GB2226562A - Hypoglycaemic amidines and guanidines - Google Patents

Hypoglycaemic amidines and guanidines Download PDF

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GB2226562A
GB2226562A GB8929260A GB8929260A GB2226562A GB 2226562 A GB2226562 A GB 2226562A GB 8929260 A GB8929260 A GB 8929260A GB 8929260 A GB8929260 A GB 8929260A GB 2226562 A GB2226562 A GB 2226562A
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formula
methyl
morpholinophenyl
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carbon atoms
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GB8929260D0 (en
GB2226562B (en
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Balasubramanian Gopalan
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Boots Co PLC
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Boots Co PLC
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Priority claimed from GB898903592A external-priority patent/GB8903592D0/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/16—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2601/14—The ring being saturated

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Abstract

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

Description

Therapeutic Agents This invention relates to-novel therapeutic agents useful as antidiabetic agents, particularly as hypoglycaemic agents, to processes for the preparation of such agents and to pharmaceutical compositions containing them.
The present invention provides compounds of formula I:
and their pharmaceutically acceptable salts in which n = O or 1; in which R1 and R2, which are the same or different, are (a) an aliphatic group containing 1 to 3 carbon atoms, said aliphatic group being optionally substituted by methoxy (b) a cycloalkyl group containing 3 to 7 carbon atoms or (c) R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring of formula II
in which R8 represents H or an alkyl group containing 1 to 3 carbon atoms and B represents an alkylene group of 2 to 4 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms or the substituents on two adjacent carbon atoms of the alkylene group form a benzene ring or B represents an alkenylene group of 3 carbon atoms; R3 is a straight or branched alkyl group containing 1 to 7 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms or a group of formula III
in which R4 and R'4, which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; in which R5 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy; in which R6 is (a) H, (b) a straight or branched aliphatic group of 1 to 6 carbon atoms optionally substituted by hydroxy or an acylated derivative thereof, by an alkoxy group containing 1 to 3 carbon atoms, by an alkylthio group containing 1 to 3 carbon atoms, by an optionally alkylated amino group, by a carbocyclic group containing 3 to 7 carbon atoms or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon atoms;; or the group R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV
in which R6 is as hereinbefore defined, Rg and R10, which are the same or different, are H or an alkyl group of 1 to 4 carbon atoms optionally substituted by methoxy and D is an oxyethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups R9 and R10 or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms; or the group R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V
in which R6 is as hereinbefore described, in which R11 is H or an alkyl group containing 7 or 2 carbon atoms, and E is an alkylene group of 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI
in which G is an alkylene group of 4 or 5 carbon atoms optionally interrupted by oxygen, sulphur or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; and R7 represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkylsulphinyl groups containing 1 to 3 carbon atoms, alkylsulphonyl groups containing 1 to 3 carbon atoms, alkoxycarbonyl groups containing 2 total of 2 or 3 carbon atoms, trifluoromethyl or cyano.
In preferred compounds of formula I in which n = 0, R1 and R2, which may be the same or different, are selected from (a) alkyl groups of 1 to 3 carbon atoms optionally substituted by methoxy (b) allyl groups or (c) cyclohexyl groups. In particularly preferred compounds of formula I in which n = 0, R1 and R2 are both alkyl, allyl or 2-methoxyethyl or R1 is methyl and R2 is 2-methoxyethyl or cyclohexyl. In especially preferred compounds of formula I in which n = 0, the group NR1R2 is dimethylamino, diethylamino, diallylamino, (2-methoxyethyl)methylamino, cvclohexylmethyl- amino or bis(2-methoxvethyl)amino.
In preferred compounds of formula I in which n = 0 and in which the group NR1R2 is a heterocyclic ring represented by formula II, R8 represents H or methyl and B represents a group selected from -(CH2)2-, -CXMeCH2-, o-phenylene, -(CH2)3-, -CH2CHMeCH2-, (CH2)4 ' -CH20CH2-, -CHMeOCHMe-, -CH2S(fH2-, -CH2S(O)CH2-, -CH2NMeCH2- or -CH=CHCH2-. In especially preferred compounds of formula I in which n = 0 and the group NR1R2 is a group of formula II, the group NR1R2 is l-pyrrolidinyl, 2-methyl-I -pyrrolidinyl, piperidino, 4-methylpiperidino, 1 -hexahydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino 1-oxide, 2-isoindolinyl, 4-methyl-1-piperazinyl or 1-(1,2,5,6-tetrahydro)pyridyl.In preferred compounds of formula I in which n = 1, the group NR1R2 is morpholino or thiamorpholino.
In preferred compounds of formula I in which R3 is an alkyl group, the group R3 contains 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, t-butyl or pentyl). In preferred compounds of formula I in which the group R3 is a cycloalkyl group, the cycloalkyl group is cyclohexyl.
In preferred compounds of formula I in which R3 is a group of formula III, R4 and R4, are H, methyl or ethyl (for example R3 is amino, methylamino, dimethylamino or ethylamino).
In preferred compounds of formula I in which the group R5 does not form part of a heterocyclic ring, the group R5 is H or an alkyl group containing 1 to 3 carbon atoms (eg methyl or ethyl) optionally substituted by methoxy (eg R5 is methoxyethyl) or allyl.
In preferred compounds of formula I, R6 is H or a straight or branched alkyl group containing 1 to 5 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl or pentyl) optionally substituted by hydroxy (e.g. R6 is 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, or 2,3-dihydroxypropyl), by an acylated derivative of hydroxy such as acetyloxy or benzoyloxy (e.g. R6 is 2-acetyloxyethyl or 2-benzoyloxyethyl) by methoxy (e.g.
R6 is 2-methoxyethyl), by methylthio (eg R6 is 2-methylthioethyl), by dimethylamino (e.g. R6 is 2-dimethylaminoethyl), by phenyl (e.g. R6 is benzyl or 2-phenylethyl) or by cyano (e.g. R6 is 2-cyanoethyl) or R6 is a straight or branched alkylene group containing 3 to 6 carbon atoms (e.g. R6 is allyl or 2-methylallyl).
In preferred compounds of formula I in which R6 is a cycloalkyl group, R6 contains 5 or 6 carbon atoms (e.g. R6 is cyclopentyl or cyclohexyl).
In particularly preferred compounds of formula I in which the groups R3 and R5 together with the nitrogen and carbon atoms to which they are attached do not form a heterocyclic ring, the group -N=C(R3)NR5R6 is: acetamidino, N-methylacetamidino, N,N-dimethylacetamidino, N,N-diethylacetamidino, N-(2-acetyloxyethyl)acetamidino, N-butylacetamidino, N-pentylacetamidino, N-rnethylpropionamidino, N ,N-dimethylpropionamidino N-ethylpropionamidino, butyramidino, N-methylbutyramidino, N,N-dimethylbutyramidino, N-ethylbutyramidino, isobutyramidino, N-methylisobutyramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, N,N-dimethylvaleramidino, pivalamidino, N-methylpivalamidino, N ,N-dimethylpivalamidino, N-methylcaproamidino N-methylcyclohexanecarboxamidino, diaminornethyleneamino, N-methylguanidino, N,N-dimethylguanidino, N,N'-dimethylguanidino, N-ethylguanidino, N-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethylguanidino, N,N'-diethylguanidino, N,N',N,-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethyl-N'-methylguanidino, l-ethyl-1,3,3-trimethylguanidino, l-butyl-1,3,3-trimethylguanidino, N-methyl-N-propylguanidino, N-butyl-N-methylguanidino, N-sec-butyl-N' -methylguanidino, N-tert-bytyl-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-methylthioethyl)guanidino, N-allyl-N-methylguanidino, N-allyl-N' -methylguanidino, l-allyl-1,3,3-trimethylguanidino, N,N-diallylguanidino, In one group of preferred compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV, R9 and R10, which may be the same or different, are H or alkyl groups containing 1 to 3 carbon atoms (for example methyl, ethyl or isopropyl) optionally substituted by methoxy (eg R9 and/or R10 are methoxyethyl), D is selected from -(CH2)2-, -(CH2)3-, -(CH2)4- -(CH2)5-, -CH2CMe2- or -O(CH2)2- and the group R6 is preferably H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl.In particularly preferred compounds of formula I, formula IV represents:2-pyrrolidinylidene, l-methyl-2-pyrrolidinylidene, 3-methyl-2-pyrrolidinylidene, 1-ethyl-2-phrrolidinylidene, l-isopropyl-2-pyrrolidinylidene, l-cyclohexyl-2-pyrrolidinylidene, 1-(2-methoxyethyl)-2-phrrolidinylidene, 1,3-dimethyl-2-pyrrolidinylidene, 5,5-dimethyl-2-pyrrolidinyiidene, 1,3,3-trimethyl-2-pyrrolidinylidene, 1 ,5 ,5-trimethyl-2-pyrrolidinylidene, 3-isopropyl-1 -methyl-2-pyrrolidinylidene, l-ethyl-3,3-dimethyl-2-pyrrolidinylidene, 3 ,3-diethyl-1 -methyl-2-pyrrolidinylidene, 2-piperidinylidene, l-methyl-2-piperidmylidene, 1,3-dimethylpiperidinylidene, 1-ethyl-2-piperidinylidene, l-isopropyl-2-piperidinylidene, 1-(2-cyanoethyl)-2-piperidinylidene, 1-(2-acetoxyethyl)-2-piperidinylidene, 3- (2-methoxyethyl) -1 -methyl-2-piperidinylidene, 2-hexahydroazepinylidene, l-methyl-2-hexahydroazepinylidene, 2-octahydroazocinylidene or 3-morpholinylidene.
In a second group of preferred compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V, E is -CH2CH2-, -CMe2CH2-, -CHMeCHMe-, -(CH2)3-, CHMeCH2- or -(CH2)4, R11 is H, methyl or ethyl and R6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxybutyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl.In particularly preferred compounds of formula I, formula V represents: 2-imldazolidinylidene, l-mejhyl-2-imidazolidinylidene, 4-methyl-2-imidazolidinylidene, 4 ,4-dimethyl-2-imidazolidinylidene, 4,5-dimethyl-2-imidazolidinylidene, l-ethyl-2-imidazolidinylidene, l-propyl-2-imidazolidinylidene, l-isopropyl-2-imidazolidinylidene, l-(n-butyl)-2-imidazolidinylidene, l-isobutyl-2-imidazolidinylidene, l-pentyl-2-imidazolidinylidene, l-allyl-2-imidazolidinylidene, 1-(2-methylallyl)-2-imidazolidinylidene, 1 - (2-hydroxyethyl) -2-imidazolidinylidene, l-(n-hvdroxvethyl)-3-methyl-2-imicazolidinylidene, 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, l-cyclohexyl-2-imidazolidinylidene, l-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-imldazolidinylidene, 1,3-dimethyl-2-imidazolidinylidene, 1,3-diethyl-2-imidazolidinylidene, l-ethyl-3-methyl-2-imidazolidinylidene, 1-butyl-3-methyl-2-imidazolidinylidene, l-isopropyl-4,4-dimethyl-2-imidazolidinylidene, l-methyl-2-perhydropyrimidinylidene or 1,3-diazacycloheptane.
In preferred compounds of formula I in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI, G represents a group selected from -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2, -(CH2)2NME(CH2)2-, -(CH2)2CHMe(CH2)2 or -CH2CHMeOCHMeCH2-. In particularly preferred compounds, the group NR5Rç is 1-pyrrolidinyl, piperidino, 4-methylpiperidino, morpholino, 2 ,6-dimethylmorpholino, thiamorpholino or 4-methyl-1-piperazinyl.In particularly preferred compounds of formula I in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI, the group -N=C(R3)NR5R6 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, 1,1-dimethyl-3,3-pentamethyleneguanidino.
In preferred compounds of formula I, R7 represents H or one or more substituents (preferably one or two substituents) selected from fluoro, chloro, methyl, ethyl, isobutyl, methylthiomethyl, methoxy, dimethoxy, methoxycarbonyl, methylthio, methylsulphinyl, methylsulphonyl, trifluoromethyl or cyano.
Specific compounds of formula I are 4-[2-(2-piperidinylideneamino)phenyllmorpholine 4-[2-(1-methyl-2-piperidinylideneamino)phenyl] morpholine 4-[2-(1-ethyl-2-piperidinylideneamino)phenyl] morpholine 4-[2-(1-isopropyl-2-piperidinylideneamino)phenyl] morpholine 4-r2-(2-hexahydroazepinylideneamino)phenyl]morpholine 4-[2-(1-methyl-2-hexahvdroazepinylideneamino)phenyl]- morpholine 4-[2-(2-octahydroazocinylideneamino)phenyl]morpholine 4-[2-(2-pyrrolidinylideneamino)phenyl]morpholine 4-[2-(1-methyl-2-pyrrolidinylideneamino)phenyl] morpho line 4-[2-(1 ,3-dimethyl-2-pyrrolidinylideneamino)- phenyl]morpholine 4-[2-(1 ,3,3-trimethyl-2-pyrrolidinylideneamino)- phenyl 1 morpho line 4-[2-(1-ethyl-2-phrrolidinylideneamino)phenyl] morpholine 4-(2-[1-(2-methoxyethyl)-2-pyrrolidinylideneamino] phenylmorpholine 4-[2-(1-cyclohexyl-2-pyrrolidinylideneamino)phenyl] morpho line 4-[2-(3,3-dimethyl-1-ethyl-2-pyrrolidinylidene amino) phenyl] morpholine 4-[2-(3,3-diethyl-1-methyl-2-pyrrolidinylideneamino) phenyllmorpholine 4-[2-(3-isopropyl-1-methyl-2-pyrrolidinylidene amino)phenyl]morpholine 4-[2-(1,3-dimethyl-2-piperidinylideneamino)phenyl] morpholine 4-[3-methyl-2-(2-piperidinylideneamino)phenyl] morpholine 4-[3-methyl-2-(1-methyl-2-piperidinylideneamino) phenyl]morpholine 4-[4-methyl-2-(2-piperidinylideneamino)phenyl] morpho line 4-[4-methyl-2-(1-methyl-2-piperidinylideneamino) phenyl 1 morpholine 4-[5-methyl-2-(2-piperidinylideneamino)phenyl] morpho line 4-[6-methyl-2-(2-piperidinylideneamino)phenyl] morpholine .
