography on neutral alumina using a 1:99 mixture of methanol and dichloromethane as eluent. The resulting oil was dissolved in methanol and treated with fumaric acid to produce 1- (n-propyl) -2- (2-morpholinophenyl) -3-methylguanidine monofumarate (mp 187-188 ° C), which was recrystallized from 1: 2 mixtures of methanol and ether.

Example 221

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (3.9 g) prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and ethanol (25 ml), were kept at room temperature for three months to obtain an oil which was dissolved in methanol and treated with fumaric acid to give l-methyl-2- (2-morpholinophenyl-3- (2-methoxyethyl) guanidine monofumarate ( 158-160 [deg.] C.) which was recrystallized from a 1: 2 mixture of methanol and ether.

-91Example 222

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiopheresol of hydroiodide (7.86 g) prepared as described in Example 210), cyclopentylamine (2.9 g), anhydrous sodium carbonate (6.36 g) and of ethanol (100 ml) was heated in a stainless steel pressure vessel, in an oil bath at 110 ° C for 24 hours. The reaction mixture was cooled, filtered and the solvent partially removed. The residue was poured onto ice and the resulting mixture extracted with dichloromethane. The extract was dried, filtered and the solvent removed to give a residue which was treated with fumaric acid to give l-cyclopentyl-2- (2-morpholinophenyl) -3-methylguanidine monofumarate (mp 220 ° C), which it was recrystallized from a 1: 1 mixture of methanol and ether.

Example 223

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (3.9 g, prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux. for two weeks to give an oil which was purified by column chromatography on neutral aluminum oxide eluting with a 1: 1 mixture of dichloromethane and hexane and then with a 1: 9 mixture of methanol and dichloromethane to give N-methyl-N ' - (2-morpholinophenyl) pyrrolidine-1-carboxamidine, which was converted to its monofumarate salt (m.p. 168-171 ° C), which was recrystallized from propan-2-ol.

Example 224

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-ethyl-2-thiopseudine hydroiodide (10 g, prepared as described in Example 212), n-butylamine (2.7 g) and t-butanol (75 ml) , was heated at 90-95 ° C for 172 hours to give

-921- (n-butyl) -2- (2-morpholinophenyl) -3-ethylguanidine, which was converted to its monofumarate salt (m.p. 159-160 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 225

Reaction of 5-chloro-2-morpholinoaniline (2.8 g) with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) at room temperature for 60 days gave 1- (n-butyl) -3- (5-chloro) -2-morpholinophenyl) thiourea (mp 150-152 ° C).

A mixture of 1- (n-butyl) -3- (5-chloro-2-morpholinophenyl) thiourea (2.6 g), methyl iodide (1.4 g) and acetone (20 ml) was heated under reflux for 3 hours to give gave 2-methyl-1- (5-chloro-2-morpholinophenyl) -3- (n-butyl) -2-thiopheresulphide hydroiodide (mp 130-132 ° C).

A mixture of 2-methyl-1- (5-chloro-2-morpholinophenyl) -3- (n-butyl) -2-thiophene hydroiodide (3.4 g) and a 33% solution of methylamine in ethanol (10 ml) was kept at room temperature. temperature in a sealed container for 8 months to give 1,3-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine (mp 145 146 ° C), which was recrystallized from hexane. In this reaction, the butylamino and methylthio groups of the starting material are replaced by the methylamino group.

Example 226

Reaction of 1- (2-aminophenyl) pyrrolidine (10 g) with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) at room temperature for 4 days gave l-methyl-3- [2- (1-pyrrolidinyl) phenyl] thiourea (mp 125-126 ° C).

A mixture of 1-methyl-3- [2- (1-pyrrolidinyl) phenyl] thiourea (18.5 g) and methyl iodide (12.3 g) and acetone (100 ml) was heated under

-93reflux for 2.5 hours to give 2-methyl-1- [2- (1-pyrrolidinyl) phenyl] ~ 3-methyl-2-thiophene urea hydroiodide (mp 161-162 ° C).

A mixture of 2-methyl-1- [2- (1-pyrrolidinyl) phenyl] -3-methyl-2-thiopseud hydroxide (14.7 g), allylamine (4.45 g) and ethanol (65 ml) was maintained at room temperature for 50 days. , it was then refluxed for 20 hours to give an oil which was treated with fumaric acid to give l-allyl-2- [2- (1-pyrrolidinyl) phenyl] -3-methylguanidine monofumarate (m.p. 162-163 ° C) which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 227

A solution of 4- (2-amino-4-methylphenyl) morpholine (5.7 g) in dichloromethane (30 ml) was treated with methylisothiocyanate (2.8 g) and the reaction mixture was kept at room temperature for 6 days to give l-methyl-3 - (5-methyl-2-morpholino-phenyl) thiourea as a colorless solid (mp 107 ° C).

A mixture of 1-methyl-3- (5-methyl-2-morpholinophenyl) thiourea (6.4 g) and methyl iodide (3.8 g) in acetone (60 ml) was refluxed for 4 hours to give 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide as a pale yellow solid (mp 160-161 ° C).

A mixture of 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thiopse hydroiodide (6 g) and a 33% solution of methylamine in absolute ethanol (250 ml) stood at room temperature for 21 days to give 1,3-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine as an oil dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1 , 3-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine fumarate (1.2 g) as a colorless solid which was recrystallized from a 1: 1 mixture of methanol and ether (mp 201-202 ° C).

-94Example 228

Mixture of 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (8.4 g, prepared as described in Example 227), N- (2-hydroxyethyl) ethylenediamine (6.8 ml) and ethanol (80 ml) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give 4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] -4-methylphenyl} morpholine sesquifumarate (mp 135 136 ° C).

Example 229

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thiopseud hydroxide (4 g, prepared as described in Example 210), potassium hydroxide (1.7 g), n-pentylamine (2.1 g), of lead acetate trihydrate (5.8 g) and ethanol (20 ml) was heated at 90-95 ° C for 40 minutes to produce an oil which was extracted with hexane to give l-methyl-2- (2-morpholinophenyl) ) -3- (n-pentyl) guanidine, which was converted into its monofumarate salt (mp 148-149 ° C), which was recrystallized from a 3: 5 mixture of methanol and ether.

Example 230

Mixture of 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (12.2 g, prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml ) was stored at room temperature for 4 months. Lead acetate trihydrate (9 g) was then added and the mixture was refluxed for 1 hour to produce 1- (n-butyl) -2- (5-methyl-2-morpholinophenyl) -3-methylguanidine, which was converted to its monofumarate salt (mp 150 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

-95Example 231

Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) at room temperature for 4 days gave N-methyl-N '- (6-methyl-2-morpholinophenyl) thiourea (mp 182-183 ° C).

A mixture of N-methyl-N '- (6-methyl-2-morpholinophenyl) thiourea (11.5 g), methyl iodide (6.75 g) and acetone (100 ml) was refluxed for 2.5 hours to produce 2-methyl- 1- (6-Methyl-2-morpholinophenyl) -3-methyl-2-thiopheresulphide hydroiodide (mp 187-188 ° C).

A mixture of 2-methyl-1- (6-methyl-2-morpholinophenyl) -3-methyl-2-thiopseudine hydroiodide (17.8 g), n-butylamine (6.4 g) and ethanol (60 ml) was kept at room temperature for 60 days. . Potassium hydroxide (2.2 g) was added and then lead acetate trihydrate (7.6 g) and the mixture was refluxed for 5 hours to produce 1- (n-butyl) -2- (6-methyl-2-morpholinophenyl) -3 -methylguanidine, which was converted to its monofumarate salt (mp 203-204 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 232

The reaction of N- (2-morpholinophenyl) isothiocyanate (4 g) in ethanol (10 ml) with a 33% solution of dimethylamine in ethanol (15 ml) at 15 ° C for four hours gave 1, 1-dimethyl-3- (2-morpholinophenyl) thiourea (mp 150-152 ° C).

A mixture of 1,1-dimethyl-3- (2-morpholinophenyl) thiourea (7.5 g), methyl iodide (1.7 ml) and acetone was refluxed for 2 hours to give 2-methyl-1- (2-morpholinophenyl) -3,3-dimethyl-2-thiopseudorine hydroiodide (mp 162-163 ° C).

