KR0168398B1 - Process for preparing hypoglycemic compounds - Google Patents

Abstract

None.

Description

Compounds useful for the treatment of diabetes and hyperglycemia and preparation methods thereof

The present invention relates to novel therapeutic agents useful as therapeutic agents for diabetes, in particular hypoglycemic agents, methods of preparing such agents and pharmaceutical compositions containing them.

The present invention provides a compound of formula (1) and pharmaceutically acceptable salts thereof.

(II)의 임의로 치환된 헤테로사이클릭 환(여기서, R₈은 H 또는 탄소수 1 내지 3의 알킬 그룹을 나타내고; B는 탄소수 1 내지 3의 알킬 그룹에 의해 임의로 치환되고 산소, 황, 설피닐 또는 질소가 임의로 개입된 탄소수 2 내지 4의 알킬렌 그룹(이러한 알킬렌 그룹은 탄소수 1 내지 3의 하나 이상의 알킬 그룹에 의해 임의로 치환되거나 이의 2개의 인접한 탄소원자 상의 치환체가 벤젠환을 형성한다)이거나, 탄소수 3의 알케닐렌 그룹을 나타낸다)을 형성하고, R₃은 탄소수 1 내지 7의 직쇄 또는 측쇄 알킬 그룹, 탄소수 3 내지 7의 사이클로알킬 그룹 또는 일반식

(III)의 그룹(여기서, R₄ 및 R'₄는 동일하거나 상이하며, H 또는 탄소수 1 내지 4의 알킬 그룹이다)이며, R₅는 H 이거나, 메톡시에 의해 임의로 치횐된 탄소수 1 내지 4의 직쇄 또는 측쇄 지방족 그룹이고, R₆은 (a) H, (b) 하이드록시 또는 이의 아실화된 유도체, 탄소수 1 내지 3의 알콕시 그룹, 탄소수 1 내지 3의 알킬티오 그룹, 임의로 알킬화된 아미노 그룹, 탄소수 3 내지 7의 카보사이클릭 그룹 또는 시아노에 의해 임의로 치환된 탄소수 1 내지 6의 직쇄 또는 측쇄 지방족 그룹 또는 (c) 탄소수 3 내지 7의 사이클로알킬환이거나; 단, NR₁R₂가 디아킬아미노이고, R₃이 일반식(III)의 그룹인 경우, R₄ R'₄, R₅또는 R₆중의 하나 이상은 H 이외의 것이고, 그룹 R₃ 및 R₅는 이들의 결합된 탄소 및 질소원자와 함께Wherein n is 0 or 1, R ₁ and R ₂ are the same or different, (a) an aliphatic group having 1 to 3 carbon atoms optionally substituted by methoxy, (b) a cycloalkyl group having 7 to 7 carbon atoms, or (c) a general formula with a nitrogen atom bound to these

Optionally substituted heterocyclic ring of (II), wherein R ₈ represents H or an alkyl group of 1 to 3 carbon atoms; B is optionally substituted by an alkyl group of 1 to 3 carbon atoms and is selected from oxygen, sulfur, sulfinyl or An alkylene group having 2 to 4 carbon atoms optionally interrupted by nitrogen (the alkylene group is optionally substituted by one or more alkyl groups having 1 to 3 carbon atoms or a substituent on two adjacent carbon atoms forms a benzene ring), or R 3 represents a straight or branched alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a general formula

Is a group of (III), wherein R 'and R' ₄ are the same or different and are H or an alkyl group having 1 to 4 carbon atoms, and R ₅ is H or an alkyl having 1 to 4 carbon atoms optionally substituted by methoxy; A straight or branched aliphatic group, R ₆ represents (a) H, (b) hydroxy or an acylated derivative thereof, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, an optionally alkylated amino group, A C1-6 straight or branched chain aliphatic group optionally substituted by a carbocyclic group having 3 to 7 carbon atoms or cyano or (c) a cycloalkyl ring having 3 to 7 carbon atoms; Provided that when NR ₁ R ₂ is dialkylamino and R ₃ is a group of formula (III), at least one of R ₄ R ' ₄ , R ₅ or R ₆ is other than H, and groups R ₃ and R ₅ are With the combined carbon and nitrogen atoms

General formula

(V) (여기서, R₆은 상기 정의한 바와 같고, R₁₁은 H 또는 탄소수 1 내지 2의 알킬이며, E는 탄소수 1 내지 3의 하나 이상의 알킬 그룹에 의해 임의로 치환된 탄소수 2 내지 4의 알킬렌 그룹이다)의 헤테로사이클릭환을 형성하거나; R₅및 R₆은 이들과 결합하고 있는 질소원자와 함께 일반식

(VI)(여기서, G는 탄소수 1 내지 3의 하나 이상의 알킬 그룹에 의해 임의로 치환되고, 산소, 황 또는 질소가 임의로 개입된 탄소수 4 또는 5의 알킬렌 그룹이다)의 헤테로사이클릭환을 형성하며; R₇은 H이거나, 할로, 메틸티오에 의해 임의로 치환된 탄소수 1 내지 4의 알킬그룹, 탄소수 1 내지 3의 알콕시 그룹, 탄소수 1 내지 3의 알킬티오 그룹, 탄소수 1 내지 3의 알킬 설피닐 그룹, 탄소수 1 내지 3의 알킬설포닐 그룹, 총 탄소수 2 또는 3의 알콕시카보닐, 트리플루오로메틸 및 시아노로 이루어진 그룹 중에서 선택된 하나 이상의 임의 치환제를 나타낸다.Wherein R ₆ is as defined above and R ₉ and R ₁₀ are the same or different and are H or an alkyl group of 1 to 4 carbon atoms optionally substituted with methoxy, and D is an oxygen atom in groups R ₉ and R Or an oxyethylene group bonded to a carbon atom linked to ₁₀ or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms); With the carbon and nitrogen atoms to which groups R ₃ and R ₅ are attached thereto

(V) wherein R ₆ is as defined above, R ₁₁ is H or alkyl of 1 to 2 carbon atoms, E is an alkylene of 2 to 4 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms Heterocyclic ring); R ₅ and R ₆ together with the nitrogen atoms which are bound to them are of the general formula

To form a heterocyclic ring of (VI), wherein G is optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms and is an alkylene group of 4 or 5 carbon atoms optionally interrupted by oxygen, sulfur or nitrogen; ; R ₇ is H, or halo, alkyl group having 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy group having 1 to 3 carbon atoms, alkylthio group having 1 to 3 carbon atoms, alkyl sulfinyl group having 1 to 3 carbon atoms, One or more optional substituents selected from the group consisting of alkylsulfonyl groups having 1 to 3 carbon atoms, alkoxycarbonyls having 2 or 3 carbon atoms, trifluoromethyl and cyano.

n is 0, R ₁ and R ₂ are the same or different, and are selected from (a) an alkyl group having 1 to 3 carbon atoms optionally substituted by methoxy, (b) allyl group, or (c) cyclohexyl group ( Preferred are the compounds of I). In particularly preferred compounds of formula (I), n is 0, R ₁ and R ₂ are both alkyl, allyl or 2-methoxyethyl or R ₁ is methyl and R 2 is 2-methoxyethyl or cyclohexyl. In particularly preferred compounds of formula (1), n is 0 and group NR ₁ R 2 is dimethylamino, diethylamino, diallylamino, (2-methoxyethyl) methylamino, cyclohexylmethyl amino or bis (2 -Methoxyethyl) amino.

In a preferred compound of formula (I), n is 0, group NR ₁ R ₂ is a heterocyclic ring of formula (II), R ₈ is H or methyl, and B is-(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 -and -CH = CHCH ₂ -represents a group selected from. In particularly preferred compounds of formula (1) wherein n is 0 and group NR ₁ R 2 is a group of formula (II), group NR ₁ R 2 is 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, py Ferridino, 4-methylpiperidino, 1-hexahydro azepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1-oxide, 2-isoindoli Nyl, 4-methyl-1-piperazinyl or 1- (1,2,5,6-tetrahydro) pyridyl. In a preferred compound of formula (1) wherein n is 1, the group NR ₁ R ₂ is morpholino or thiamorpholino.

In a preferred compound of formula (1) wherein R ₃ is an alkyl group, group R ₃ contains 1 to 5 carbon atoms (eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl). In a preferred compound of formula (I) wherein R ₃ is a cycloalkyl group, the cycloalkyl group is cyclohexyl.

In preferred compounds of formula (I) wherein R ₃ is a group of formula (III), R 'and R ₄ ′ are H. methyl or ethyl (eg R ₃ is amino, methylamino, dimethylamino or ethylamino )to be.

R ₅ is in the unity of the general formula (I) do not form a heterocyclic ring part, the group R ₅ is H or methoxy-substituted alkyl group having 1 to 3 carbon atoms optionally substituted by (e.g., methyl or ethyl; methoxy Examples of when substituted by methoxyethyl) or allyl.

In preferred compounds of formula (I), R ₆ is H or a straight or branched chain alkyl group having 1 to 5 carbon atoms (e.g. methyl, ethyl.propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert- Butyl or pentyl), which is optionally substituted by hydroxy (eg R ₆ is 2-hydroxyethyl, 3-hydroxy propyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy- 2-methylpropyl, or 2,3-dihydroxypropyl), or an acylated hydroxy derivative such as acetyloxy or benzoyloxy (for example R ₆ is 2-acetyloxyethyl or 2-benzoyl Oxyethyl), substituted by methoxy (eg R ₆ is 2-methoxyethyl), substituted by methylthio (eg R ₆ is 2-methylthioethyl), or by dimethylamino or substituted (e.g. R ₆ is 2-dimethylaminoethyl) phenyl Or substituted (e.g. R ₆ is benzyl or a 2-phenylethyl), or are substituted by cyano (e. G. R ₆ is a 2-cyanoethyl), and R ₆ is a straight chain of 3 to 6 carbon atoms Or branched alkylene groups (eg R ₆ is allyl or 2-methylallyl).

In a preferred compound of formula (I) in which R ₆ is a cycloalkyl group, R ₆ contains 5 to 6 carbon atoms (eg R ₆ is cyclopentyl or cyclohexyl).

In a particularly preferred compound of formula (I) in which R ₃ and R ₅ do not form a heterocyclic ring with the nitrogen and carbon atoms to which they are attached, the group -N = C (R₃) NR ₅ R ₆ is

Acetamidino,

N-methylacetamidino.

N, N-dimethylacetamidino,

N, N-diethylacetamidino,

N- (2-acetyloxyethyl) acetamino,

N-butyl acetamidino,

N-pentylacetamino,

N-methylpropionamidino,

N, N-dimethylpropionamidino,

N-ethylpropionamidino,

Butyr Amidino,

N-methylbutyramidino,

N, N-dimethylbutyramidino,

N-ethylbutyramidino,

Isobutyramidino,

N-methylisobutyramidino,

N, N-dimethylisobutyramidino,

Valeramidino,

N-methyl valeleramidino,

N, N-dimethylvaleramidino,

Pivalamidino,

N-methylpivalamidino,

N, N-dimethylpivalamidino,

N-methylcaproamidino,

N-methylcyclohexanecarboxamidino,

Diaminomethyleneamino,

N-methylguanidino,

N, N-dimethylguanidino,

N, N'-dimethylguanidino,

N-ethylguanidino,

N-butyl guanidino,

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-tert-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,

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

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

N-allyl-N-methylguanidino,

N-allyl-N'-methylguanidino,

1-allyl-1,3,3-trimethylguanidino, or

N, N-diallylguanidino.

In any of the preferred compounds of formula (I) in which groups R ₃ and R ₅ together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula (IV), R ₉ and R ₁₀ are the same Alkyl groups having 1 to 3 carbon atoms (eg methyl, ethyl or isopropyl, optionally substituted by methoxy, which are H or different), for example R ₉ and / or R ₁₀ is methoxyethyl), D is-(CH ₂ ) ₂ -,-(CH ₂ ) ₃ -,-(CH ₂ ) ₄ -,-(CH ₂ ) _5- , -CH ₂ CMe ₂ -or Is selected from -O (CH ₂ ) _2- , and group R ₆ is preferably H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl. In particularly preferred compounds of general formula (I), general formula (IV)

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-dimethylpyridinylidene,

1-ethyl-2-piperidinylidene,

1-isopropyl-2-pyridinylidene,

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

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

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

2-hexahydroazinylidene,

1-methyl-2-hexahydroazinylidene,

2-octahydroazononylidene or

3-morpholinylidene.

In a second group of preferred compounds of formula (I) in which groups R ₃ and R ₅ 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 ) ₄ , R ₁₁ is H, methyl or ethyl, R ₆ is H, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-bezoyloxyethyl, 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 general formula (I), general 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) -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-dimethyl-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.

In a preferred compound of formula (I) wherein R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI), G is-(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 —} group. In particularly preferred compounds, group NR ₅ R ₆ is 1-pyrrolidinyl, piperidino, 4-methylpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholino or 4-methyl- 1-piperazinyl. In a particularly preferred compound of formula (I) in which R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI), the group -N = C (R₃) NR ₅ R ₆ is

N, N- (3-oxapentamethylene) guanidino,

1,1-dimethyl-3,3- (3-oxatamtamethylene) 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'-tetramethyleneguanidine.

N, N-pentamethyleneguanidino,

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

In a preferred compound of formula (I), R 7 is H or fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, methoxycarbonyl, methylthio, methylsulfinyl, methylsulfonyl , At least one substituent (preferably one or two substituents) selected from trifluoromethyl and cyano.

Specific compounds of the general formula (I),

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

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

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

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

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

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

N- (2-pyridinophenyl) 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-ethyl-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,

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

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

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

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

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

4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) benzyl] morpholine,

4- [4-chloro-2- (1,3-dimethyl-2-imidazolidinylideneamino) benzyl] morpholine,

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

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

One group of preferred compounds of formula (I) is n is 0, -NR ₁ R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, and R ₃ is -NH ₂ R ₅ is an aliphatic group having 1 to 4 carbon atoms (eg methyl, ethyl or allyl), and R ₆ is an aliphatic group having 1 to 4 carbon atoms optionally substituted by methoxy or methylthio (eg methyl, ethyl, Allyl, methoxyethyl or methylthio ethyl), or R ₅ and R ₆ together with the nitrogen atom to which they are attached form a heterocyclic ring of formula (VI) (eg morpholino or thiamorpholino) And a compound of formula (I) wherein R ₇ is H, fluoro, chloro, methyl, ethyl, methylthio methyl or methylthio.

Certain compounds belonging to one group of preferred compounds,

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-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) phenyl] guanidine,

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

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

In a preferred compound of formula (I), the second group is n is 0, -NR ₁ R ₂ is morpholino or thiamorpholino, and R ₃ is a group of general formula (III), wherein An alkyl group having 1 to 4 carbon atoms (eg methyl) and R ₄ 'is H], R ₅ is H and R ₆ is an aliphatic group having 1 to 4 carbon atoms optionally substituted by methoxy (eg methyl , Butyl or tert-butyl, substituted in methoxy, for example R ₆ is methoxyethyl) and R ₇ is H, fluoro, methyl, methylthio or methylthiomethyl It includes.