4-[4-ethyl-2-(2-piperidinylideneamino)phenyl] morpho line 4-[3-chloro-2-(2-piperidinylideneamino)phenyll morpho line 4-[4-chloro-2-(2-piperidinylideneamino)phenyll - morpholine 4-[4-chloro-2-(1 -methyl-2-piperidlnylideneamino) phenyl 1 morpholine 4-[5-chloro-2-(2-piperidinylideneamino)phenyll morpholine 4-[6-chloro-2-(2-piperidinylideneamino)phenyl]- morpholine 4-[4-fluoro-2-(2-piperidinylideneamino)phenyll morpholine 4-[4-fluoro-2-(1-methyl-2-piperidinylideneamino) phenyl]morpholine 4-[4-methoxy-2-(2-piperidinylideneamino)phenyll morpholine 4-[4-methoxycarbonyl-2- (2-piperidinylideneamino) phenyl]-morpholine 4-[4-methylsulphonyl-2-(2-piperidinylideneamino) phenyl 1 morpholine 4-(2-[1-(2-acetoxyethyl)-2-piperidinylideneamino] phenyl)morpholine 4-f2-[1-methyl-3-(2-methoxyethyl)-2-piperidinylidene- anino3phenyl3morpholine 4-[2-(3-methyl-2-pyrrolidinylideneamino)phenyl]- morpholine N-methyl-N'-(2-morpholinophenyl)acetamidine N-(2-morpholinophenyl)-N'-propylacetamidine N-(n-butyl)-N'-(2-morpholinophenyl)acetamidine N-(n-pentyl)-N'-(2-morpholinophenyl)acetamidine N-(2-acetoxyethyl)-N'-(2-morpholinophenyl) acetamidine N,N-dimethyl-N'-(2-morpholinophenyl)acetamidine N,N-diethyl-N'-(2-morpholinophenyl)acetamidine N-methyl-N'-(2-morpholinophenyl)propionamidine N-ethyl-N'-(2-morpholinophenyl)propionamidine N,N-dimethyl-N'-(2-morpholinophenyl)propionamidine N-methyl-N'-(2-morpholinophenyl)butyramidine N-ethyl-N'-(2-morpholinophenyl)butyramidine N,N-dimethyl-N'-(2-morpholinophenyl)butyramidine N-methyl-N' -(2-morpholinophenyl) -2-methyl- propionamidine N,N-dimethyl-N'-(2-morpholinophenyl)-2-methyl- propionamidine N-methyl-N'-(2-morpholinophenyl)valeramidine N,N-dimethyl-N'-(2-morpholinophenyl)valeramidine N-methyl-N'-(2-morpholinophenyl)pivalamidine N,N-dimethyl-N'-(2-morpholinophenyl)pivalamidine N-methyl-N'-(2-morpholinophenyl)hexanamidine N-methyl-N'-[2-(1-pyrrolidinyl)phenyl]butyramidine N-methyl-N'-[2-(1-pyrrolidinyl)phenyl]pivalamidine N-methyl-N'-(2-morpholinophenyl)cyclohexane carboxamidine N-methyl-N'-(2-piperidinophenyl)pivalamidine 1-[2-(2-piperidinylideneamino)phenyl]pyrrolidine 1 -[2-(1 -methyl-2-piperidinylideneamino)phenyl] - pyrrolidine 1-[2-(1-ethyl-2-piperidinylideneamino)phenyl] pyrrolidine l-[L-chloro-2-(1-methyl-2-piperidinylideneamino)- phenyl 1 pyrrolidine 1 -[3-methyl-2-(1 -methyl-2-piperidinylideneamino) phenyl 1 pyrrolidine 1-[2-(1-methyl-2-pyrrolidinylideneamino)phenyl] pyrrolidine 1-[2-(1,3-dimethyl-2-pyrrolidinylideneamino) phenyl) pyrrolidine 1 - [ 2-(1 -methyl-2-hexahydroazepinylideneamino)phenyll - pyrrolidine 1-[4-methyl-2-(2-piperidinylideneamino)phenyl] pyrrolidine 1-[4-chloro-2-(2-piperidinylideneamino)phenyl] pyrrolidine 1-[3-methyl-2-(2-piperidinylideneamino)phenyl] pyrrolidine 1-[6-methyl-2-(2-piperidinylideneamino)phenyl] pyrrclidine 4-[2-(2-piperidinylideneamino)phenyl]thiamorpholine 1-[2-(2-piperidinylideneamino)phenyl]piperidine 1-[2-(1-methyl-2-piperidinylideneamino)phenyll piperidine 1-[2-(2-piperidinylideneamino)phenyl]hexahydroazepine 2,6-dimethyl-4-[2-(2-piperidlnylideneamino)phenyl]- morpho line 4-methyl-1-[2-(2-piperidinylideneamino)phenyl] piperidine 1-[2-(2-piperidinylideneamino)phenyl]-1,2,5,6 tetrahydropyridine 2-methyl-1-[2-(2-piperidinylideneamino)phenyl] pyrrolidine 2-[2-(2-piperidinylideneamino?phenyl]isoindoline 4-[2-(1-methyl-2-piperidinylideneamino)phenyl] thiamorpholine 4-[4-methyl-2-(2-piperidinylideneamino) phenyll thiamorpholine N-(2-methoxyethyl)-N-[2-(2-piperidinylideneamino) phenyl]methylamine N-[2-(2-piperidinylideneamino)phenyl]dimethylamine N-[2-(2-piperidinylideneamino)phenyl]diallylamine N-cyclohexyl-N-[2-(2-piperidinylideneamino)phenyl]- methylamine N-[2-(2-piperidinylidineaminophenyl)-bis-(2-methoxy- ethyl) amine 4-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino) phenvl]thlamorpholine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino) phenyl 1 piperidine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino)phenyl] 4 -methylpiperaz ine 1-[2-(1,3,3-trimethyl-2-pyrrolidinylidineamino) phenyl]pyrrolidine 4-[4-methyl-2-(1,3,3-trimethyl-2-pyrrolidinylidene amino)phenvl]morpholine 1 -[2-(1 -methyl-2-pyrrolidinylideneamino)phenyl] piperidine 1-[2-(1,3-dimethyl-2-pyrrolidinylideneamino)phenyl] piperidine 4-[2-(5,5-dimethyl-2-pyrrolidinylideneamino)phenyll morpholine 4-[1,5,5-trimethyl-2-pyrrolidinylideneamino)phenyl] morpholine N-[2-(1,3,3-trimethyl-2-pyrrolidinylideneamino)phenyl] bis-(2-methoxyethyl)amine N-(2-morpholinophenyl)acetamidine N- (5-methyl-2-morpholinophenyl)acetamidine N- (2 -morpholinophenyl) propionamidine N- (2-morpholinophenyl) butyramidine N- (2 -morpholinophenyl) isobutyramidine N-(5-methylthio-2-morpholinophenyl)isobutyramidine N-(5-fluoro-2-morpholinophenyl)isobutyramidine N-(2-morpholinophenyl)valeramidine N-(2-morpholinophenyl)pivalamidine 4-{2-[1-(cyanoethyl)-2-piperidinylideneamino]phenyl} morpholine 4-[2-(3-morpholinylideneamino)phenyl]morpholine 4-[2-(2-piperidinylideneamino)benzyl]morpholine 4-[2-(1-methyl-2-pyrrolidinylideneamino)benzyl] morpho line 4-[4-chloro-2-(2-piperidinylideneamino)benzyl]- morpholine 4-[2-(1,3,3-trimethyl-2-pyrrolidinylideneamino) benzyl]morpholine N-methyl-N'-(2-morpholinomethylphenyl)pivalamidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4 fluorophenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-3 methylphenyl]morpholine 4-[2-(1 ,3-dimethyl-2-imidazolidinylideneamino)-4 methylphenyl]morpholine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-5 methylphenyl]morpholine 4-[4-chloro-2-(1,3-dimethyl-2-imidazolidinylidene amino) phenyl morpho line 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)-4 methoxyphenyl]morpholine 4-[4,5-dimethoxy-2-(1,3-dimethyl-2-imidazolidinylidene amino) phenyl 1 morpholine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl] pyrrolidine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino) 3-methylphenyl]pyrrolidine 1-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl]- piperidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl] thiamorpholine 2,6-dimethyl-4-[2-(1,3-dimethyl-2-imidazolidinylidene amino)phenyl]morpholine N-[2-(1,3-dimethyl-2-imidazolidinylideneamino)phenyl] diethylamine 1-[2-(1,3-dimethvl-2-imidazolidinylideneamino)phenyl]- 2-methylpyrrolidine 4-[3-chloro-2-(1,3-dimethyl-2-imidazolidinylidene amino)phenyl]morpholine 1-[2-(1,3-dimethyl-2-imidazlidinylideneamino)-4 methylphenyl]pyrrolidine N-[2-(1,3-dimethyl-2-imidazolidinylidene amino)phenyl]-bis-(2-methoxyethyl)amine 4-[2-(1,3-diethyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(1 ,3-dimethyl-2-imidazolidinylideneamino)-6 methylphenyl]pyrrolidine 4-[2-(1-ethyl-3-methyl-2-imidazolidinylideneamino) phenyl]morpholine 4-[2-(1-n-butyl-3-methyl-2-imidazolidinylideneamino) phenyl]morpholine 4-22-tl-(2-benzovloxyethyl)-3-methyl-2-imiåazolinyl- ideneamino]phenylmorpholine 2-(2-morpholinophenyl)-1,1,3,3-tetramethylguanidine 1-ethyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine l-n-butyl-2-(2-mc~phollnophenyl)-1,3,3-trimethyl- guanidine l-pentyl-2-(2-morpholinophenyl)-1,3,3-trimethyl- guanidine 4-f2-[1-methyl-3-(2-methoxyethyl)-2-imidazolidinyl- ideneamino]phenylmorpholine 4-22-[1-methyl-3-(2-hydroxyethyl)-2-imidazolidinyl- ideneamino] phenyl morpholine N,N-dimethyl-N'-(2-morpholinophenyl)morpholine-4 carboxamidine N,N-dimethyl-N'-(2-morpholinophenyl)piperidine-1 carboxamidine 4-[2-(1,3-dimethyl-2-imidazolidinylideneamino) phenyl] thiamorpholine-1 -oxide 4-[2-(2-imidazolidinylideneamino)phenyl]morpholine 4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(1-ethyl-2-imidazolidinylideneamino)phenyl]- morpholine 4-[2-(1-n-propyl-2-imidazolidinylideneamino)phenyl]- morpholine 4-[2-(1-isopropyl-2-imidazolidinylideneamino)phenyl] morpho line 4-[2-(1-n-butyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(1 -isobutyl-2-imidazolidinylamino)phenyl]- morpho line 4-[2-(1 -pentyl-2-imidazolidinylamino)phenyl]- morpho line 4-[2-(1-allyl-2-imidazolidinylideneamino)phenyl] 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylideneaminol phenylmorpholine 4-t2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-3 methylphenyl)morpholine 4-{2-[1-(2-methoxyethyl)-2-imidazolidinylideneamino] phenylmorpholine 4-[2-(1-cyclohexyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(1-benzyl-2-imidazolidinylideneamino)phenyl]- morpholine 4-{2-[1-(2-phenylethyl)-2-imidazolidinylideneamino] phenylmorpholine 4-22-[1-(2-dimethylaminoethyl)-2-imidazolidinylidene- amino]phenylmorpholine 4-{2-[1-2,3-dihydroxypropyl)-2-imidazolidinylidene amino]phenyl3morpholine 4-t2-[1-(2-methylallyl)-2-imidazolidinylideneamino]- phenylmorphollne N-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]bis (2-methoxyethyl)amine N-t2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]- phenylgbis-(2-methoxyethyl)amine 4-[2-(1-methyl-2-imidazolïdinylideneamino)phenyl] thiamorpholine 1-[2-(1-methyl-2-imidazolidinylideneamino)phenyl] pyrrolidine 4-[2-(1-n-butyl-2-imidazolidinylideneam.ino)phenyl]- thiamorpholine 4-[2-(1-methyl-2-imidazolldinylideneamino)-3-methyl- phenyl]morpholine 4-[2-(1-methyl-2-imidazolidinylideneamino)-4-methyl phenyl]morpholine 1 2-[1-(2-hydroxyethyl)-2-imidazolindinylideneaminol- phenylpyrrolidine 1-(2-[1-(2-hydroxyethyl)-2-imidazolindinylideneamino] phenyl3 -2-methylpyrrolidine 4-[4-methyl-2-(1-n-butyl-2-imidazolidinylidene) phenyl]morphol.ne 1-[2-(2-imidazolidinylideneamino)phenyl]piperidine 1-[2-(1-methyl-2-imidazolidinylideneamino)phenyl] p iperidine 1-[2-(1-methyl-2-imidazolidinylideneamino)-3-methyl phenyl]piperidine 4-{2-[1-(2-hydroxyethyl)-2-imidazolidinylidene amino]phenyl thiamorpholine 1-{2-[1-(2-hydroxyethyl)-2-imidazolidinylidene amino]phenylipiperidine 4-{2-[1-(3-hydroxypropyl)-2-imidazolidinylideneamino] phenyl}morpholine 4-{2-[1-(2-hydroxypropyl)-2-imidazolidinylideneamino] phenyl}morpholine 4-22-[1-(2-kydroxybutyl)-2-imidazolidinylideneamino]- phenyl morpho line 4-{2-[1-(2-hydroxy-2-methylpropyl)-2-imidazolidinyl ideneamino]phenylXmorpholine 4-[2-(4-methyl-2-imidazolidinylideneamino)phenyl] morpholine 4-[2-(4,5-dimethyl-2-imidazolidinylideneamino)phenyl] morpholine 4-2-[4,5-dimethyl-1-(2-hydroxyethyl)-2-imldazolidinyl- ideneamino]phenylmorpholine 4-[2-(1-isopropyl-4,4-dimethyl-2-imidazolidinylidene amino) phenyl] morpholine 4-[2-(1-methylperhydropyrimidin-2-ylideneamino) phenyl]morpholine 2-(2-morpholinophenylimino)-1,3-diazacycloheptane 1,1-dimethyl-2-(2-morpholinophenyl) guanidine 1,3-dimethyl-2-(2-morpholinophenyl) guanidine 1,3,3-trimethyl-2-(2-morpholinophenyl)guanidire l-ethyl-2-(2-morpholinophenyl)-3-methyl guanidine 1,3-diethyl-2-(2-morphclinophenyl)guanidine 4-{2-[1-(2-acetyloxyethyl)-2-imidazolidinylidene amino]phenylmor?holine 4-f2-[1-(2-benzoyloxyethyl)-2-imidazolidinylidene- amino]phenyl)morpholine l-(n-butyl)-2-(2-morpholinophenyl)-3-methyl- guanidine 1-(2-methoxyethyl)-2-(2-piperidinophenyl)guanidine 1-(2-methylthioethyl)-2-(2-morpholinophenyl)guanidine 1-(2-methoxyethyl)-2-(2-morpholinephenyl)guanidine l-(n-propyl)-2-(2-morpholinophenyl)-3-methylguanidine 1-(2-methoxyethyl)-3-methyl-2-(2-morpholinophenyl) guanidine l-cyclopentyl-2-(2-morpholinophenyl)-3-methyl guanidine N-methyl-N'-(2-morpholinophenyl)pyrrolidine-1 carboxamidine l-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine 1 ,3-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine 1-allyl-2-[2-(1-pyrrolidinyl)phenyl)-3 methylguanidine 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl) guanidine 4-t2-[1-(2-hydroxyethyl)-2-imidazolidinylideneamino]- 4-methylphenylXmorpholine 1 -methyl-2-(2-morpholinophenyl)-3-(n-pentyl)guanidine l-(n-butyl)-2-(5-methyl-2-morpholinophenyl)-3- methylguanidine l-(n-butyl)-2-(6-methyl-2-morpholinophenyl)-3- methylguanidine l-(n-butyl)-2-(5-fluoro-2-morpholinophenyl)-3- methylguanidine l-(n-butyl)-2-(5-methylthio-2-morpholinophenyl)-3 methylguanidine l-isobutyl-2-(2-morpholinophenyl)-3-methylguanidine l-sec-butyl-2-(2-morpholinophenyl)-3-methylguanidine 1 -tert-butyl-2-(2-morpholinophenyl) -3-methylguanidine l-allyl-2-(2-morpholinophenyl)-3-methylguanidine l-(n-butyl)-2-(2-thiamorpholinophenyl)-3-methyl guanidine 1,1-dimethyl-2-(2-morpholino-5-trifluoromethyl phenyl)guanidine 1,1-dimethyl-2-(5-cyano-2-morpholinophenyl)guanidine 1,3-di-(n-propyl)-2-(2-morpholinophenyl)guanidine 2 - (2 -morpholinophenyl) guanidine 1,1-dimethyl-2-(5-methyl-2-morpholinophenyl) guanidine 1,1-dimethyl-2-(6-methyl-2-morpholinophenyl) guanidine 1,1-dimethyl-2-(4-chloro-2-morpholinophenyl) guanidine 1,1-dimethyl-2-(3-chloro-2-morpholinophenyl) guanidine 1,1-dimethyl-2-(5-methoxy-2-morpholinophenyl) guanidine 1,1-dimethyl-2-(5-methylthio-2-morpholinophenyl) guanidine 1 , 1 -dimethyl-2-(4-methyl-2-morpholinophenyl)guanidine 1 ,1 -dimethyl-2-(5-ethyl-2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-methylthiomethyl-2-morpholino phenyl)guanidine 1 ,1 -diethyl-2-(2-morpholinophenyl)guanidine l-(n-butyl)-l-methvl-2-(2-morpholinophenyl)guanidine 1,1-bis(2-methoxyethyl)-2-(2-morpholinophenyl) guanidine N-(2-morpholinophenyl)morpholine-4-carboxamidine N-(2-morpholinophenyl)pyrrolidine-1-carboxamidine 1,1-dimethyl-2-(2-piperidinophenyl)guanidine 1,1-dimethyl-2-[2-(1-pyrrolidinyl)phenyl]guanidine 1,1-dimethyl-2-(2-thiamorpholinophenyl)guanidine 1,1-dimethyl-2-(2-dimethylaminophenyl)guanidine 1,1-dimethyl-2-t2-[N-(2-methoxyethyl)-N-methylamino] phenyl guanidine 1,1-dimethyl-2-p2-(4-methyl-1-piperazinyl)phenyl] guanidine N-(2-piperidinophenyl)morpholine-4-carboxamidine N-(2-piperidinophenyl)piperidine-1-carboxamidine 1,1-dimethyl-2-(5-methoxycarbonyl-2-morpholino phenyl)guanidine l-methyl-2-(2-morpholinophenyl)guanidine 1-ethyl-2-(2-morpholinophenyl)guanidine 1-butyl-2-(2-morpholinophenyl)guanidine l-ethyl-l-methyl-2-(2-morpholinophenyl)guanidine l-methyl-1-(2-methylthioethyl)-2-(2- morpholinophenyl) guanidine 1 -(2-methoxyethyl)-1 -methyl-2-(2-morpholinophenyl) guanidine 1-allyl-1-methyl-2-(2-morpholinophenyl)guanidine l-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 carb oxamidine N-(2-morpholinophenyl)thiamorpholine-4-carbox amidine N-(2-morpholinophenyl)-4-methylpiperidine-1 carboxamidine N- (2-morpholiniphenyl) 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-methylsulphinyl-2-morpholino phenyl)guanidine 4-[2-(1 ,3-dimethyl-2-imidazolidinylideneamino)- benzyl]morpholine 4-[4-chloro-2-(1,3-dimethyl-2-imidazolidinylidene amino)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 includes compounds of formula I in which n = 0, -NR1R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R3 is -NH2, R5 is an aliphatic group containing 1 to 4 carbon atoms (eg methyl, ethyl or allyl), R6 is an aliphatic group of 1 to 4 carbon atoms optionally substituted by methoxy. or methylthio (eg methyl, ethyl, allyl, methoxyethyl or methylthioethyl) or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI (e.g. morpholino or thiamorpholino) and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
Specific compounds falling within this one group of preferred compounds include:1,1-dimethyl-2-(2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-fluoro-2-morpholinophenyl)guanidine 1,1-dimethyl-2-(5-chloro-2-morpholinophenyl)guanidine 1 ,1 -dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine 1 , 1 -dimethyl-2-(6-methyl-2-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 l-ethyl-l-methyl-2-(2-morpholinophenyl)guanidine 1,1-diethyl-2-(2-morpholinophenyl) guanidine 1-(2-methoxyethyl)-1-methyl-2-(2-morpholinophenyl) guanidine l-methyl-1-(2-methylthioethyi)-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)phenylJguanidine N-(2-morpholinophenyl)morpholine-4-carboxamidine N-(2-morpholinophenyl)thiamorpholine-4-carboxamidine and pharr'ceutically acceptab'e salts thereof.
A second group of preferred compounds of formula I includes compounds of formula I in which n = O, -NR1R2 is morpholino or thiamorpholino, R3 is a group of formula III in which R4 is an alkyl group containing 1 to 4 carbon atoms (eg methyl) and R4, is H, R5 is H, R6 is an aliphatic group containing 1 to 4 carbon atoms (eg methyl, butyl or t-butyl) optionally substituted bv methoxy (e.g. R6 is methoxyethyl) and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
Specific compounds falling within this second group of preferred compounds include:l-butyl-3-methyl-2-(2-morpholinophenyl)guanidine l-methyl-3-tert-butyl-2-(2-morpholinophenyl)guanidine l-methyl-3-tert-butyl-2-(4-fluoro-2-morpholinophenyl) guanidine l-methyl-3-tert-butyl-2-(4-methyl-2-morpholinophenyl) guanidine l-methyl-3-tert-butyl-2-(4-methylthio-2-morpholino phenyl) guanidine l-methyl-3-tert-butyl-2-(4-methylthiomethyl-2- morpholinophenyl) guanidine 1-(2-methoxyethyl)-3-methyl-2-(2-morpholinophenyl) guanidine 1 ,3-dimethyl-2-(2-thiamorpholinophenyl)guanidine l-methyl-3-tert-butyl-2-(2-thiamorpholinophenyl) guanidine and pharmaceutically acceptable salts thereof A further group of preferred compounds of formula I includes compounds of formula I in which n = 0, -NR1R2 is morpholino, thiamorpholino, morpholinomethyl or thiamorpholinomethyl, R3 is an alkyl group of 1 to 4 carbon atoms (eg methyl and t-butyl), R5 and R6 are H and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
Specific compounds falling within this further group of preferred compounds include: N-(2-morpholinophenyl)acetamidine N-(4-fluoro-2-morpholinophenyl) acetamidine N-(4-methyl-2-morphelinophenyl)acetam~dflne N- (4-methylthio-2-morpholinophenyl)acetamidine N-(4-methylthiomethyl-2-morpholinophenyl)acetamidine M-(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 hydrochlorides, hydrobromides, hydroiodides, sulphates, nitrates, maleates, acetates, citrates, fumarates, tartrates, succinates, benzoates, pamoates and salts with acidic amlno acids such as glutamic acid. Compounds of formula I and their salts may exist in the form of solvates (for example hydrates).
Some compounds of formula I contain one or more asymmetric carbon atoms and exist in different optically active forms. When the compounds of formula I contain one chiral centre the compounds exist in two enantiomeric forms and the present invention includes both enantiomeric forms and mixtures thereof. IVhen the compounds of formula I contain more than one chiral centre, the compounds may exist in diastereoisomeric forms. The present invention includes each of these diastereoisomeric forms and nixtures thereof.
The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I together with a pharmaceutically acceptable diluent or carrier.
In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus the therapeutic 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 carriers suitable for use in such compositions are well known in the art of lubricating agents, for example magnesium stearate, and tableting the mixture by known methods. The tablets may be formulated in a manner known to those skilled in the art so as to give a sustained release of the compounds of the present invention. Such tablets may, if desire, be provided with enteric coatings by known methods, for example by the use of cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without added excipients, may be prepared by conventional means and, if desired, provided with enterlc coatings in a known manner. The tablets and capsules may conveniently each contain 50 to 500 mg of the active compound.Other compositions for oral administration include, for example, aqueous solutions containing the active compound, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethylcellulose, and oily suspensions containing a compound of the present invention in a suitable vegetable oil, for example arachis oil.
In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling.
In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients.
The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I may be used to treat hyperglycaemia in human beings. In such treatment the amount of the compound of formula I administered per day is in the range 50 to 3000 mg. The preferred administration route is oral administration.
Processes for the preparation of compounds of formula I will now be described. These processes form a further aspect of the present invention.
Compounds of formula I may be prepared by the reaction of an aminophenyl compound of formula VII
with an amide or a urea of formula R3.CO.NR5R6 in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulphonyl chloride.
Compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula IV may be prepared by the reaction of an aminophenyl compound of formula VII with a) a lactam of formula VIII
in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, cyanuric chloride, phosgene, carbon tetrachloride/triphenylphosphine, phosphorus pentachloride or benzenesulphonyl chloride.
b) a compound of formula IX
in which R12 is chloro, -O-POC12, -O-SOC1, -OCOCI or -OSO2Ph and B is an anion such as halo (e.g. C1 ) or POCl42-, c) a compound of formula X
in which R13 is an alkyl group and B is an anion such as fluoroborate or methosulphate.
d) when R6 is H, a ketoxime of formula XI
in the presence of a sulphonyl chloride (for example benzene sulphonyl chloride).
Compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula V may be prepared by the reaction of an aminophenyl compound of formula VII with a urea of formula XII
in the presence of a condensing agent such as phosphorus oxychloride, thlonyl chloride, phosgene, phosphorus pentachloride or benzenesulphonyl chloride.
Compounds of formula I in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula V may be prepared by the reaction of a compound of formula XIII
optionally in the form of a salt (e.g. a hydroiodide salt) in which R14 and R15 are H with a diamine of formula XIV RllNHENHRe XIV Compounds of formula I in which R3 is a straight or branched alkyl group of 1 to 7 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms and the group NR5R6 is NH2 may be prepared by the reaction of a compound of formula VII optionally in the form of a salt (e.g. a hydrochloride salt) with a cyano compound of formula R3CN, optionally in the presence of aluminium chloride.
Compounds of formula I in which the group R3 is NH2 may be prepared by the reaction of a compound of formula VII optionally in the form of a salt (e.g. a hydrochloride salt) with a cyanamide compound of formula R5R6NCN. The reaction may be performed in a liquid reaction medium (for example m-cresol) or by heating the reactants together in the absence of a liquid carrier.
Compounds of formula I in which the group R3 is NH2 may be prepared by the reaction of compounds of formula XV
with amines of formula NHR5R6 optionally in a liquid reaction medium (for example ethanol).
Compounds of formula I in which R3 is a group of formula III in which R4 is alkyl and R4' is H or alkyl may be prepared by the reaction of a compound of formula XIII in which R14 is the group R4 and R15 is the group R4, with an amine of formula HNR5R6. The reaction may be performed in an alcoholic medium (e.g.
ethanol or n-butanol) optionally in the presence of a base such as pyridine or triethylamine or in the presence of potassium hydroxide and lead acetate. When HNRfRe is ammonia, the ammonia may be dissolved in the alcoholic medium and the reaction may be performed under elevated pressure in a sealed reaction vessel.
Compounds of formula I in which R3 is a group of formula III in which R4 is alkyl and R4' is H or alkyl may be prepared by the reaction of a thiourea of formula XVI
In which RX k is the group R4 and R15 is the group R4, with an amine of formula HNR5R6. The reaction may be performed in the presence of a base (such as potassium hydroxide or potassium carbonate) and lead acetate.
When HNR5R6 is ammonia, the ammonia may be dissolved in an alcoholic medium (e.g. ethanol) and the reaction may be performed under elevated pressure in a sealed reaction vessel.
Compounds of formula I in which R3 is a group of formula III in which R4 is alkyl and R4, is H and in which R5 is H may be prepared by the reaction of a carbodiimide of formula XVII
with an amine of formula H2NR6.
Compounds of formula I in which n = 0 and NR1R2 is a morpholino, thiamorpholino, l-pyrrolidinyl or piperidino group may be prepared by the reaction of a compound of formula XVIII
with a disubstituted compound of formula XIX K(CH2)2L(CR2)2K XIX in which K is a leaving group such as halo (e.g. bromo or chloro) or tosyloxy and L is -O-, -S-, a direct bond or -CH2-.
Compounds of formula I in which R3 is a group of formula III in which R4 is propyl and R4' is H and in which R5 is H and R6 is propyl may be prepared by the reaction of an amine of formula H 2NR6 in which R6 is propyl with a thiourea of formula XVI in which R14 and R15 are both methyl in the presence of potassium hydroxide and lead acetate. In this reaction the amino group -NHR6 replaces both the thioxo group and the dimethylamino group.
Compounds of formula I in which R3 is a group or formula III and in which R4 is methyl and R4, is H and in which R5 is H and R6 is methyl may be prepared by the react Ion of an amine of formula H2NR6 in which R6 is methyl with a compound of formula XIII in which the group NR14R15 is butylamino. In this reaction the amino group -NHR6 replaces both the methylthio group and the amino group -NR14R15.
Compounds of formula I in which NR1R2 is a thiamorpholino-l-oxide group may be prepared by the oxidation (for example using sodium metaperiodate) of a compound of formula I in which -NR1R2 is thiamorpholino.
Compounds of formula I in which R6 is substituted by an acyloxy group may be prepared by acylation (e.g.
acetylation or benzoylation) of the corresponding compound of formula I in which R6 is substituted by hydroxy.
Compounds of formula I in which R7 is an alkylsulphinyl group may be prepared by oxidation (for example using sodium metaperiodate) of compounds of formula I in which R7 is an alkylthio group.
Compounds of formula VII may be prepared by the reduction of the nitro group in a compound of formula XX
for example (a) using hydrogen and a Raney nickel catalyst, (b) hydrogen and a palladium/carbon catalyst, (c) sodium sulphide, (d) stannous chloride dihydrate in hydrochloric acid, ethyl acetate or ethanol or (e) iron in the presence of acid.
Compounds of formula IX in which R12 is a group of formula OPOCl2, OSOCI, OCOC1 and OSO2Ph may be prepared by the reaction of compounds of formula VIII with phosphorus oxychloride, thionyl chloride, phosgene or benzenesulphonyl chloride respectively.
Compounds of formula X may be prepared by the reaction of compounds of formula VIII with alkylating agents such as dialkylsulphate, trialkyloxonium fluoroborate or borontrifluoride etherate/diazoalkanes followed by basification with sodium carbonate or sodium hydroxide solution.
Compounds of formula XIII may be prepared by the reaction of methyl iodide with thioureas of formula XVI.
Compounds of formula XV may be prepared by the reaction of potassium hydroxide with compounds of formula XIII in which R14 and R15 are both H or in which R14 is benzoyl and R15 is H in the presence of lead acetate.
Compounds of formula XV may be prepared by the reaction of thioureas of formula XVI in which R14 and R15 are H with sodium chlorite in the presence of a base such as sodium carbonate and a copper catalyst such as a mixture of cuprous and cupric chlorides.
Thioureas of formula XVI in which R14 and R15 are H may be prepared by the reaction of ammonia with an isothiocyanate of formula XXI
Compounds of formula XVI in which R14 is an alkyl group and R15 is H may be prepared by the reaction of an aminophenyl of formula VII with an alkylisothiocyanate of formula R14NCS.
Carbodiimides of formula XVII may be prepared by the reaction of a thiourea of formula XVI in which R14 is the group R4 and Rl5 is H with sodium chlorite.
Compounds of formula XVI II may be prepared by the reduction for example by hydrogen and Raney nickel of compounds cf formula XXII
Compounds of formula XX in which n = 0 and Nor12 is a morpholino, thiamorpholino, l-pyrrolidinyl or piperidino group may be prepared by the reaction of a 2-nitroaniline with a compound of formula XIX.
Compounds of formula XX in which n = 0 and -NR1R2 is morpholino, thiamorpholino, l-pyrrolidinyl, piperidino, l-hexa-hydroazepinyl or 4-methyl-1-piperazinyl may be prepared by the reaction of morpholine, thiamorpholine, pyrrolidine, piperidine, l-hexahydroazepine and 4-methyl-1-piperazine respectively with a halonitrobenzene (e.g. 2-fluoronitrobenzene or 2-chloronitrobenzene) in the absence or presence of a solvent such as benzene, ethanol or acetonitrile.
Compounds of formula XXI may be prepared by the reaction of a compound of formula VII with thiophosgene in a liquid reaction medium such as dioxan.
Compounds of formula XXII may be prepared by the reaction of an amide or urea of formula R3.CO.NR5R6 with a 2-nitroaniline in the presence of a condensing agent (such as phosphorus oxychloride or thionylchloride). Compounds of formula XXII may be prepared by the reaction of an amidine or guanidine of formula R3.CNH.NR5R6 with a 2-halonitrobenzene (e.g.
2-fluoronitrobenzene or 2-chloronitrobenzene).
The hypoglycaemic activity of the compounds of formula I which are given in the following Examples has been demonstrated by the following test. Rats weighing between 150 and 200 g were fasted for 18 hours and then were subcutaneously injected with glucose (800 mg/4 ml/kg) followed by an oral dose of the compound to be tested (x mg in either 4 or 5 ml of 0.2% Agar/kg). After 2 and 4 hours blood was collected by orbital bleeding and the plasma glucose estimated on a Beckman glucose analyser using the specific glucose oxidase method (Kadish A H, Little R L and Sternberg J C, Clin chem 14 116 [1968]). The percentage reduction of plasma glucose when compared to control animals which had not been given the compound to be tested, but which had been given 0.2% Agar homogenate, was then calculated.Compounds are considered to have hypoglycaemic activity in this test if they show a 15% or greater reduction in plasma glucose at any value of.
x up to 200 at either or both of 2 and 4 hours.
The results obtained at any value of x in the above tests were then reviewed and the hypoglycaemic activity of each compound was classified on the following scale. Where more than one set of results is available at a particular value of x, the mean value of the % reduction is used to classify the activity of the compounds.
A greater than 25% reduction at both 2 and 4 hours.
B greater than 25% reduction at 2 hours but less than 25 reduction at 4 hours.
C reduction in the range 15 to 25 > at 2 hours but greater than 25% reduction at 4 hours.
D reduction in the range 15 to 25% at both 2 and 4 hours.
E reduction in the range 15 to 25% at 2 hours but less than 15% reduction at 4 hours.
F less than 15% reduction at 2 hours but greater than 15% reduction at 4 hours.
The activities of the compounds described in the Examples given hereinafter are given below in Table A.
Table A Example x Activity Example x Activity 1 25 A 2 25 B 3 25 B 4 25 B 5 25 A 6 25 E 7 25 B 8 36 B 9 200 E 10 25 B 11 25 A 12 25 A 13 50 D 14 200 A 15 100 E 16 25 D 17 50 B 18 25 E 19 40 A 20 25 A 21 25 C 22 25 B 23 50 A 24 25 B 25 25 D 26 25 B 27 25 A 28 25 A 29 25 E 30 25 D 31 50 D 32 25 D Table continued Example x Activity Example x Activity 33 25 B 34 25 B 35 25 D 36 200 F 37 200 E 38 200 D 39 200 A 40 200 A 41 200 A 42 36 D 43 25 B 44 200 A 45 200 D 46 36 B 47 37 B 48 200 A 49 38 E 50 36 A 51 200 D 52 36 B 53 36 B 54 37 B 55 36 A 56 35 A 57 25 A 58 25 B 59 35 A 60 37 E 61 36 D 62 25 C 63 100 A 64 25 B 65 25 A 66 36 D 67 200 A 68 25 C 69 43 D 70 36 A 71 36 A 72 25 B 73 25 A 74 25 A 75 50 F 76 25 D 77 25 E 78 25 F 79 200 A 80 25 D 81 200 D 82 50 E 83 25 A 84 25 E 85 25 D 86 25 F 87 200 D 88 200 F Table A continued Example x Activity Example x Activity 89 200 C 90 25 E 91 200 A 92 25 B 93 25 C 94 200 C 95 25 E 96 25 F 97 50 D 98 50 A 99 25 A 100 25 B 101 25 B 102 200 A 103 25 B 104 27 A 105 37 E 106 37 E 107 25 B 108 25 B 109 25 B 110 36 B 111 25 B 112 36 B 113 25 D 114 25 E 115 25 D 116 25 B 117 25 B 118 25 A 119 25 D 120 25 B 121 25 E 122 25 A 123 38 B 124 37 B 125 36 B 126 200 A 127 25 E 128 25 A 129 25 B 130 100 B 131 50 B 132 200 A 133 25 B 134 25 A 135 25 A 136 25 B 137 25 B 138 25 B 139 25 B 140 100 A 141 25 E 142 25 A Table A continued Example x Activity Example x Activity 143 25 B 144 25 B 145 25 C 146 200 A 147 36 D 148 25 D 149 36 D 150 68 F 151 25 C 152 25 D 153 25 B 154 39 D 155 133 B 156 25 D 157 25 A 158 25 A 159 50 D 160 26 D 161 34 A 162 35 B 163 25 B 164 25 D 165 200 B 166 25 D 167 25 B 168 25 B 169 25 A 170 25 A 171 25 D 172 25 D 173 25 D 174 25 B 175 25 B 176 35 C 177 25 B i78 200 A 179 25 D 180 25 E 181 43 D 182 25 D 183 25 D 184 34 F 185 200 D 186 25 A 187 25 A 188 25 B 189 25 A 190 25 A 191 36 D 192 25 B 193 25 A 194 200 - C 195 12.5 A 196 25 A Table A continued Example x Activity Example x Activity 197 25 D 198 25 A 199 25 B 200 25 A 201 25 E 202 25 B 203 100 A 204 200 A 205 200 A 206 200 C 207 50 A 208 30 D 209 25 B 210 30 D 211 36 A 212 25 F 213 50 D 214 25 E 215 25 E 216 35 A 217 30 E 218 200 D 219 200 D 220 36 A 221 200 A 222 35 A 223 35 D 224 35 C 225 25 B 226 200 A 227 25 F 228 35 A 229 35 A 230 35 C 231 35 F 232 25 B 233 25 B 234 25 B 235 34 A 236 38 C 237 35 A 238 35 A 239 35 A 240 36 A 241 34 A 242 200 A 243 200 B 244 200 E 245 25 B 246 200 D 247 37 A 248 36 A 249 36 B 250 25 E 251 35 E 252 200 A 253 35 A 254 36 B Table A continued Example X Activity Example X Activity 255 36 A 256 34 B 257 36 A 258 35 E 259 34 D 260 35 B 261 36 C 262 37 B 263 38 B 264 36 B 265 200 E 266 200 E 267 200 E 268 35 B 269 35 B 270 25 B 271 25 B 272 25 B 273 200 C 274 128 D 275 25 E 276 36 B 277 34 B 278 35 B 279 25 B 280 35 B 281 35 A 282 200 C 283 200 E 284 200 E 285 200 B 286 35 B 287 36 B 288 38 E 289 200 A 290 25 D 291 25 B 292 85 C 293 35 A 294 25 B 295 25 B 296 25 D 297 35 B 298 35 E 299 34 E 300 200 A 301 25 B 302 38 A 303 39 B 304 40 B 305 28 A 306 29 A 307 30 B 308 NT 309 100 D 310 200 D 311 200 E 312 200 E NT = Not Tested The present invention will be illustrated by the following Examples which are given by way of example only. The final product of each of the Examples was characterised by elemental analyses.
Example 1 A solution of delta-valerolactam (24 g) in dry benzene (100 ml) was cooled to 100C in ice-water and treated with freshly distilled phosphorus oxychloride (22.2 ml) under nitrogen over a period of 10-15 minutes. The initial white solid formed changed to a clear yellow oil over 3 hours. A solution of 4-(2-aminophenyl)morpholine (36 g) in dry benzene (150 ml) was added and the mixture heated at 65"C with stirring for 32 hours. The benzene layer was decanted, the oil washed twice with benzene (2 x 40 ml), ether (100 ml) was added and the mixture cooled in ice treated with 10% aqueous sodium hydroxide solution to alkaline pH, with stirring. The aqueous layer was extracted with ether (2 x 100 ml) and the combined ether extracts washed with water, brine and dried. The solution was filtered and the solvent removed to give a thick oil which solidified on trituration with hexane.
The crude solid was crystallised from hot hexane to yield 4-[2-(2-piperidinylideneamino)phenyl]morpholine (m.p. 89-900C).
Example 2 A solution of the product of Example 1 (10.2 g) in dry methanol (30 ml) was treated with fumaric acid (4.6 g). The resulting solid was filtered and crystallised from methanol to yield 4-[2-(2-piperi dinylideneamino)phenyl]morphoine fumarate as a colourless crystalline solid [m.p. 210 C (dec)].
Examples 3 to 35 In a similar manner to that described above in Example 1 the compounds listed in Table I were prepared by the reaction of an aminophenyl compound of formula VII in which NR1R2 is morpholino (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70 C.
Notes to Table I (1) Product recrystallised from hexane.
(2) The product was purified by chromatography on an alumina column using a 1:1 mixture of dichloromethane and hexane as eluant.
(3) Product isolated as its hydroiodide salt which was recrystallised from a 1:1 mixture of methanol and ether.
(4) Coupling reaction performed at ambient temperature.
(5) Product recrystallised from ether.
(6) The compound of formula VIII was dissolved in a mixture of benzene (60ml) and acetonitrile (40ml).
(7) The product was purified by chromatography on an alumina column using the following eluants sequentially:- hexane, a 1:9 mixture of dichloro methane and hexane, a 3:7 mixture of dichloro methane and hexane, a 1:1 mixture of dichloromethane and hexane and dichloromethane.
(8) The product was isolated as its monofumarate salt which was recrystallised from 1:1 mixture of methanol and ether.
(9) The product was isolated as its monohydroiodide salt which was recrystallised from a 2:3 mixture of methanol and ether.
(10) Coupling reaction performed at ambient temperature for 24 hours and at 70"C for 8 hours.
(11) Product isolated as its fumarate salt which was recrystallised from propan-2-ol.
(12) Product isolated as its sesquifumarate salt which was recrystallised from a 1:1 mixture of methanol and ether.
(13) The compound of formula VIII was dissolved in acetonitrile (120 ml).
(14) The product was purified by chromatography on an alumina column using a 99:1 mixture of dichloromethane and methanol as eluant. The product was recrystallised from a 1:1 mixture of dimethoxyethane and hexane.
Table I
Ex. A B C D E F m R7 R9 R10 R6 mp( C) Notes 3 17.8 75 16.4 100 13.3 6 3 H H H Me 130 (1) 4 5.3 20 5.7 40 4.1 4 3 H H H Et 92-93 (1) 5 5.4 25 6.3 50 4.1 2 3 H H H i-Pr 104-105 (1) 6 5 25 4 25 3.3 40 4 H H H H 96-98 (1)(2) 7 5.4 30 7.5 50 5.5 6 4 H H H Me 79-80 (1) 8 10 25 12.7 50 9 6 5 H H H H 231-232 (3) 9 3.6 10 2 20 2.4 6 2 H H H H 143 (1) 10 10.7 60 7.2 120 7.2 8 2 H H H Me 89-90 (1) 11 3.6 10 2.8 20 2.4 6 2 H Me H Me 105-107 (1)(4) Ex.A B C D E F m R7 R9 R10 R6 mp( C) Notes 12 3.6 10 3.2 30 2.4 14 2 H Me Me Me 72-75 (1) 13 4.5 10 3.5 25 3 5 2 H H H Et 94-96 (1) 14 3.6 25 4.3 50 2.7 5 2 H H H CH2CH2OMe 140-142 (7)(9) 15 7.1 80 10 40 5.5 8 2 H H H cyclohexyl 110-112 (1) 16 3.5 10 3.4 30 2.4 5 2 H Me Me Et 72-74 (1) 17 3.6 30 3.8 15 2.4 2 H Me Et Me 190 (10)(11) 18 3.4 15 3.3 25 2.4 12 2 H i-Pr H Me 70 (1) 19 2.5 30 1.9 60 1.4 10 3 H Me H Me 184 (12) 20 6.8 30 8 50 7.3 5.5 3 3-Me H H H 167-168 (1) 21 3.1 25 2.7 25 2.2 4 3 3-Me H H Me 110-111 (1) 22 6.8 30 8 50 7.3 4.5 3 4-Me H H H 114 (1) 23 3.8 25 2.7 25 2.2 4 3 4-Me H H H 108-109 (1) 24 6 30 6.3 50 5.8 10 3 5-Me H H H 119 (1) 25 2.5 10 3 20 2.7 10 3 6-Me H H H 98 (1) 26 4.1 20 4 30 3.7 5 3 4-Et H H H 204-205 (7)(8) Table I cont.