-96A mixture of 2-methyl-1- (2-morpholinophenyl) -3,3-dimethyl-2-thiopseud hydroxide (2 g), saturated ammonia in ethanol (10 ml) and pyridine (10 ml) was heated at 90-95 ° C for 19 hours in a pressurized stainless steel container. The pyridine was removed by evaporation under reduced pressure and the residue was suspended in water.

1.1-dimethyl-2- (morpholinophenyl) guanidine (mp 142-143 ° C) was collected by filtration, washed with water, dried and recrystallized from hexane.

Example 233

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiophene hydroiodide (3.8 g), 33% dimethylamine solution in ethanol (5 ml) and pyridine (25 ml) was heated at 80 ° C for 6 hours. The pyridine was removed by evaporation under reduced pressure and the residue was treated with a mixture of ice and water to give

1,1- Dimethyl-2- (2-morpholinophenyl) guanidine (mp 142-144 ° C), which was recrystallized from hexane.

Example 234

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thiophene hydroiodide (3.8 g), 33% dimethylamine solution in ethanol (5 ml) and triethylamine (25 ml) was heated at 80 ° C for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue was treated with a mixture of ice and water to give

1,1-dimethyl-2- (2-morpholinophenyl) guanidine (m.p. 141-143 ° C) recrystallized from hexane.

Examples 235 to 241

The compounds of formula (I) listed in Table 8 were prepared by heating a mixture of a thiourea of formula (XVI) in which methyl and Rg are hydrogen (A grams) of potassium

-97hydroxide (B grams), an amine of formula H ₂ NRg (C grams), lead acetate trihydrate (D grams) and ethanol (E milliliters) at 90-95 ° C for F hours to give the oil which was dissolved in methanol and treated with fumaric acid to give the monofumarate salt of the compound of formula (I). The melting point of the monofumarate salt is indicated in the soil column. The solvent from which this salt was recrystallized is mentioned in the footnotes.

Notes to Table 8 (59) The salt was recrystallized from methanol.

(60) The initial thiourea was prepared by reaction of 4- (2-amino-4-fluorophenyl) morpholine (6 g) with methyl isothiocyanate (2.6 g) in dichloromethane (50 ml) at room temperature for 25 days to give 1-methyl-3- (5-fluoro-2-morpholinophenyl) thiourea (mp 145-148 ° C).

(61) The free base was purified by column chromatography on neutral aluminum oxide using dichloromethane as eluent.

(62) The initial thiourea was prepared by reaction of 4- (2-amino-4-methylthiophenyl) morpholine (9.5 g) with methyl isothiocyanate (3.1 g) in dichloromethane (100 ml) at room temperature for 30 days to give 1-methyl-3- (5-methylthio-2-morpholinophenyl) thiourea (mp 132-133 ° C).

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

(64) The salt was recrystallized from propan-2-ol.

-98TABELA_8 cn

N?

NR, R

o CN Φ kO X yes s X “N z- ^ s- \ z ^ z —- s x * \ z * · *. 0 σ> , - <r cn X co cn a oo X kO x X kO m o *> - ✓ \ _Z * x · ^ ~ z. CN CO., LTD z- ^ <r Oh cO in 0 CN (Oh o co Okay <o 0 Φ , - 1— Φ I- r— r ~ * ! I X) 1 I 1 • '--z' Oh r- ' CN Okay CN and — 1 CN CN UO o CO., LTD co kO (0 and— Ι- r— Γ-- 1-- * r— r ~ Jj CN Ο ' 2 fp ω Γ '- J I X <r <r K X X K X rH □ 0 _ 3 .3 >> 3 CQ X CQ X X r ^- H CQ X 1 1 l 1 1 r-1 1 X C C • H « in X C

O rt

0 o o Oh o 0 • H rp c rt c c c C 0 Ή • H ♦ p • H • rt 'Rt <P CN X rH r— ( rH Ή rrt rrt P Oh 0 o Oh o 0 Oh U-i mp Mrt Lp Srt Irt S r " p P rt P ' rt rt Π3 X 0 Oh Oh 0 o o • H 2 β e e e e E P

C /

x X X X • • • « X CN r * " CN CN co <r CN Oh o Oh Oh o o o X <T X X CN X X X <7 X X r- ' X X LO o n- Γ- r- X r- X CO., LTD CN CN Os Os X r— • • • • • ♦ ω CN CN CN * - CN X CN <r CN CN CN I— CN X X » • • • • • • X CN CN CN * - CN CN <7 OS X Os • • • • < o x UO CN X X CO., LTD x X TO OS Oh r ~ P X X X X X <r <r P- » CN CN CN CN CN CN CN

-99Example 242

Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene (8.6 g) in dioxane (30 ml) and water (100 ml) at 0 ° C for 30 minutes and then at room temperature for 2 hours gave a residue which was extracted with dichloromethane to give 2-morpholino-5-trifluoromethylphenyl isothiocyanate as a yellow ol.

Reaction of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with a 33% solution of ammonia in ethanol (50 ml) at room temperature for 2 hours gave 1- (2-morpholino-5-trifluoromethylphenyl) ) thiourea (mp 196-197 ° C).

A mixture of 1- (2-morpholino-5-trifluoromethylphenyl) thiourea (6.1 g), potassium hydroxide (2.2 g), 33% dimethylamine solution in ethanol (5.6 ml), lead acetate trihydrate (7.5 g) and ethanol (40 ml) ) was heated at 90-95 ° C for 2 hours to give 1,1-dimethyl-2- (2-morpholino-5-trifluoromethylphenyl) guanidine (mp 132-135 ° C) which was recrystallized from ethyl acetate and converted to its fumarate salt (mp 228-230 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 243

Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxane (2 ml) and water (25 ml) at 0 ° C for 30 minutes and then at room temperature for 2 hours gave a residue which we extracted it with dichloromethane to give

5-cyano-2-morpholinophenyl isothiocyanate as an oil.

Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with a 25% aqueous ammonia solution (1 ml) at

-100 room temperature for 1 hour gave 1- (5-cyano-2-morpholinophenyl) thiourea (mp 193-194 ° C).

A mixture of 1- (5-cyano-2-morpholinophenyl) thiourea (5.2 g), potassium carbonate (8.3 g), 33% dimethylamine solution in ethanol, lead acetate trihydrate and ethanol (25 ml) was heated under reflux for 3 hours to give 1,1-dimethyl-2- (5-cyano-2-morpholinophenyl) guanidine (mp 125-127 ° C), which was converted to its monofumarate salt [m.p. 223-225 ° C (decomposition)], which was recrystallized from methanol.

Example 244

A mixture of 1,1-dimethyl-3- (2-morpholinophenyl) thiourea (2.65 g, prepared as described in Example 232), n-propylamine (1.6 ml), lead acetate trihydrate (3.8 g), potassium hydroxide (1.2 g ) and ethanol (25 ml) were refluxed for 4 hours. A further amount of n-propylamine (1.6 ml) was added and the mixture was stirred under reflux for a further 8 hours. The reaction mixture gave a residue which was extracted with ether. The extract was decolourised with activated carbon, filtered and the solvent removed to give a sticky solid which was dissolved in methanol (10 ml) and treated with fumaric acid to give 1,3-di- (n-propyl) - 2- (2-morpholinophenyl) guanidine hemifumarate (mp 212-214 ° C), which was recrystallized from a 1: 2 mixture of methanol and ether.

Example 245

A mixture of 1,1-dimethyl-3- (2-morpholinophenyl) thiourea (2.65 g, prepared as described in Example 232), lead acetate trihydrate (3.8 g), saturated ammonia solution in ethanol (25 ml), potassium hydroxide ( 1.12 g) and ethanol (20 ml) were heated at 90-95 ° C in a sealed stainless steel pressure vessel for 5 hours. Reactionary

The mixture was filtered and the collected solid was washed with ethanol. Ethanol from the wash was added to the filtrate and the volume was reduced by evaporation. Ice was added and the solid thus formed was collected by filtration, washed with water and dried to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (m.p. 141-142 ° C), which was recrystallized from hexane.

Examples 246 to 269

The reaction of the compound of formula (VII) in the form of its hydrochloride salt (K grams) and the compound of formula NC-NR ^ Rg (L grams) in m-cresol (M milliliters) was heated at 90-95 ° C for N hours to give the compounds listed in Table 9.

Notes to Table 9

Notes (32), (38), (44) and (45) have the meanings given previously.