Specific compounds belonging to the second group of preferred compounds,

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-morpholino-phenyl) 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 and pharmaceutically acceptable salts thereof.

Other preferred compounds of formula (I) are those in which n is 0, -NR ₁ R ₂ is morpholino, thiamorpholino, morpholinomethyl or thiamorpholinomethyl, and R ₃ is 1-4 carbon atoms. Alkyl groups such as methyl and t-butyl, R ₅ and R ₆ are H and R ₇ is H, fluoro, methyl, methylthio or methylthiomethyl.

Certain compounds belonging to other groups of preferred compounds,

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) acetamide,

N- (2-thiamorpholinophenyl) acetamidine,

N- (2-morpholinomethylphenyl) acetamidine,

N- (2-morpholinophenyl) pivalamidine,

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

Compounds of formula (I) may exist as salts with pharmaceutically acceptable acids. Examples of such salts include acidic amino acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, maleate, acetate, citrate, fumarate, tartrate, succinate, benzoate, pamoate, and glutamic acid. Contains salts. The compounds of formula (I) and salts thereof may be present in the form of solvates (eg hydrates).

Some compounds of formula (I) contain one or more asymmetric carbon atoms and exist in different optically active forms. When the compound of general formula (I) contains one chiral center, the compound is present in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof. If the compound of formula (I) contains one or more chiral centers, the compound may exist in diastereoisomeric form. The present invention includes each of these diastereomeric forms and mixtures thereof.

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

For therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Accordingly, the pharmaceutical compositions of the present invention may take the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable diluents or carriers suitable for use in such compositions are known in the pharmaceutical art. The composition of the present invention may contain 0.1 to 90% by weight of the active compound. Compositions of the present invention are generally prepared in unit dosage form.

Compositions for oral administration are preferred compositions of the invention and are in the form of known pharmaceutical forms for oral administration, such as tablets, capsules, syrups and aqueous or oily suspensions. Excipients used in the formulation of these compositions are excipients known in the pharmaceutical art. Tablets may be prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of a disintegrant such as corn starch and a lubricant such as magnesium stearate and then tableting the mixture by known methods. Tablets may be formulated by methods known to those skilled in the art to slowly release the compounds of the present invention. If desired, such tablets may be provided as enteric skin preparations by known methods using, for example, cellulose acetate phthalate. Similarly, capsules containing active compounds, with or without excipients, such as hard or soft gelatin capsules, can be prepared by conventional methods and, if necessary, provided as enteric skin preparations by known methods. Tablets and capsules may typically contain 50 to 500 mg of the active compound, respectively. Other compositions for oral administration include, for example, aqueous solutions containing the active compounds, aqueous suspensions containing the active compounds in an aqueous medium in the presence of non-toxic suspending agents such as sodium carboxymethylcellulose, and suitable vegetable oils ( For example, horse oil) includes an oily suspension containing a compound of the present invention.

In some formulations, it may be advantageous to use the compounds of the present invention in the form of various fine particles, such as obtained by fluid energy milling.

In the compositions of the present invention, the active compound can be mixed with other pharmacologically active ingredients, if necessary.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) can be used to treat human hyperglycemia. The amount of the compound of formula (I) administered daily in this treatment is 50-3000 mg. Preferred route of administration is oral administration.

The method for preparing the compound of formula (I) is as follows. In another aspect of the present invention, the following method is provided.

The compound of formula (I) is a compound of formula R ₃ CONR ₅ R _{6 in} the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulfonyl chloride It can be prepared by reacting with amide or urea.

Wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and n are as defined above.

Compounds of the general formula (I) which form a ring of the general formula (IV) together with the carbon and nitrogen atoms to which the groups R ₃ and R ₅ are bonded thereto include an aminophenyl compound of the general formula (i), (a) Reacting with a lactam of the general formula in the presence of a condensing agent such as phosphorus oxychloride, thienyl chloride, cyanuric chloride, phosgene, carbon tetrachloride / triphenylphosphine, phosphorus pentachloride or benzenesulfonylchloride, or (b) Reacted with a compound of formula (iii), (c) with a compound of formula (d), or (d) when R ₆ is H, a sulfonyl chloride (e.g., benzene sulfonyl chloride) It can be prepared by reacting with ketoxime of formula (XI) in the presence.

Wherein R ₆ , R ₉ , R ₁₀ and D are as defined above,

R ₁₂ is chloro, -O-POCl _2, and -O-SOCl, -OCOCl, or -OSO ₂ Ph, B ^- is represented by the general formula (Ⅸ) in the halo (for example: Cl ^-) or POCR _l4 ^- anion, such as a In general formula (i), it is an anion like fluoroborate or methosulfate, and R <_13> is an alkyl group.

A compound of formula (I), in which the groups R ₃ and R ₅ form a ring of formula (V) together with the carbon and nitrogen atoms to which they are attached, wherein the amino phenyl compound of formula (V) is oxychloride. It can be prepared by reacting with urea of general formula (XII) in the presence of a condensing agent such as onyl chloride, phosgene, phosphorus pentachloride or benzenesulfonyl chloride.

Wherein R ₆ , E and R ₁₁ are as defined above.

Compounds of formula (I) in which the groups R ₃ and R ₅ together with the carbon and nitrogen atoms to which they are attached form a ring of formula (V), are optionally in salt form (e.g. hydroiodide salts) It can be prepared by reacting a compound of formula (XIII) with a diamine of general formula (XIV).

R ₁ NHENHR ₆ (XIV)

Wherein R ₁ , R ₂ , R ₆ , R ₇ , R ₁₁ and n are as defined above and R ₁₄ and R ₁₅ are H.

The compound of formula (I) wherein R ₃ is a straight or branched chain alkyl group having 1 to 7 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, and group NR ₅ R ₆ is NH ₂ is optionally in salt form (e.g. hydrochloride salt) The compound of phosphorus general formula (VII) can be prepared by reacting with a cyano compound of the general formula R ₃ CN, wherein R ₃ is as defined above, optionally in the presence of aluminum chloride.

Compounds of formula (I) wherein R ₃ is NH ₂ may be prepared by reacting a compound of formula (VII), optionally in salt form (e.g., hydrochloride salt), with a cyanamide compound of formula R ₅ R ₆ NCN have. The reaction can be carried out in a liquid reaction medium (eg m-cresol) or by heating the reactants together in the absence of a liquid carrier.

Compounds of formula (I) wherein R ₃ is NH ₂ may be selected from compounds of formula (XV), optionally in an amine of formula NHR ₅ R _{6 in} a liquid reaction medium such as ethanol, wherein R ₅ , and R ₆ As defined above).

Wherein R ₁ , R ₂ , R ₇ and n are as defined above.

R ₃ is a group of formula (3) (wherein, R ₄ is alkyl and R ₄ 'is H or alkyl), a compound of formula (1) is a compound represented by the general formula (13) (wherein, R ₄ is a group R ₄ and R ₅ is group R ₄ ′), which may be prepared by reacting with an amine of the general formula NHR ₅ R ₆ . The reaction can be carried out optionally in an alcoholic medium (eg ethanol or n-butanol) in the presence of a base such as pyridine or triethylamine or in the presence of potassium hydroxide or lead acetate. If NHR ₅ R ₆ is ammonia, the ammonia can be dissolved in the alcoholic medium and the reaction can be carried out under elevated pressure in a sealed reaction vessel.

R ₃ is a group of formula (III) (wherein, R ₄ is alkyl, R ₄ 'is H or alkyl), a compound of general formula (I) of the general formula NHR a thiourea of the general formula (XVI) ₅ It can be prepared by reacting with an amine of R ₆ .

Wherein R ₁ , R ₂ , R ₇ and n are as defined above, R ₁₄ is a group R ₄ and R ₁₅ is a group R ₄ ′.

The reaction can be carried out in the presence of a base (eg potassium hydroxide or potassium carbonate) and lead acetate. If HNR ₅ R ₆ is ammonia, the ammonia can be dissolved in alcoholic medium (eg ethanol) and the reaction can be carried out under elevated pressure in a vessel.

A compound of formula (1) wherein R ₃ is a group of formula (III) wherein R ₄ is alkyl and R ₄ ′ is H and a compound of formula (1) wherein R ₅ is H are represented by Can be prepared by reacting the carbodiimide of XVII) with an amine of the general formula H ₂ NR ₆ , wherein R ₆ is as defined above.

Wherein R ₁ , R ₂ , R ₄, R ₇ and n are as defined above.

A compound of formula (1) wherein n is 0 and NR ₁ R ₂ is a morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino group is a compound of formula (XIX) It can be prepared by reacting with a disubstituted compound of.

Wherein R ₃ , R ₅ , R ₆ and R ₇ are as defined above, K is a leaving group such as halo (eg bromo or chloro) or tosyloxy, and L is -0-, -S- , Direct bond or -CH _2- .

A compound of formula (I) wherein R ₃ is a group of formula (III) wherein R ₄ is propyl and R ₄ ′ is H and a compound of formula (I) wherein R ₅ is H and R ₆ is propyl The compound comprises an amine of the formula H ₂ NR ₆ , wherein R ₆ is propyl, of thiourea of formula (XII), wherein R ₁₄ and R ₁₅ are both methyl in the presence of potassium hydroxide and lead acetate. It can be prepared by reacting with. In this reaction the ano group -NHR ₆ replaces both the thioxo group and the dimethylanino group.

R ₃ is a group and R ₄ is methyl in the formula (III), R ₄ 'is H the compounds of formula (I) R ₅ is H and R ₆ is methyl may be represented by the general formula H ₂ NR _6-amine ( Wherein R ₆ is methyl, prepared by reacting with a compound of formula XIII, wherein group NR ₁₄ R ₁₅ is butylamino. In this reaction the amino group -NRHR ₆ replaces both the methylthio group and the group -NR ₁₄ R ₁₅ .

Compound of formula (I) NR ₁ R ₂ is thiazol-morpholino-1-oxide group is a compound represented by the general formula (I) (wherein, -NR ₁ R ₂ is a poly-thiazol know furnace) oxide (e. For example using sodium metaperiodate).

R ₆ of formula (1) is substituted by the acyl group, the compound is a compound represented by the general formula (I) corresponding to (wherein, R ₆ is substituted by hydroxy), the acylation (e.g. acetylation or benzoyl It can be prepared by the).

R ₇ compounds of general formula (I), the alkyl sulfinyl group is to be prepared by the compound oxide (where, R7 is an alkylthio group) (for example, use of sodium meta-periodate) of formula (I) Can be.

Compounds of formula (VII) may comprise (a) hydrogen and Raney nickel catalysts, (b) hydrogen and palladium / carbon catalysts, (c) sodium sulfite in the presence of nitro groups of compounds of formula (XX) , (d) tin chloride dihydrate in hydrochloric acid, ethyl acetate or ethanol or (e) iron.

Wherein R ₁ , R ₂ , R ₇ and n are as defined above.

Compounds of the general formula (IX) wherein R ₁₂ is a group of the general formulas OPOCl ₂ , OSOCl, OCOCl and OSO ₂ -Ph may be substituted by compounds of the general formula (VIII) with phosphorus oxy chloride, thionyl chloride It can manufacture by reacting with.

The compound of general formula (X) reacts the compound of general formula (VIII) with an alkylating agent such as dialkyl sulfate, trialkyloxonium fluoroborate or boron trifluoride etherate / diazoalkanes and with sodium carbonate or sodium hydroxide solution It can be prepared by basifying.

Compounds of formula (XIII) can be prepared by reacting methyl iodide with thiourea of formula (XVI).

Compounds of the general formula (XV) may contain potassium hydroxide as a general formula (XIII) wherein R ₁₄ and R ₁₅ are both H, or a compound of formula (13) wherein R ₁₄ is benzoyl and R ₁₅ is H, and the presence of lead acetate It can be prepared by reacting under.

Compounds of formula (XV) are prepared by the reaction of thiourea of formula (XVI), wherein R ₁₄ and R ₁₅ are H, with a base such as sodium carbonate and a copper catalyst such as a mixture of cuprous chloride and cupric chloride It can be prepared by reacting with sodium chlorite under.

Thioureas of formula (XVI), wherein R ₁₄ and R ₁₅ are H, can be prepared by reacting ammonia with isothiocyanate of formula (XXI).

Wherein R ₁ , R ₂ , R ₇ and n are as defined above.

Compounds of formula (XVI), wherein R ₁₄ is an alkyl group and R ₁₅ is H, can be prepared by reacting an aminophenyl of formula (VII) with an alkylisothiocyanate of formula R ₁₄ NCS have.

Carbodiimides of the general formula (XVII) can be prepared by reacting thiourea of the general formula (XVI), wherein R ₁₄ is group R ₄ and R ₁₅ is H.

Compounds of formula (XVIII) can be prepared by reducing the compounds of formula (XXII) with, for example, hydrogen and ranickel.

n is 0 and NR ₁ R ₂ is morpholino, thiamorpholino, 1-pyrrolidinyl, or

Compounds of formula (XX), which are piperidino groups, can be prepared by reacting 2-nitroaniline with a compound of formula (XIX). wherein n is 0 and -NR ₁ R ₂ is morpholino, thiamorpholino, 1-pyrrolidinyl, piperidino, 1-hexa-hydroazinyl or 4-phenyl-1-piperazinyl Compounds of (XX) are morpholine, thiamorpholine, pyrrolidine, piperidine, 1-hexahydroazepine and 4-methyl-1-piperazine, respectively, with halogenotrobenzenes (e.g. 2-fluoronitrobenzene Or 2-chloronitrobenzene) and in the presence or absence of a solvent such as benzene, ethanol or acetonitrile.

Compounds of formula (XXI) may be prepared by reacting compounds of formula (VII) with thiophosgene in a liquid reaction medium such as dioxane.

Compounds of formula (XXII) may be prepared by reacting an amide or urea of formula R ₃ CONR ₅ R ₆ with 2-nitroaniline in the presence of a condensing agent such as phosphorus oxychloride or thionyl chloride. Compounds of formula (XXII) may be prepared by reacting amidine or guanidine of formula R ₃ CNHNR ₅ R ₆ with 2-halonitrobenzene, such as 2-fluoronitrobenzene or 2-chloronitrobenzene. .

The hypoglycemic activity of the compounds of formula (I) given in the Examples below is demonstrated by the following test. Fasting for 18 hours with a ratrol of 150-200 g body weight, then subcutaneously injected with glucose (800 mg / 4 ml / kg) and orally administering the compound to be tested (0.2% agar 4 or 5 mg per kg body weight Xmg). Blood was collected by arm and bleeding after 2 and 4 hours and plasma glucose was collected using Beckman's method using the specific glucose oxidase method [Kadish AH, Little RL and Sternberg JC, Clin Chem 14 116 [1968]). Measured on a Beckman glucose analyzer. The percent reduction in plasma glucose is calculated in comparison to control animals that did not administer the compound to be tested but received 0.2% agar homogenate. Compounds are considered to have hypoglycemic activity in this test if they exhibit a plasma glucose reduction of at least 15% at any particular value X of 200 or less at 2 and / or 4 hours.