Ex. A B C D E F m R7 R9 R10 R6 mp( C) Notes 27 3 10 3 20 2.7 5 3 3-Cl H H H 166-167 (5) 28 5 40 5.25 30 3.4 8 3 4-Cl H H H 109-110 (1) 29 4.2 25 2.7 25 2.2 4 3 4-Cl H H Me 108-109 (1) 30 6.3 25 6 50 5.5 4.5 3 5-Cl H H H 140-141 (1) 31 6.3 20 6 40 5.8 4 3 6-Cl H H H 115-116 (1) 32 5 50 6 30 5.6 5 3 4-F H H H 82-83 (1) 33 3.7 25 2.7 25 2.2 4 3 4-F H H Me 110-111 (1) 34 3.1 20 3 30 2.7 5 3 4-OMe H H H 103-104 (1) 35 4.6 4 40 3.6 4 3 4-COOMe H H H 112-114 (1)(6) 36 5.1 8 60 2.2 3 3 4-SO2Me H H H 151-152 (13)(14) 37 6.3 30 6.8 40 3.4 7 3 H H H CH2CH2OAc 66-67 (1) Example 38 In a similar manner to that described in Examples 1 and 2, 1-methyl-3-(2-methoxyethyl)-2-piperidone (2.56 g) in benzene (30 ml) was reacted with 4-(2aminophenyl)morpholine (2.49 g) in benzene (30 ml) in the presence of phosphorus oxychloride (1.37 ml) for 12 hours at 700C.The resulting product was methyl-3- (2-methoxyethyl) -2-piperidinylideneamino] - phenyl)morpholine sesquifumarate (m.p. 1740C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 39 In a similar manner to that described in Example 1, 1-benzyl-3methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70"C to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinylideneamino)phenyl]morpholine (m.p. 96-97"C) which was recrystallised from hexane.
The recrystallised product (2 g) from the previous 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-methyl-2-pyrrolidinylidene- amino)phenyl]morpholine as an oil. This oil (1 g) was dissolved in methanol (20 ml) and a solution of fumaric acid (0.47 g) in methanol was added to yield 4-[2-(3-methyl-2-pyrrolidinylideneamino)phenyl]- morpholine fumarate (m.p. 185"C) which was recrystallised from an 1:1 mixture of methanol and ether.
Examples 40-62 In a similar manner to that described in Example 1 the compounds listed in Table II were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with an amide of formula R3.CO.NR5R6 (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-700C.
Notes to Table II Notes (1) and (8) has the meaning given in respect of Table I (15) The product was isolated as its monofumarate salt which was recrystallised from methanol.
(16) Coupling reaction performed at 800C.
(17) Coupling reaction performed at 750C.
(18) Product obtained as a monohydrate.
(19) Product recrystallised twice from n-pentane.
(20) The product was obtained as an oil, the boiling point of which was not determined. The oil was purified by chromatography on an alumina column using the following eluants sequentially: hexane, a 1:1 mixture of dichloromethane and hexane and dichloromethane.
Table II
Ex. A B C D E F NR1R2 R3 R5 R6 R7 mp( C) Notes 40 7.1 30 7.3 50 9.1 6 morpholino Me H Me H 132-133 (1) 41 6.3 35 4 25 3.5 10 morpholino Me H Pr H 78-79 (1) 42 7.2 35 5.1 25 4 9 morpholino Me H n-Bu H 178-179 (15) 43 7.2 35 5.7 25 4 9 morpholino Me H n-C5H11 H 163-164 (15) 44 10.8 40 10 50 6.3 18 morpholino Me H (CH2)2OAc H 185-186 (15) 45 3.5 20 2.5 20 2.3 8 morpholino Me Me Me H 68-70 (1) 46 3.5 20 3 20 2.3 40 morpholino Me Et Et H 166-168 (8) 47 8.9 30 6.5 70 6.9 12 morpholino Et H Me H 70 (8) 48 5.3 30 4 20 3.7 5 morpholino Et H Et H 105-107 (1)(16) Table II Cont.
Ex. A B C D E F NR1R2 R3 R5 R6 R7 mp( C) Notes 49 8.9 30 7.6 70 6.9 12 morpholino Et Me Me H 170 (8)(17)(18) 50 8.9 30 7.6 75 6.9 45 morpholino Pr H Me H 180 (8) 51 5.3 30 4.5 20 3.7 3 morpholino Pr H Me H 75-77 (16)(19) 52 8.9 30 8.6 75 6.9 45 morpholino Pr Me Me H 135-137 (8) 53 8.9 30 7.6 70 6.9 12 morpholino i-Pr H Me H 220 (8)(17) 54 8.9 30 8.6 70 6.9 12 morpholino i-Pr Me Me H 156-160 (8)(17) 55 7.2 30 5.1 35 4 16 morpholino Bu H Me H 168-169 (17) 56 8.9 30 10.7 80 6.9 12 morpholino Bu Me Me H 121-122 (8) 57 5.3 30 5.2 40 4.1 8 morpholino -CMe3 H Me H 128-129 (1) 58 5 20 5.5 20 4 14 morpholino -CMe3 Me Me H (20) 59 8.9 50 9.7 100 6.9 10 morpholino pentyl H Me H 134-135 (8) 60 8.1 50 7 80 6.4 8 1-pyrrol- Pr H Me H 135-137 (8) idinyl 61 3.7 20 3.9 30 3.1 8 1-pyrrol- -CMe3 H Me H 193-194 (8) idinyl 62 5 30 4.3 25 2.6 9 morpholino cyclo H Me H 93-94 (1) bexyl Example 63 A mixture of N-methylpivalamide (11.5 g) in benzene (120 ml) and phosphorus oxychloride (9.2 ml) was stirred at room temperature for 3 days. A solution of 1-(2-aminophenyl)piperidine (14 g) in benzene (80 ml) was added and the mixture heated at 65-70 C for four days to give N-methyl-N'-(2piperidinophenyl)pivalamidine (m.p. 78"C) which was recrystallised from hexane. The product was obtained as a 0.25 hydrate.
Examples 64-75 In a similar manner to that described in Example 1 the compounds listed in Table III were prepared by the reaction of an aminophenyl compound of formula VII in which NR1R2 is 1-pyrrolidinyl (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range of 60-700C.
Notes to Table III Notes (1), (4) and (8) have the meaning given in respect of Table I.
(21) The product was isolated as its monofumarate salt which was recrystallised from a 1:2 mixture of methanol and ether.
(22) The product was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether.
Table III
Ex. A B C D E F m R7 R9 R10 R6 mp( C) Notes 64 3.2 20 3 20 2.8 6 3 H H H H 82-84 (1) 65 3 25 2.7 25 2.2 5 3 H H H Me 99-101 (1) 66 4.9 20 5.7 30 4.1 7 3 H H H Me 143-144 (21) 67 4 25 2.7 25 2.2 6 3 4-Cl H H Me 77-78 (1) 68 3.5 25 4 25 3.3 14 3 3-Me H H Me 92-93 (1) 69 4 25 3 25 2.7 8 2 H H H Me 157-158 (8) 70 4.8 25 4 30 3.3 8 2 H Me H Me 152-154 (22) 71 4.8 20 5.7 30 4.1 8 4 H H H Me 159-160 (21) 72 8.8 90 10 60 9.2 8 3 4-Me H H H 112-113 (1) Table III cont.
Ex. A B C D E F m R7 R9 R10 R6 mp( C) Notes 73 1.8 30 2 20 1.8 24 3 4-Cl H H H 138-139 (1) 74 8.8 60 10 60 9.2 5 3 3-Me H H H 113-115 (1) 75 4 30 4.5 30 4.2 14 3 6-Me H H H 83-85 (1)(4) Examples 76-91 In a similar manner to that described in Example 1 the compounds listed in Table IV were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with a 2-piperidone (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70"C.
Notes to Table IV Note (1), (8), (11) and (21) have the meaning given for Tables I and III (23) Coupling reaction performed at 75-80"C.
(24) Product isolated as its monofumarate salt which was recrystallised from methanol.
(25) Product was recrystallised from a 1:2 mixture of dimethoxyethane and hexane.
(26) Product recrystallised from hexane and then a mixture of dimethoxyethane and hexane.
(27) Product was purified by column chromatography on an alumina column using a 49:1 mixture of dichloromethane and methanol as eluant. The product was isolated as its dihydroiodide salt which was recrystallised from a 1:1 mixture of ethanol and ether.
(28)Coupling reaction performed at 90-1000C.
Table IV
Ex. A B C D E F NR1R2 R7 R6 mp( C) Notes 76 3.5 10 2.4 20 2.4 5 thiamorpholino H H 215-217 (8) 77 14 40 16 120 15.2 12 piperidino H H 70-72 (1) 78 3.4 25 2.7 25 2.2 8 piperidino H Me 87-89 (1)(23) 79 2.8 25 3 30 2.7 5 1-hexahydro- H H 152-153 (18) azepinyl 80 5 25 5 50 47 4 2,6-dimethyl- H H 132-135 (1) morpholino 81 7.6 40 8 60 7.3 7 4-methyl- H H 145-146 (24) piperidino 82 5 25 6 50 5.5 7 1-(1,2,5,6-tetra- H H 62 (1) hydro)pyridyl Table IV cont.
Ex. A B C D E F NR1R2 R7 R6 mp( C) Notes 83 5.3 15 6 30 6 24 2-methyl-1- H H 71 (1) pyrrolidinyl 84 2.8 40 3 20 2.7 4 2-isoindolinyl H Me 124-125 (25) 85 3.7 25 2.6 25 2.2 6 thiamorpholino H H 124-125 (1) 86 4.2 60 4 40 3.6 5 thiamorpholino 4-Me H 150-151 (26) 87 7.2 30 8 40 7.3 7 N(Me)CH2CH2OMe H H 135-136 (27) 88 5.4 30 8 40 7.3 5 NMe2 H H 175-176 (8) 89 4.2 20 4.6 40 4.3 4 N(allyl)2 H H 62-63 (1) 90 6.1 25 4.5 50 4.2 14 N(Me)cyclohexyl H H 183-185 (11)(28) 91 4.2 25 2.7 25 2.2 8 N(CH2CH2OMe)2 H Me 129-130 (21) Examples 92-101 In a similar manner to that described in Example 1, the compounds listed in Table V were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with a methyl-substituted-2pyrrolidinone (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours at a temperature in the range 60-70"C.
Notes to Table V Notes (1) and (4) has the meaning given for Table I (29) Product isolated as its dihydroiodide salt which was recrystallised from a 1:1 mixture of methanol and ether.
(30) Coupling reaction performed at ambient temperature for F hours.
(31) Product isolated as its dihydroiodide salt which was recrystallised from a 1:3 mixture of ethanol and ether.
Table V
Ex. A B C D E F NR1R2 A G R6 R7 mp( C) Notes 92 2.5 20 2 20 1.5 4 thiamorpholino CMe2 CH2 Me H 120-122 (1) 93 3.6 20 3.2 20 2.4 17 piperidino CMe2 CH2 Me H 62-63 (1) 94 4.7 10 3.9 30 3 6 4-methyl-1- CMe2 CH2 Me H 280 (29) piperazinyl 95 4.8 20 4.6 40 2.8 8 1-pyrrolidinyl CMe2 CH2 Me H 85-86 (1) 96 8 80 7.2 70 5.2 20 morpholino CMe2 CH2 Me 4-Me 182-183 (11) 97 6 10 4.2 20 7.4 4 piperidino CH2 CH2 Me H 65-66 (1)(4)(30) 98 3.5 20 2.8 20 2.4 5 piperidino CHMe CH2 Me H 75-76 (1)(4)(30) 99 7.1 40 6.8 40 5.5 18 morpholino CH2 CMe2 H H 130-131 (1) 100 7.1 50 6.1 25 4.4 4 morpholino CH2 CMe2 Me H 63-64 (1) 101 4.4 10 3.1 20 2.4 20 N(CH2CH2OMe)2 CMe2 CH2 Me H 178 (31) Example 102 A mixture of 4-(2-aminophenyl)morpholine (5.34 g), acetonitrile (4.52 ml) and anhydrous aluminium chloride (12 g) was heated at 160-1700C for 4 hours to yield N-(2-morpholinophenyl)acetamidine (m.p. 140-141 0C) which was recrystallised from hexane.
Example 103 A mixture of 4-(2-amino-4-methylphenyl)morpholine (5.76 g), acetonitrile (3.5 g) and anhydrous aluminium chloride (12 g) was heated at 160-1700C for 5 hours to yield N-(5-methyl-2-morpholinophenyl)acetamidine (m.p.
121"C) which was recrystallised from hexane.
Example 104 A mixture of 4-(2-aminophenyl)morpholine (5.34 g), propionitrile (4.7 g) and anhydrous aluminium chloride (12 g) was heated at 160-170eC for six hours to yield N-(2-morpholinophenyl)propionamidine (m.p. 11 40C) which was recrystallised from hexane.
Example 105 A mixture of 4-(2-aminophenyl)morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) was heated at 1700C in a sealed stainless steel pressure vessel for 60 hours. Excess n-butyronitrile was removed and the residue dissolved in water, basified with 10% aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and then brine, dried and the solvent removed. The residue was purified by chromatography on a neutral alumina column.Elution with a 1:1 mixture of dichloromethane and hexane removed unreacted starting material and then elution with a 1:99 mixture of methanol and dichloromethane yielded a solid which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give N-(2-morpholinophenyl) butyramidine monofumarate (m.p. 168-170"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 106 Powdered anhydrous aluminium chloride (12 g) was added portion-wise to a stirred slurry of 4-(2-aminophenyl)morpholine (5.34 g) and n-butyronitrile (6 g) at 40-50"C. The mixture was then heated at 160-1700C for 6 hours, allowed to cool and then digested with 40% aqueous sodium hydroxide solution. The solution was extracted with ether and the extract washed with water and brine and dried. Removal of the solvent gave a residue which was crystallised from a 1:1 mixture of ethylacetate and hexane to give N-(2-morpholinophenyl)butyramidine (m.p. 131") which was converted into its monofumarate salt (m.p. 173"C) which was recrystallised from propan-2-ol.
Example 107 A mixture of 4-(2-aminophenyl)morpholine hydrochloride (10 g) and isobutyronitrile (60 ml) was heated at 1650C for 26 hours in a sealed stainless steel pressure vessel to yield N-(2-morpholinophenyl)isobutyramidine (m.p. 140-141"C) which was recrystallised from hexane.
Example 108 A mixture of 4-(2-aminophenyl)morpholine (5.34 g), isobutyronitrile (6 g) and anhydrous aluminium chloride (12 g) was heated at 160-170"C for 6 hours to give N-(2-morpholinophenyl)isobutyramidine (m.p. 138"C) which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Example 109 A mixture of 5-methylthio-2-morpholinoaniline (1.8 g), isobutyronitrile (1.66 g) and anhydrous aluminium chloride (3.2 g) was heated at 1400C for 2 hours to give N- (5-methylthio-2-morpholinophenyl) isobutyramidine (m.p. 155"C) which was recrystallised from hexane.
Example 110 A mixture of 5-fluoro-2-morpholinoaniline (1.96 g) isobutyronitrile (2 g) and anhydrous aluminium chloride was heated at 1500C for four hours to give N-(5-fluoro-2-morpholinophenyl) isobutyramidine (m.p. 1420C) which was recrystallised from hexane and converted into its fumarate salt (m.p.
172"C) which was recrystallised 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) were heated at 160-165 C under nitrogen for 25 hours and then cooled. The mixture was treated with aqueous sodium hydroxide and the basified mixture was extracted with dichloromethane. The solvent was removed by evaporation and the residue distilled-under a pressure of 50mm Hg to remove half the unreacted valeronitrile.
A solid separated on cooling which was separated by filtration, washed with hexane (50 ml) and recrystallised from hexane to give N-(2-morpholinophenyl)valeramidine. (m.p. 135-136"C).
Example 112 A mixture of 4-(2-aminophenyl)morpholine (3.56 g), pivalonitrile (5 g) and anhydrous aluminium chloride (8 g) was heated at 160-170"C for six hours to yield N-(2-morpholinophenyl)pivalamidine (m.p. 126"C) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 211"C) which was recrystallised from methanol.
Examples 113-125 In a similar manner to that described in Example 2, the compounds prepared in the Examples listed below were converted into their fumarate salts which were recrystallised from the solvents given below: mp of Starting Recrystallisation fumarate Ex. Example solvent salt ("C) 113 20 methanol 212 114 22 methanol 229-230 115 32 methanol 213 116 34 methanol 180(dec) 117 64 methanol 197(dec) 118 72 methanol 188 119 73 methanol:ether(1:2) 208-210 120 99 methanol:ether(1 :2) 204-205 121 100 methanol 117-118 122 74 methanol:ether(1:2) 179-180 123 102 methanol:ether(1:1) 189 124 107 methanol:ether(1:1) 162-163 125 111 isopropanol 156-158 Example 126 The product of Example 1 (2.6 g) was reacted at room temperature with excess acrylonitrile (5 ml). The product was recrystallised from ethylacetate to give 4-22-[1-(2-cyanoethyl)-2-piperidinylideneamino] phenylmorpholine. (m.p. 1480C).
Example 127 A mixture of 3-morpholinone (4 g) in dry acetonitrile (40 ml), 4-(2-aminophenyl)morpholine (3.6 g) in dry acetonitrile (20 ml) and phosphorous oxychloride (3.6 ml) was heated for 40 hours at 65-700C to-give oil which was purified by column chromatography on neutral alumina (72 g) using (a) hexane, (b) dichloromethane:hexane (1:1) and (c) dichloromethane as eluant. The resulting oil was treated with a saturated solution of hydrogen chloride in methanol (25 ml) to give a pale yellow solid which was recrystallised from a 1:1 mixture of methanol and ether to give 4-[ 2- (3-morpholinylideneamino)phenyl] -morpholine hydrochloride (m.p. 262-263"C).
Example 128 A mixture of 2-piperidone (3.6 g) in benzene (30 ml), 4-(2-aminobenzyl)morpholine (5.7 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70 C for 48 hours to yield 4-[2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 108-110 C) which was recrystallised from hexane.
Example 129 A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated at 60-650C for 5 hours to give 4-[4-chloro 2-(2-piperidinylideneamino)benzyl]morpholine (m.p.
121-122 C) which was recrystallised from hexane.
Example 130 A mixture of 1-methyl-2-pyrrolidone (4.8 g) in benzene (20 ml), 4-(2-aminobenzyl)morpholine (7.6 g) in benzene (50 ml) and phosphorus oxychloride (4.8 ml) was heated at 65-700C for 18 hours to yield an oil which was dissolved in methanol (30 ml). Treatment with 57% hydroiodic acid (10.l ml) gave 4-[2-(1-methyl2-pyrrolidinylideneamino)benzyl]morpholine dihydroiodide (m.p. 230-232"C) which was recrystallised from ethanol.