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

(66) The product was isolated as its monofumarate salt, which was recrystallized from a 1: 1 mixture of methanol and ether.

(67) The reaction was carried out at 90-95 ° C for 8 hours and then at 115-120 ° C for 4 hours.

(68) The reaction was carried out at 120-125 ° C.

(69) The reaction mixture was heated at 90-95 ° C for 9 hours and then at 120 ° C for 21 hours.

(70) The reaction mixture gave an oil which was extracted with boiling hexane to give a free base which was

-102 converted to its monofumarate salt, which was recrystallized from a 1: 3 mixture of methanol and ether.

(71) The reaction mixture gave an oil which was extracted with hexane to give a free base in the form of an oil. The base was purified by column chromatography on neutral alumina using the following eluent sequence: hexane, 1: 1 mixture of dichloromethane and hexane, dichloromethane and 1:99 mixture of methanol and dichloromethane. The resulting base was converted to its monofumarate salt, which was recrystallized from a 2: 7 mixture of methanol and ether.

-103

TABLE 9

Φ in n io τν ti z

J V <7 (I.

z z

cz

0 z — s z-s Z — M z — S z »-» X ~ * z »** \ X ~ \. a <r m CM m <r m m m m o <r <r cn <r <r <r <r <r <r Ί-Η- > -z V-z —S s — z Z— «L X — M LO n r— CM CJ LO in , - CM cn cn dl CM 0 CM , - CM r— E CM 1 1 1 I * —Z L « cn m CM o CM o o o m rd 00 , - CM m 1ΖΊ cn CM CM CM (d , - CM r— CM r— 1- CM CM CM E <u d) ι-H and — 1 d) d) r> 2 2 o o 2 2 dl E E E 1 <T 1 cn m 1 MO Oh 1 ω 1 s 1 <r- m io dl d) d) d) d) d) dl d) E ►t · ⁴ 2 2 2 2 2 2 2 2 m <u dl d) d) dl d) dl dl E E 2 2 2 2 2 2 2 2 o o C Oh o 0 Oh o o e C c c a £ C c • r4 Ή • H 'H • H • H • H Ή CM i — i t — i I ”1 T-1 and —H i — l i — l Γ-Η »H E 0 o o 0 Oh 0 o o 0 M-l M-l Me Me M-l M-l ME me ME E μ μ μ μι μ μ » μ μ Oh 0 Oh Oh o o Oh o o 2 e E S E E E E E E tn m « » o CM Oh oo CO., LTD 2 cn m m Γ “ <r tn r— ^i— ' LO m o m m o o tn o tn 2 CM 00 CM <r m m CM <r CM m ? <T <T m <n 00 m m tn r- CM d • • • • • • • • E σι m un cn cn CM <r CM CM <r 00 cn CM cn 00 P- lO cn r- o p- p- lO MO m E r— - lO r- · 00 cn o r— CM cn <T • <r <T <r <r m m m m and μ CM CM CM CM CM CM CM CM CM P-

-104TABLE 9 - continued

<D Mr Rücker Z—. and <r n- MO L ^ z z — s MO MO .z-s m <T m <r m <r 00 lO cn ΙΟ z-s m <r L_z Z ~ o UO <r \ z Z-S Oh z—. n- ^ z z- \ 00 co L — z m <r s — z 0 Pf o z - * \ and <r s_z z-s 00 co \ ~ z m <r <_z z z - >> co MO • ^ z zv and <r 00 o <r co CM co 00 Oh CM o co MO σ \ r- in 1— o σ \ 00 MO o co σι Oh and— MO CO., LTD co Γ— 0 CM | CM | t 1 | CM | CM | | CM 1 CN 1 CM t CM CN n. 00 1 co r-- o CN o> 1 1 cn co 1 CM 1 m .L 00 1 KO r-t and— σ \ σι 00 MO Oh CO., LTD co o o CO., LTD MO co CO., LTD , - fO CM 1— l— 1— and— CN CN , - CM CM | - p— CM • CM CN in OJ Z— < Γ'- • U) ω cd W CM Cr ¹ X X X X X X X X X X X X X <r ►Jz Oh 1 OJ <· 2 Oh 1 1 CM CN • CM z- \ z- \ z- ^ CM cN CM X X 1 X | MO oj OJ 4J b U U <r OJ 0) OJ OJ OJ OJ in m X 2 s ω « S-Z · 2 2 2 2 2 2 o CN o CN OJ CN ►Τ- CM X 2 z— «. Ο o Oh CN x «z CM x — z CM X 1 X 1 in o CN \ _Z V__ ' X 1 OJ OJ 0) OJ OJ 0) 1 UO D 0) 4J OJ in 2 2 2 2 2 2 X 2 S w 2 OJ 2 0 Oh rd c CM and — 1 0 • id • id Z 1 · Η -0 o o o 0 0 o 0 £ C rd U —And C c o c c C c c c c • H • id 0 CM 1 -H • rd c CM H * H • H • H • P • rd • rd XI <4- | X i — t CM • P X »—1 I — 1 rd rd rd rd rd • id • id P 00 • rl Cfl • P rd r—— o Oh Oh Oh Oh C Oh Li rd 0 4J U P o rF, uu Cf. Cf. Cf. <+4 UP CJ Oh CM 0) 0) 0) ω u-t h—— P P M P P Su Su cl P 5 d) 2 E Cl CL P S Oh 0 0 Oh 0 0 0 • rd • id • P X 1 -H • p 0 ε ε ε ε ε e ε CL O- 4J z Z X (X CL B

co and CM MO o co Z cn CM r ~ 00 1 n- r- MO co 00 r— m Oh o o co o o CO., LTD co m Oh o o ' m m 2 CM <r co <T m CM <r co <r CM m CM CM CN m m CM r-. <r σ \ c- 00 00 CM CO., LTD · - CO., LTD n- m m 00 P CN m m MO co m KO m <r CN CM - co m m cn co 00 <r KO MO · " m CM MO CM MO m co CO., LTD m X <r m 00 CO., LTD co M0 Oh co 00 <r <r <r r-. Γ-. »- r— r—

• m MO n * 00 σ> o r— CM CO., LTD <r m MO n- 00 σ> P n. m m and m m MO MO MO MO KO MO MO M0 MO MO kP CM CM CN CM CM CM CM CM CM CN CM CM CM CM CM

-105Example 270

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (2.1 g) and N, N-dimethylcyanamide (7 ml) was heated under nitrogen atmosphere at 165-170 ° C for 12 hours. The reaction mixture was cooled to 10 ° C and the precipitate was collected by filtration, washed with ether and stirred with 40% aqueous sodium hydroxide solution. The resulting mixture was extracted with dichloromethane and the extract was washed with brine and dried. Removal of the solvent gave a residue which was recrystallized from hexane to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (mp 144-145 ° C).

Example 271

A mixture of 4- (2-amino-4-methoxycarbonylphenyl) morpholine (2.7 g), N, N-dimethyl cyanamide (Ig) and m-cresol (15 ml) was heated at 90-95 ° C for 10 hours. Ice was added and the reaction mixture was acidified to pH 4 by the addition of 2N hydrochloric acid and the resulting mixture was extracted with ether. The aqueous layer was cooled, basified to pH 8 with the addition of solid sodium bicarbonate and extracted with dichloromethane. The extract was dried and the solvent removed to give an oily residue, which was purified by column chromatography on neutral aluminum oxide eluting with a 1:99 mixture of methanol and dichloromethane to give 1, 1-dimethyl-2- (5- methoxycarbonyl-2-morpholinophenyl) guanidine (mp 152-154 ° C).

Example 272

1- (2-morpholinophenyl) thiourea (10.6 g) was suspended in boiling water (80 ml) and a solution of potassium hydroxide (25.2 g) in hot water (70 ml) was added. The mixture was heated at 90 ° C, aliquots of lead acetate trihydrate (17.5 g) in water (80 ml) were added, the mixture was heated under reflux for 10 minutes and

-106 cooled to room temperature. The mixture was filtered and the filtrate acidified with acetic acid to pH 6. The precipitated solid was separated by filtration, washed with water and recrystallized from ethyl acetate to give N- (2-morpholinophenyl) cyanamide (m.p. 175 -176 ° C).