The results obtained at specific X values of the test are reviewed and the hypoglycemic activity of each compound is classified according to the following criteria. When one or more results are obtained at the property X value, the average of the percent reduction is used to classify the activity of the compound.

A> 25% reduction in both 2 and 4 hours

B decreased by more than 25% in 2 hours but decreased by 25% in 4 hours

C reduced to 2 hours and 15 to 25%, but reduced to more than 25% at 4 hours

D reduced to 15-25% in 2 and 4 hours

E ranged from 15 to 25% in 2 hours but less than 15% in 4 hours

F reduced to 15% or less at 2 hours but reduced to 15% or more at 4 hours The activities of the compounds described in the examples are listed in Table A below.

The present invention will be described by the following examples which are provided for illustration only. The final product of each example is characterized by elemental analysis.

Example 1

A solution of δ-valerolactam (24 g) in anhydrous benzene (100 ml) is cooled to 10 ° C. in ice water and treated with freshly distilled phosphorus oxychloride (22.2 ml) over a period of 10 to 15 minutes under nitrogen. The initially formed white solid changes to a clear yellow oil over 3 hours. A solution of 4- (2-aminophenyl) morpholine (36 g) in anhydrous benzene (150 ml) is added and the mixture is heated at 65 ° C. with stirring for 32 hours. The benzene layer is discarded and the oil is washed twice with benzene (2 x 40 ml), ether (100 ml) is added and treated with 10% aqueous sodium hydroxide solution until the pH is alkaline while stirring the cooled mixture in ice. The aqueous layer is extracted with ether (2 x 100 ml) and the combined ether extracts are washed with water and brine and dried. The solution is filtered and the solvent is removed to give a concentrated oil which is solidified by grinding with hexane. The crude solid is crystallized from hot hexanes to give 4- [2- (2-piperidinylideneano) phenyl] phoroline (melting point 89-90 ° C.).

Example 2

A solution of the product of Example 1 (10.2 g) in anhydrous methanol (30 ml) is treated with fumaric acid (4.6 g). The resulting solid is filtered and crystallized from methanol to give 4- [2- (2-piperidinylideneamino) phenyl] morpholine fumarate as a colorless crystalline solid. [Melting point 210 ° C. (decomposition)]

[Examples 3 to 37]

In a similar manner to the compounds described in Table 1, the aminophenyl compounds of the general formula (VII) (F) for F hours at a temperature of 60 to 70 ° C. in the presence of phosphorus oxychloride (Eml) NR ₁ R ₂ is morpholino (A g in benzene Bml) is prepared by reacting a compound of formula (VIII) (C g in benzene Dml).

Footnote to Table 1

(1) product recrystallized from hexane

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

(3) The product is isolated as a hydroiodide salt thereof, recrystallized from a 1: 1 mixture of methanol and ether.

(4) The coupling reaction is carried out at ambient temperature.

(5) The product is recrystallized from ether.

(6) The compound of formula (8) is dissolved in a mixture of benzene (60 ml) and acetotrile (40 ml).

(7) The product was purified by chromatography on an alumina column using the following eluents in this order: hexane, 1: 9 mixture of dichloromethane and hexane, 3: 7 mixture of dichloromethane and hexane, 1 of dichloromethane and hexane : 1 mixture and dichloromethane

(8) The product is isolated as a monofumarate salt thereof, recrystallized from a 1: 1 mixture of methanol and ether.

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

(10) The coupling reaction is carried out for 24 hours at ambient temperature and 8 hours at 70 ℃.

(11) The product is separated from its propan-2-ol as its fumarate salt recrystallized.

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

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

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

Example 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 substituted with phosphorus oxychloride (1.37 ml) Is reacted with 4- (2-aminophenyl) morpholine (2.49 g) in benzene (30 ml) at 70 ° C. for 12 h. The resulting product is 4- (2- [1-methyl-3- (2-methoxyethyl) -2-piperidinylideneamino] -phenyl) morpholine sesquifumarate (melting point 174 ° C), methanol and ether Recrystallize from a 1: 1 mixture of.

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 added to benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml). 4- (2-aminophenyl) morpholine (8.9 g) was reacted at 70 ° C. for 24 hours for 4- [2- (1-benzyl-3-methyl-2-pyrrolidinylideneamino) phenyl] morpholine (Melting point 96-97 ° C.) is obtained and recrystallized from hexane.

The recrystallized product (2 g) in the above paragraph was heated at reflux with cyclohexene (6 ml), 10% Pd / C (1.5 g) and methanol (100 ml) for 4 hours to give 4- [2- (3 as oil. -Methyl-2-pyrrolidinylidene amino) phenyl] morpholine is obtained. Oil (1 g) was dissolved in methanol (20 ml) and a solution of fumaric acid (0.47 g) in methanol was added to 4- [2- (3-methyl-2-pyrrolidinylideneamino) phenyl] morpholine fumarate (melting point 185 ° C.) is obtained and recrystallized from a 1: 1 mixture of methanol and ether.

[Examples 40 to 62]

In the same manner as described in Example 1, the compounds described in Table II were prepared in which the aminophenyl compounds of the general formula It is prepared by reacting with an amide of the general formula R ₃ CONR ₅ R ₆ (Cg in benzene Dml) for F hour.

Footnotes to Table II

Notes (1) and (8) are as defined in Table I.

(15) The product is separated from methanol as its monofumarate salt recrystallized.

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

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

(18) The product is obtained as monohydrate.

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

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

Example 63

A mixture of N-methylpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) is 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 4 days to give N-methyl-N '-(2-piperidinophenyl) Pivalamidine (melting point 78 ° C.) is obtained and it is recrystallized from hexane. The product is obtained as 0.25 hydrate.

[Examples 64 to 75]

Compounds described in Table III were prepared in the same manner as described in Example 1, in which an aminophenyl compound of the general formula (VII), wherein NR ₁ R ₂ is 1-pyrrolidinyl) (Ag in Bml of benzene) It is prepared by reacting a compound of the general formula (Cg in benzene Dml) for F hour at a temperature of 60 to 70 ° C in the presence of phosphorus oxychloride (Eml).

Footnote to Table III

Notes (1), (4) and (8) are as defined in Table I.

(21) The product is isolated as a monofumarate salt thereof, recrystallized from a 1: 2 mixture of methanol and ether.

(22) The product is isolated as a monofumarate salt thereof, recrystallized from a 1: 3 mixture of methanol and ether.

[Examples 76 to 91]

In a similar manner to the method described in Example 1, the compounds described in Table IV were prepared by reacting the aminophenyl compound of general formula (Ag in benzene Bml) at a temperature of 60 to 70 캜 in the presence of phosphorus oxychloride (Eml). Prepared by reaction with 2-piperidone (Cg in benzene Dml) for F hour.

[Note on Table IV]

Notes (1), (8), (11) and (21) are as defined in Tables I to III.

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

(24) The product is separated from methanol as recrystallized monofumarate salt.

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

(26) The product is recrystallized from hexane followed by a mixture of dimethoxyethane and hexane.

(27) The product was purified by column chromatography on an alumina column using a 49: 1 mixture of dichloromethane and methanol as eluent. The product is separated as its dihydroiodide salt recrystallized from a 1: 1 mixture of ethanol and ether.

(28) The coupling reaction is carried out at 90 to 100 ° C.

[Examples 92 to 101]

In a manner analogous to that described in Example 1, the compounds described in Table V were prepared by reacting the aminophenyl compound of the general formula (Ag in benzene Bml) at a temperature of 60 to 70 캜 in the presence of phosphorus oxychloride (Eml). Prepared by reaction with methyl-substituted-2-pyrrolidinone (Cg in benzene Dml) for F hours.

Footnotes to Table V

Notes (I) and (IV) are as defined in Table I.

(29) The product is isolated as its dihydroiodide salt which is recrystallized from a 1: 1 mixture of methanol and ether.

(30) The coupling reaction is carried out at ambient temperature for F hours.

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

Example 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 give N- (2-morpholinophenyl Acetamidine (melting point 140-141 ° C.) is obtained and 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 give N- (5-methyl 2-Morpolynophenyl) acet amidine (melting point 121 ° C.) is obtained and it is 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 6 hours to give N- (2-morpholino Phenyl) propionamidine (melting point 114 ° C.) is obtained and it is recrystallized from hexane.

Example 105

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) is heated in a sealed stainless steel pressurized vessel at 170 ° C. for 60 hours. Excess n-butynitrile is removed, the residue is dissolved in water, basified with 10% aqueous sodium hydroxide solution until pH 12 and extracted with dichloromethane. The extract is washed with water and brine, dried and the solvent is removed. The residue is purified by chromatography on a neutral alumina column. Eluted with a 1: 1 mixture of dichloromethane and hexane to remove unreacted starting material, then eluted with a 1:99 mixture of methanol and dichloromethane to give a solid which was dissolved in methanol (10 ml) and fumaric acid (0.48 g). ) To give N- (2-morpholinophenyl) butyramidine monofumarate (melting point 168-170 ° C.) which is recrystallized from a 1: 2 mixture of methanol and ether.

Example 106

Powdery anhydrous aluminum chloride (12 g) is added dropwise at 40-50 ° C. to a stirred slurry of stirred 4- (2-amino phenyl) morpholine (5.34 g) and n-butyronitrile (6 g). The mixture is then heated at 160-170 [deg.] C. for 6 hours, cooled, and broken down to 40% aqueous sodium hydroxide solution. The solution is extracted with ether and the extract is washed with water and brine and dried. The solvent was removed to give a residue, which was crystallized from a 1: 1 mixture of ethyl acetate and hexane to give N- (2-morpholinophenyl) butyramidine (melting point 131 DEG C), which was a monofumarate salt (melting point). 173 ° C.) and recrystallize it from propan-2-ol.

Example 107

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated in a sealed stainless steel pressurized vessel at 165 ° C. for 26 hours to give N- (2-morph polynophenyl Isobutyramidine (melting point 140-141 ° C.) is obtained and 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 at 160-170 ° C. for 6 hours to give N- (2-morpholino Phenyl) isobutyramidine (melting point 138 ° C.) is obtained and 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 give N- (5-methylthio -2-morpholinophenyl) isobutyramidine (melting point 155 ° C.) is obtained and 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 give N- (5-fluoro-2-morpholine Nophenyl) isobutyramidine (melting point 142 ° C.) is obtained which is recrystallized from hexane and converted to its fumarate salt (melting point 172 ° C.) and recrystallized from a 1: 1 mixture of methanol and ether.

Example 111

A mixture of 4- (2-aminophenyl) morpholine hydrochloride (6.5 g) and valeronitrile (35 ml) is heated under nitrogen at 160-165 ° C. for 25 hours and then cooled. The mixture is treated with aqueous sodium hydroxide and the basified mixture is extracted with dichloromethane. The solvent is evaporated off and the residue is distilled off under pressure of 50 mm Hg to remove half of the non-reactive vareronitrile. The cold separated solid, which was separated by filtration, was washed with hexane (50 ml) and recrystallized from hexane to give N- (2-morpholinophenyl) valeric amidine (melting point 135-136 ° C.).

Example 112

A mixture of 4- (2-aminophenyl) morpholine (3.56g), pivalonitrile (5g) and anhydrous aluminum chloride (8g) was heated at 160-170 ° C. for 6 hours to give N- (2-morpholinophenyl ) Pivalamidine (melting 126 ° C.) is obtained which is recrystallized from hexane to convert to its monofumarate salt (melting point 211 ° C.) and it is recrystallized from methanol.

Example 113-125

In a similar manner to the method described in Example 2, the compounds prepared in the Examples described below are converted to their fumarate salts and recrystallized from the following solvents.

Example 126

The product of Example 1 (2.6 g) is reacted with excess acrylonitrile (5 ml) at room temperature. The product is recrystallized from etaacetate to give 4- (2- [1- (2-cyanoethyl) -2-piperidinylideneamino] phenyl) morpholine (melting point 148 ° C.).

Example 127

A mixture of 3-morpholinone (4 g) in anhydrous acetonitrile (40 ml), 4- (2-aminophenyl) morpholine (3.6 g) and phosphorus oxychloride (3.6 ml) in anhydrous acetonitrile (20 ml) Heated at 70 ° C. for 40 hours to give an oil which was subjected to column chromatography on neutral alumina (72 g) using (a) hexane, (b) dichloromethane: hexanes (1: 1) and (c) dichloromethane as eluent. Purify by chromatography. The oil formed was treated with a saturated solution of hydrogen chloride in methanol (25 ml) to give a pale yellow solid which was recrystallized from a 1: 1 mixture of methanol and ether to give 4- [2- (3-morpholinylideneamino) phenyl] -mor Pauline hydrochloride (melting point 262-263 ° C.) is obtained.

Example 128

A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4- (2-aminobenzyl) morpholine (5.7 g) and phosphorus oxychloride (3.6 ml) in benzene (20 ml) was 48 at 65-70 ° C. Heating for time gives 4- [2- (2-piperidinylideneamino) benzyl] morpholine (melting point 108-110 ° C.) and recrystallises it from hexane.

Example 129

A mixture of 2-piperidone (6 g) in benzene (50 ml), 4- (2-amino-4-chlorobenzyl) morpholine (6.8 g) and phosphorus oxychloride (5.5 ml) in benzene (50 ml) was added from 60 to 65 Heating at &lt; RTI ID = 0.0 &gt; C &lt; / RTI &gt;

Example 130

A mixture of 1-methyl-2-pyrrolidone (4.8 g) in benzene (20 ml), 4- (2-aminobenzyl) morpholine (7.6 g) and phosphorus oxychloride (4.8 ml) in benzene (50 ml) was prepared. Heating at -70 [deg.] C. for 18 hours yields an oil which is dissolved in methanol (30 ml). Treatment with 57% hydroiodic acid (10.1 ml) gave 4- [2- (1-methyl-2-pyrrolidinylideneamino) benzyl] morpholine dihydroiodide (melting point 230-232 ° C.) Recrystallize from ethanol.

Example 131

Of 1, 3, 3-trimethyl-2-pyrrolidinone (3 g) in benzene (20 ml), 4- (2-aminobenzyl) morpholine (3.8 g) and phosphorus oxychloride (2.1 ml) in benzel (10 ml) The mixture is left at room temperature for 28 hours and then heated at 60-65 ° C. for 14 hours to give an oil (2.9 g) which is dissolved in methanol (15 ml). 4- [2- (1,3,3-trimethyl-2-pyrrolidinylidene amino) benzyl] morpholine dihydroiodide (melting point 256-258 ° C.) treated with 57% hydroiodic acid (2.8 ml) Is obtained and it is recrystallized from the 1: 1 mixture of ethanol and ether.

Example 132

A mixture of N-methylpivalamide (6.2 g) in benzene (50 ml), 4- (2-aminobenzyl) morpholine (9 g) and phosphorus oxychloride (5 ml) in benzene (40 ml) was added at 80 to 85 ° C. Heat for hours to give a solid which is dissolved in methanol (25 ml) and treated with fumaric acid (1.4 g) to give N-methyl-N- (2-morpholinomethyl phenyl) pivalamidine monofumarate (melting point 167-168). ° C) is obtained and it is recrystallized from propan-2-ol.