Example 131 A mixture of 1,3,3-trimethyl-2-pyrrolidinone (3 g) in benzene (20 ml), 4-(2-aminobenzyl)morpholine (3.8 g) in benzene (10 ml) and phosphorus oxychloride (2.1 ml) was allowed to stand at room temperature for 28 hours and then heated at 60-650C for 14 hours to yield an oil (2.9 g) which was dissolved in methanol (15 ml).
Treatment with 57% hydroiodic acid (2.8 ml) gave 4-[2-(1 ,3,3-trimethyl-2-pyrrolidinylideneamino)benzyl] morpholine dihydroiodide (m.p. 256-258"C) which was recrystallised from a 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) in benzene (40 ml) and phosphorus oxychloride (5 ml) was heated at 80-85"C for 12 hours to yield a solid which was dissolved in methanol (25 ml) and treated with fumaric acid (1.4 g) to give N-methyl-N'-(2 morpholinomethylphenyl)pivalamidine monofumarate (m.p.
167-168"C) which was recrystallised from propan-2-ol.
Example 133 A mixture of 1,3-dimethyl-2-imidazolidinone (7 g) in benzene (45 ml), phosphbrus- oxychloride (6 ml) and 4-(2-aminophenyl)morpholine (8.5 g) in benzene (30 ml) was heated for 30 hours at 65-700C. The product was recrystallised from hexane to give 4-[2-(1,3-dimethyl 2-imidazolidinylideneamino) phenyl ] morpholine (m.p. 133-1340C).
Examples 134 to 154 In a similar manner to that described in Example 133 the compounds listed in Table VI were prepared by the reaction of an aminophenyl compound of formula VII (A grammes in B ml benzene) with a compound of formula VIII (C grammes in D ml benzene) in the presence of phosphorus oxychloride (E ml) for F hours' at a temperature in the range 65-70"C.
Notes to Table VI (32) Product recrystallised from hexane.
(33) Coupling reaction performed at 90-95"C.
(34) Coupling reaction performed at 70-750C.
(35) Coupling reaction performed at 60-65"C.
(36) The product was isolated as its fumarate salt which was recrystallised from a 2:1 mixture of isopropanol and ether.
(37) Coupling reaction performed at 75-80"C.
(38) The product was isolated as its monofumarate salt which was recrystallised from a 1:2 mixture of methanol and ether.
(39) The product was isolated as its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether.
(40) Coupling reaction performed at 80-85"C.
(41) The product was purified by column chromatography on an alumina column using dichloromethane as eluant.
(42) Coupling reaction performed at 80-850C for 48 hours and at 90-95"C for 14 hours. The product was purified by column chromatography on an alumina column using a 99:1 mixture of dichloro methane and methanol as eluant.
(43) The product was isolated as its sesquifumarate salt which which was recrystallised from a 1:2 mixture of methanol and ether.
Table VI
Ex. A B C D E F NR1R2 R6 R11 R7 mp( C) Notes 134 3.8 25 2.7 40 2.1 21 morpholino Me Me 4-F 135 9.8 25 12.6 10 7.3 50 morpholino Me Me 3-Me 136 2.9 30 2.6 30 2.1 23 morpholino Me Me 4-Me 137 5 25 4.2 35 3.7 35 morpholino Me Me 5-Me 138 8.5 40 9.1 60 7.3 18 morpholino Me Me 4-Cl 139 4 40 2.7 30 2.2 23 morpholino Me Me 4-OMe 140 3.5 30 2.5 30 2.3 6 morpholino Me Me 4,5-(OMe)2 141 3.2 20 2.7 30 2.2 28 1-pyrrolidinyl Me Me H 142 5.2 30 5.1 30 4.1 70 1-pyrrolidinyl Me Me 3-Me 143 8.8 60 8.5 50 6.8 10 piperidino Me Me H Table VI Cont.
Ex. A B C D E F NR1R2 R6 R11 R7 mp( C) Notes 144 5.8 50 5.1 60 4 26 thiamorpholino Me Me H 96-98 (32) 145 8.2 80 6.8 40 5.4 14 2,6-dimethyl- Me Me H 86-86 (32)(37) morpholino 146 6.3 30 6.8 40 5.4 28 MEt2 Me Me H 164-165 (38)(37) 147 3.6 60 3.4 40 2.7 90 2-methyl-1- Me Me H 183-184 (39)(40) pyrrolidinyl 148 5.3 25 4.3 25 3.4 80 morpholino Me Me 3-Cl 86-88 (32)(33)(41) 149 4.8 40 5.1 40 4.8 24 1-pyrrolidinyl Me Me 4-Me 165-167 (38)(40) 150 8.9 50 6.8 50 5.4 12 N(CH2CHOMe)2 Me Me H 105-106 (38)(37) 151 5.2 40 6.4 30 4.3 48 morpholino Me Me H 154-155 (42)(38) 152 7.6 30 6.8 30 5.5 14 morpholino Me Me 6-Me 106-108 (40)(32) 153 7.1 60 7.6 80 5.6 70 morpholino Et Me H 75-76 (40)(32) 154 4.4 20 5.9 50 4.4 60 morpholino Bu Me H 135-136 (40)(41)(43) Example 155 A mixture of N-(2-hydroxyethyl)ethylenediamine (31.2 g), urea (23.4 g) and water (3 ml) was heated at 1300C for 3 hours and at 2100C for 8 hours and then distilled directly from the reaction mixture to give 1-(2-hydroxyethyl)-2-imidazolidinone (30 g) as an oil [(b.p. 150-160 C (0.2 mm)] which solidified to give a solid (m.p. 50-51).
A mixture of 1-(2-hydroxyethyl)-2-imidazolidinone (2.28 g), benzoic anhydride (4.5 g), triethylamine (2.4 g), 4-dimethylaminopyridine (0.1 g) and 1,2dimethoxyethane (20 ml) was stirred at room temperature for 8 hours. Saturated sodium bicarbonate solution (15 ml) was added and the mixture extracted with dichloromethane (100 ml). The extract was washed with water, brine and then dried and filtered. The solvent was removed to give 1-(2-benzoyloxyethyl)-2- imidazolidinone (m.p. 130-132 C) which was recrystallised from ethylacetate.
A mixture of 1-(2-benzoyloxyethyl)-2- imidazolidinone (2.3 g) and methyl-4-toluenesulphonate (2 g) was heated at 90-95 C for 48 hours. The reaction mixture was then cooled to room temperature, treated with saturated sodium bicarbonate solution (10 ml) and extracted with ethyl acetate (6 x 20 ml). The extract was washed with water and brine and then dried and filtered. The solvent was removed to give an oily residue (2 g) which was purified by column chromatography on silica gel (80 g, 100-200 mesh) using a 1:1 mixture of ethylacetate and hexane as eluant to give 1 -(2-benzoyloxyethyl)-3-methyl-2-imidazolidinone as an oil.
In a similar manner to that described in Example 133, 1 -(2-benzoyloxyethyl)-3-methyl-2-imidazolidone (8.8 g) in benzene (30 ml) was reacted with 4-(2-aminophenyl)morpholine (5.2 g) in benzene (20 ml) in the presence of phosphorus oxychloride (3.3 ml) for 35 hours at 80-85"C to yield an oil. The oil was dissolved in methanol (10 ml) and treated with fumaric acid (1.8 g). The solvent was removed by evaporation and the residue washed with ether and then dissolved in water. The aqueous solution was basified with aqueous sodium carbonate solution to pH 9-10 and extracted with ether to yield an oil which was purified by chromatography on an alumina column using dichloromethane as eluant.The purified base (0.8 g) in methanol (10 ml) was treated with fumaric acid (0.23 g) to give 4-22-[1 (2-benzoyloxyethyl)-3-methyl- 2-imidazolidinylideneamino]phenyl3morpholine monofumarate (m.p. 132-133"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 156 Reaction of tetramethylurea (10.4 g, 10.7 ml) in dry benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.2 g) in dry benzene (100 ml) in the presence of phosphorus oxychloride (8.3 ml) for 30 hours at 65-70"C gave an oil which was purified by column chromotography on a neutral alumina column (100 g) eluted with hexane to give as an oil. A solution of this base (2.5 g) in methanol (10 ml) was treated with 57% hydroiodic acid (1.3 ml) to give 2-(2-morpholinopheny1)-1,1,3,3- tetramethylguanidine hydroiodide as a pale yellow crystalline solid (m.p. 215-2160C) which was recrystallised from a 2:3 mixture of methanol and ether.
Example 157 Reaction of 3-ethyl-1,1,3-trimethylurea (6.57 g) in benzene (70 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) fot 45 hours at 65-700C gave 1-ethyl-2-(2-morpholinophenyl)-1 ,3,3-trimethyl- guanidine (bp. 1400C at 0.2 mm Hg).
Example 158 Reaction of 3-allyl-1 ,1 ,3-trimethylurea (7.17 g) in benzene (50 ml) with 4-(2-aminophenyl)morpholine (6 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.71 ml) for 45 hours at 70 C gave 1-allyl-2-(2-morpholinophenyl)-1,3,3-trimethyl- guanidine (bp. 148-150"C at 0.2 mm Hg).
Example 159 Reaction of 3-n-butyl-1,1,3-trimethylurea (7 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (7.2 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4 ml) for 18 hours at 80-85 C gave 1-n-butyl-2-(2-morpholinophenyl)-1,3,3-trimethyl guanidine (bp. 162-163 C at 0.7 mm Hg).
Example 160 Reaction of 3-pentyl-1 ,1 ,3-trimethylurea (7.5 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (6.46 g) in benzene (30 ml) in the presence of phosphorus oxychloride (4.06 ml) for 45 hours at 70 C gave 1 -pentyl-2-(2-morpholinophenyl) -1,3 ,3-trimethyl guanidine (b.p. 98 C at 1.5 mm Hg).
Example 161 Reaction of 1 - (2-hydroxyethyl) -2-imidazolidinone (13 g) in dry dimethylformamide (125 ml) with sodium hydride (50% suspension in paraffin oil 12 g) at 700C for 3 hours was followed by treatment with methyl iodide (35.5 g) over a period of one hour. The mixture was stirred at ambient temperature for 18 hours gave 1-methyl-3-(2-methoxyethyl)-2-imidazolidinone (b.p. 110-114 C at 0.4 mm).
Reaction of 1 -methyl-3-(2-methoxyethyl)-2 imidazolidinone (11.4 g) in benzene (60 ml) with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7.2 ml) for 30 hours at 80-850C gave an oil a portion of which (1.8 g) was dissolved in methanol (10 ml) and treated with fumaric acid (0.9 g) to give 4-(2-[1-methyl-3-(2- methoxyethyl)-2-imidazolidinylideneamino] phenyl)morpholine monofumarate (m.p. 127-129 C) which was recrystallised from propan-2-ol.
Example 162 Reaction of 1 -methyl-3-(2-hydroxyethyl)-2- imidazolidinone (13 g) with acetic anhydride (9.2 g) in dichloromethane (60 ml) in the presence of triethylamine (9 g) and 4-dimethylaminopyridine (0.1 g) for 18 hours at ambient temperature gave 1-methyl-3-(2-acetoxyethyl)-2-imidazolidinone as an oil.
Reaction of 1 -methyl-3-(2-acetoxyethyl)-2- imidazolidinone (13.4 g) in benzene (80 ml) with 4-(2-aminophenyl)morpholine (10.6 g) in benzene (80 ml) in the presence of phosphorus oxychloride (7 ml) for 30 hours at 80-85 C gave 4-(2-[1-methyl-3-(2-acetoxy ethyl)-2-imidazolidinylideneaminoXphenylzmorpholine.
Reaction of 4-22-[1-methyl-3-(2-acetoxyethyl)-2- imidazolidinylideneamino]phenyl)morpholine (2.7 g) in dimethylformamide (10 ml) with sodium hydroxide (0.4 g) in water (10 ml) for one hour at 10 C gave an oil which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give 4-22-[1-methyl-3-(2- hydroxyethyl)-2-imidazolidinylideneamino]phenyl morpholine (m.p. 129-1310C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 163 Reaction of 4-dimethylcarbamoylmorpholine (3.8 g) in benzene (25 ml) with 4-(2-aminophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride (2.1 ml) for 40 hours at 80-85"C gave N,N-dimethyl-N' (2-morpholinophenyl)morpholine-4-carboxamidine (m.p.
126-128"C) which was recrystallised from hexane.
Example 164 Reaction of 1-dimethylcarbamoylpiperidine (3.7 g) in benzene (25 ml) with 4-(2-morpholinophenyl)morpholine (3.5 g) in the presence of phosphorus oxychloride for 35 hours at 80-85"C gave N,N-dimethyl N'-(2-morpholinophenyl)piperidine-1-carboxamidine (m.p.
88-90"C) which was recrystallised from petroleum ether (b.p. 40-60"C) Example 165 Reaction of 4-[2-(1,3-dimethyl-2-imidazolidinyl ideneamino)phenyl]thiamorpholine (1.5 g prepared as described in Example 144) in methanol (20 ml) and sodium metaperiodate (1.4 g) in water (4 ml) for 4 hours at 10 C yielded 4-[2-(1,3-dimethyl-2-imidazol- idinylideneamino)phenyl]thiamorpholine-1-oxide monohydrate (m.p. 103-105 C) which was recrystallised from a 1:1 mixture of 1,2-dimethoxyethane and hexane.
Example 166 A solution of 2-morpholinophenyl isothiocyanate (2.3 g) was treated with a saturated solution of ammonia in ethanol (20 ml) and the reaction mixture was stirred at room temperature for 3 hours. The resulting solid was filtered, washed with ethanol and dried to give 1-[2-(4-morpholino)phenyl]thiourea (m.p.
194-195"C).
A solution of 1.-(2-morpholinophenyl)thiourea (7.2 g) in dry methanol (30 ml) was heated at reflux with methyliodide (4.2 g) for 2 hours. The solvent was removed under reduced pressure and dry ether (15 ml) was added and on scratching gave 2-methyl-1-(2 morpholinophenyl)-2-thiopseudourea hydroiodide (m.p.
151-152"C).
A mixture of 2-methyl-1-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (5 g) and ethylenediamine (2.4 g), in dry ethanol (50 ml) was heated at reflux for 6 hours, the solvent removed under reduced pressure to give an oil which was dissolved in dichloromethane (50 ml), cooled, basified with 20% sodium hydroxide and the organic layer was washed successively with water, brine and dried (Na2SO4), filtered and the solvent removed to get a solid (4 g) which on recrystallisation from ethyl acetate gave 4-[2-(2-imidazolidinylideneamino)phenyl]morpholine (m.p. 185-186 C).
Example 167 A mixture of 2-methyl-1 -(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (3 g prepared as described in Example 166), N-methylethylenediamine (2 ml) and absolute ethanol (35 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(1-methyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 156"C).
Examples 168 to 202 In a similar manner to that described in Example 167, the compounds listed in Table VII were prepared by heating a mixture of a compound of formula XIII in which R14 and R15 are H, (G grammes), an N-substituted ethyl-enediamine of formula H2N(CH2)2NHR6 (H grammes) in dry ethanol (I ml) under reflux for J hours.
Note to Table VII Notes (32), (38), (39) and (41) has the meaning given with respect to earlier Tables.
(44) Product recrystallised from ethylacetate.
(45) Product isolated as its monofumarate salt which was recrystallised from methanol.
(46) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure A.
(47) Product isolated as its fumarate salt which was recrystallised from a 1:2 mixture of methanol and propan-2-ol.
(48) Product recrystallised from a 1:4 mixture of l,2-dimethoxyethane and petroleum ether (b.p.
40-60"C).
(49) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure B.
(50) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure C.
(51) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure D.
(52) Product recrystallised from a 1:2 mixture of ethylacetate and hexane.
(53) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure E.
(54) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure F.
(55) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure G.
(56) Product was purified by chromatography on an alumina column using the following eluents sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane and then dichloromethane.
(57) The preparation of the compound of formula XIV is given hereinafter as Preparative Procedure H.
(58) Product recrystallised from a 1:1 mixture of ethylacetate and hexane.
Table VII
Ex. G H I J NR1R2 R6 R7 mp( C) Notes 168 3.8 2.7 45 8 morpholino Et H 107-109 (32) 169 2.8 2.6 35 10 morpholino Pr H 131-132 (32) 170 3.8 3 45 14 morpholino i-Pr H 121-122 (32) 171 5.7 5.2 65 7 morpholino Bu H 88-89 (32) 172 3.8 3.5 45 12 morpholino i-Bu H 136-138 (32) 173 7.5 7.8 90 14 morpholino pentyl H 72-74 (32) 174 3.8 3 50 8 morpholino allyl H 126-128 (32) 175 3.8 3.1 45 25 morpholino CH2CH2OH H 131-132 (44) Table VII Cont.
Ex. G H I J NR1R2 R6 R7 mp( C) Notes 176 7.9 6.2 90 150 morpholino CH2CH2OH 3-Me 198-199 (45)(46) 177 3.8 3.8 45 9 morpholino CH2CH2OMe H 74-75 (32) 178 3.8 4.2 40 24 morpholino cyclohexyl H 189-189 (44) 179 5.7 6.75 70 12 morpholino CHPh H 96-97 (32) 180 7.6 9.8 90 8 morpholino CH2CH2Ph H 106-108 (32) 181 11.4 8.3 150 24 morpholino CH2CH2NMe2 H 151 (47) 182 5.7 6 70 24 morpholino CH2CHOHCH2OH H 144-145 (44) 183 3.8 3.4 45 18 morpholino CH2C(Me)=CH2 H 141-143 (48) 184 4.2 2.4 45 8 N(CH2CH2OMe)2 Me H 140-141 (39)(49) 185 3.0 2.2 30 40 N(CH2CH2OMe)2 CH2CH2OH H 110-111 (38)(49) 186 7.9 4.4 90 8 thiamorpholino Me H 115-117 (32)(50) 187 5.4 3.3 70 10 1-pyrrolidinyl Me H 117-118 (32)(51) 188 3.9 3.5 45 8 thiamorpholino Bu H 106-108 (32)(50) 189 7.8 4.4 90 75 morpholino Me 3-Me 120-1211 120-121 (52)(46) 190 9.8 5.9 115 12 morpholino Me 4-Me 122-123 122-123 (32)(53) Table VII Cont.
Ex. G H I J NR1R2 R6 R7 mp( C) Notes 191 7.2 6.4 90 24 1-pyrrolidinyl CH2CH2OH H 166-167 (38)(51) 192 3.7 3.1 45 32 2-methyl-1- CH2CH2OH H 81 (32)(54) pyrrolidinyl 193 5.9 5.2 75 12 morpholino Bu 4-Me 114-116 (32) 194 7.5 3.6 150 24 piperidino H H 163 (38)(55) 195 7.5 5.5 90 14 piperidino Me H 75-76 (41)(32)(55) 196 5.9 3.4 70 70 piperidino Me 3-Me 86-87 (56)(32)(57) 197 2.8 2.2 40 24 thiamorpholino CH2CH2OH H 99-101 (58)(50) 198 3.7 3.1 45 18 piperidino CH2CH2OH H 105-107 (32)(55) 199 5.6 5.3 65 39 morpholino (CH2)3OH H 139-140 (44) 200 5.9 3.4 70 70 morpholino CH2CH(OH)Me H 147-148 (44) 201 7.6 8 90 23 morpholino CH2CH(OH)Et H 112-113 (56) 202 3.8 3.9 45 14 morpholino CH2C(OH)Me2 H 132-133 (44) Preparative Procedure A Reaction of 6-methyl-2-morpholinoaniline (9.6 g) in dioxan (25 ml) and water (100 ml) with thiophosgene (5.7 ml) at 0 C for 30 minutes and at room temperature for 3 hours gave 6-methyl-2-morpholinophenyl isothiocyanate as an oil.