N- (2-morpholinophenyl) cyanamide (2 g) was refluxed with 33% dimethylamine solution in ethanol (15 ml) for 4 hours. The mixture was then cooled and the solvent removed by evaporation to give a residue which was suspended in 20% aqueous sodium hydroxide solution. The suspension was extracted with dichloromethane (3 x 25 ml) and the extracts were washed with water, then brine, dried and evaporated to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (mp 142-143 ° C). ) which was recrystallized from hexane.

Examples 273-285

In a manner similar to that described in Example 272, N- (2-morpholinophenyl) cyanamide (P grams) was heated under reflux with an amine of the formula HNR ^ Rg (Q grams) and ethanol (R ml) for T hrs. gave the compounds listed in Table 10.

Notes to Table 10

Notes (32), (38), (44) and (45) have the meanings given previously.

(72) A 33% solution of methylamine in ethanol (25 ml) was used as the reagent.

(73) The reaction was carried out at 90-95 ° C.

(74) The product was isolated as its monofumarate salt, which was recrystallized from a 2: 3 mixture of methanol

-107in ether.

(75) The product was recrystallized from a 1: 1 mixture of hexane and ethyl acetate.

(76) The reaction was carried out at room temperature for 2 hours and then at 90-95 ° C for 20 minutes.

(77) The product was recrystallized from a 3: 7 mixture of ethyl acetate and hexane.

(78) The reaction was carried out for 4 hours at room temperature and then refluxed for 4 hours.

108

TABLE 10

, CO., LTD <r m VO C- c » σν Oh t— L r ** r- n ~ r> Γ-. i ^. CO., LTD 00 CL CM CM CM CM CM CM CM CM CM

-109TABLE 10 - continued r -'-

Z “\ z “* \ Z “\ z ~ \ cs <r CS cs co <r CO., LTD co s-z s-z —S

and Oh <r r- cn m r ~ r ^- | I I kO UO co 00 <r co <r r " r * ~ r— and—

m of io

From

I I

l CM CM CS E z— \ 1 z— \ Oh CM CM cs 0) K z— ' E V! o CM o E v-z o ω in Φ o <u o co CM CS E CM z ^ » z — s. o z-s CM CS CM cs K E m o o U o o kZ 1 x_z |

I I

H CM MO CO of o o and cm

CM r • · CM

C / m r— <r cm

Pu m cm <r co

cs m <r and 00 co co co cs CM CM CM

-110Example 286

Reaction of 4- (2-amino-4-chlorophenyl) morpholine (8.5 g) with thiophosgene (4.6 ml) in dioxane (25 ml) and water (100 ml) for 0 minutes at 0 ° C and 3 hours at room temperature gave

5-chloro-2-morpholinophenyl isothiocyanate as a pale yellow solid (mp 86-87 ° C).

Reaction of 5-chloro-2-morpholinophenyl isothiocyanate (10 g) with a 33% solution of ammonia in alcohol (60 ml) at room temperature for 14 hours gave 1- (5-chloro-2-morpholinophenyl) thiourea as a yellow solid. (mp 174-175 ° C).

A mixture of 1- (5-chloro-2-morpholinophenyl) thiourea (5.97 g), suspended in water (40 ml), lead acetate trihydrate (8.75 g) in water (40 ml) and potassium hydroxide (12.6 g) in water (35 ml) was refluxed for 15 minutes to give N- (5-chloro-2-morpholinophenyl) cyanamide as a white solid (mp 305-308 ° C).

In a manner similar to that described in Example 272, N- (5-chloro-2-morpholinophenyl) cyanamide (2.3 g) in ethanol (10 ml) and 33% dimethylamine solution in ethanol (6 ml) were heated under reflux for 4 hours to obtain 1,1-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine (mp 135 138 ° C), which was recrystallized from hexane and then converted to its monofumarate salt (mp 223-225 ° C) recrystallized from methanol.

Example 287

A mixture of 5-fluoro-2-morpholino aniline (6 g) with thiophosgene (5.2 g) in dioxane (20 ml) and water (40 ml) was stirred for 15 minutes at 0 ° C and for 1 hour at room temperature to give the residue which was extracted with dichloromethane to give an oil which

It was purified by silica gel column chromatography (mesh 100-200) using a 1: 9 mixture of ethyl acetate and hexane as eluent to give 5-fluoro-2-morpholinophenyl isothiocyanate as an oil.

Reaction of 5-fluoro-2-morpholinophenyl isothiocyanate (5.8 g) with a 33% solution of ammonia in ethanol (30 ml) at room temperature for 3 hours gave 1- (5-fluoro-2-morpholinophenyl) thiourea as a white solid (mp 195-196 ° C).

A mixture of 1- (5-fluoro-2-morpholinophenyl) thiourea (5.1 g), suspended in water (36.5 ml), lead acetate trihydrate (7.95 g) in water (36 ml) and potassium hydroxide (11.45 g) in water (32 ml) was refluxed for 25 minutes to give N- (5-fluoro-2-morpholinophenyl) cyanamide as a white solid (mp 168-170 ° C).

In a manner similar to that described in Example 286, N- (5-fluoro-2-morpholinophenyl) cyanamide (2.2 g) in ethanol (10 ml) and 33% dimethylamine solution in ethanol (6 ml) were heated under reflux for 20 minutes to obtain

1, 1-dimethyl-2- (5-fluoro-2-morpholinophenyl) guanidine (mp 137-138 ° C), which was recrystallized from hexane and converted to its fumarate salt (mp 222-224 ° C), which was recrystallized from methanol.

Example 288

Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water (200 ml) for 30 minutes at 0 ° C and 2 hours at room temperature gave the product which was extracted with dichloromethane to give 3-methyl-2-morpholinophenyl isothiocyanate as an oil.

Reaction of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) v

-112 ethanol (5 ml) with saturated ammonia solution in ethanol (60 ml) at room temperature for 4 hours gave 1- (3-methyl-2-morpholinophenyl) thiourea (mp 178-179 ° C).

A mixture of 1- (3-methyl-2-morpholinophenyl) thiourea (6 g) suspended in water (40 ml), lead acetate trihydrate (9 g) in water (40 ml) and potassium hydroxide (13.5 g) in water (35 ml) was heated at 90-95 ° C for 1 hour to give N- (3-methyl-2-morpholinophenyl) cyanamide (mp 137-138 ° C), which was recrystallized from ethyl acetate.

In a manner similar to that described in Example 286, N- (3-methyl-2-morpholinophenyl) cyanamide (2.5 g) in ethanol (8 ml) and 33% dimethylamine solution in ethanol (3.5 ml) were heated under reflux for one hour. A further amount of 33% dimethylamine solution in ethanol (3.5 ml) was added and the mixture was stirred under reflux for an additional hour to give

1, 1-dimethyl-2- (3-methyl-2-morpholinophenyl) guanidine (m.p. 100 ° C), which was recrystallized from hexane and converted to its monofumarate salt (m.p. 180 ° C), which was recrystallized from a 1: 1 mixture of methanol and ether.

Example 289

Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) with thiophosgene (2.9 ml) in dioxane (25 ml) and water (75 ml) for 30 minutes at 0 ° C and 3 hours at room temperature gave the residue was extracted with dichloromethane to give 4-methoxy-2-morpholinophenyl isothiocyanate as an oil.

Reaction of 4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) with saturated ammonia solution in ethanol (30 ml) at room temperature for 24 hours gave 1- (4-methoxy-2-morpholinophenyl) thiourea (m.p. 175 ° C). .

-113A mixture of 1- (4-methoxy-2-morpholinophenyl) thiourea (3.8 g), suspended in water (26 ml), lead acetate trihydrate (5.7 g) in water (24 ml) and potassium hydroxide (8.4 g) in water ( 24 ml) was heated at 90-95 ° C for 30 minutes to give N- (4-methoxy-2-morpholinophenyl) cyanamide.

A mixture of N- (4-methoxy-2-morpholinophenyl) cyanamide (1.9 g) and 33% dimethylamine solution in ethanol (2.5 ml) was heated under reflux for 15 minutes to give 1,1-dimethyl-2- ( 4-Methoxy-2-morph olinophenyl) guanidine (mp 135 ° C) recrystallized from hexane.