Example 133

A mixture of 1, 3-dimethyl-2-imidazolidinone (7 g), phosphorus oxychloride (6 ml) in benzene (45 ml) and 4- (2-amino phenyl) morpholine (8.5 g) in benzene (30 ml) Heated at 65-70 ° C. for 30 h. The product is recrystallized from hexane to give 4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl] morpholine.

Example 134-154

The compounds described in Table VI were prepared in the same manner as described in Example 133, in which the aminophenyl compound of formula (VII) (Ag in benzene Bml) was subjected to F hours at 65 to 70 ° C in the presence of phosphorus oxychloride (Eml). It is prepared by reacting with a compound of formula (VIII) (Cg in benzene Dml).

Footnote to Table VI

(32) The product is recrystallized from hexane.

(33) The coupling reaction is carried out at 90 to 95 ° C.

(34) The coupling reaction is carried out at 70 to 75 占 폚.

(35) The coupling reaction is carried out at 60 to 65 ° C.

(36) The product is separated as its fumarate salt, which is recrystallized from a 2: 1 mixture of isopropanol and ether.

(37) The coupling reaction is carried out at 75 to 80 ° C.

(38) The product is separated into its monofumarate salt, which is recrystallized from a 1: 2 mixture of methanol and ether.

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

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

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

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

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

Example 155

A mixture of N- (2-hydroxyethyl) ethylhendiamine (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 directly from the reaction mixture. Distillation gave 1- (2-hydroxyethyl) -2-imidazolidinone (30 g) [(boiling point 150-160 ° C. (0.2 mm)] as an oil and solidified to obtain a solid (melting point 50-51 ° C.). To obtain.

1- (2- (hydroxyethyl) -2-imidazolidinone (2.28g), benzoic anhydride (4.5g), triethylamine (2.4g), 4-dimethylamino pyridine (0.1g) and 1.2-dime The mixture of oxyethane (20 ml) is stirred for 8 hours at room temperature Saturated sodium bicarbonate solution (15 ml) is added and the mixture is extracted with dichloromethane (100 ml) The extract is washed with water and brine, dried and filtered. Is removed to give 1- (2-benzoyloxyethyl) -2-imidazolidinone (melting point 130-132 ° C.) which is recrystallized from ethyl acetate.

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

In a similar manner to Example 133, 1- (2-benzoyloxyethyl) -3-methyl-2-imidazolidone (8.8 g) in benzene (30 ml) was added to 80 to 80 in the presence of phosphorus oxychloride (3.3 ml). Reaction with 4- (2-aminophenyl) morpholine (5.2 g) in benzene (20 ml) at 85 ° C. for 35 hours yields an oil, which is dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g). . The solvent is removed by evaporation and the residue is washed with ether and dissolved in water. The aqueous solution is basified with an aqueous sodium carbonate solution at pH 9-10 and extracted with ether to give an oil, which is purified by chromatography on an alumina column using dichloromethane as eluent. 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-imidazolidinylideneamino] Phenyl) morpholine monofumarate (melting point 132-133 ° C.) is obtained and recrystallized from a 1: 2 mixture of methanol and ether.

Example 156

Tetramethylurea (10.4 g, 10.7 ml) in anhydrous benzene (80 ml) was converted to 4- (2-aminophenyl) mol in anhydrous benzene (100 ml) for 30 hours at 65-70 ° C. in the presence of phosphorus oxychloride (8.3 ml). Reaction with Pauline (10.2 g) yields an oil which is purified by column chromatography on a neutral alumina column (100 g) eluted with hexane to give as an oil. Base (2.5 g) solution in methanol (10 ml) was treated with 57% hydroiodic acid (1.3 ml) to yield 2- (2-morpholinophenyl) -1,1,3,3, -tetramethyl as a pale yellow crystalline solid. Guanidine hydroiodide (melting point 215-216 ° C.) is obtained and recrystallized from a 2: 3 mixture of methanol and ether.

Example 157

3-ethyl-1,1,3-trimethylurea (6.57 g) in benzene (70 ml) was diluted with 4- (2- in benzene (30 ml) for 45 hours at 65-70 ° C. in the presence of phosphorus oxychloride (4.71 ml). Reaction with aminophenyl) morpholine (6g) affords 1-ethyl-2- (2-morpholinophenyl) -1,3,3-trimethyl-guanidine (boiling point 140 ° C. at 0.2 mmHg).

Example 158

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

Example 159

3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) and 4- (2-aminophenyl) morpholine (7.2 g) in benzene (30 ml) were added to phosphorus oxychloride (4 ml). In the presence of 1-n-butyl-2- (2-morpholinophenyl) -1,3,3-trimethylguanidine (boiling point of 162 to 163 ° C at 0.7 mmHg) is obtained by reacting for 18 hours at 80 to 85 ° C. .

Example 160

3-pentyl-1,1,3-trimethylurea (7.5 g) in benzene (80 ml) and 4- (2-aminophenyl) morpholino (6.46 g) in benzene (30 ml) phosphorus oxychloride (4.06 ml) Reaction was carried out at 70 ° C. for 45 hours in the presence of 1-pentyl-2- (2-morpholinophenyl) -1,3,3-trimethyl guanidine (boiling point 98 ° C. at 1.5 mmHg).

Example 161

1- (2-hydroxyethyl) -2-imidazolidinone (13 g) in anhydrous dimethylformamide (125 ml) was reacted with sodium hydride (50% suspension in 12 g of paraffin oil) at 10 ° C. for 3 hours, and then 1 Treat with methyl iodide (35.5 g) over time. The mixture is stirred at ambient temperature for 18 hours to afford 1-methyl-3- (2-methoxyethyl) -2-imidazolidinone (boiling point 110 to 114 ° C. at 0.4 mm Hg).

1-Methyl-3- (2-methoxyethyl) -2-imidazolidinone (11.4 g) in benzene (60 ml) was combined with 4- (2-aminophenyl) morpholine (8.9 g) in benzene (80 ml). Reaction was carried out at 80 to 85 ° C. for 30 hours in the presence of phosphorus oxychloride (7.2 ml) to obtain an oil, of which part (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to 4- ( 2- [1-methyl-3- (2-methoxyethyl) -2-imidazolidinylidene amino] phenyl) -morpholine monofumarate (melting point 127-129 ° C.) was obtained, which yielded propane 2- Recrystallize from ol.

Example 162

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

1-Methyl-3- (2-acetoxyethyl) -2-imidazolidinone (13.4 g) in benzene (80 ml) was mixed with benzene (80 ml for 30 hours at 80 to 85 ° C in the presence of phosphorus oxychloride (7 ml). Reaction with 4- (2-aminophenyl) morpholine (10.6 g) in 4- (2- [1-methyl-3- (2-acetoxyethyl) -2-imidazolidinylideneamino] phenyl To obtain morpholine.

4- (2- [1-methyl-3- (2-acetoxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (2.7 g) in dimethylformamide (10 ml) was added at 1O &lt; 0 &gt; C. Reaction with sodium hydroxide (0.4 g) in water (10 ml) for an hour 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 (melting point 129-131 ° C.) is obtained and recrystallized from a 1: 2 mixture of methanol and ether.

Example 163

4-dimethylcarbamoyl morpholine (3.8 g) and 4- (2-aminophenyl) morpholine (3.5 g) in benzene (25 ml) were reacted for 40 hours at 80 to 85 ° C. in the presence of phosphorus oxychloride (2.1 ml). Reaction gives N, N-dimethyl-N '-(2-morpholinophenyl) morpholine-4-carboxamidine (melting point 126-128 ° C.) which is recrystallized from hexane.

Example 165

1-dimethylcarbamoylpiperidine (3.7 g) in benzene (25 ml) was reacted for 35 hours at 80-85 ° C. in the presence of 4- (2-morpholinophenyl) -morpholine (3.5 g) and phosphorus oxychloride. Reaction gives N, N-dimethyl-N '-(2-morpholinophenyl) piperidine-1-carboxamidine (melting point 88-90 ° C.) which is petroleum ether (boiling point 40- ° C.) Recrystallize from

Example 165

4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl] thiamorpholine (1.5 g, prepared as prepared in Example 144) and water (4 ml) in benzene (25 ml) Sodium metaperiodate (1.4 g) in the reaction) was reacted at 10 DEG C for 4 hours to 4- [2- (1,3-dimethyl-2-imidazolidinylideneamino) phenyl] thiamorpholine-1-oxide Monohydrate (melting point 103-2105 DEG C) is obtained and recrystallized from a 1: 1 mixture of 1,2-dimethoxy ethane and hexane.

Example 166

The solution of 2-morpholinophenyl isothiocyanate (2.3 g) is treated with a saturated ammonia solution in ethanol (20 ml) and the reaction mixture is stirred at room temperature for 3 hours. The resulting solid is filtered, washed with ethanol and dried to give 1- [2- (4-morpholino) phenyl] thio urea (melting point 194-195 ° C.).

A solution of 1- (2-morpholinophenyl) thiourea (7.2 g) in anhydrous methanol (30 ml) is heated with methyl iodide (4.2 g) at reflux for 2 hours. The solvent is removed under reduced pressure and anhydrous ether (15 ml) is added and scratched to afford 2-methyl-1- (2-morpholinophenyl) -2-thioshudo urea hydroiodide (melting point 151 to 152 ° C.).

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydroiodide (5 g) and ethylenediamine (2.4 g) in dry ethanol (50 ml) was heated at reflux for 6 hours. The solvent was removed under reduced pressure to give an oil which was dissolved in dichloromethane (50 ml), cooled and basified with 20% sodium hydroxide, the organic layer was washed successively with water and brine and dried (Na ₂ SO ₄ ), Filtered to remove solvent, to obtain a solid (4 g) which was recrystallized from ethyl acetate to give 4- [2- (2-imidazolidinylideneamino) phenyl] morpholine (melting point 185 to 185 ° C). To obtain.

Example 167

2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydroiodide (3 g, prepared as described in Example 166), N-methylethylenediamine (2 ml) and anhydrous ethanol (35 ml) of the mixture was heated under reflux for 8 hours to give a solid which was recrystallized from ethyl acetate to give 4- [2- (methyl-2-imidazolidinylideneamino) phenyl] morpholine (melting point 156 ° C.) To obtain.

[Examples 168 to 202]

In a similar manner as described in Example 167, the compounds described in Table VII are compounds of formula IV, wherein R ₁₄ and R ₁₅ are H. (Gg), general in anhydrous ethanol (Iml) Prepared by heating a mixture of formula H ₂ N (CH ₂ ) ₂ NHR ₆ N-substituted ethylenediamine (Hg) under reflux for J hours.

[Footnote to Table]

Notes 32, 38, 39, and 41 are as defined in the table above.

(44) The product is recrystallized from ethyl acetate.

(45) The product is isolated as its monofumarate and it is recrystallized from methanol.

(46) The preparation of the compound of formula (XIV) is as defined in Preparation Step A below.

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

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

(49) Preparation of the compound of formula (XIV) is as defined in Preparation B below.

(50) The preparation of the compound of formula (XIV) is as defined in the following Preparation Process C.

(51) The preparation of the compound of formula (XIV) is as defined in the following Preparation Procedure D.

(52) The product is recrystallized from a 1: 2 mixture of ethyl acetate and hexanes.

(53) The preparation of the compound of formula (XIV) is as defined in Preparation Step E below.

(54) Preparation of the compound of formula (XIV) is as defined in the following preparation procedure F.

(55) The preparation of the compound of formula (XIV) is as defined in Preparation Step G below.

(56) The product was purified by chromatography on an alumina column using hexane, dichloromethane, and a 1: 1 mixture of hexane, dichloromethane and hexane in turn as eluent.

(57) Preparation of the compound of formula (XIV) is the same as the preparation step H below.

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

[Manufacturing Process A]

6-Methyl-2-morpholinoaniline (9.6 g) and thiophosgen (5.7 mL) in dioxane (25 mL) and water (100 mL) were reacted at 0 ° C. for 30 minutes and at room temperature for 3 hours. 6-methyl-2-morpholinophenyl isothiocyanate is obtained.

6-Methyl-2-morpholinophenylisothiocyanate (8.8 g) was reacted with 33% alcoholic ammonia solution (60 mL) for 5 hours at room temperature to give 1- (6-methyl-2-mor as a pale yellow solid Polynophenyl) thiourea (9 g) (melting point 199 ° C.) is obtained and recrystallized from the 1: 1 mixture of ethyl acetate and hexane.

A mixture of 1- (6-2-morpholinophenyl) -thiourea (9 g) and methyl iodide (2.5 mL) in anhydrous acetone (100 mL) was heated at reflux temperature of 90 to 95 DEG C for 2.5 hours. 2-methyl-1- (6-methyl-2-morpholinophenyl) _- 2-thioshudourea hydroiodide is obtained.

[Manufacturing Process B]

A solution of N, N-bis (2-methoxyethyl) benzene-1,2-diamine (7.5 g) in dioxane (10 mL) was added to a mixture of thiophosgen (4 mL) and water (60 mL) and Cool to 0 ° C. The temperature of the mixture is raised to ambient temperature and the mixture is stirred for 4 hours. Ice water (50 mL) is added and the mixture is extracted with ether (3x20 mL). The extract was washed with water (50 mL) and brine (50 mL), dried and evaporated to give a residue which was heated at 45 ° C. under vacuum (100 mm / Hg) to give 2- [bis (2-methoxy) as an oil. Ethyl) amino] phenyl isothiocyanate is obtained.

To a mixture of 2- [bis (2-methoxyethyl) amino] phenyl isothiocyanate (7.5 g) and ethanol (10 ml) cooled to 10 ° C. in ethanol (40 ml) over 40 minutes. Add. The mixture is stirred at 0 ° C. for 8 hours and for 16 hours without cooling. Then the solvent was removed by evaporation and the residue was 1: 4 mixture of ethyl acetate and hexane. Then purified by chromatography on a silica column extracted from a 1: 1 mixture of ethyl acetate and hexane to give 1- (2- [bis (2-methoxyethyl) amino] phenyl) thiourea (melting point 118-119 ° C). To obtain.

A mixture of 1- (2- [bis (2-methoxyethyl) amino] phenyl) thiourea (5 g), methyl iodide (1.4 mL) and acetone (25 mL) is heated at 40 ° C. for 2 hours. The solvent was removed to give a residue, which was then triturated with ether to give 2-methyl-1 (2- [bis (2-methoxyethyl) amino] phenyl) -2-thioshudorea hydroiodide (melting point 111-112 ° C.). ).

[Manufacturing Process C]

A solution of 2-thiamorpholinoaniline (14.6 g) in dioxane (10 mL) was added over 15 minutes to a mixture of thiophosgen (8.77 mL) and water (120 mL) cooled to 0 ° C. The mixture is stirred and its temperature raised to ambient temperature. The mixture is washed for 4 hours and ice / water (200 mL) is added. The mixture was extracted with ether (2x100 mL) and the extract was washed with water (50 mL) and brine (100 mL) and the solvent was evaporated to remove the residue to obtain a residue which was obtained at 40-45 ° C. under vacuum (100 mm / Hg). Heating for 2 hours yields 2-thiamorpholinophenyl isothiocyanate (melting point 55-56 ° C.).