Reaction of 6-methyl-2-morpholinophenyl isothiocyanate (8.8 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 5 hours gave 1-(6-methyl-2-morpholinophenyl)thiourea (9 g) as a pale yellow solid, m.p. 1990C which was recrystallised from a 1 :1 mixture of ethylacetate and hexane.
A mixture of 1 (6-methyl-2-morpholinophenyl)- thiourea (9 g) and methyl iodide (2.5 ml) vin dry acetone (100 ml) was heated at reflux at 90-950C for 2.5 hours to give 2-methyl-1-(6-methyl-2-morpholinophenyl)-2-thiopseudourea hydroiodide.
Preparative Procedure B A solution of N,N-bis(2-methoxyethyl)benzene-1 ,2diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to OOC. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture extracted with ether (3 x 20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 450C under vacuum (100 mm/Hg) to give 2-[bis (2-methoxyethyl)amino]phenyl isothiocyanate as an oil.
A saturated solution of ammonia in ethanol (40 ml) was added over 40 minutes to a mixture of 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate (7.5 g) and ethanol (10 ml) which had been cooled to 100C. The mixture was stirred at OOC for 8 hours and then stirred without cooling for 16 hours. The solvent was then removed by evaporation and the residue purified by chromatography on a silica column eluted with a 1:4 mixture of ethyl acetate and hexane and then a 1:1 mixture of ethyl acetate and hexane to give 1-{2-[bis(2-methoxyethyl)amino]phenyl} thiourea (m.p.
118-119"C).
A mixture of 1-22-[bis(2-methoxyethyl)amino] phenyl3thiourea (5 g), methyl iodide (1.4 ml) and acetone (25 ml) was heated at 400C for 2 hours.
Removal of the solvent gave a residue which was triturated with ether to give 2-methyl-1-02-[bis(2- methoxyethyl)amino]phenyl3-2-thiopseudourea hydroiodide (m.p. 111-112 C).
Preparative Procedure C A solution of 2-thiamorpholinoaniline (14.6 g) in dioxane (10 ml) was added over 15 minutes to a mixture of thiophosgene (8.77 ml) and water (120 ml) which had been cooled to OOC. The mixture was stirred and its temperature was allowed to rise to ambient. The mixture was then stirred for 4 hours and ice/water (200 ml) was added. - The mixture was extracted with ether (2 x 100 ml) and the extracts washed with water (50 ml) and then brine (100 ml) and the solvent removed by evaporation to give a residue which was heated at 40-45"C under vacuum (100 mm/hg) for two hours to give 2-thiamorpholinophenyl isothiocyanate (m.p. 55-560C).
25% Aqueous ammonia solution (100 ml) was added to a mixture of 2-thiamorpholinophenyl isothiocyanate (14 g) and ethanol (40 ml) at 10 C. The mixture was stirred at 30"C for 24 hours and then cooled to 10 C.
1 (2-thiamorpholinophenyl)thiourea was collected by filtration, washed with water (100 ml) and dried (m.p.
170-171 C) A mixture of 1-(2-thiamorpholinophenyl)thiourea (12.6 g), methyl iodide (7.1 g) and acetone (60 ml) was heated at 90-950C for 21/2 hours. The solvent~ was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-thiamorpholinophenyl)-2-thiopseudourea hydroiodide (m.p.
176-177"C).
Preparative Procedure D Benzoylisothiocyanate (10 ml) was added over 30 minutes to a mixture of 2-(1-pyrrolidinyl)aniline (10.6 g) and dichloromethane (30 ml). The mixture was then stirred at 30 C for 4 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) for 30 minutes and triturated with ether. 3-Benzoyl-1-[2-(1 -pyrrolidinyl)phenyl]thiourea was collected by filtration, washed with ether and dried (m.p. 172-173 C).
A mixture of 3-benzoyl-1 -[2-(1 -pyrrolidinyl)- phenyl]thiourea (18.1 g), sodium hydroxide (5 g) and water (50 ml) was heated at 90-95"C for 4 hours. Ice and then 50% aqueous hydrochloric acid were added. The mixture was filtered and the filtrate treated with saturated sodium bicarbonate solution to pH 8. 1-[2 (1-Pyrrolidinyl)phenyl]thiourea was collected by filtration, washed with water and dried (m.p.
185-1865C).
A mixture of 1 -[2-(1 -pyrrolidinyl)phenyl] thiourea (12.2 g), acetone (100 ml) and methanol (20 ml) was heated to 90-95 C. Methyl iodide (8.36 g) was added and the mixture heated under reflux for 3 hours. The solvent was removed by eväporation to give a residue which was dried under vacuum (5 mm/Hg) to give 2-methyl-1-[2-(1-pyrrolidinyl)phenyl]-2-thiopseudourea hydroiodide (m.p. 139-1410C).
Preparative Procedure E Reaction of 5-methyl-2-morpholinoaniline (20 g) in dioxan (80 ml) and water (200 ml) at 0 C for 30 minutes and at room temperature for 2 hours gave 5-methyl-2-morpholinophenyl isothiocyanate, (m.p.
91-920C).
Reaction of 5 -methyl-2 -morpholinophenyl isothiocyanate (15 g) with 33% ethanolic ammonia solution for 48 hours at room temperature gave 1-(5-methyl-2-morpholinophenyl)thiourea as a pale yellow solid (m.p. 181-182 C).
A mixture of 1 - (5-methyl-2-morpholinophenyl) - thiourea (14 g), methyl iodide (7.9 g) in methanol (50 ml) was heated at reflux for 2 hours to give 2methyl-1-(5-methyl-2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid, m.p. 157-159 C.
Preparative Procedure F A mixture of 2-methyl-1-(2-aminophenyl) pyrrolidine (9.1 g) and benzoyl isothiocyanate (9.2 g) 7.7 ml) and dichloromethane (100 ml) was stirred at room temperature for 8 hours and left overnight.
Removal of the solvent and trituration with ether gave 1 -benzoyl-3-[2-methyl-1 -pyrrolidinyl) phenyl] thiourea, (m.p. 105-106 C).
A mixture of 1-benzoyl-3-[2-(2-methyl-1-pyrrol- idinyl)phenyl]thiourea (9 g), sodium hydroxide (1 g, as pellets) and water (10 ml)-' was heated at 90-950C for 48 hours to give 1 -[2-(2-methyl-1 -pyrrolidinyl)phenyl] thiourea (m.p. 145-148"C) which was purified by column chromatography on silica gel using a 1:1 mixture of ethylacetate and hexane as eluant.
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 and the solvent removed to give 2-methyl-l-[2-methyl-1- pyrrolidinyl)phenyl]-2-thiopseudourea hydroiodide (3.7 g) as a thick oil.
Preparative Procedure G A solution of 2-piperidinoaniline (17.6 g) in dioxane (100 ml) was added over 25 minutes to a mixture of thiophosgene (10.2 ml) and water (200 ml) which had been cooled to OOC. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice (200 g) and water (200 ml) were added and the mixture extracted with ether (6 x 50 ml). The combined extracts were washed with water (100 ml) and brine (100 ml), dried and evaporated to give a residue which purified by chromatography on a silica column eluted with hexane to give 2-piperidinophenyl isothiocyanate as an oil.
25% Aqueous ammonia solution (60 ml) was added to a mixture of 2-piperidinophenyl isothiocyanate (12 g) and ethanol (25 ml) which had been cooled to 10 C. The mixture was stirred at 30"C for 24 hours and then cooled to 10 C. 1-(2-Piperidinophenyl)thiourea was collected by filtration, washed with water and dried (m.p. 143-1450C).
A mixture of 1-(2-piperidinophenyl)thiourea (10.1 g), methyl iodide (5.35 g) and methanol (50 ml) was heated at 50-55"C for' 2 hours. The solvent was removed by evaporation and the residue dried under vacuum (5 mm/Hg) to give 2-methyl-1-(2-piperidinophenyl)-2-thiopseudourea hydroiodide (m.p. 160-162 C).
Preparative Procedure H Reaction of 6-methyl-2-piperidinoaniline (6.4 g) in dioxan (20 ml) and water (65 ml) with thiophosgene (5.7 g) at 0 C for 30 minutes and at room temperature for 2 hours gave 6-methyl-2-piperidinophenyl isothiocyanate as an oil.
Reaction of 6-methyl-2-piperidinophenyl isothiocyanate (6.8 g) with 25% aqueous ammonia solution (65 ml) in ethanol (20 ml) for 8 hours at room temperature gave 1-(6-methyl-2-piperidinophenyl) thiourea as a pale yellow solid (m.p. 197-198"C).
A mixture of 1-(6-methyl-2-piperidinophenyl)- thiourea (7 g) and methyl iodide (4.38 g) in dry methanol (100 ml) was heated under reflux for 3 hours to give 2-methyl-1 - (6-methyl-2-piperidinophenyl) -2- thiopseudourea hydroiodide as a pale yellow solid, (m.p. 204-205 C).
Example 203 A mixture of 2-methyl-1-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 2-methylethylenediamine (2.2 g) and ethanol (45 ml) was heated under reflux for 8 hours to give a solid which was recrystallised from ethyl acetate to give 4-[2-(4-methyl-2-imidazol idinylideneamino)phenyl]morpholine (m.p. 173-174 C). Example 204 A mixture of 2-methyl-l-(2-morpholinophenyl)-2- thiopseudourea hydroiodide (7.6 g prepared as described in Example 166), 1 ,2-dimethylethylenediamine (5.3 g) and ethanol (90 ml) was heated under reflux for 70 hours to give a solid which was recrystallised from ethylacetate to give 4-[2-(4,5-dimethyl-2-imidazolidinylideneamino)phenyl]morpholine (m.p. 142-143 C).
Example 205 Ethylene oxide generated from 2-chloroethanol (36 g) and potassium hydroxide pellets (20 g) in methanol (60 ml) was reacted with 1,2-dimethylethylenediamine (22.6 g) in methanol (50 ml) at -150C to give N-(2-hydroxyethyl)-1 ,2-dimethylethylenediamine as a colourless liquid (b.p. 89-91"C at 1 mmHg).
A mixture of 2-methyl-1 (2-morpholinophenyl) 2-thiopseudourea (12.5 g) and N-(2-hydroxyethyl)-1,2- dimethylethylenediamine (8 g) in dry ethanol (150 ml) was heated under reflux at 90-95"C for 6 days to give a dark brown oil which was purified by column chromatography on neutral alumina (250 g) using a 1:9 mixture of dichloromethane and hexane to give [4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidinylidene amino]phenylmorpholine as a colourless solid (m.p.
108-109 C) which was recrystallised from hexane.
Example 206 A mixture of 2-methyl-i -(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), N'-isopropyl-2-methyl-1 ,2propanediamine (3.95 g) and ethanol (45 ml) was heated under reflux for 28 hours to yield an oil which was purified by column chromatography on a neutral alumina column using dichloromethane as eluant. The resultant oil (1.5 g) was dissolved in methanol (10 ml) and fumaric acid (0.5 g) was added to give 4-[2-(1-iso- propyl-4,4-dimethyl-2-imidazolidinylidenamino)phenyl]morpholine monofumarate (mp 206-208"C) which was recrystallised from a 1:3 mixture of methanol and ether.
Example 207 A mixture of 2-methyl-i -(2-morpholinophenyl) - 2-thiopseudourea hydroiodide (3.8 g prepared as described in Example 166), 3-methylaminopropylamine (2.6 g) and absolute ethanol (40 ml) was heated under reflux for 6 hours to give a solid which was recrystallised from ether to give 4-[2-(i-methylper- hydropyrimidin-2-ylideneamino)phenyl]morpholine (m.p.
138-139"C).
Example 208 A mixture of 2-methyl-i -(2-morpholinophenyl) - 2-thiopseudourea hydroiodide (7.6 g) and 1 ,4-diaminobutane (5.3 g) in ethanol (150 ml) was heated under reflux for 60 hours to give a white solid (m.p. 135"C) which was recrystallised 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 (m.p. 220-222"C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 209 A mixture of 2-methyl-1-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (1 g), dimethylamine (1 ml of a 33% solution in ethanol) and ethanol (2 ml) was kept at ambient temperature for 48 days. The mixture was then cooled in an ice bath. The resulting solid was separated by filtration, treated with dilute aqueous sodium hydroxide solution (5 ml) and the resulting mixture extracted with dichloromethane (2 x 50 ml). The extract was washed with brine, dried and the solvent removed by evaporation to give 1,1 -dimethyl-2-(2-morpholinophenyl)guanidine (m.p.
143-144"C) which was recrystallised from hexane.
Example 210 A solution of 4-(2-aminophenyl)morpholine (5.3g) in dichloromethane (25 ml) was treated with methyl isothiocyanate (3.2g) and the mixture stirred at room temperature for 36 hours to yield l-(2-morpholino phenyl)-3-methylthiourea (m.p. 115-116"C) which was recrystallised from a 4:1 mixture of ethyl acetate and hexane.
A mixture of 1 -(2-morpholinophenyl)-3-methyl- thiourea (5 g) and methyliodide (2.8 g) in acetone (30 ml) was heated at reflux for 4 hours to yield 2-methyl1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (m.p. 163-164"C) which was recrystallised from a 1:3 mixture of methanol and ether.
A mixture of 2-methyl-I - (2-morpholinophenyl) - 3-methyl-2-thiopseudourea hydroiodide (3.9 g) and 33% methylamine in solution in absolute ethanol (40 ml) was heated for 28 hours at 50-55"C to yield 1 ,3dimethyl-2-(2-morpholinophenyl)guanidine which was recrystallised from hexane (m.p. 137-138"C).
Example 211 A mixture of 2-methyl-i -(2-morpholinophenyl)- 3-methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210) and dimethylamine (25 ml of a 33% solution in ethanol) was kept at ambient temperature for 25 days. Removal of the solvent gave a residue which was purified by chromatography on an alumina column using a 1:49 mixture of methanol and dichloromethane as eluant. The resulting solid was dissolved in methanoL and treated with fumaric acid to give 1 ,3 ,3-trimethyl-2- (2-morpholinophenyl)guanidine monofumarate (m.p. 192-194"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 212 Reaction of 2-morpholinophenyl isothiocyanate (3.3 g) with ethylamine generated from ethylamine hydrochloride (12.18 g) and sodium methoxide [generated from sodium (3.5 g) and methanol (100 ml)] gave 1-ethyl-3-(2-morpholinophenyl)thiourea (m.p.
118-120"C) which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
A mixture of l-ethyl-3-(2-morpholinophenyl) thiourea (3.2 g) and methyliodide (2 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl 3-ethyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide as a pale yellow solid (m.p. 170a172cC) which was recrystallised from acetone.
A mixture of 2-methyl-3-ethyl-l -(2-morpholino- phenyl)-2-thiopseudourea hydroiodide (6 g) and 33% methylamine in absolute ethanol solution (250 ml) was heated initially for 24 hours at 45"C and then left at room temperature for 14 days to yield 1-ethyl-2-(2 morpholinophenyl) -3-methylguanidine as a colourless solid (m.p. 118-119"C) which was recrystallised from hexane.
Example 213 Sodium (23 g) was added to ethanol (300 ml) and the resulting solution of sodium ethoxide was reacted with ethylamine hydrochloride to give a solution of ethylamine which was stirred at room temperature for 30 days with 2-methyl-3-ethyl-1 -(2-morpholinophenyl)- 2-thiopseudourea hydroiodide (6 g prepared as described in Example 212) to yield 1 ,3-diethyl-2-(2-morpholinophenyl)guanidine (m.p. 101-1020C) which was recrystallised from hexane.
Example 214 Reaction of 4- 2-[1-(2-hydroxyethyl)-2-imidazol- idinylideneamino]phenylmorpholine (3 g prepared as described in Example 175) in dichloromethane (20 ml) with acetic anhydride (0.86 g) yielded acetyloxyethyl)-2-imidazolidinylideneamino]phenyl 3 - morpholine (m.p. 89-910C) which was recrystallised from hexane.
Example 215 Reaction of 4-22-[1 -(2-hydroxyethyl)-2-imidazol idinylideneamino]phenylmorpholine (2.9 g prepared as described in Example 175) in dichloromethane (60 ml) with benzoic anhydride (2.4 g) in the presence of dry triethylamine (2 ml) and 4-dimethylaminopyridine (50 mg) gave an oil which was purified by chromatography on an alumina column using dichloromethane as eluant to give 4-22-[1-(2-benzoyloxyethyl)- 2-imidazolidinylideneamino]phenylzmorpholine (m.p. 92-940C) which was recrystallised from a 1:1 mixture of ethyl acetate and hexane.
Example 216 A solution of 4-(2-aminophenyl)morpholine (5.8 g) in dichloromethane (60 ml) was treated with n-butyl isothiocyanate (5 g) and mixture stirred at room temperature for 4 days to yield 1-(n-butyl)-3-(2morpholinophenyl)thiourea as a pale yellow solid (m.p.105 C).
A mixture of 1 -(n-butyl)-3-(2-morpholino phenyl)thiourea (5.8 g) and methyliodide (3.1 g) in acetone (25 ml) was heated at reflux for 4 hours to yield 2-methyl-3-(n-butyl)-1-(2-morpholinophenyl)- 2-thiopseudourea hydroiodide as a colourless solid m.p 154-156"C.
A mixture of 2-methyl-3-(n-butyl)-1 -(2-morphol'ino- phenyl)-2-thiopseudourea hydroiodide (4.0 g) and 33% methylamine in absolute ethanol solution (200 ml) was heated intially for 24 hours at 45" and then left at room temperature for 21 days to yield 1-(n-butyl)-2-(2morpholinophenyl)-3-methylguanidine as an oil; a solution of which in methanol (25 ml) on treatment with fumaric acid (0.7 g) gave a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether to give 1 (n-butyl)-2- (2-morpholinophenyl) -3-methylguanidine monofumarate (m.p. 170-172"C).
Example 217 A mixture of 2-methyl-I (2-piperidino)phenyl] - 2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G), 2-methoxyethylamine (2 ml) and ethanol (40 ml was stirred at ambient temperature for 20 days. Removal of the solvent gave a residue which was dissolved in methanol and treated with fumaric acid to give 1-(2-methoxyethyl)-2-(2- piperidinophenyl)guanidine hemifumarate (m.p.
218-220"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 218 A mixture of 2-methyl-l -(2-morpholinophenyl)-2- thiopseudourea hydroiodide (1.7 g) prepared as described in Example 166, 2-methylthioethylanine (1.8 g) and ethanol (25 ml) was heated at 90-95"C for 22 hours to give l-(2-methylthioethyl)-2-(2- morpholinophenyl)guanidine (m.p. 115-116 C) which was recrystallised from hexane.