Example 290

A mixture of 5-isobutyl-2-morpholinoaniline hydrochloride (4.1 g), N, N-dimethylcyanamide (1.77 g) and m-cresol (15 ml) was heated at 90-95 ° C for 6 hours to give the residue it was extracted with hot hexane, decolorized with activated carbon and purified by chromatography on an alumina column eluting with a 2:98 mixture of methanol and dichloromethane. The resulting product was recrystallized from a 1: 3 mixture of ethyl acetate and hexane. The first precipitate was removed by filtration and the filtrate was evaporated to dryness to give a residue which was recrystallized from a 1: 3 mixture of ethyl acetate and hexane to give 1,1-dimethyl-2- (5-isobutyl-2- morpholinophenyl) guanidine.

Example 291

Sodium chlorite (5.6 g), cupric chloride (0.2 g), cupric chloride dihydrate (0.34 g) were added to a solution of sodium carbonate (3.75 g) in water (25 ml). The mixture was cooled to 20 ° C and a solution of N- (2-morpholinophenyl) thiourea (6 g) in dichloromethane (45 ml) was added over 15 minutes. The temperature was raised to 45 ° C and maintained at this level for 4.5 hours. Added

-114 water (100 ml) and dichloromethane (200 ml) were stirred and the mixture was stirred for ten minutes. The organic layer was separated and the aqueous layer was washed with dichloromethane. The combined organic layers were washed with brine and dried. Removal of the solvent gave a residue which was mixed with a 20% aqueous sodium hydroxide solution (100 ml) and heated in a steam bath and then filtered. The filtrate was washed with ether, acidified to pH 4 with acetic acid and extracted with dichloromethane. The extract was washed with brine, dried and the solvent removed to give a residue which was purified by chromatography on a silica gel column eluted with hexane to which ethyl acetate (up to 30%) was gradually added to increase polarity. N- (2-morpholinophenyl) cyanamide (mp 175-176 ° C) was obtained.

A mixture of N- (2-morpholinophenyl) cyanamide (1.5 g) and 33% dimethylamine solution in ethanol (12 ml) was refluxed for 4 hours. Removal of the solvent gave a residue which was added dichloromethane (100 ml) and brine (50 ml). The mixture was stirred for 5 minutes and the organic layer was separated and dried. Removal of the solvent gave 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (m.p. 144-145 ° C), which was recrystallized from hexane.

Example 292

1,1-dimethyl-2- (5-methylthio-2-morpholinophenyl) guanidine as a free base (1.3 g) prepared from Example 253, sodium metaperiodate (lg), methanol (10 ml) and water (4 ml) was kept at room temperature for 20 hours to obtain

1,1-dimethyl-2- (5-methylsulfinyl-2-morpholinophenyl) guanidine n (mp 160-161 ° C) recrystallized from ethyl acetate.

-115Example 293

A solution of 1-methyl-2- (2-morpholinophenyl) thiourea (6.2 g) in dichloromethane (30 ml) was added to a stirred mixture of aqueous sodium carbonate solution (3.75 g in 25 ml), sodium chlorite (5.6 g), cupric chloride over 15 minutes. (0.2 g), dihydrate chloride cups (0.34 g) and benzyltrimethyl ammonium chloride (0.6 g). The resulting mixture was stirred for 2 hours, sodium chlorite (2.4 g) and benzyltrimethylammonium chloride (0.4 g) were added and the mixture was stirred for 1.5 hours. Water (50 ml) and dichloromethane (200 ml) were added and the aqueous layer was extracted with dichloromethane (2 x 100 ml). The extracts were combined, washed with brine, dried and filtered. Removal of the solvent gave a residue which was purified by chromatography on a silica gel column using hexane and then a 1: 4 mixture of ethyl acetate and hexane as eluent to give N-methyl-N (morpholinophenyl) carbodiimide (m.p. 67-68 °). C).

A mixture of N-methyl-n (2-morpholinophenyl) carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (5 ml) was heated at 90-95 ° C for four hours. The solvent was removed by evaporation and the residue was dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered. Removal of the solvent gave 1- (n-butyl) -2- (2-morpholinophenyl) -3-methylguanidine, which was converted to its monofumarate salt (mp 178-179 ° C).

Examples 294 to 300

In a manner similar to that described in Example 2, the products of the examples below were converted to their fumarate salts, which were recrystallized from the solvents indicated:

-116-

Example Beginners example Solvent for recrystallization Tal. fumaratne salts (° C) 294 133 1: 2 methanol: ether 173-175 295 134 1: 2 methanol: ether 183-184 296 167 2: 1 methanol: ether 192-193 297 175 1: 1 methanol-ether 159-160 298 200 propan-2-ol 142-143 J » 299 201 1: 1 methanol: ether 151-152 300 204 1: 2 methanol: ether 170-171 Example 301 Mixture 2 -morpholinoaniline hydrochloride (19.2 g), m-cresol (80

ml) and dimethylcyanamide (9.45 g) were heated at 100 ° C for 5 hours, cooled and added to a mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid was collected by filtration, washed with water and dissolved in dichloromethane. The solution was dried and the solvent removed to give a residue, which was recrystallized from hexane to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (mp 142-143 ° C).

Examples 302 - 304

The reaction of the products of Examples 175, 248 and 300 in the form of their free bases in methanol with L (+) tartaric acid gave the following compounds, which were recrystallized from methanol.

302 4 - (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenylmorpholine monotartrate (mp 147-148 ° C).

303 1,1-Dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine monotartrate (mp 183-184 ° C).

-117304 1,1-dimethyl-2- (2-morpholinophenyl) guanidine monotartrate (mp 184-185 ° C).

Examples 305 and 306

Methanol and acetyl chloride were regressed for 30 min to give hydrogen chloride, which reacted with the products of Examples 248 and 301 to give the products listed below. The product was recrystallized from the solvents indicated in parentheses.

305 1,1-Dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine monohydrochloride (mp 161-162 ° C) (1: 1 mixture of isopropanol and ether).

306 1,1-Dimethyl-2- (2-morpholinophenyl) guanidine monohydrochloride (mp 200-201 ° C) (isopropanol).

Example 307

The reaction of the product of Example 301 in acetone with concentrated sulfuric acid gave 1,1-dimethyl-2- (2-morpholinophenyl) guanidine hemisulfate (mp 234-235 ° C), which was recrystallized from a 1: 1 mixture of methanol and ether .

Example 308

Reaction of pamoic acid with the product of Example 301 in pyridine gave 1,1-dimethyl-2- (2-morpholinophenyl) guanidine hemipamoate, m.p. Mp 158-160 ° C.

Example 309

A mixture of 1,3-dimethyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4- (2-aminobenzyl) morpholine in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70 ° C. for 20 hours,

-118 gave 4- [2- (1,3-dimethyl-2-imidazolidinylidenamino) benzylmorpholine oline (m.p. 56-58 ° C), which was recrystallized from hexane.

Example 310

A mixture of 1,3-dimethyl-2-imidazolidinone (10.95 g) in benzene (100 ml), 4- (2-amino-4-chlorobenzyl) morpholine (13.6 g) in benzene (50 ml) and phosphorus oxychloride (8.8 ml) was heated at 60-65 ° C for 8 hours to give an oil which was purified by chromatography on an alumina column using hexane, a 9: 1 mixture of hexane and dichloromethane, a 1: 1 mixture of hexane and dichloromethane and then dichloromethane as eluent. The resulting product (3.2 g) was dissolved in methanol (50 ml) and treated with fumaric acid (1.2 g) to give 4- [4-or o-2- (1,3-dimethyl-2-imidazolidinylidenamino) benzylmorpholine monofumarate (m.p. 169-170 [deg.] C.) recrystallized from a 1: 1 mixture of methanol and ether.

Example 311

A mixture of 4- (2-aminobenzyl) morpholine dihydrochloride (10.6 g) and N, N-dimethylcyanamide (4.2 g) in m-cresol (40 ml) was heated at 90-95 ° C for 13 hours to give a solid ( mp 120-121 ° C), one part of which (2 g) was dissolved in methanol (15 ml). Treatment with fumaric acid (0.9 g) gave N, N-dimethyl-N '- [(2-morpholinomethyl) phenylguanidine monofumarate (mp 164-165 ° C) recrystallized from propan-2-ol.

Example 312

A mixture of 4- (2-aminophenyl) morpholine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90-95 ° C for 12 hours to give N- (2-morpholinomethylphenyl) morpho- 119lin-4-carboxamidine (mp 118-119 ° C), which was recrystallized from hexane and then converted to its difumarate salt (mp 166-167 ° C), which was recrystallized from propan-2-ol.