A mixture of 2-thiamorpholinopheny isothiocyanate (14 g) and ethanol (40 mL) was added at 10 ° C in 25% aqueous ammonia solution (100 mL). The mixture is stirred at 30 ° C. for 24 hours and cooled to 10 ° C. The 1- (2-thiamorpholinophenyl) thiourea is collected by filtration, washed with water (100 mL) and dried (melting point 170-171 ° C.).

1- (2-thiamorpholinophenyri) thiourea (12.6 g). The mixture of methyl iodide (7.1 g) and acetone (60 mL) is heated at 90-95 ° C. for 2 and a half hours. The solvent was evaporated off and the residue was dried under vacuum (5 mm / Hg) to afford 2-methyl-1 (2-thiamorpholinophenyl) -2-thiashdourea hydroiodide (melting point 176-177 ° C.) do.

[Manufacturing Process D]

Benzoylisothiocyanate (10 mL) is added to a mixture of 2- (1-pyrrolidinyl) aniline (10.6 g) and dichloromethane (30 mL) over 30 minutes. The mixture is stirred at 30 ° C. for 4 hours. The solvent is evaporated off and the residue is dried under vacuum (5 mm / Hg) for 30 minutes and triturated with ether. 3-benzoyl-1- [2- (1-pyrrolidinyl) phenyl] thiourea is collected by filtration, washed with ether and dried (melting point 172-173 ° C.).

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

1- [2- (1-pyrrolidinyl) phenyl] thiourea (12.2 g). The mixture of acetone (100 mL) and methanol (20 mL) is heated to 90-95 ° C. Methyl iodide (8.36 g) is added and the mixture is heated to reflux for 3 hours. The solvent was evaporated off to give a residue which was evaporated under vacuum (5 mm / Hg) to give 2-methyl-1- [2- (1-pyrrolidinyl) phenyl] -2-thio pseudourea hydroiodide (melting point 139 to 141 ° C.).

[Manufacturing Process E]

5-methyl-2-morpholino aniline (20 g) in dioxane (80 mL) and water (200 mL) was reacted for 30 minutes at 0 ° C. and for 2 hours at room temperature to yield 5-methyl-2-morpholino. Phenyl isothiocyanate (melting point 91-92 ° C.) is obtained.

5-methyl-2-morpholinophenyl isothiocyanate (15 g) was reacted with a 33% ethanol ammonia solution for 48 hours at room temperature to yield 1- (5-methyl-2 as a pale yellow solid (melting point 181 to 182 ° C). -Mor polynophenyl) thiourea is obtained.

A mixture of 1- (5-methyl-2-morpholinophenyl) -thio urea (14 g) and methyl iodide (7.9 g) in methanol (50 mL) was heated at reflux for 2 hours to obtain 2 as a pale yellow solid. -Methyl-1- (5-methyl-2-morpholinophenyl) -2-thioshudourea hydroiodide (melting point 157-159 ° C.) is obtained.

[Manufacturing Process F]

A mixture of 2-methyl-1 (2-aminophenyl) pyrrolidine (9.1 g) and benzoyl isothiocyanate (9.2 g) and dichloromethane (100 mL) is stirred at room temperature for 8 hours and left overnight. The solvent is removed and triturated with ether to give 1-benzoyl-3- [2-methyl-1-pyrrolidinyl] phenyl] thio urea (melting point 105-106 ° C.).

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

A mixture of 1- [2- (2-methyl-1-pyrrolidinyl) phenyl] thiourea (3.4 g) and methyl iodide (2.1 g) in acetone (60 mL) was heated at 90-95 ° C. for 3 hours. Heat and remove solvent to afford 2-methyl-1- [2-methyl-1-pyrrolidinyl] phenyl] -2-thioshudourea hydroiodide (3.7 g) as a concentrated oil.

[Manufacturing Process G]

A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 mL) was added to the mixture of thiophosgen (10.2 mL) and water (200 mL) cooled to 0 ° C. over 25 minutes. The temperature of the mixture is raised to ambient temperature and the mixture is stirred for 4 hours. Ice (200 g) and water (200 mL) are added and the mixture is extracted with ether (6x50 mL). The combined extracts were washed with water (100 mL) and brine (100 mL), dried and evaporated to afford a residue, which was purified by chromatography on a silica column eluted with hexanes to give 2-piperidinophenyl isothio as an oil. Obtain cyanate.

A 25% aqueous ammonia solution (60 mL) was added to a mixture of 2-piperidinophenyl isothiocyanate (12 g) and ethanol (25 mL) cooled to 10 ° C. The mixture is stirred at 30 ° C. for 24 hours and cooled to 10 ° C. The 1- (2-piperidinophenyl) thiourea is collected by filtration, washed with water and dried (melting point 145-146 ° C.).

1- (2-piperidinophenyl) thiourea (10.1 g). A mixture of methyl iodide (5.35 g) and methanol (50 mL) is heated at 50-55 ° C. for 2 hours. The solvent was evaporated off and the residue was dried under vacuum (5 mm / Hg) to afford 2-methyl-1- (2-piperidinophenyl) -2-thioshudorea hydroiodide (melting point 160-162 ° C.) do.

[Manufacturing Process H]

6-methyl-2-piperidino aniline (6.4 g) in dioxane (20 mL) and water (65 mL) was reacted with thiophosgene (5.7 g) for 30 minutes at 0 ° C. and for 2 hours at room temperature to give an oil. 6-methyl-2-piperidino phenyl isothiocyanate is obtained.

6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) and 25% aqueous ammonia solution (65 ml) in ethanol (20 ml) were reacted for 8 hours at room temperature to yield 1- (6-methyl as a pale yellow solid. 2-piperidinophenyl) thiourea (melting point 197-198 ° C.) is obtained.

A mixture of 1- (6-methyl-2-piperidinophenyl) -thiourea (7 h) and methyl iodide (4.38 g) in anhydrous methanol (100 mL) was heated under reflux for 3 hours to yield a pale yellow solid. 2-Methyl-1- (6-methyl-2-piperidinophenyl) -2-thioshudorea hydroiodide (melting point 204-205 ° C.) is obtained.

Example 203

2-methyl-1- (2-morpholinophenyl) -2-thioshudorea hydro iodide (3.8 g), prepared as described in Example 166), 2-methylethylenediamine (2.2 g) And a mixture of ethanol (45 mL) was heated under reflux for 8 hours to give a solid which was recrystallized from ethyl acetate to give 4- [2- (4-methyl-2-imidazolidinylideneamino) phenyl] A morpholine (melting point 173-174 DEG C) is obtained.

Example 204

2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydroiodide (7.6 g), prepared as described in Example 166), 1,2-dimethylethylenediamine (5.3 g) and a mixture of ethanol (90 mL) were heated under reflux for 70 hours to give a solid which was recrystallized from ethyl acetate to give 4- [2- (4,5-dimethyl-2-imidazolidinylideneamino ) Phenyl] morpholine (melting point 142-143 degreeC) is obtained.

Example 205

Ethylene oxide prepared from 2-chloroethanol (36 g) and potassium hydroxide pellets (20 g) in methanol (6 mL) was reacted with 1,2-dimethylethylenediamine (22.6 g) in methanol (50 mL) at -15 ° C. N- (2-hydroxyethyl) -1,2-dimethylethylenediamine is obtained as a colorless liquid (1 mm / Hg) with a boiling point of 89 to 91 ° C.

2-methyl-1- (2-morpholinophenyl) -2-thioshudorea (12.5 g) and N- (2-hydroxyethyl) -1,2-dimethyl ethylenediamine in anhydrous ethanol (150 mL) ( 8 g) was heated under reflux at 90-95 ° C. for 6 days to give a dark brown oil which was purified by column chromatography using a 1: 9 mixture of dichloromethane and hexane in neutral alumina (250 g) as a colorless solid. 4- (2- [4,5-dimethyl-1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (melting point 108 to 109 ° C.) was obtained, which was obtained from hexane. Recrystallize.

Example 206

2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydro iodide (3.8 g, prepared as described in Example 166), N'-disopropyl-2-methyl A mixture of -1,2-propanediamine (3.95 g) and ethanol (45 mL) was heated under reflux for 28 hours to give an oil which was purified by column chromatography on a neutral alumina column 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 4- [2- (1-isopropyl-4,4-dimethyl-2-imidazolidinylidene amino) Phenyl] -morpholine monofumarate (melting point 206-208 ° C.) is obtained and recrystallized from a 1: 3 mixture of methanol and ether.

Example 207

2-methyl-1- (2-morpholinophenyl) -2-thioshudorea hydroiodide (3.8 g, prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) And a mixture of anhydrous ethanol (40 mL) was heated under reflux for 6 hours to give a solid which was recrystallized from ether to give 4-[2- (1-methylperhydropyrimidin-2-ylidene amino) phenyl ] Morpholine (melting point 138-139 ° C.) is obtained.

Example 208

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydroiodide (7.6 g) and 1,4-diaminobutane (5.3 g) in ethanol (150 mL) was refluxed. Under heating for 60 hours to give a white solid (melting point 135 ° C.) which is recrystallized from ethyl acetate. The solid (2.7 g) was dissolved in methanol (20 mL) and treated with fumaric acid to give 2- (2-morpholinophenylimino) -1,3-diazocycloheptane fumarate (melting point 220-222 ° C.). And it is recrystallized from a 1: 1 mixture of methanol and ether.

Example 209

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thioshudorea hydro iodide (1 g), dimethylamine (1 mL of 33% solution in ethanol) and ethanol (2 mL) was added to ambient temperature. Leave on for 48 hours. The mixture is cooled in an ice bath. The resulting solid is filtered off, treated with dilute sodium hydroxide solution (5 mL) and the resulting mixture is extracted with dichloromethane (2x50 mL). The extract is washed with brine, dried and the solvent is evaporated off to afford 1,1-dimethyl-2- (2-morpholino phenyl) guanidine (melting point 143-144 ° C.) which is recrystallized from hexane.

Example 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 give 1- (2- Morpholinophenyl) -3-methylthiourea (melting point 115 to 116 ° C.) is obtained and recrystallized from the 4: 1 mixture of ethyl acetate and hexane.

A mixture of 1- (2-morpholinophenyl) -3-methyl-thiourea (5 g) and methyl iodide (2.8 g) in acetone (30 mL) was heated under reflux for 4 hours to afford 2-methyl-1 -(2-morpholinophenyl) -3-methyl-2-thioshudo urea hydroiodide (melting point 163-164 ° C.) is obtained and recrystallized from a 1: 3 mixture of methanol and ether.

A mixture of 2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (3.9 g) with 33% methylamine in anhydrous ethanol (40 mL) solution Heating at 55 ° C. for 28 hours gives 1,3-dimethyl-2- (2-morpholinophenyl) guanidine which is recrystallized from hexane (melting point 137-138 ° C.).

Example 211

2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (3.9 g, prepared as described in Example 210) and dimethylamine (33 in ethanol) 25 ml of% solution) is left for 25 days at ambient temperature. The solvent is removed to give a residue, which is 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 give 1,3,3-trimethyl-2- (2-morpholinophenyl) guanidine mono fumarate (melting point 192-194 ° C.), which was obtained from methanol and ether. : 2 Recrystallize from the mixture.

Example 212

2-morpholinophenyl isothiocyanate (3.3 g) was reacted with ethylamine formed from ethylamine hydrochloride (12.18 g) and sodium methoxide (formed from sodium (3.5 g) and methanol (100 mL)). Ethyl-3- (2-morpholinophenyl) thiourea (melting point 118-120 ° C.) is obtained and recrystallized from the 1: 1 mixture of ethyl acetate and hexane.

A mixture of 1-ethyl-3- (2-morpholinophenyl) thio urea (3.2 g) and methyl iodide (2 g) in acetone (25 mL) was heated at reflux for 4 hours to give 2- as a pale yellow solid. Methyl-3-ethyl-1- (2-morpholinophenyl) -2-thioshudourea hydroiodide (melting point 170-172 ° C.) is obtained and recrystallized from acetone.

Initially a mixture of 2-methyl-3-ethyl-1- (2-morpholinophenyl) -2-thioshudorea hydroiodide (6 g) and 33% methylamine in anhydrous ethanol solution (250 mL) was initially prepared. After heating for 24 hours at &lt; RTI ID = 0.0 &gt; C, &lt; / RTI &gt; Recrystallize from.

Example 213

Sodium (23 g) was added to ethanone (300 ml) and the resulting solution of sodium ethoxide was reacted with ethylamine hydrochloride to give a urea of ethylamine, which was 2-methyl-3-ethyl-1- for 30 days at room temperature. Stirred with (2-morpholinophenyl) -2-thioshudorea hydro iodide (6 g, prepared as described in Example 212) to 1,3-diethyl-2- (2-morpholi Nophenyl) guanidine (melting point 101-102 ° C.) is obtained and it is recrystallized from hexane.

Example 214

4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (3 g, prepared as in Example 175) in dichloromethane (20 ml) was prepared with acetic anhydride ( 0.86 g) to give 4- (2- [1- (2-acetyloxyethyl) -2-imidazolidinylideneamino] phenyl) -morpholine (melting point 89-91 ° C.), which is obtained from hexane Recrystallize.

Example 215

4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (2.9 g, prepared as described in Example 175) in dichloromethane (60 ml) ) Was reacted with benzoic anhydride (2.4 g) in the presence of anhydrous triethylamine (2 ml) and 4-dimethylaminopyridine (50 ml) to give an oil which was purified by chromatography on an alumina column using dichloromethane. To 4- (2- [1- (2-benzoyloxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine (melting point 92 to 94 DEG C) to give 1: 1 of ethyl acetate and hexane. Recrystallize from the mixture.

Example 216

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

Colorless by heating a mixture of 1- (n-butyl) -3- (2-morpholinophenyl) thio urea (5.8 g) and methyl iodide (3.1 g) in acetone (25 ml) at reflux for 4 hours. As a solid, 2-methyl-3- (n-butyl) -1- (2-morpholinophenyl) -2-thioshudorea hydroiodide (melting point 154 to 156 ° C) is obtained.

A mixture of 2-methyl-3- (n-butyl) -1- (2-morpholinophenyl) -2-thioshudo urea hydroiodide (4.0 g) and 33% methylamine in anhydrous ethanol solution (200 ml) Was initially heated at 45 ° for 24 hours and left at room temperature for 21 days to yield 1- (n-butyl) -2- (2-morpholinophenyl) -3-methylguanidine as an oil, methanol (25 ml The solution in) was treated with fumaric acid (0.7 g) to give a colorless solid which was recrystallized from a 1: 1 mixture of methanol and ether to give 1- (n-butyl) -2- (2-morpholinophenyl) 3-methyl-guanidine mono fumarate (melting point 170-172 ° C.) is obtained.

Example 217

2-methyl-1- (2-piperidino) phenyl-2-thioshudorea hydroiodide (7.5 g, prepared as described in Preparation Process G). A mixture of 2-methoxyethylamine (2 ml) and ethanol (40 ml) is stirred at ambient temperature for 20 days. Solvent was removed to give a residue which was dissolved in methanol and treated with fumaric acid to give 1- (2-methoxyethyl) -2- (2-piperidinophenyl) guanidine hemifumarate (melting point 218-220 ° C.) And it is recrystallized from a 1: 2 mixture of methanol and ether.