Example 219 A mixture of 2-methyl-l-(2-morpholinophenyl)-2- thiopseudourea hydroiodide (7.6 g), 2-methoxyethylamine (2 ml) and ethanol (45 ml) was stirred at ambient temperature for 14 days to give l-(2-methoxyethyl')-2- (2-morpholinophenyl)guanidine (m.p. 125-128"C) which was recrystallised from 1,2-dimethoxyethane and converted into its fumarate salt (m.p. 136-1380C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 220 A mixture of 2-methyl-l-(2-morpholinophenyl)-3methyl-2-thiopseudourea hydroiodide (7.8 g prepared as described in Example 210), n-propylamine (1.3 g) and ethanol (50 ml) was stirred at ambient temperature for 45 days to yield an oil which was purified by chromatography on a neutral alumina column using a 1:99 mixture of methanol and dichloromethane as eluent. The resulting oil was dissolved in methanol and treated with fumaric acid to give 1 -(n-propyl)-2-morpholino- phenyl)-3-methylguanidine monofumarate (m.p. 187-188"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 221 A mixture of 2-methyl-l-(2-morpholinophenyl)-3- methyl-2-thiopseudourea hydroiodide (3.9 g prepared as described in Example 210), 2-methoxyethylamine (0.82 g) and ethanol (25 ml) was stored at ambient temperature for three months to yield an oil which was dissolved in methanol and treated with fumaric acid to give 1-methyl-2-(2-morpholinophenyl)-3-(2-methoxyethyl)guanidine monofumarate (m.p. 158-160 C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 222 A mixture of 2-methyl-l-(2-morpholinophenyl)-3methyl-2-thiopseudourea hydriodide (7.86 g prepared as described in Example 210), cyclopentylamine (2.9 g), anhydrous sodium carbonate (6.36 g) and ethanol (100 ml) was heated in a stainless steel pressure vessel in an oil bath at llO"C for 24 hours. The reaction mixture was cooled, filtered and the solvent was partially removed. The residue was poured onto ice and the resulting mixture extracted with dichloromethane. The extract was dried, filtered and the solvent removed to give a residue which was treated with fumaric acid to give l-cyclopentyl-2-(2- morpholinophenyl) -3 -methylguanidine monofumarate (m.p.
220"C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 223 A mixture of 2-methyl-I -(2-morpholinophenyl)-3- methyl-2-thiopseudourea hydriodide (3.9 g prepared as described in Example 210), pyrrolidine (1 ml) and ethanol (40 ml) was heated under reflux for two weeks to yield an oil which was purified by chromatography on a neutra alumina column eluted with a 1:1 mixture of dichloromethane and hexane and then a 1:9 mixture of methanol and dichloromethane to give N-methyl-N'-(2- morpholinophenyl)pyrrolidine-I -carboxamidine which was converted into its monofumarate salt (m.p. 168-171"C) which was recrystallised from propan-2-ol.
Example 224 A mixture of 2-methyl-l-(2-morpholinophenyl)-3ethyl-2-thiopseudourea hydriodide (10 g prepared as described in Example 212), n-butylamine (2.7 g) and t-butanol (75 ml) was heated at 90-950C for 172 hours to yield 1-(n-butyl)-2-(2-morpholinophenyl)-3-ethylguanidine which was converted into its monofumarate salt (m.p. 159-160 ) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 225 Reaction of 5-chloro-2-morpholinoaniline (2.8 g) with n-butyl isothiocyanate (1.5 g) in ethanol (20 ml) at room temperature for 60 days yielded 1-(n-butyl)-3- (5-chloro-2-morpholinophenyl)thiourea (m.p. 150-1520C).
A mixture of 1-(n-butyl)-3-(5-chloro-2-morphol- inophenyl)thiourea (2.6 g), methyl iodide (1.4 g) and acetone (20 ml) was heated under reflux for 3 hours to give 2-methyl-1-(5-chloro-2-morpholinophenyl)-3-(nbutyl)-2-thiopseudourea hydroiodide (m.p. 130-132 C).
A mixture of 2-methyl-1-(5-chloro-2-morpholinophenyl)-3-(n-butyl)-2-thiopseudourea hydroiodide (3.4 g) and a 33% ethanolic solution of methylamine (10 ml) were stored at ambient temperature in a sealed container for 8 months to yield 1,3-dimethyl-2-(5 chloro-2-morpholinophenyl)guanidine (m.p. 145-146 C) which was recrystallised from hexane. In this reaction the butylamino and the methylthio group of the starting material are replaced by a methylamino group.
Example 226 Reaction of 1-(2-aminophenyl)pyrrolidine (10 g) with methyl isothiocyanate (6.3 g) in dichloromethane (45 ml) at room temperature for 4 days gave l-methyl-3 [2-(1-pyrrolidinyl)phenyl]thiourea (m.p. 125-126"C).
A mixture of 1-methyl-3-[2-(1 -pyrrolidinyl)phenyl]thiourea (18.5 g) and methyl iodide (12.3 g) and acetone (100 ml) was heated under reflux for 2.5 hours to give 2-methyl-l-[2-(1-pyrrolidinyl)phenyl]- 3-methyl-2-thiopseudourea hydroiodide (m.p. 161 -1620C).
A mixture of 2-methyl-7-[2-(1-pyrrolidinyl)- phenyl]-3-methyl-2-thiopseudourea hydroiodide (14.7 g), allylamine (4.45 g) and ethanol (65 ml) was stored at ambient temperature for 50 days and was then heated under reflux for 20 hours to give an oil which was treated with fumaric acid to give 1-allyl-2-[2 (1 -pyrrolidinyl)phenyl] -3-methylguanidine monofumarate (m.p. 162-163 C) which was recrystallised 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 kept at room temperature for 6 days to yield 1-methyl3-(5-methyl-2-morpholinophenyl)thiourea as a colourless solid (m.p. 107"C).
A mixture of 1 -methyl-3-(5-methyl-2-morpholino- phenyl)thiourea (6.4 g) and methyl iodide (3.8 g) in acetone (60 ml) was heated at reflux for 4 hours to give 2-methyl-1-(5-methyl-2-morpholinophenyl)-3- methyl-2-thiopseudourea hydroiodide as a pale yellow solid (m.p. 160-161"C).
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (6 g) and 33% methylamine in absolute ethanol solution (250 ml) was kept at room temperature for 21 days to yield 1 ,3dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine as an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1,3-dimethyl-2-(5methyl-2-morpholinophenyl)guanidine fumarate (1.2 g) as a colourless solid which was recrystallised from a 1:1 mixture of methanol and ether (m.p.201-202"C).
Example 228 A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (8.4 g prepared as described in Example 227), N-(2-hydroxyethyl)ethylenediamine (6.8 ml) and ethanol (80 ml)) was heated under reflux for 30 hours to give an oil which was treated with fumaric acid in methanol to give [1-(2-hydroxyethyl)-2-imidazolidinylideneamino]-4- methylphenyltmorpholine sesquifumarate (m.p.
135-136"C).
Example 229 A mixture of 2-methyl-l-(2-morpholinophenyl)-3- methyl-2-thiopseudourea (4 g prepared from the hydroiodide salt described in Example 210), potassium hydroxide (1.7 g), n-pentylamine (2.1 g), lead acetate trihydrate (5.8 g) and ethanol (20 ml) were heated at 90-95"C for 40 minutes to yield an oil which was extracted with hexane to give 1-methyl-2-(2-morpholinophenyl)-3-(n-pentyl)guanidine which was converted into its monofumarate salt (m.p. 148-149"C) which was recrystallised from a 3:5 mixture of methanol and ether.
Example 230 A mixture of 2-methyl-i (5-methyl-2-morpholino- phenyl)-3-methyl-2-thiopseudourea hydroiodide (12.2 g prepared as described in Example 227), n-butylamine (2.4 g) and ethanol (80 ml) was stored at ambient temperature for 4 months. Lead acetate trihydrate (9 g) was then added and the mixture heated under reflux for one hour to yield 1-(n-butyl)-2-(5-methyl-2- morpholinophenyl) 3-methylguanidine which was converted into its monofumarate salt (m.p. 1500C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 231 Reaction of 6-methyl-2-morpholinoaniline (8.75 g) with methyl isothiocyanate (4.7 g) in dichloromethane (50 ml) at room temperature for four days yielded N-methyl-N' -(6-methyl-2-morpholinophenyl) thiourea (m.p.
182-183 C).
A mixture of N-methyl-N' -(6-methyl-2-morpholino- phenyl)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)-3methyl-2-thiopseudourea hydroiodide (m.p. 187-188 C).
A mixture of 2-methyl-l-(6-methyl-2-morpholino- phenyl)-3-methyl-2-thiopseudourea hydroiodide (17.8 g), n-butylamine (6.4 g) and ethanol (60 ml) was stored at ambient temperature for 60 days. Potassium hydroxide (2.2 g) and then lead acetate trihydrate (7.6 g) were added and the mixture was heated under reflux for 5 hours to yield 1-(n-butyl)-2-(6-methyl-2-morpholino- phenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 203-204"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 232 Reaction of N-(2-morpholinophenyl) isothiocyanate (4 g) in ethanol (10 ml) with 33% ethanolic dimethylamine solution (15 ml) at 150C for four hours gave 1 , 1 -dimethyl-3-(2-morpholinophenyl)thiourea (m.p.
150-152"C).
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 give 2-methyl-l- (2-morpholinophenyl)-3,3-dimethyl-2-thiopseudourea (m.p. 162-1630C).
A mixture of 2-methyl-1-(2-morpholinophenyl)-3,3- dimethyl-2-thiopseudourea hydroiodide (2 g), a saturated ethanolic ammonia solution (10 ml) and pyridine (10 ml) was heated at 90-95"C for 19 hours in a sealed stainless steel pressure vessel. Pyridine was removed by evaporation under reduced pressure and the residue suspended in water. 1,1-Dimethyl-2-(morpholinophenyl)guanidine (m.p. 142-1430C) was collected by filtration, washed with water, dried and recrystallised from hexane.
Example 233 A mixture of 2-methyl-l-(2-morpholinophenyl)-2- thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and pyridine (25 ml) was heated at 800C for 6 hours. Pyridine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1dimethyl-2-(2-morpholinophenyl)guanidine (m.p.
142-144"C) which was recrystallised from hexane.
Example 234 A mixture of 2-methyl-i (2-morpholinophenyl)-2- thiopseudourea hydroidide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80"C for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p.
141-143"C) which was recrystallised from hexane. Examples 235 to 241 The compounds of formula I listed in Table VIII were prepared by heating å mixture of a thiourea of formula XVI in which R14 is methyl and R15 is H (A g), potassium hydroxide (B g), an amine of formula H2NR6 (C g), lead acetate trihydrate (D g) and ethanol (E ml) at 90-950C for F hours to yield an oil which is dissolved in methanol and treated with fumaric acid to give the monofumarate salt of the compounds of formula I. The melting point of the monofumarate salt is given in the column headed "m.p." and the solvent from which the salt was recrystallised is identified by the following Notes.
Notes to Table VIII (59) Salt recrystallised from methanol.
(60) The thiourea starting material was prepared by the reaction of 4-(2-amino-4-fluorophenyl)morpholine (6 g) with methyl isothiocyanate (2.6 g) in dichloromethane (50 ml) at room temperature for 25 days to give 1-methyl-3-(5-fluoro-2-morpholino- phenyl)thiourea (m.p. 145-148"C).
(61) The free base was purified by chromatography on a neutral alumina column using dichloromethane as eluent.
(62) The thiourea starting material was prepared by the reaction of 4-(2-amino-4-methylthiophenyl) morpholine (9.5 g) with methyl isothiocyanate (3.1 g) in dichloromethane (100 ml) at room temperature for 30 days to give l-methyl-3 (5-methylthio-2-morpholinophenyl) thiourea (m.p.
132-133"C).
(63) Salt recrystallised from a 1:2 mixture of methanol and ether.
(64) Salt recrystallised from propan-2-ol.
Table VIII
Ex A B C D E F NR1R2 R6 R7 mp( C) Notes 235 5.4 2.2 2.2 7.4 40 2 morpholino n-Bu 4-F 212(dec) (59)(60) 236 5.9 2.24 2.2 7.6 60 1.5 morpholino n-Bu 4-SMe 120-122 (61)(62)(63) 237 5 2.2 2.9 7.6 50 2 morpholino i-Bu H 157-158 (64) 238 2.5 1.1 1 3.7 20 2 morpholino s-Bu H 170(dec) (63) 239 5 2.2 2.93 7.6 50 3.5 morpholino t-Bu H 182-184 (63) 240 5 2.2 2.3 7.6 50 4.5 morpholino allyl H 189-190 (63) 241 3.9 1.64 2.1 5.5 50 2.5 thiamorpholino n-Bu H 162-163 (59) Example 242 Reaction of 2-morpholino-5-trifluoromethylaniline (12 g) with thiophosgene (8.6 g) in dioxan (30 ml) and water (100 ml) at OOC for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 2-morpholino-5trifluoromethylphenyl isothiocyanate as a yellow oil.
Reaction of 2-morpholino-5-trifluoromethylphenyl isothiocyanate (12 g) in ethanol (20 ml) with 33% ethanolic ammonia solution (50 ml) at room temperature for 2 hours gave 1-(2-morpholino-5-trifluoromethyl- phenyl)thiourea (m.p. 196-197"C).
A mixture of 1-(2-morpholino-5-trifluoromethyl- phenyl)thiourea (6.1 g), potassium hydroxide (2=2 g), a 33% ethanolic solution of dimethylamine (5.6 ml), lead acetate trihydrate (7.5 g) and ethanol (40 ml) was heated at 90-95"C for 2 hours to yield 1,1-dimethyl2-(2-morpholino-5-trifluoromethylphenyl)guanidine (m.p.
132-135"C) which was recrystallised from ethylacetate and converted into its fumarate salt (m.p. 228-2300C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 243 Reaction of 5-cyano-2-morpholinoaniline (2 g) with thiophosgene (1.15 ml) in dioxan (2 ml) and water (25 ml) at 0 C for 30 minutes and then at room temperature for 2 hours yielded a residue which was extracted with dichloromethane to give 5-cyano-2morpholinophenyl isothiocyanate as an oil.
Reaction of 5-cyano-2-morpholinophenyl isothiocyanate (2.5 g) in ethanol (10 ml) with 255 aqueous ammonia solution (1 ml) at room temperature for 3 hours gave I - (5-cyano-2-morpholinophenyl) thiourea (m.p. 193-194 C).
A mixture of 1-(5-cyano-2-morpholinophenyl)- thiourea (5.2 g), potassium carbonate (8.3 g), a 33% ethanolic solution of dimethylamine (15 ml), lead acetate trihydrate and ethanol (25 ml) was heated under reflux for 3 hours to yield 1,1-dimethy1-2- (5-cyano-2-morpholinophenyl)guanidine (m.p. 125-127 C) which was converted into its monofumarate salt [m.p.
223-225"C (dec)1 which was recrystallised from methanol.
Example 244 A mixture of 1 ,1-dimethyl-3-(2-morpholinophenyl)- thiourea (2.65 g prepared as described in 'Example 232), n-propylamine (1.6 ml), lead acetate trihydrate (3.8 g), potassium hydroxide (1.2 g) and ethanol (25 ml) was heated under reflux for 4 hours. A further amount of n-propylamine (1.6 ml) was added and the mixture heated under reflux for a further 8 hours. The reaction mixture yielded a residue which was extracted with ether. The extract was decolourised with charcoal, filtered and the solvent removed to leave a sticky solid which was dissolved in methanol (10 ml) and treated with fumaric acid to give 1,3-di-(npropyl)-2-(2-morpholinophenyl)guanidine hemifumarate (m.p. 212-214"C) which was recrystallised from a 1:2 mixture of methanol and ether.
Example 245 A mixture of 1 ,l -dimethyl-3 - (2 -morpholinophenyl) thiourea (2.65 g prepared as described in Example 232), lead acetate trihydrate (3.8 g), saturated ethanolic ammonia solution (25 ml), potassium hydroxide (1.12 g) and ethanol (20 ml) where heated at 90-95"C is a sealed stainless steel pressure vessel for 5 hours.
The reaction mixture was filtered and the solid collected washed with ethanol. The washings were added to the filtrate and the volume reduced by evaporation.
Ice was added and the resulting solid was collected by filtration, washed with water and dried to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p.
141-142 C) which was recrystallised from hexane.
Examples 246 to 269 Reaction of a compound of formula VII in the form of its hydrochloride salt (K grammes) and a compound of formula NC-NR5R6 (L grammes) in m-cresol (M ml) was heated at 90-950C for N hours to give the compounds identified in Table IX.
Notes to Table IX Notes (32),(38), (44) and (45). have the meaning given hereinbefore.
(65) Reaction performed at llO0C.
(66) The product was isolated as its monofumarate salt which was recrystallised from a 1:1 mixture of methanol and ether.
(67) Reaction performed at 90-95 C for 8 hours and then at 115-1200C for 4 hours.
(68) Reaction performed at 120-1250C.
(69) The reaction mixture was heated at 90-950C for 9 hours and then at 1200C for 21 hours.
(70) The reaction mixture yielded an oil which was extracted with boiling hexane to yield the free base which was converted into its monofumarate salt which was recrystallised from a 1:3 mixture of methanol and ether.
(71) The reaction mixture yielded an oil which was extracted with hexane to yield the free base as an oil which was purified by chromatography on a neutral alumina column using the following eluents sequentially:- hexane, a 1:1 mixture of dichloromethane and hexane, dichloromethane and a 1:99 mixture of methanol and dichloromethane to give the base which was converted into its monofumarate salt which was recrystallised from 2:7 mixture of methanol and ether.
Table IX
Ex K L M N NR1R2 R5 R6 R7 mp( C) Notes 246 6.4 1.8 25 3.5 morpholino H H H 189 (44) 247 19.2 9.45 80 5 morpholino Me Me H 215-216 (45) 248 7.4 5.5 25 5.5 morpholino Me Me 4-Me 122-123 (32) 249 10.8 5 45 10 morpholino Me Me 3-Me 230-231 (45)(65) 250 7.3 3.54 50 42 morpholino Me Me 5-Cl 152 (44) 251 7.2 3.54 50 50 morpholino Me Me 6-Cl 190-192 (45) 252 6.3 2.7 25 18 morpholino Me Me 4-OMe 220 (45) 253 6.8 4.25 40 18 morpholino Me Me 4-SMe 220(dec) (45) 254 5.7 2.93 25 6 morpholino Me Me 5-Me 225-226 (45) Table IX continued Ex K L M N NR1R2 R5 R6 R7 mp( C) Notes 255 4.9 2.1 25 9 morpholino Me Me 4-Et 217-218 (45) 256 5.4 5.4 40 20 morpholino Me Me 4-CH2SMe 198-200 (38) 257 8.6 5.9 30 15 morpholino Et Et H 193-194 (45) 258 8.6 6.7 40 8 morpholino Me Bu H 187-188 (45) 259 8.1 8.8 50 - morpholino (CH2)2OMe(CH2)2OMe H 160-162 (66)(67) 260 6.5 5 20 7 morpholino -(CH2)2O(CH2)2- H 202-203 (45) 261 10.2 6.8 40 12 morpholino -(CH2)4- H 237-238 (45) 262 10.6 5.25 30 16 piperidino Me Me H 189-190 (68)(45) 263 8.2 4.3 40 pyrrolidinyl Me Me H 201-202 (45)(69) 264 4.6 2.1 25 1 thiamorpholino Me Me H 209-210 (45) 265 4.5 2.3 50 6 NMe2 Me Me H 188 (70) 266 4.33 1.75 10 8 N(Me)CH2CH2OMe Me Me H 162-163 (71) 267 11.38 3.52 20 10 4-methyl-1- Me Me H 205-206 (38) piperazinyl 268 7 5.5 25 13 piperidino -(CH2)2O(CH2)2- H 208-209 (68)(45) 269 7.5 5.8 25 morpholino -(CH2)5- H 216-217 (45) Example 270 A mixture of 4-(2-aminophenyl)morpholine hydrochloride (2.1 g) and N,N-dimethylcyanamide (7 ml) was heated under nitrogen at 165-1700C for 12 hours.