Example 313

The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated below. The term active compound refers to any of the compounds of this invention, but in particular compounds that represent the end products of the preceding Examples.

a) Capsules

In the manufacture of the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are ground and mixed. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose of the active compound or a portion thereof.

b) Tablets

The tablets were obtained from the following ingredients:

Mass fraction

The active compound prepared as in Example 1 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3

The active compound, lactose and part of the starch are crushed and mixed and the resulting mixture granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with magnesium stearate and starch residue. The mixture is then compressed in a tablet machine,

-120 to obtain tablets, each containing a unit dose of the active compound or a portion thereof.

c) Enterologically coated tablets

The tablets are prepared according to the procedure described in b). The tablets were enterologically coated in the usual manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of the active compound is mixed into 1300 parts by weight of the triglyceride base for suppositories and the resulting mixture formulated into suppositories, each containing a therapeutically effective amount of the active ingredient.

Claims (5)

PATENT APPLICATIONS A new hypoglycemic agent, characterized in that it has Formula I and pharmaceutically acceptable salts thereof, in which n = 0 or 1; in which and R ₂ may be the same or different, s represent (a) a C 1-8 aliphatic group which is optionally substituted by methoxy, (b) a cycloalkyl group, or (c) R 16 and R ₂ together with the nitrogen atom to which they are attached form a heterocyclic ring optionally substituted by formula II -N ^B II wherein R represents hydrogen or Cg_g alkyl group, B is a C ₂ _ ₄ alkylene group which is optionally interrupted by an oxygen or sulfur atom, a sulphinyl group or a nitrogen, which is optionally substituted with C ^ _g alkyl group, wherein said alkylene group is optionally substituted by one or more C 1-10 g alkyl groups, or substituents on two adjacent carbon atoms in the alkylene group form a benzene ring, or B represents a C g alkylene group; or Rg is an alkyl group with straight or branched chain or Cg_ ₇ cycloalkyl group or a group of formula III: Γ ^ R ', in which the groups R ^ and R' ₄ represent the same or -122different, H or C 1-4 alkyl group; wherein R8 is hydrogen or a C 1-4 straight or branched chain aliphatic group optionally substituted by methoxy; wherein Rg is (a) hydrogen, (b) a C 1-8 straight or branched chain aliphatic group optionally substituted by an OH group or its acylated derivative, a C 1-6 alkoxy group, a C 1-6 alkylthio group, with an amino group optionally alkylated, with a Cg- ₇ carbocyclic group or CN, or (c) a Cg- ₇ cycloalkyl ring; provided that, when NR ^ R represents a dialkylamino, and where R represents a group of formula (III), at least one of R ^, R _'4, R or R is different from hydrogen; or the Rg group and the Rg group together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV in which Rg, as defined above, Rg and R- q q, which may be the same or different, represent H or alkyl group, which is optionally substituted by methoxy and D is the oxyethylene group, in which the oxygen atom bonded to the carbon atom which carries the group R, and R q, or ^c 2-5 alkylene group which is optionally substituted by one or more Cg_g alkyl groups; or the Rg group and the Rg group together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V You N I R. -123v wherein R is as defined above, is H or C ^ _2 alkyl group, E is a C2-4 alkylene group which is optionally substituted by one or more C ^ _ ₃ alkyl groups; or Rg and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI VI wherein GC ^ _g alkylene group which is optionally interrupted by an oxygen atom, sulfur or nitrogen, which is optionally substituted with C ^ _ ₃ alkyl group, wherein said alkylene groups are optionally substituted by one or more Cj_ ₃ alkyl groups; Ry is H or one or more substituents selected from halogen, C ^ _4 alkyl groups, which are, where appropriate, be substituted by methylthio, C ^ _ ₃ alkoxy groups, C ₃ _ ₃ alkylthio group, a C ₃ _ ₃ alkylsulfinyl groups Cg_ ₃ alkylsulfonyl groups, alkoxycarbonyl groups containing a total of 2 or 3 carbon atoms, trifluoromethyl or cyano. 2. Compounds of formula I in accordance with claim 1, characterized in that n = 0, and R2, which are identical or different, are selected from (a) Ci_ ₃ alkyl groups, each optionally substituted by methoxy ( b) allyl groups and (c) cyclohexyl groups. Compounds of formula I according to claim 2, characterized in that R1 and R2 are both alkyl, allyl or 2-methoxyethyl or R8 is methyl and R2 is 2-methoxyethyl or cyclohexyl. Compounds of formula I according to claim 2, characterized in that the NRgRg group is dimethylamino, diethylamino, diallylamino, (2-methoxyethyl) methylamino, cyclohexylmethylamino or bis (2-methoxyethyl) amino. -1245. Compounds of formula I according to claim 1, characterized in that n = 0, the group -NR- ^ Rg ίθ is a heterocyclic ring represented by formula II, Rg represents H or methyl, and B represents a group selected from - (CH ₂ ) ₂ ~, -CHMeCH ₂ -, o-phenylene, - (CH ₂ ) ₃ ~, -CH ₂ CHMeCH ₂ -, - (CH ₂ ) ₄ -, -CH ₂ OCH ₂ -, -CHMeOCHMe-, -CH ₂ -SCH ₂ ~, -CH ₂ S (O) CH ₂ ~. -CH ₂ NMeCH ₂ ~ or -ch = chch ₂ -. Compounds of formula I according to claim 5, characterized in that the group NR 1 -R 8 is 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methyl-piperidino, 1-hexahydroazepinyl, morpholino, 2, 6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl or 1- (1,2,5,6-tetrahydro) -pyridyl. 7. Compounds of Formula I v accord by claim 1, marked with by being n = 1, the group NR- ^ R ₂ is morpholino but tiamor- folino. 8. Compounds of formula I v accord by claim 1, marked with because Rg is methyl, ethyl, propil, isopropyl, butyl, t-butyl. pentyl, cyclohexyl, amino, methylamino, dimethylamino or ethylamino. Compounds of formula I according to claim 1, wherein R8 is H, methyl, ethyl or methoxyethyl. Compounds of formula I according to claim 1, characterized in that Rg is hydrogen or a C 1-6 alkyl straight or branched chain alkyl group optionally substituted by a hydroxyl group or an acylated derivative thereof by methoxy, methylthio , dimethylamino, phenyl or cyano, Rg is a straight or branched Cg_g alkenyl group, or Rg is a Cg_g cycloalkyl group. -12511. Compounds of formula I according to claim 10, wherein R8 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl. tert-butyl. pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, benzyl, 2-phenylethyl, 2-cyanoethyl, allyl, 2-methylallyl, cyclopentyl or cyclohexyl. Compounds of formula I according to claim 1, characterized in that the group -N = C (Rg) NRgRg: acetamidino, N-methylacetamidino, N, N-dimethylacetamidino, N, N-diethylacetamidino> N- (2-acetyloxyethyl) acetamidino, N-butylacetamidino, N-pentylacetamidino, N-methylpropionamidino, N, N-dimethylpropionamidino, N-ethylpropionamidino, butyramidino, N-methylbutyramidino, N, N-dimethylbutyramidine, N-ethylbutyramidine, isobutyramidine, N-methylisobutyramidino, N, N-dimethylisobutyramidine, valeramidine, N-methylvaleramidino, N, N-dimethylvaleramidine pivalamidine, N-methylpivalamidino, N, N-dimethylpivalamidino, N-methylpropamidino, -126N-methylcyclohexanecarboxamidino, diaminomethyleneamino, N-methylguanidino, N, N-dimethylguanidino, N, N'-dimethylguanidino, N-ethylguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N, N-diethylguanidino, N, N'-diethylguanidino, N, N ', N'-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethyl-N'-methylguanidino, 1-ethyl-1,3,3-trimethylguanidino, 1-butyl-1,3,3-trimethylguanidino, N-methyl-N-propylguanidino, N-butyl-N-methylguanidino, N-sec-butyl-N'-methylguanidino, N-tert-butyl-N'-methylguanidino, N-isobutyl-N'-methylguanidino, N-butyl-N'-methylguanidino, N-butyl-N'-ethylguanidino, N-methyl-N'-pentylguanidino, N-cyclopentyl-N'-methylguanidino, N- (2-methoxyethyl) guanidino, N- (2-methoxyethyl) -N-methylguanidino, N- (2-methoxyethyl) -N'-methylguanidino, N-ethyl-N- (2-methoxyethyl) guanidino, Ν, Ν-bis (2-methoxyethyl) guanidino, N-methyl-N- (2-methylthioethyl) guanidino, N-allyl-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino and N, N-diallylguanidino. -12713. Compounds of formula I in accordance with claim 1, characterized in that the groups R and R together with the carbon atoms and nitrogen atoms to which they are bonded, form a heterocyclic ring of formula IV, Rg and R _lo, which may be identical or different, represent H or C 1-3 alkyl groups optionally substituted by methoxy, D is selected from - (CH ₂ ) ₂ -, - (CH ₂ ) g -, - (CH ₂ ) ₄ -, - (CH ₂ ) g ~, -CH ₂ CMe ₂ - or -O (CH ₂ ) ₂ ~ and the group Rg is H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl. Compounds of formula I according to claim 13, characterized in that formula IV represents; 2- pyrrolidinylidene, 1-methyl-2-pyrrolidinylidene, 3- methyl-2-pyrrolidinylidene, 1-ethyl-2-pyrrolidinylidene, 1-isopropyl-2-pyrrolidinylidene, 1-cyclohexyl-2-pyrrolidinylidene, 1- (2-methoxyethyl) -2-pyrrolidinylidene, 1,3- dimethyl-2-pyrrolidinylidene, 5.5- dimethyl-2-pyrrolidinylidene, 1.3.3- trimethyl-2-pyrrolidinylidene, 1.5.5- trimethyl-2-pyrrolidinylidene, 3-isopropyl-1-methyl-2-pyrrolidinylidene, 1- ethyl-3,3-dimethyl-2-pyrrolidinylidene, 3.3-diethyl-1-methyl-2-pyrrolidinylidene, 2- piperidinylidene, 1-methyl-2-piperidinylidene, 1.3- dimethylpiperidinylidene, 1-ethyl-2-piperidinylidene, 1-isopropyl-2-piperidinylidene, 1- (2-cyanoethyl) -2-piperidinylidene, 1- (2-acetoxyethyl) -2-piperidinylidene, 3- (2-methoxyethyl) -1-methyl-2-piperidinylidene, 2- hexahydroazepinylidene, -1281- methyl-2-hexahydroazepinylidene, 2- octahydroazocinylidene or 3- morpholinylidene. Compounds of formula I according to claim 1, characterized in that the groups Rg and Rg together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V, E is -CH ₂ CH ₂ -, -CMe ₂ CH ₂ -, -CHMeCHMe-, - (CH ₂ ) ₃ -, CHMeCH ₂ ~ or - (CH ₂ ) ₂ -, R 4 is H, methyl or ethyl and R 8 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl. Compounds of formula I according to claim 15, characterized in that formula (V) represents: 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, 1- (n-butyl) -2-imidazolidinylidene, 1-isobutyl-2-imidazolidinylidene, 1-pentyl-2-imidazolidinylidene, 1-allyl-2-imidazolidinylidene, 1- (2-methylallyl) -2-imidazolidinylidene, 1- (2-hydroxyethyl) -2-imidazolidinylidene, 1- (2-hydroxyethyl) -3-methyl-2-imidazolidinylidene, 1- (2-acetoxyethyl) -2-imidazolidinylidene, 1- (2-benzoyloxyethyl) -2-imidazolidinylidene, 1- (2-benzoyloxyethyl) -3-methyl-2-imidazolidinylidene, -1294,5-dimethyl-1- (2-hydroxyethyl) -2-imidazolidinylidene, 1- (2-methoxyethyl1-2-imidazolidinylidene, 1- (2-methoxyethyl) -3-methyl-2-imidazolidinylidene, 1-cyclohexyl-2-imidazolidinylidene, 1-benzyl-2-imidazolidinylidene, 1- (2-phenylethyl) -2-imidazolidinylidene, 1- (2-dimethylaminoethyl) -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-diazacycloheptan-2-ylidene Compounds of formula I according to claim 1, characterized in that Rg and Rg together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI and G represents a group selected from - (O) 4 -, - (CH ₂ ) ₂ O (CH ₂ ) ₂ -, - (CH ₂ ) ₂ S (CH ₂ ) ₂ -, - (CH ₂ ) ₂ NMe (CH ₂ ) 2- (CH ₂ ) ₂ CHMe (CH ₂ ) ₂ - or -CH ₂ CHMeOCHMeCH ₂ -. Compounds of formula I according to claim 17, characterized in that the group NRgRg is 1-pyrrolidinyl, piperidino, 4-methylpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholine or 4-methyl-1-piperazinyl. Compounds of formula I according to claim 17, characterized in that the group -N = C (Rg) NRgRg: N, N- (3-oxapentamethylene) guanidino, -1301, 1-dimethyl-3,3- (3-oxapentamethylene) guanidino, N, N- (2,4-dimethyl-3-oxapentamethylene) guanidino, N, N- (3-thiapentamethylene) guanidino, N, N- (3-methylpentamethylene) guanidino, N, N- (N-methyl-3-azapentamethylene) guanidino, N-methyl-N ', N'-tetramethyleneguanidino, N, N-pentamethyleneguanidino, 1,1-dimethyl-3,3-pentamethyleneguanidino. Compounds of formula I according to claim 1, characterized in that it represents H or one or more substituents selected from fluoro, chloro, methyl, ethyl, isobutyl, methylthio-methyl, methoxy, methoxycarbonyl, methyl-thio, methylsulfinyl, methylsulfonyl, trifluoromethyl or cyano. Compounds of formula I according to claim 1, characterized in that n = O, -NR ^ R 2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R 8 is -NH 2, R 5 is a C _1-4 aliphatic group. Rg is Cg_ ₄ aliphatic group, if necessary substituted by methoxy or methylthio, or R and R together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio. Compounds of formula I according to claim 21, characterized in that Rg is methyl, ethyl or allyl, Rg is methyl, ethyl, allyl, methoxyethyl or methylthioethyl or the group -NRgRg is morpholino or thiamorpholino and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio. Compounds of formula I according to claim 1, characterized in that n = O, -NR ^ Rg is morpholino or thiamorpholine, Rg is a group of formula III in which R _{4 is an} alkyl group and R ₄ 'is H , Rg is H, Rg is Cg_ ₄ aliphatic group, which is optionally substituted with methoxy, Ry is H, fluoro, methyl, -131methylthio or methylthiomethyl. Compounds of formula I according to claim 23, characterized in that it is methyl, R ₄ 'is H, Rg is H, and R _g is methyl, butyl, t-butyl, or methoxyethyl. 25. Compounds of formula I in accordance with claim 1, characterized in that n = 0, -NR ^ R l ^e morpholino or tiamorfolino, Rg is C ^ _ ₄ alkyl group, R g and R _g are H, R ? and H is fluoro, methyl, methylthio or methylthiomethyl. Compounds of formula I according to claim 1, characterized in that they are selected from the following, such as: 1,1- dimethyl-2- (2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-fluoro-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (6-methyl-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-ethyl-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-methylthiomethyl-2-morpholinophenyl) guanidine, 1,1-dimethyl-2- (5-methylthio-2-morpholinophenyl) guanidine, 1-ethyl-1-methyl-2- (2-morpholinophenyl) guanidine, 1.1- diethyl 1-2 (2-morpholinophenyl) guanidine, 1- (2-methoxyethyl) -1-methyl-2- (2-morpholinophenyl) guanidine, 1-methyl-1- (2-methylthioethyl) -2- (2-morpholinophenyl) guanidine, 1,1- dimethyl-2- (2-thiamorpholinophenyl) guanidine, 1,1-dimethyl-2- (2-piperidinophenyl) guanidine, 1,1-dimethyl-2- [2- (1-pyrrolidinyl) phenylguanidine, N- (2-morpholinophenyl) morpholine-4-carboxamidine, N- (2-morpholinophenyl) thiamorpholine-4-carboxamidine, 1-butyl-3-methyl-2- (2-morpholinophenyl) guanidine, 1-methyl-3-tert-butyl-2- (2-morpholinophenyl) guanidine 1,3-dimethyl-2- (2-thiamorpholinophenyl) guanidine, N- (2-morpholinophenyl) acetamidine, -132Ν- (4-methyl-2-morpholinophenyl) acetamidine, N- (2-morpholinophenyl) pivalamidine and their pharmaceutically acceptable salts. Pharmaceutical compositions comprising a therapeutically active amount of a compound of formula I according to any one of the preceding claims, in combination with a pharmaceutically acceptable diluent or carrier. 