Example 218

2-methyl-1- (2-morpholinophenyl) -2-thioshudorea hydro iodide (1.7 g, prepared as described in Example 166). A mixture of 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 ( Melting point 115-116 ° C.) is obtained and it is recrystallized from hexane.

Example 219

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thioshudourea hydro iodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was added at ambient temperature. Stir for days to give 1- (2-methoxyethyl) -2- (2-morpholinophenyl) guanidine (melting point 125-128 ° C.), which is recrystallized from 1,2-dimethoxyethane and its fumarate Convert to a salt (melting point 136-138 ° C.) and recrystallize from a 1: 2 mixture of methanol and ether.

Example 220

2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (7.8 g, prepared as described in Example 210). A mixture of n-propylamine (1.3 g) and ethanol (50 ml) was stirred for 45 days at ambient temperature to give an oil which was chromatographed on a neutral alumina column using a 1:99 mixture of methanol and dichloromethane as eluent. Purify by graphy. The resulting oil was dissolved in methanol and treated with fumaric acid to give 1- (n-propyl) -2-morpholinophenyl-3-methylguanidine monofumarate (melting point 187-188 ° C.), which was obtained from methanol and ether. : 2 Recrystallize from the mixture.

Example 221

2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (3.9 g, prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and a mixture of ethanol (25 ml) were stored for 3 months at ambient temperature to give an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2- (2-morpholino phenyl) -3- (2-methoxyethyl) -guanidine monofumarate (melting point, 158-160 ° C.) is obtained and recrystallized from a 1: 2 mixture of methanol and ether.

Example 222

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

Example 223

2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (3.9 g, prepared as described in Example 210). A mixture of pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was eluted with a 1: 1 mixture of dichloromethane and hexane and a 1: 9 mixture of methanol and dichloromethane. Purification by chromatography on column yields N-methyl-N '-(2-morpholinophenyl) pyrrolidine-1-carboxamidine, which is converted to its monofumarate salt (melting point 168-171 ° C). And recrystallize from propan-2-ol.

Example 224

2-methyl-1- (2-morpholinophenyl) -3-ethyl-2-thioshudorea hydroiodide (10 g, prepared as described in Example 212). A mixture of n-butylamine (2.7 g) and t-butanol (75 ml) was heated at 90 to 95 ° C. for 172 hours to give 1- (n-butyl) -2- (2-morpholinophenyl) -3-ethyl Obtain guanidine and convert it to its monofumarate salt (melting point 159-160 ° C.) which is recrystallized from a 1: 2 mixture of methanol and ether.

Example 225

5-chloro-2-morpholinoaniline (2.8 g) was reacted with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) for 60 days at room temperature to give 1- (n-butyl) -3- ( 5-Chloro-2-morpholinophenyl) thiourea (melting point 150-152 ° C.) is obtained.

Mixture of 1- (n-butyl) -3- (5-chloro-2-morpholinophenyl) thiourea (2.6 g), methyl iodide (1.4 g) and acetone (20 ml) for 3 hours to reflux Heating affords 2-methyl-1- (5-chloro-2-morpholino phenyl) -3- (n-butyl) -2-thioshudorea hydroiodide (melting point 130-130 ° C.).

33% ethanol of 2-methyl-1- (5-chloro-2-morpholinophenyl) -3- (n-butyl) -2-thioshudorea hydroiodide (3.4 g) and methylamine (10 ml) The mixture of aqueous solutions was stored for 8 months at ambient temperature in a sealed container to yield 1,3-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine (melting point 145-146 ° C.) and from hexane Recrystallize. In this reaction, the butylamino and methylthio groups of the releasing substance are replaced with methylamino groups.

Example 226

1- (2-aminophenyl) pyrrolidine (10 g) was reacted with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) for 4 days at room temperature to yield 1-methyl-3- [2- (1- Pyrrolidinyl) phenyl] thiourea (melting point 125-126 ° C.) is obtained.

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 reflux for 2.5 hours to give 2 -Methyl-1 [2- (1-pyrrolidinyl) phenyl] -3-methyl-2-thioshudorea hydroiodide (melting point 161 to 162 ° C) is obtained.

2-methyl-1- [2- (1-pyrrolidinyl) -phenyl] -3-methyl-2-thioshudourea hydroiodide (14.7 g), allylamine (4.45 g) and ethanol (65 ml) The mixture was stored at ambient temperature for 50 days and then heated at a rate of 20 hours to obtain an oil which was treated with fumaric acid to treat 1-allyl-2- [2- (1-pyrrolidinyl) phenyl] -3-methyl Guanidine monofumarate (melting point 162-163 ° C.) is obtained and it is 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 left at room temperature for 6 days to give a colorless solid 1-methyl-3- (5-methyl-2-morpholinophenyl) thiourea (melting point 107 ° C.) is obtained.

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 heated to reflux for 4 hours to light yellow 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thioshudorea hydro iodide (melting point 160-161 ° C.) is obtained as a solid.

A mixture of 2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thioshudo urea hydroiodide (6 g) and 33% methylamine in anhydrous ethanol solution (250 ml) It was kept at room temperature for 21 days to give 1,3-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine as an oil, which was dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g). , 3-dimethyl-2- (5-methyl-2-morpholinophenyl) guanidine fumarate (1.2 g) was obtained as a colorless solid which was recrystallized from a 1: 1 mixture of methanol and ether (melting point 201-202 DEG C). Make it angry.

Example 228

2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thioshudorea hydroiodide (8.4 g, prepared as described in Example 227), N- A mixture of (2-hydroxyethyl) ethylenediamine (6.8 ml) and ethanol (80 ml) was heated to 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 (melting point 135-136 ° C.) is obtained.

Example 229

2-methyl-1- (2-morpholinophenyl) -3-methyl-2-thioshudorea (4 g, prepared from hydroiodide salts as described in Example 210). A mixture of potassium hydroxide (1.7 g), n-pentylamine (2.1 g), lead acetate trihydrate (5.8 g) and ethanol (20 ml) was heated at 90-95 ° C. for 40 minutes to give an oil which was extracted with hexane To 1-methyl-2- (2-morpholinophenyl) -3- (n-petyl) guanidine which is converted to its monofumarate salt (melting point 148-149 ° C.) to give 3: 5 of methanol and ether. Recrystallize from the mixture.

Example 230

2-methyl-1- (5-methyl-2-morpholinophenyl) -3-methyl-2-thioshudo urea hydroiodide (12.2 g, prepared as described in Example 227), n- A mixture of butylamine (2.4 g) and ethanol (80 ml) is stored at ambient temperature for 4 months. Lead acetate trihydrate (9 g) was added and the mixture was reversible under reflux for 1 hour to afford 1- (n-butyl) -2- (5-methyl-2-morpholinophenyl) -3-methyl guanidine, which was Convert to monofumarate salt (melting point 150 ° C.) and recrystallize from methanol and ether and 1-2 mixture.

Example 231

6-Methyl-2-morpholinoaniline (8.75 g) and methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) were reacted at room temperature for 4 days to give N-methyl-N '(6-methyl-2 -Morpholinophenyl) thiourea (melting point 182-183 degreeC) is obtained.

A mixture of N-methyl-N '-(6-methyl-2-morpholinophenyl) thiourea (11.5 g), methyl iodide (6.75 g) and acetone (100 ml) was heated under reflux for 2.5 hours to give 2 -Methyl-1- (6-methyl-2-morpholinophenyl) -3-methyl-2-thioshudourea hydroiodide (melting point 187-188 ° C.) is obtained.

2-methyl-1- (6-methyl-2-morpholinophenyl) -3-methyl-2-thioshudourea hydroiodide (17.8 g), n-butylamine (6.4 g) and ethanol (60 ml) Is stored at ambient temperature for 60 days. Potassium hydroxide (2.2 g) followed by lead acetate trihydrate (7.6 g) was added and the mixture was heated at reflux for 5 hours to yield 1- (n-butyl) -2- (6-methyl-2-morpholinophenyl)-. 3-methylguanidine is obtained which is converted to its fumarate salt (melting point 203-204 ° C.) and recrystallized from a 1: 2 mixture of methanol and ether.

Example 232

N-2-morpholinophenyl) isothiocyanate (4 g) and 33% ethanol dimethylamine solution (15 ml) in ethanol (10 ml) were reacted at 15 ° C. for 4 hours for 1,1-dimethyl-3-2. -Morpholinophenyl) thio urea (melting point 150-152 ° C) is obtained.

A mixture of 1,1-dimethyl-3- (2-morpholinophenyl) -thiourea (7.5 g), methyl iodide (1.7 ml) and acetone was heated under reflux for 2 hours to afford 2-methyl-1- (2-morpholinophenyl) -3,3-dimethyl-2-thio pseudourea (melting point 162 to 163 ° C) is obtained.

A mixture of 2-methyl-1- (2-morpholinophenyl) -3,3-dimethyl-2-thioshudourea hydroiodide (2 g), saturated ethanol ammonia solution (10 ml) and pyridine (10 ml) Heated at 90-95 ° C. for 19 hours in a sealed stainless steel pressurized vessel. Pyridine is evaporated off under reduced pressure and the residue is suspended in water. 1,1-dimethyl-2- (morpholinophenyl) guanidine (melting point 142-143 ° C.) is collected by filtration, washed with water, dried and recrystallized from hexane.

Example 233

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thioshudorea hydroiodide (3.8 g), a 33% ethanol solution of dimethylamine (5 ml) and pyridine (25 ml) was heated to 80 ° C. Heat for 6 hours. The pyridine is evaporated off under reduced pressure and the residue is treated with a mixture of water and ice to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (melting point 142-144 ° C.) which is recrystallized from hexane. .

Example 234

A mixture of 2-methyl-1- (2-morpholinophenyl) -2-thithioshudourea hydro iodide (3.8 g), 33% ethanol solution of dimethylamine (5 ml) and triethylamine (25 ml) Is heated at 80 ° C. for 8 h. The preethylamine was evaporated off under reduced pressure and the residue was treated with a mixture of ice and water to give 1,1-methyl-2- (2-morpholinophenyl) guanine (melting point 141 to 143 ° C) which was recrystallized from hexane Make it angry.

[Examples 235 to 241]

Compounds of formula (I) described in Table (VIII) are prepared as thiourea of formula (XVI), wherein R ₁₄ is R ₁₅ is H (A g), potassium hydroxide (B g), and general formula H ₂ A mixture of an amine (C g), lead acetate trihydrate (D g) and ethanol (Eml) of NR ₆ was heated at 90-95 ° C. for F hours to give an oil which was dissolved in methanol and treated with fumaric acid. It is prepared by obtaining the monofumarate salt of the compound of (I). The melting point of the mono fumarate salt is represented by mp and the solvent crystallizing the salt is identified by the following footnotes.

Footnote to Table 8

(59) The salt is recrystallized from methanol.

(60) The thiourea starting material was reacted with 4- (2-amino-4-fluorophenyl) morpholine (6 g) with methyl isothiocyanate (2.6 g) in dichloromethane (50 ml) for 25 days at room temperature. It is prepared by obtaining 1-methyl-3- (5-fluoro-2-morpholinophenyl) thiourea (melting point 145 to 148 ° C).

(61) The free base is purified by chromatography on a neutral alumina column using dichloromethane as eluent.

(62) Thiourea starting material was reacted with 4- (2-amino-4-methylthiophenyl) -morpholine (9.5 g) with methyl isothiocyanate (3.1 g) in dichloromethane (100 ml) at room temperature. -Methyl-3- (5-methyl thio-2-morpholinophenyl) thiourea (melting point 132-133 degreeC) is obtained.

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

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

Example 242

2-morpholino-5-trifluoromethylaniline (12 g) and thiophosgen (8.6 g) in dioxane (30 ml) and water (100 ml) were reacted at 0 ° C. for 30 minutes and at room temperature for a period of time to obtain a residue. Obtained and extracted with dichloromethane to give 2-morpholino-5-trifluoro methylphenyl isothiocyanate as yellow oil.

2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) was reacted with a 33% ethanol solution of ammonia (50 ml) for 2 hours at room temperature for 1- (2-morpholino -5-trifluoro methylphenyl) thiourea (melting point 196-197 ° C) is obtained.

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

Example 243

5-Cyano-2-morpholinoaniline (2 g) was reacted with diophosgene (1.15 ml) in dioxane (2 ml) and water (25 ml) at 0 ° C. for 30 minutes and at room temperature for 2 hours to obtain a residue. It is extracted with dichloromethane to give 5-cyano-2-morpholinophenyl isothiocyanate as an oil.

5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) was reacted with a 25% aqueous ammonia solution (1 ml) for 3 hours at room temperature, followed by 1- (5-cyano-2- Morpholinophenyl) thio urea (melting point 193-194 ° C.) is obtained.

1- (5-cyano-2-morpholinophenyl) -thiourea (5.2 g), potassium carbonate (8.3 g), 33% ethanol solution of dimethylamine (15 ml), lead acetate trihydrate and ethanol (25 ml ) Is heated under reflux for 3 hours to give 1,1-dimethyl-2- (5-cyano-2-morpholinophenyl) guanidine (melting point 125-127 ° C.), which is a monofumarate salt thereof ( Melting point 223 to 225 ° C. (decomposition) and it is recrystallized from methanol.

Example 244

1,1-dimethyl-3- (2-morpholinophenyl) -thiourea (2.65 g, prepared as described in Example 232). A mixture of n-propylamine (1.6 ml), lead acetate trihydrate (3.8 g), potassium hydroxide (1.2 g) and ethanol (25 ml) is heated under reflux for 4 hours. An additional amount of n-propylamine (1.6 ml) is added and the mixture is heated for 8 hours under lubrication. A residue is obtained in the reaction mixture which is extracted with ether. The extract was decolorized with charcoal, filtered, and the solvent was removed to give a viscous substance which was dissolved in methanol (10 ml) and treated with fumaric acid to give 1,3-di- (n-propyl) -2- (2-morpholine Nophenyl) guanidine hemifumarate (melting point 212-214 ° C.) is obtained and it is recrystallized from a 1: 2 mixture of methanol and ether.

Example 245

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

Half the mixture is filtered and the collected solid is washed with ethanol. Washes are added to the filtrate and the volume is reduced by evaporation. Ice is added and the resulting solid is collected by filtration, washed with water and dried to give 1,1, -dimethyl-2- (2-morpholinophenyl) guanidine (melting point 141 to 142 ° C.) which is recrystallized from hexane. .

[Examples 246 to 269]

The reaction of the compound of formula (VII) in its hydrochloride form (kg) and the compound of formula NC-NRR (L g) in m-cresol (Mml) was heated at 90-95 ° C. for N hours, as indicated in Table IX. Obtain the compound.

Footnote to Table 9

Notes (32), (38), (44) and (45) are as defined above.

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

(66) The product is isolated as its monofumarate salt and recrystallized from the 1: 1 mixture of methanol and ether.

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

(68) The reaction is carried out at 120 to 125 ° C.

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

(70) An oil is obtained from the reaction mixture which is extracted with boiling hexane to give the free base which is converted to its monofumarate salt and recrystallized from the 1: 3 mixture of methanol and ether.

(71) Obtain an oil from the reaction mixture, which was then extracted with hexane to give a free base as an oil, which in turn was a 1: 1 mixture of hexane, dichloromethane and hexane as eluent, dichloromethane and 1: 99 of methanol and dichloromethane. The mixture is subsequently purified by column chromatography on a neutral alumina column to give a base which is converted to its monofumarate salt and recrystallized from a 2: 7 mixture of methanol and ether.

Example 270

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

Example 271

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

Example 272

1- (2-morpholinophenyl) thiourea (10.6 g) is suspended in boiling water (80 ml) and a solution of potassium hydroxide (25.2 g) in warm water (70 ml) is added. The mixture is heated to 90 ° C. and an aliquot of a hot solution of lead acetate trihydrate (17.5 g) in water (80 ml) is added and the mixture is heated at reflux for 10 minutes and cooled to ambient temperature. The mixture is filtered and the filtrate is acidified with acetic acid until pH 6. The solid formed was separated by filtration, washed with water and recrystallized from ethyl acetate to obtain N- (2-morpholino phenyl) cyanamide (melting point 175 to 176 ° C).

N- (2-morpholinophenyl) cyanamide (2 g) is heated under reflux with a 33% solution of dimethylamine in ethanol (15 ml) for 4 hours. The mixture is cooled and the solvent is evaporated off to give a residue which is suspended in 20% aqueous sodium hydroxide solution. The suspension is extracted with dichloromethane (3 × 25 ml) and the extract is washed with water and brine, dried and evaporated to 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (melting point 142-143 ° C.) Is obtained and it is recrystallized from hexane.

Examples 273 to 285

In a similar manner to Example 272, N- (2-morpholinophenyl) cyanamide (P g) was heated under reflux with an amine of the general formula HNR5R6 (Q g) and ethanol (Rml) for T hours, to Table X Obtain the compound described in.

Footnote to Table X

Notes (32), (38), (44) and (45) are as defined above.

(72) A 33% ethanol solution of methylamine (25 ml) is used as reactant.

(73) The reaction is carried out at 90 to 95 ° C.

(74) The product is separated into its monofumarate salt and recrystallized from a 2: 3 mixture of methanol and ether.

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

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

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

(78) The reaction is carried out at ambient temperature for 4 hours and heated at reflux for 4 hours.

Example 286

4-2-amino-4-chlorophenyl) morpholine (8.5 g) and thiophosphene (4.6 ml) in dioxane (25 ml) and water (100 ml) for 30 minutes at 0 ° C and 3 hours at room temperature. Reaction yields 5-chloro-2-morpholinophenyl isothiocyanate (melting point 86-87 ° C) as a pale yellow solid.

5-chloro-2-morpholinophenylisothiocyanate (10 g) and 33% alcoholic ammonia solution (60 ml) were reacted at room temperature for 14 hours to give 1- (5-chloro-morpholinophenyl) thio as a yellow solid. Urea (melting point 174-175 C) is obtained.

1- (5-chloro-2-monopolinophenyl) thiourea (5.97 g) suspended in water (40 ml), lead acetate trihydrate (8.75 g) in water (40 ml) and potassium hydroxide (12.6) in water (35 ml) The mixture of g) is heated under reflux for 15 minutes to afford N- (5-chloro-2-morpholinophenyl) cyanamide (melting point 305-308 ° C.) as a white solid.

In a manner similar to that described in Example 272, a 33% ethanol solution (6 ml) of N- (5-chloro-2-morpholinophenyl) cyanamide (2.3 g) and dimethylamine in ethanol (10 ml) was added. Heated under reflux for 4 hours to convert to 1,1-dimethyl-2- (5-chloro-2-morpholinophenyl) guanidine (melting point 135-138 ° C.), which is recrystallized from methanol.

Example 287

A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosphene (5.2 g) and water (40 ml) in dioxane (20 ml) was stirred at 0 ° C. for 15 minutes and at room temperature for 1 hour. To give a residue, which was extracted with dichloromethane to obtain an oil, which was purified by chromatography on a silica gel column (mesh 100 to 200) using a 1: 9 mixture of ethyl acetate and hexane as eluent to give 5- as oil. Obtain fluoro-2-morpholinophenyl isothiocyanate.

5-fluoro-2-morpholinophenyl isothiocyanate (5.8 g) and 33% ethanololic ammonia solution (30 ml) were reacted at room temperature for 3 hours to obtain 1- 1 as a white solid (melting point 195-196 ° C). (5-fluoro-2-morpholinophenyl) thiourea is obtained.

In 1- (5-fluoro-2-morpholino phenyl) -thiourea (5.1 g) suspended in water (36.5 ml), lead acetate trihydrate (7.95 g) in water (36 ml) and in water (32 ml) The mixture of potassium hydroxide (11.45 g) is heated under reflux for 25 minutes to afford N- (5fluoro-2-morpholinophenyl) cyanamide (melting point 168-170 ° C.) as a white solid.

In a manner similar to that described in Example 286, a 33% ethanol solution of N- (5-fluoro-2-morpholinophenyl) cyanamide (2.2 g) and dimethylamine (6 ml) in ethanol (10 ml) Was heated at reflux for 20 minutes to afford 1,1-dimethyl-2 (5-fluoro-2-morpholinophenyl) guanidine (melting point 137-138 ° C.), which was recrystallized from hexane and its fumarate salt thereof. (Melting point 222-224 ° C.) and it is recrystallized from methanol.

Example 288

3-methyl-2-morpholinoaniline (9.4 g) and thiophosgen (6 ml) in dioxane (50 ml) and water (20 ml) were reacted at 0 ° C. for 30 minutes at room temperature for 2 hours to obtain a product. This is extracted with dichloromethane to give 3-methyl-2morpholinophenyl isothiocyanate as red oil.

3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) and saturated ammonia saturated solution in ethanol (60 ml) were bubbled at room temperature for 4 hours to give 1- (3-methyl-2-morpholi. Nophenyl) thiourea (melting point 178-179 ° C.) is obtained.

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) in water (35 ml) g) is heated at 90-95 ° C. for 1 hour to afford N- (3-methyl-2-morpholinophenyl) cyanamide (melting point 137-138 ° C.) which is recrystallized from ethyl acetate .

In a similar manner as described in Example 286, a 33% ethanol solution in N- (3-methyl-2-morpholinophenyl) cyanamide (2.5 g) and dimethylamine (3.5 ml) in ethanol (8 ml) was added. Heat at reflux for 1 h. An additional 33% ethanol solution of dimethylamine (3.5 ml) was added and the mixture was further heated under reflux for 1 hour to yield 1,1-dimethyl-2 (3-methyl-2-morpholinophenyl) guanidine (melting point 100 °). C) is obtained which is recrystallized from hexane and converted to its monofumarate salt (melting point 180 ° C.) which is recrystallized from a 1: 1 mixture of methanol and ether.

Example 289

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

4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) and a saturated ammonia solution in ethanol (30 ml) were reacted at room temperature for 24 hours to thereby react 1- (4-methoxy-2-morpholinophenyl. ) -Thiourea (melting point 175 ° C.) is obtained.

1- (4-methoxy-2-morpholinophenyl) -thiourea (3.8 g) suspended in water (26 ml), lead acetate trihydrate (5.7 g) in water (26 ml) and hydroxide in water (24 ml) The mixture of potassium (8.4 g) is heated at 90-95 ° C. for 30 minutes to afford N- (4-methoxy-2-morpholinophenyl0cyanamide.

A mixture of N- (4-methoxy-2-morpholinophenyl) -cyanamide91.9 g) and 33% ethanol dimethylamine solution (2.5 ml) was heated to reflux for 15 minutes to give 1,1-dimethyl-2 Obtain (4-methoxy-2-morpholinophenyl) guanidine (melting point 135 ° C.) and recrystallize it from hexane.

Example 290

A mixture of 5-isobutyl-2-morpholinoaniline hydrochloride (4.1 g), N, N-dimethylcyanamide (1.77 g) m-cresol (15 ml) was heated at 90-95 ° C. for 6 hours to give a residue. Is obtained, extracted with hot hexane, bleached with charcoal and purified by chromatography on an alumina column eluted with a 2:98 mixture of methanol and dichloromethane. The product formed is crystallized from a 1: 3 mixture of ethyl acetate and hexanes. The initial precipitate was filtered off and the filtrate was evaporated to dryness to afford 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 is obtained.

Example 291

Sodium chlorite (5.6 g), cuprous chloride (0.2 g) and cupric chloride dihydrate (0.34 g) are added to a solution of sodium carbonate (3.75 g) in water (25 ml). The mixture is cooled to 20 ° C. and a solution of N- (2-morpholinophenyl) thiourea (6 g) in dichloromethane (45 ml) is added over 15 minutes. The temperature is raised to 40 ° C and maintained at this level for 4.5 hours. Water (100 ml) and dichloromethane (200 ml) are added and the mixture is stirred for 10 minutes. The organic layer is separated and the aqueous layer is washed with dichloromethane. The combined organic layers are washed with brine and then dried. After the solvent was removed, the residue was stirred with 20% aqueous sodium hydroxide solution (100 ml), heated in a steam bath, and filtered. The filtrate is washed with ether, acidified with ph4 with acetic acid and extracted with dichloromethane. The extract is washed with brine, dried and the solvent is removed, and the residue is purified by chromatography on an eluted silica column by increasing the polarity by slowly adding ethyl acetate (30% or less). N- (2-morpholinophenyl) cyanamide (melting point 175-176 ° C.).

A mixture of N- (2-morpholinophenyl) cyanamide (1.5 g) and 33% ethanol solution (12 ml) of dimethylamine is heated at reflux for 4 hours. After removing the solvent, a residue was obtained, to which dichloromethane (100 ml) and brine (50 ml) were added. The mixture is stirred for 5 minutes and the organic layer is separated and dried. The solvent is removed to give 1.1-dimethyl-2 (2-morpholinophenyl) guanidine (melting point 144-145 ° C.) and recrystallize from hexane.

Example 292

1,1-dimethyl-2- (5-methylthio-2-morpholinophenyl) -guanidine (1.3 g), sodium metaperiodate (1 g), methanol in freebase form obtained from the product of Example 253 ( 10 ml) and water (4 ml) were allowed to stand at ambient temperature for 20 hours to obtain 1,1-dimethyl-2- (5-methylsulfinyl-2-morpholinophenyl) guanidine (melting point 160-161 ° C.) Recrystallize from ethyl acetate.

Example 293

A solution of 1-methyl-2- (2-morpholinophenyl) -thiourea (6.2 g) in dichloromethane (30 ml) was added to an aqueous solution of sodium carbonate (3.75 g in 25 ml), sodium chlorite (5.6 g), and chloride 1 To a stirred mixture of copper (0.2 g), cupric chloride dihydrate (0.34 g) and benzyltrimethylammonium chloride (0.6 g) is added over 15 minutes. The resulting mixture is stirred for 2 hours, then sodium chlorite (2.4 g) and benzyltrimethylammonium chloride (0.4 g) are added and the mixture is stirred for 1.5 hours. Dichloromethane (200 ml) and water (50 ml) are added and the aqueous layer is extracted with tichloromethane (2 × 100 ml). The extracts are combined, washed with brine, dried and filtered. The solvent was removed and the residue obtained was purified by chromatography on a silica gel column using hexane as a eluent, followed by a mixture of ethyl acetate and hexane (1: 4) to give N-methyl-N '-(2-morpholine Nophenyl) carbodiimide (melting point 67-68 ° C.) is obtained.

A mixture of N-methyl-N '-(2-morpholinophenyl) -carbodiimide (1 g), n-butyl amine (0.5) and tert-butanol (5 ml) at 90-95 ° C. for 4 hours Heat. The solvent is removed by evaporation and the residue is dissolved in dichloromethane (100 ml) and the resulting solution is washed with water, dried and filtered. The solvent is removed to give 1- (n-butyl) -2- (2-morpholinophenyl) -3-methyl guanidine which is then converted to its monofumarate salt (melting point 178-179 ° C.).

[Examples 294 to 300]

In a similar manner as described in Example 2, the products of the examples described below are converted to their fumarate salts and then recrystallized from the solvents described:

Example 301

A mixture of 2-morpholinoaniline hydrochloride (19.2 g) m-cresol (80 ml) and dimethylcyanamide (9.45 g) was heated at 100 ° C. for 5 hours, cooled and then cooled to 40% aqueous sodium hydroxide solution (300 ml). And ice (300 g). Water (300 ml) is added and the resulting solid is separated by filtration, washed with water and dissolved in dichloromethane. After the solution is dried, the solvent is removed and the residue is re-crystallized from hexane to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine (melting point 142-143 ° C.).

Examples 303 and 304

The products of Examples 175, 248 and 300 in their free base form in methanol, respectively, are reacted with L (+) tartaric acid to give the following compounds which are recrystallized from methanol.

301 4- (2- [1- (2-hydroxyethyl) -2-imidazolidinylideneamino] phenyl) morpholine monotartrate (melting point 147-148 ° C)

303 1,1-dimethyl-2- (5-methyl-2-morpholinophenyl) -guanidine monotartrate (melting point 183 to 184 ° C)

304 1,1-dimethyl-2- (2-morpholinophenyl) guanidine monotartrate (melting point 184 to 185 ° C)

Examples 305 and 306

Reaction of methanol and acetylchloride for 30 minutes yields hydrogen chloride which is then reacted with the products of Examples 248 and 301 to give the following products. The product is recrystallized from the solvent given in parentheses.

305 1,1-dimethyl-2- (5-methyl-2-morpholinophenyl) -guanidine monohydrochloride (melting point 161 to 162 ° C) (1: 1 mixture of isopropanol and ether)

306 1,1-dimethyl-2- (2-morpholinophenyl) guanidine monohydrochloride (melting point 200 to 201 ° C) (isopropanol)

Example 307

The product of Example 301 in acetone was reacted with concentrated sulfuric acid to give 1,1-dimethyl-2- (2-morpholinophenyl) guanidine hemisulfate (melting point 234-235 ° C.), which was obtained by mixing 1: 1 with methanol and ether. Recrystallize from the mixture.

Example 308

Pamoic acid is reacted with the product of 301 in the run in pyridine to give 1,1-dimethyl-2 (2-morpholinophenyl) guanidine hemifamoate (melting point 158-160 ° C.).

Example 309

Of 1,3-dimethyl-2-imidazolidinone (4.6 g), benzene (4- (2-aminobenzyl) -morpholine (3.8 g) and phosphorus oxychloride (3.6 ml) in benzene (40 ml) The mixture was heated at 65 to 70 ° for 20 hours to give 4- [2- (1.2-dimethyl-2-imidazolidinylideneamino) benzyl] morpholine (melting point 56 to 58 ° C), which was obtained from hexane Recrystallize.