28. A process for the preparation of novel hypoglycemic agents of the formula: and pharmaceutically acceptable salts thereof, in which n = 0 or 1; R ₂ and R ₂ , which may be the same or different, represent a C 1-8 aliphatic group which is optionally substituted by methoxy, a C _3-7 cycloalkyl group, or R 1. i ^{n R} 2 together with the nitrogen atom to which they are attached form, if necessary, a substituted heterocyclic ring of formula CHR (II) wherein R represents hydrogen or Cg_g alkyl group, B is C ₂ _4 alkylene group which is optionally interrupted by an oxygen or sulfur atom, a sulphinyl group or a nitrogen, which is optionally substituted with C ^ _g alkyl group, wherein said alkylene groups are optionally substituted by one or more C ^ _ ₃ alkyl groups, or substituents on two The -133 adjacent C atoms in the alkylene group form a benzene ring, or B represents a Cg alkenylene group; R 8 is a C _1-7 alkyl group with a straight or branched chain or a C _3-7 cycloalkyl group or a group of the formula: / ^R 4 - N (m) ^R 4 in which ^R 4 and R ₁₄ are the same or different, hydrogen or alkyl; Rg is hydrogen or A C 1-4 straight or branched aliphatic group optionally substituted by methoxy; Rg is hydrogen, a straight or branched chain aliphatic group optionally substituted by a hydroxyl group or an acylated derivative thereof, a C 1-6 alkoxy group, a C 1-6 alkylthio group, an amino group optionally alkylated, with Cg_ ₇ carbocyclic group or by cyano, or Cg_ ₇ cycloalkyl ring; provided that when NR- ^ Rg is a dialkylamino and when Rg is a group of formula (III), at least one of R ^, R '^, Rg or Rg must be other than hydrogen; or Rg and Rg together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of the formula: N ^R 6 where R 8 is as defined above, R 8 and R 4 O 'may be the same or different represent hydrogen or a C 1-4 alkyl group which is optionally substituted by methoxy and D is an oxyethylene group in which the atom is oxygen bonded to a carbon atom bearing a substituent Rg and R ^ q or a Cg_g alkylene group which is optionally substituted by one or more C ^ _g -134alkyl groups; or the groups Rg and Rg together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of the formula: R N I R (V) wherein R is as defined above, and Rgg is hydrogen or Cg_ ₃ alkyl group, E represents a C ₃ -4 ^a lkil ^ens to ° group, which is optionally substituted by one or more Cg_ ₃ alkyl groups; or Rg and Rg, together with the nitrogen atom to which they are attached, form a heterocyclic ring of the formula: wherein GC ^ _g alkylene group which is optionally interrupted by an oxygen atom, sulfur or nitrogen, which is optionally substituted with Cg_g alkyl group, wherein said alkylene groups are optionally substituted by one or more Cg_ ₃ alkyl groups; and R7 represents hydrogen, or where appropriate, one or more substituents selected from halogen, Cg_4 alkyl groups which are, where appropriate, be substituted by methylthio, Cg_ ₃ alkoxy groups, Cg_ ₃ alkylthio groups Cg_ ₃ alkylsulfinyl groups Cg_ ₃ alkylsulfonyl groups, alkoxycarbonyl groups containing a total of 2-3 carbon atoms, trifluoromethyl or cyano, wherein the aminophenyl compound of the formula: R ^{(CH 2 '} n ^NR l ^R 2 (VII) -135v wherein n, R, R and R ₇ are as defined above, is reacted with an amide or urea of the formula: r ₃ .co.nr ₅ r ₆ in which Rg, Rg and Rg are as defined above in the presence of a condensing agent. A method according to claim 28, characterized in that the compound of the formula: R. ^(CH 2 '' ^BR 1 ^R 2 (vn: reacts with a lactam of the formula ^R 9 / ^R 10 o = c (VIII) N I R, in which Rg, Rg, R- ^ g and D, as defined above, are in the presence of a condensing agent; or with a compound of the formula: and R _p R, (ix) where R _g , Rg, R ^ g and D, as defined above, R- ^ g 3 ^is chloro, -O-POClg, -O-SOCl, -OCOCl or -OSOgPh and Βθ is an anion , -136 such as halogen or POCl ₄ ; or with a compound of the formula: (X) R, in which Rg, Rg, R ₁₀ and D, as defined above, is an alkyl group and Βθ is an anion, such as fluoroborate or metosulfate; or when Rg represents hydrogen, with a ketoxime of the formula: HON = C (xi) wherein Rg, R ^ q and D are as defined above in the presence of sulfonyl chloride; or with the urea of the formula: (XII) wherein Rg, Rf and E are as defined above in the presence of a condensing agent. Process according to claim 28 or 29, characterized in that the condensing agent is selected from phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulfonyl chloride. A method according to claim 28, characterized in that -137 consists when Rg and Rg together with the carbon atom and nitrogen to which they are attached form a heterocyclic ring of formula (V) from the reaction of a compound of formula: (XIII) in which n,, Rg and R-y, as defined above, are optionally in the form of a salt in which R1 and R6 are hydrogen atoms, with a diamine of the formula: R ₁₁ NHENHR ₆ (XIV) wherein Rg, R4 and E are as defined above. 32. A method in accordance with claim 28, characterized in that it consists, where R represents an alkyl group with straight or branched chain or Cg_ ₇ cycloalkyl group, and where the group NRgRg represents NH, reacting a compound of the formula: ( ^CH 2) _n ^NR i ^R 2 (VII) nh ₂ optionally in the form of a salt, with a cyano compound of formula RgCN, wherein Rg, as defined above, is optionally in the presence of aluminum chloride. A process according to claim 28, characterized in that when Rg represents NHg, the reaction of a compound of formula (VII), optionally in the form of a salt, with a cyanamide of the formula RgRgNCN, wherein Rg and Rg are as defined above . -13834. The process according to claim 28, characterized in that when Rg represents NH ₂ , the reaction of the compounds of formula: (CH) NR.R2 n 12 R. (xv) NHCN in which n, Rg, R ₂ and R - are as defined above with the amines of the formula NHRgRg, wherein Rg and Rg are as defined above. A process according to claim 28, characterized in that when Rg represents a group of formula (III) in which R1 is alkyl and R4 is hydrogen or alkyl, from the reaction of a compound of formula: R (CH) NRR is known as Z ^ SMe ^{N = C} \ '(XIII) in which R44 represents the group R4 and Rgg is a group R ^, with an amine of the formula HNRgRg, optionally in the presence of a base or in the presence of potassium hydroxide and lead acetate . A process according to claim 28, characterized in that when R 8 represents a group of formula (III) in which R 4 is alkyl and R ₁₄ is hydrogen or alkyl, from the reaction of a thiourea of formula: R. NH.CS.N (XVI) -139 in which n, Rg, R ₂ and R ^ are as defined above, Rg ₄ is a group Rg and Rgg is a group R ' ₄ , with an amine of the formula HNRgRg, wherein Rg and Rg, as defined above, are required in the presence of base and lead acetate. A process according to claim 28, characterized in that when Rg represents a group of formula (III) in which Rg is alkyl and R'g is hydrogen, and when Rg represents hydrogen, a reaction of a carbodiimide of the formula: χΧχ / ^(CH 2 ⁾ n ^NR l ^R 2 (XVII) in which n, Rg, R ₂ and R-? , as defined above, with an amine of formula H ₂ NRg, wherein Rg is as defined above. 38. The process according to claim 28, characterized in that when n = 0 and when the group NRgR ₂ represents morpholino, thiamorpholino, l-pyrrolidinyl or piperidino, from the reaction of a compound of the formula: NH. (XVIII) N □ ^R 6 in which Rg is disubstituted Rg, Rg and R-y, as defined above, are compounds of the formula: k (ch ₂ ) ₂ l (ch ₂ ) ₂ r (XIX) where K is a prominent group and L is -O-, -S-, chemical or -CH ₂ -. embroidery -14039. The use of the compounds of formula I according to any one of claims 1 to 26, characterized in that these compounds are used in the manufacture of medicines for the treatment of diabetes. Use of compounds of formula I according to any one of claims 1 to 26, characterized in that these compounds are used in the manufacture of medicaments for the treatment of hyperglycemia.