Example 310

1,3-dimethyl-2-imidazolidinone (10.95 g) in benzene (100 ml), 4- (2-amino-4-chlorobenzyl) morpholine (13.6 g) and phosphorus oxychloride in benzene (50 ml) 8.8 ml) was heated at 60 to 65 ° C. for 8 hours to give an oil, which was used as a eluent for a 9: 1 mixture of hexane, hexane and dichloromethane, a 1: 1 mixture of hexane and dichloromethane, and dichloromethane. Purified by column chromatography on an alumina column. The resulting product (3.2 g) was dissolved in methanol (50 ml) and treated with fumaric acid (1.2 g) to give 4- [4-chloro-2 (1,3-dimethyl-2-imidazolidinylideneamino) benzyl] mor. Pauline monofumarate (melting point 169-170 ° C.) is obtained and recrystallized from a 1: 1 mixture of methanol and ether.

Example 311

A mixture of 4- (2-aminobenzyl) morpholine dihydrocollide (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 obtain a solid (melting point 120-121 ° C.), of which part (2 g) is dissolved in methanol (15 ml). Treatment with fumaric acid (0.9 g) yields N, N-dimethyl-N '-[2-morpholinomethylphenyl] guanidine monofumarate (melting point 164-165 ° C.) and recrystallizes from propan-2-ol .

Example 312

A mixture of 4- (2-aminobenzyl) 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 Obtain morpholinomethylphenyl) morpholine-4-carboxamidine (melting point 118-119 ° C.) and recrystallize it from hexane and convert it to the difumarate salt (melting point 166-167 ° C.) and propane- Recrystallize from 2-ol.

Example 313

The use of the compounds of the present invention in preparing pharmaceutical compositions is described below. The term active compound in the art may refer to any compound of the invention, but in particular refers to the end product of any of the above examples.

a) capsule

In the preparation of the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are mixed without aggregation. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound.

b) tablets

Tablets are made from the following ingredients.

Some of the active compound, lactose and starch are not agglomerated, combined and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. Anhydrous granules are combined with magnesium stearate and residual starch. The mixture is compressed into tableting machines to obtain tablets containing a unit dose of the active compound or a portion of the unit dose or unit dose.

c) enteric skin

Tablets are prepared by the method described in (b) above. The tablets are coated by enteric skin in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) suppositories

In preparing suppositories, 100 parts by weight of the active compound are incorporated into 1300 parts by weight of the triglyceride suppository base and the mixture is molded into each suppository containing a pharmaceutically effective amount of the active ingredient.

Claims (31)

A compound of formula (I) and a pharmaceutically acceptable salt thereof, excluding 2-alkylaminophenyl guanidine.

Wherein n is 0 or 1, and R ₁ and R ₂ are the same or different and are unsubstituted or substituted by alkyl groups, allyl groups or cyclohexyl groups of 1 to 3 carbon atoms, R ₁ and R ₂ Together with the nitrogen atoms to which they are attached 1-pyrrolidinyl, 2-methyl-1-pyrrolidinyl, piperidino, 4-methylpiperidino, 1-hexahydroazinyl, morpholino, 2.6-dimethyl Morpholino, thiamorpholino- thiamorpholino-1-oxide, 2-isoindolinyl, 4-methyl-1-pyrazinyl and 1- (1,2,5,6, -tetrahydro) pyridine To form a radical selected from the group consisting of dill. R ₃ is a straight or branched alkyl group having 1 to 7 carbon atoms, and having 3 to 7 carbon atoms.

Is a group of (III), wherein R ₄ and R ₄ ′ are the same or different and are H or an alkyl group having 1 to 4 carbon atoms, and R ₅ is H, unsubstituted or substituted by methoxy 4 is a straight or branched chain aliphatic group, R ₆ is (a) H, (b) hydroxy or an acylated derivative thereof, an alkoxy group having 1 to 3 carbon atoms, an alkylthio group having 1 to 3 carbon atoms, unalkalized or An alkylated amino group, a carbocyclic group of 3 to 7 carbon atoms or a straight or branched chain aliphatic group of 1 to 6 carbon atoms, unsubstituted or substituted by cyano, or (c) a cycloalkyl ring of 3 to 7 carbon atoms, or a group R₃ And R ₅ together with the carbon and nitrogen atoms to which they are attached

Forms a radical selected from the group consisting of 1,3-diazacycloheptan-2ylidene, and R ₅ and R ₆ together with the nitrogen atom to which they are attached are 1-pyrrolidinyl, piperidino, 4- Forms a radical selected from the group consisting of methylpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholino, and 4-methyl-1piperazinyl, and R ₇ is H, or halo, substituted Alkyl groups having 1 to 4 carbon atoms, alkoxy groups having 1 to 3 carbon atoms, alkylthio groups having 1 to 3 carbon atoms, alkoxycarbonyl groups having 2 to 3 carbon atoms, trifluoromethyl and cya At least one substituent selected from the group consisting of noses. The compound of formula (I) according to claim 2, wherein R ₁ and R ₂ are both alkyl, alkyl, allyl or 2-methoxyethyl, or R ₁ is methyl and R ₂ is 2-methoxyethyl or cyclohexyl. compound. The general formula of claim 2, wherein the group NR ₁ R ₂ is dimethylamino, diethylamino, diallylamino, (2-methoxyethyl) methylamino, cyclohexylmethylamino or bis (2-methoxyethyl) amino Compound of (I). The compound of formula (I) according to claim 1, wherein n is 1 and R ₁ and R ₂ together with the nitrogen atom to which they are attached form morpholino or thiamorpholino. The compound of formula (I) according to claim 1, wherein R ₃ is methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, cyclohexyl, amino, methylamino, dimethyl amino or ethylamino. The compound of formula (I) according to claim 1, wherein R ₅ is H, methyl, ethyl or methoxyethyl. The compound of claim 1, wherein R ₆ is H; Straight or branched chain alkyl groups of 1 to 5 carbon atoms which are unsubstituted or substituted by hydroxy, acylated derivatives of hydroxy, methoxy, methylthio, dimethylamino, phenyl or cyano; Straight or immediate chain alkenyl groups having 3 to 6 carbon atoms; Or a cycloalkyl group having 5 or 6 carbon atoms. The compound of claim 10, wherein R ₆ is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy Hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2,3-dihydroxypropyl, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methylthio A compound of formula (I) which is ethyl, 2-dimethylaminoethyl, benzyl, 2-phenylethyl, 2-cyanoethyl, allyl, 2-methylallyl, cyclopentyl or cyclohexyl. The compound of claim 1, wherein the group —N═C (R ₃ ) NR ₅ R ₆ is Acetamidino, N-methylacetamidino, N, N-dimethylacetamidino, N, N-diethylacetamidino, N- (2-acetyloxyethyl) acetamino, N-butyl acetamidino, N-pentylacetamino, N-methylpropionamidino, N, N-dimethylpropionamidino, N-ethylpropionamidino, Butyr Amidino, N-methylbutyramidino, N, N-dimethylbutyramidino, N-ethylbutyramidino, Isobutyramidino, N-methylisobutyramidino, N, N-dimethylisobutyramidino, Valeramidino, N-methyl valeleramidino, N, N-dimethylvaleramidino, Pivalamidino, N-methylpivalamidino, N, N-dimethylpivalamidino, N-methylcaproamidino, N-methylcyclohexanecarboxamidino, Diaminomethylene amido, N-methylguanidino, N, N-dimethylguanidino, N, N'-dimethylguanidino, N-ethylguanidino, N-butyl guanidino, 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-prefilguanidino, Nbutyl-Nmethylguanidino, N-tert-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, N, N-bis (2-methoxyethyl) guanidino, N-methyl-N- (2-methoxyethyl) guanidino, N-allyl-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino or A compound of formula (I) which is N, N-diallylguanidino. 18. The compound of claim 17, wherein group -N = C (R ₃ ) NR ₅ R ₆ is 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'-tetramethyleneguanidine, N, N-pentamethyleneguanidino or A compound of formula (I) wherein 1,1-dimethyl-3,3-pentamethyleneguanidino The compound of claim 1, wherein R ₇ is H, fluoro chloro, methyl, ethyl, isobutyl, methylthio-methyl, methoxy, methoxycarbonyl, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethyl And at least one substituent selected from cyano. The compound according to claim 1, wherein n is 0 and R ₁ and R ₂ together with the nitrogen atom to which they are bonded form morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, wherein ₃ is -NH ₂ , R ₅ is a C 1-4 Civa group and R ₆ is an unsubstituted or substituted C1-C4 aliphatic group or R ₅ and R ₆ are With the nitrogen atoms to which they are bound, 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-hexahydroazinylidene, 1-methyl-2-hexahydroazinylidene, 2-octahydroazorynylidene and To form a radical selected from the group consisting of 3-morpholinylidene, A compound of formula (I) wherein R ₇ is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio. 13. The compound of claim 12, wherein R ₅ is methyl, ethyl or allyl and R6 is methyl, ethyl, allyl, methoxyethyl or methylthioethyl, or R ₅ and R ₆ together with the nitrogen atom to which they are attached A compound of formula (I) which forms a polyno or thiomorpholino and wherein R ₇ is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio. The compound according to claim 1, wherein n is 0, R ₁ and R ₂ together with the nitrogen atom to which they are bonded form morpholino or thiamorpholino, and R ₃ is R ₄ having 1 to 4 carbon atoms Is an alkyl group of and R ₄ 'is H, a group of general formula (III) wherein R ₅ is H, R ₆ is an unsubstituted or substituted aliphatic group having 1 to 4 carbon atoms, R ₇ is H , Fluoro, methyl, methylthio or methylthiomethyl. The compound of claim 23, wherein R ₄ is methyl, R ₄ ′ is H, R ₅ is H, and R ₆ is methyl. A compound of formula (I) which is butyl, t-butyl or methoxyethyl. The compound of claim 1, wherein n is 0, R ₁ and R ₂ together with the nitrogen atom to which they are attached form a morpholino or thiamorpholino, and R ₃ is an alkyl group having 1 to 4 carbon atoms And R ₅ and R ₆ are H and R ₇ is H, fluoro, methyl, methylthio or methylthiomethyl. The method of claim 1, 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-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) phenyl] guanidine, 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, N- (4-methyl-2-morpholinophenyl) acetamidine and A compound of formula (I) selected from N- (2-morpholinophenyl) pivalamidine and a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a therapeutically active amount of a compound of formula (I) according to any one of claims 1 to 17 together with a pharmaceutically acceptable diluent or carrier. Use of a compound of formula (I) as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment of diabetes. Use of a compound of formula (I) as claimed in any one of claims 1 to 17 for the manufacture of a medicament for the treatment of hyperglycemia. A method of preparing a compound of formula (I) according to claim 1, comprising reacting an aminophenyl compound of formula (VII) with an amide or urea of formula (A) in the presence of a condensing agent.

Wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ and n are as defined in claim 1. A compound represented by the general formula (VII) (a) a lactam of general formula (VIII) in the presence of a condensing agent, (b) B ^- is Cl ^- halo or POCl _4, including ^- anion of the general formula (IX) containing the Of a compound of formula (X) wherein (c) B ⁻ is an anion comprising fluoroborate or methosulfate, and (d) when R ₆ is H, of formula (XI) in the presence of sulfonyl chloride A process for preparing a compound of formula (I) according to claim 1 comprising reacting with ketoxime or (e) an urea of formula (XII) in the presence of a condensing agent.

Wherein R ₁ , R ₂ , R ₃ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ , n, D and E are as defined in claim 1, R ₁₂ is chloro,- O-POCl ₂ , -O-SOCl, -OCOCl or -OSO ₂ Ph, R ₁₃ is an alkyl group. A process for preparing a compound of formula (I) according to claim 1 comprising reacting a compound of formula (XIII) or a salt thereof with dimine of formula (XIV).

Wherein R ₁ , R ₂ , R ₆ , R ₇ , R ₁₁ , E and n are as defined in claim 1, and groups R ₃ and R ₅ together with the carbon and nitrogen atoms to which they are attached, 2-imidazolidinylidene, 1-methyl-2-imidazolidinylidene, 4-methyl-2-imidizolidinylidene, 4,4-dimethyl-2-imidizolidinylidene, 4,5-dimethyl-2-imidazolidinylidene, 1-ethyl-2-imidazolininidinylidene, 1-propyl-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) -2-imidazolidinylidene, 1- (2-methoxyethyl) -3-methyl-2-imidazolidinylidene, 1-cyclohexyl-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-perhydroxypyrimidinylidene and Forms a radical selected from the group consisting of 1,3-diazacycloheptan-2-ylidene, and R ₁₄ and R ₁₅ are H. A process for preparing the compound of formula (I) according to claim 1 comprising reacting a compound of formula (VII) or a salt thereof with a cyano compound of formula (B) in the presence or absence of aluminum chloride

Wherein R ₁ , R ₂ , R ₇ and n are as defined in claim 1, R ₃ is a straight or branched chain alkyl group having 1 to 7 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, group NR ₅ R ₆ is NH ₂ . A process for preparing the compound of formula (I) according to claim 1, comprising reacting a compound of formula (V) or a salt thereof with a cyanamide compound of formula (C).

Wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and n are as defined in claim 1 and R ₃ is NH ₂ . A process for preparing the compound of formula (I) according to claim 1 comprising reacting a compound of formula (XV) with an amine of formula (D).

Wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and n are as defined in claim 1 and R ₃ is NH ₂ . A compound of formula (I) according to claim 1, comprising reacting a compound of formula (XIII) with an amine of formula (D) in the presence or absence of a base or in the presence of potassium hydroxide and lead acetate How to prepare.

Wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and n are as defined in claim 1, and R ₃ is a general formula

Is a group of (III) wherein R ₄ is alkyl and R ₄ ′ is H or alkyl, R ₄ is alkyl and R ₅ is H or alkyl. A process for preparing a compound of formula (I) according to claim 1 comprising reacting thiourea of formula (VI) with an amine of formula (D) in the presence or absence of a base and lead acetate.

Wherein R ₁ , R ₂ , R ₅ , R ₆ , R ₇ and n are as defined in claim 1, and R ₃ is a general formula

Is a group of (III), wherein R ₄ is alkyl, R ₄ ′ is H or alkyl, R ₁₄ is alkyl, and R ₁₅ is H or alkyl. A process for preparing the compound of formula (I) according to claim 1, comprising reacting carbodiimide of formula (VIII) with an amine of formula (E).

Wherein R ₁ , R ₂ , R ₆ , R ₇ and n are as defined in claim 1, and R ₃ is a general formula

Is a group of (III) wherein R ₄ is alkyl and R ₄ ′ is H and R ₅ is H. A process for preparing a compound of formula (I) according to claim 1, comprising reacting a compound of formula (VII) with a disubstituted compound of formula (XI ′).

Wherein R ₁ and R ₂ together with the nitrogen atom to which they are attached form morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino, n is 0 and R ₃ , R ₅ , R ₆ and n are as defined in claim 1, K is a leaving group, L is -O-, -S-, a direct bond or -CH _2-, respectively. 34. The process according to claim 32 or 33, wherein the condensing agent is selected from thionyl chloride, phosgene, phosphorus pentachloride and benzenesulfonyl chloride.