The reaction mixture was cooled to 10 C and the precipitate collected by filtration, washed with ether and stirred with 40% aqueous sodium hydroxide solution.
The resulting mixture was extracted with dichloromethane and the extract washed with brine and dried. Removal of the solvent yielded a residue which was recrystallised from hexane to give 1,1-dimethyl-2 (2-morpholinophenyl)guanidine (m.p. 144-145 C).
Example 271 A mixture of 4-(2-amino-4-methoxycarbonylphenyl)morpholine (2.7 g), N,N-dimethyl cyanamide (1 g) and m-cresol (15 ml) was heated at 90-950C for 10 hours.
Ice was added and the reaction mixture acidified to pH 4 by the addition of 2N hydrochloric acid and the resultant mixture extracted with ether. The aqueous layer was cooled, basified to pH 8 by the addition of solid sodium bicarbonate and then extracted with dichloromethane. The extract was dried and the solvent removed to yield 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-morpholinophenylguanidine (m.p. 152-154 C).
Example 272 1-(2-morpholinophenyl)thiourea (10.6 g) was suspended in boiling water (80 ml) and a solution of potassium hydroxide (25.2 g) in hot water (70 ml) was added. The mixture was heated to 90 C and aliquot portions of a hot solution of lead acetate trihydrate (17.5 g) in water (80 ml) added and the mixture heated under reflux for 10 minutes and cooled to ambient temperature. The mixture was filtered and the filtrate acidified with acetic acid to pH 6. The solid which formed was separated by filtration, washed with water and recrystallised from ethylacetate to give N-(2morpholinophenyl)cyanamide (m.p. 175-176"C).
N-(2-morpholinophenyl)cyanamide (2 g) was heated under reflux with a 33% solution of dimethylamine in ethanol (15 ml) for 4 hours. The mixture was then cooled and the solvent removed by evaporation to give a residue which was suspended in 20% aqueous sodium hydroxide solution. The suspension was extracted with dichloromethane (3 x 25 ml) and the extracts were washed with water, and then brine, dried and evaporated to give 1 , 1 -dimethyl-2- (2-morpholinophenyl) guanidine (m.p. 142-143"C) which was recrystallised from'hexane.
Examples 273-285 In a similar manner to that described in Example 272, N-(2-morpholinophenyl)cyanamide (P g) was heated under reflux with an amine of formula HNR5R6 (Q g) and ethanol (R ml) for T hours to give the compounds listed in Table X.
Notes to Table X Notes (32), (38), (44) and.(45) have the meaning given hereinbefore (72) A 33% ethanolic solution of methylamine (25 ml) was used as reactant.
(73) Reaction performed at 90-95"C.
(74) Product isolated as its monofumarate salt which was recrystallised from a 2:3 mixture of methanol and ether.
(75) Product recrystallised from a 1:1 mixture of hexane and ethyl acetate.
(76) Reaction performed at ambient temperature for 2 hours and then at 90-950C for 20 minutes.
(77) Product recrystallised from a 3:7 mixture of ethylacetate and hexane.
(78) Reaction performed at ambient temperature for 4 hours and then heated under reflux for 4 hours.
Table X
Ex P Q R T R5 R6 mp( C) Notes 273 2.5 2 H Me 171-172 (72)(73)(74) 274 2 1.3 15 1 H Et 103-105 (75) 275 2 2.2 15 3 H Bu 114-116 (44)(73) 276 2 3.4 20 Me Et 130-132 (76)(32) 277 4 6 25 1 Me CH2CH2SMe 230(dec) (45)(73) 278 3 4.6 30 1.25 Me CH2CH2OMe 192-193 (38) 279 2 2.2 10 1.5 Me allyl 125 (73)(77) 280 4 6.2 30 1.5 Et CH2CH2OMe 168-170 (38) 281 4 2.5 25 2 allyl allyl 188-190 (73)(38) Table X Continued Ex P Q R T R5 R6 mp( C) Notes 282 5 5 50 2 -(CH2)2NMe(CH2)2- 146-147 (32) 283 2 1.7 20 6 -CH2CHMeOCHMeCH2- 175-177 (44) 284 4 4.1 40 3 -(CH2)2CHMe(CH2)2- 133-135 (32) 285 3 22 40 -(CH2)2S(CH2)2- 148-150 (32)(78) Example 286 Reaction of 4-(2-amino-4-chlorophenyl)morpholine (8.5 g) with thiophosgene (4.6 ml) in dioxan (25 ml) and water (100 ml) for 30 minutes at OOC and for 3 hours at room temperature gave 5-chloro-2-morpholinophenyl isothiocyanate as a pale yellow solid (m.p.
86-87"C).
Reaction of 5-chloro-2-morpholinophenyl isothiocyanate (10 g) with 33% alcoholic ammonia solution (60 ml) at room temperature for 14 hours gave 1-(5-chloro-2-morpholinophenyl)thiourea as a yellow solid (m.p. 174-175"C).
A mixture of 1-(5-chloro-2-morpholinophenyl) thiourea (5.97 g) suspended in water (40 ml), lead acetate trihydrate (8.75 g) in water (40 ml) and potassium hydroxide (12.6 g) in water (35 ml) was heated under reflux for 15 minutes to give N-(5 chloro-2-morpholinophenyl)cyanamide as a white solid (m.p. 305-3080C).
In a similar manner to that described in Example 272, N-(5-chloro-2-morpholinophenyl)cyanamide (2.3 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) were heated under reflux for 4 hours to give 1 ,1-dimethyl-2-(5-chloro-2-morpholino- phenyl)guanidine (m.p. 135-138 C) which was recrystallised from hexane and then was converted into its monofumarate salt (m.p. 223-225"C) which was recrystallised from methanol.
Example 287 A mixture of 5-fluoro-2-morpholino aniline (6 g) and thiophosgene (5.2 g) in dioxan (20 ml) and water (40 ml) was stirred at OOC for 15 minutes and at room temperature for one hour to yield a residue which was extracted with dichloromethane to give an oil which was purified by chromatography on a silica gel column (mesh 100-200) using a 1:9 mixture of ethylacetate and hexane as eluant to give 5-fluoro-2-morphoinophenyl isothiocyanate as an oil.
Reaction of 5-fluoro-2-morpholinophenyl isothiocyanate (5.8 g) with 33% ethanolic ammonia solution (30 ml) at room temperature for 3 hours gave 1-(5fluoro-2-morpholinophenyl)thiourea as a white solid (m.p. 195-196).
A mixture of 1-(5-fluoro-2-morpholinophenyl)- thiourea (5.1 g) suspended in water (36.5 ml), lead acetate trihydrate (7.95 g) in water (36 ml) and potassium hydroxide (11.45 g) in water (32 ml) was heated under reflux for 25 minutes to give N-(5fluoro-2-morpholinophenyl)cyanamide as a white solid (m.p. 168-170"C).
In a similar manner to that described in Example 286, N-(5-fluoro-2-morpholinophenyl)cyanamide (2.2 g) in ethanol (10 ml) and a 33% ethanolic solution of dimethylamine (6 ml) was heated under reflux for 20 minutes to give 1 ,1-dimethyl-2-(5-fluoro-2-morphol- inophenyl)guanidine (m.p. 137-138"C) which was recrystallised from hexane and converted into its fumarate salt (m.p. 222-2240C) which was recrystallised from methanol.
Example 288 Reaction of 3-methyl-2-morpholinoaniline (9.4 g) with thiophosgene (6 ml) in dioxane (50 ml) and water (200 ml) at 0 C for 30 minutes and at room temperature for 2 hours gave a product which was extracted with dichloromethane to give 3 -methyl-2 -morpholinophenyl isothiocyanate as a red oil.
Reaction of 3-methyl-2-morpholinophenyl isothiocyanate (8 g) in ethanol (5 ml) with a saturated solution of ammonia in ethanol (60 ml) at room temperature for 4 hours gave 1-(3-methyl-2-morpholinophenyl)thiourea (m.p. 178-1790C).
A mixture of 1 - (3-methyl-2-morpholinophenyl) - thiourea (6 g) suspended in water (40 ml), lead acetate trihydrate (9 g) in water (40 ml), potassium hydroxide (13.5 g) in water (35 ml) was heated at 90-950C for 1 hour to give N- (3-methyl-2-morpholinophenyl) cyanamide (m.p. 137-138"C) which was recrystallised from ethyl acetate.
In a similar manner to that described in Example 286, N-(3-methyl-2-morpholinophenyl)cyanamide (2.5 g) in ethanol (8 ml) and a 33% ethanolic solution of dimethylamine (3.5 ml) were heated under reflux for 1 hour. A further amount of the 33% ethanolic solution of dimethylamine (3.5 ml) was added and the mixture heated under reflux for a further hour to give 1,1dimethyl-2-(3-methyl-2-morpholinophenyl)guanidine (m.p.
100"C) which was recrystallised from hexane and converted into its monofumarate salt (m.p. 1800C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 289 Reaction of 4-methoxy-2-morpholinoaniline (4.7 g) and thiophosgene (2.9 ml) in dioxan (25 ml) and water (75 ml) for 30 minutes at 0 C and 3 hours at room temperature yielded a residue which was extracted with dichloromethane to give 4 -methoxy-2 -morpholinophenyl isothiocyanate as an oil.
Reaction of 4-methoxy-2-morpholinophenyl isothiocyanate (4.1 g) with a saturated solution of ammonia in ethanol (30 nit) for 24 hours at room temperature gave 1-(4-methoxy-2-morpholinophenyl)thiourea (m.p. 175 C).
A mixture of 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 potassium hydroxide (8.4 g) in water (24 ml) was heated at 90-95 C for 30 minutes to give N-(4-methoxy-2morpholinophenyl) cyanamide.
A mixture of N- (4-methoxy-2-morpholinophenyl) - cyanamide (1.9 g) and 33% ethanolic dimethylamine solution (2.5 ml) was heated under reflux 'for 15 minutes to give 1,1-dimethyl-2-(4-methoxy-2-morpholinophenyl)guanidine (m.p. 1350C) which was recrystallised from hexane.
Example 290 A mixture of 5-isobutyl-2-morpholinoaniline hydrochloride (4.1 g), N,N-dimethylcyanamide (1.77 g) and m-cresol (15 ml) was heated at 90-950C for 6 hours to yield a residue which was extracted with hot hexane, decolourised with charcoal and purified by chromatography on an alumina column eluted with a 2:98 mixture of methanol and dichloromethane. The resulting product was crystallised from a 1:3 mixture of ethylacetate and hexane. The initial precipitate was removed by filtration and the filtrate evaporated to dryness to give a residue which was recrystallised from a 1:3 mixture of ethylacetate and hexane to give 1 ,1 -dimethyl-2-(5-isobutyl-2-morpholinophenyl)- guanidine.
Example 291 Sodium chlorite (5.6 g), cuprous chloride (0.2 g), cupric chloride dihydrate (0.34 g) were added to a solution of sodium carbonate (3.75 g) in water (25 ml).
The mixture was cooled to 20"C and a solution of N-(2-morpholinophenyl)thiourea (6 g) in dichloromethane (45 ml) was added over 15 minutes. The temperature was raised to 40eC and maintained at this level for 4.5 hours. Water (100 ml) and dichloromethane (200 ml) were added and the mixture stirred for ten minutes.
The organic layer was separated and the aqueous layer washed with dichloromethane. The combined organic layer was washed with brine and dried. Removal of the solvent gave a residue which was stirred with 20% aqueous sodium hydroxide solution (100 ml) and heated on a steam bath and then filtered. The filtrate was washed with ether, acidified to pH 4 with acetic acid and extracted with dichloromethane. The extract was washed with brine, dried and the solvent removed to give a residue which was purified by chromatography on a silica column which was eluted with hexane to which ethylacetate (up to 30%) was added progressively to raise the polarity. N- (2-morpholinophenyl) cyanamide (m.p. 175-176"C).
A mixture of N- (2-morpholinophenyl) cyanamide (1.5 g) and a 33% ethanolic solution of dimethylamine (12 ml) was heated under reflux for 4 hours. Removal of solvent gave a residue to which was added dichloromethane (100 ml) and brine (50 ml). The mixture was stirred for 5 minutes and the organic layer separated and dried. Removal of the solvent gave 1 , 1 -dimethyl-2- (2-morpholinophenyl)guanidine (m.p.
144-145 C) which was recrystallised from hexane.
Example 292 1 ,1-dimethyl-2-(5-methylthio-2-morpholinophenyl)- guanidine in the form of its free base (1.3 g) obtained from the product of Example 253, sodium metaperiodate (1 g), methanol (10 ml) and water (4 ml) were stored at ambient temperature for 20 hours to yield 1,1-dimethyl2-(5-methylsulphinyl-2-morpholinophenyl)guanidine (m.p.
160-161 C) which was recrystallised from ethyl acetate.
Example 293 A solution of 1-methyl-2-(2-morpholinophenyl)thiourea (6.2 g) in dichloromethane (30 ml) was added over 15 minutes to a stirred mixture of aqueous sodium carbonate solution (3.75 g in 25 ml), sodium chlorite (5.6 g), cuprous chloride (0.2 g), cupric chloride dihydrate (0.34 g) and benzyltrimethylammonium chloride (0.6 g). The resulting mixture was stirred for 2 hours and then sodium chlorite (2.4 g) and benzyltrimethylammonium chloride (0.4 g) were added and the mixture stirred for 1 hours. Dichloromethane (200 ml) and water (50 ml) were added and the aqueous layer extracted with dichloromethane (2 x 100 ml). The extracts were combined, washed with brine, dried and filtered.Removal of the solvent gave a residue which was purified by chromatography on a silica gel column using hexane and then a 1:4 mixture of ethyl acetate and hexane as eluant to give N-methyl-N'-(2morpholinophenyl)carbodiimide (m.p. 67-68eC).
A mixture of N-methyl-N' - (2-morpholinophenyl)- carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (5 ml) was heated at 90-95"C for four hours. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered.
Removal of the solvent gave l-(n-butyl,)-2-(2-morphol- inophenyl) -3-methylguanidine which was converted into its monofumarate salt (m.p. 178-179"C).
Examples 294 to 300 In a similar manner to that described in Example 2 the products of the Examples set out below were converted into their fumarate salts which were recrystallised from the solvent shown: M.P. of Starting Recrystallisation fumarate Example Example Solvent Salt("C) 294 133 1:2 methanol:ether 173-175 295 134 1:2 methanol:ether 183-184 296 167 2:1 methanol:ether 192-193 297 175 1:1 methanol:ether 159-160 298 200 propan-2-ol 142-143 299 201 1:1 methanol:ether 151-152 300 204 1:2 methanol:ether 170-171 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 five hours, cooled and added to a mixture of 40% aqueous sodium hydroxide solution (300 ml) and ice (300 g). Water (300 ml) was added and the resulting solid separated by filtration, washed with water and dissolved in dichloromethane.
The solution was dried and the solvent removed to give a residue which was recrystallised from hexane to give 1 , 1 -dimethyl-2-(2-morpholinophenyl)guanidine (m.p.
142-143"C).
Example 303-304 Reaction of the products of Examples 175, 248 and 300 in the form of its free base respectively in methanol with L(+) tartaric acid gave the following compounds which were recrystallised from methanol.
301 4-(2-[1-(2-hydroxyethyl)-2-imidazolidinylidene amino]phenyl) morpholine monotartrate (m.p.
147-148 C).
303 1,1-dimethyl-2-(5-methyl-2-morpholinophenyl) guanidine monotartrate (m.p. 183-1840C).
304 1,1-dimethyl-2-(2-morpholinophenyl)guanidine monotartrate (m.p. 184-1850C).
Examples 305 and 306 Methanol and acetylchloride were reacted' for 30 minutes to give hydrogen chloride which was reacted with the products of Example 248 and 301 respectively to give the products identified below. The products were recrystallised from the solvents given in parenthesis.
305 1,1-dimethyl-2-(5-methyl-2-morpholinophenyl) guanidine monohydrochloride (m.p. 161-1 620C) (a 1:1 mixture of isopropanol and ether).
306 1,1-dimethyl-2-(2-morpholinophenyl)guanidine monohydrochloride (m.p. 200-201 C) (isopropanol).
Example 307 Reaction of the product of Example 301 in acetone with concentrated sulphuric acid gave 1,1-dimethyl-2-( 2-morpholinophenyl ) guanidine hemisulphate (m.p.
234-235 C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 308 Reaction of pamoic acid with the product of Example~ 301 in pyridine yielded 1,1-dimethyl-2-(2morpholinophenyl)guanidine hemipamoate (m.p.
158-160"C).
Example 309 A mixture of 1,3-dimethyl-2-imidazolidinone (4.6 g) in benzene (40 ml), 4-(2-aminobenzyl)morpholine (3.8 g) in benzene (20 ml) and phosphorus oxychloride (3.6 ml) was heated at 65-70"C for 20 hours to yield 4-[2-(1 ,3-dimethyl-2-imidazolidinyl- ideneamino)benzyl]morpholine (m.p. 56-58eC) which was recrystallised from hexane.
Example 310 A mixture of 1 ,3-dimethyl-2-imidazolidinone (10.95 g) in benzene (100 ml), 4-(2-amino-4-chlorobenzyl)morpholine (13.6 g) in benzene (50 ml) and phosphorus oxychloride (8.8 ml) was heated at 60-650C for 8 hours to yield an oil which was purified by column chromatography on an alumina column using hexane, a 9:1 mixture of hexane and dichloromethane, a 1:1 mixture of hexane and dichloromethane and then dichloromethane as eluant. The resulting product (3.2 g) was dissolved in methanol (50 ml) and treated with fumaric acid (1.2 g) to yield 4-[4-chloro-2 (1,3-dimethyl-2-imidazolidinylideneamino)benzyl]- morpholine monofumarate (m.p. 169-170"C) which was recrystallised from a 1:1 mixture of methanol and ether.
Example 311 A mixture of 4-(2-aminobenzyl)morpholine dihydrochloride (10.6 g) and N,N-dimethylcyanamide (4.2 g) in m-cresol (40 ml) was heated at 90-95"C for 13 hours to yield a solid (m.p. 120-121"C) a portion of which (2 g) was dissolved in methanol (15 ml).
Treatment with fumaric acid (0.9 g) gave N,N-dimethyl N'-[2-morpholinomethylphenyl)guanidine monofumarate (m.p. 164-165"C) which was recrystallised from propan-2-ol.
Example 312 A mixture of 4-(2-aminobenzyl)morph & ine dihydrochloride (6.8 g), 4-cyanomorpholine (4.3 g) and m-cresol was heated at 90-950C for 12 hours to yield N- (2-morpholinomethylphenyl)morpholine-4-carboxamidine (m.p. 118-119 C) which was recrystallised from hexane and then converted into its difumarate salt (m.p.
166-167 C which was recrystallised from propan-2-ol.
Example 313 The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples.
a) Capsules In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound.
b) Tablets Tablets are prepared from the following ingredients.
Parts bv weight Active compound prepared as in Example 1 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 Magnesium stearate 3 The active compound, the lactose and some of the starch are de-aggregated, blended and the resulting mixture is granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate is blended with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tab letting machine to give tablets each containing a unit dose or a part of a unit dose of active compound.
(c) Enteric coated tablets Tablets are prepared by the method described in (b) above. The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol:dichloromethane (1:1).
d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound is incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount of active ingredient.

Claims (41)

Claims
1. Compounds of formula I
and their pharmaceutically acceptable salts in which n = 0 or 1; in which R1 and R2, which are the same or different, are (a) an aliphatic group containing 1 to 3 carbon atoms, said aliphatic group being optionally substituted by methoxy (b) a cycloalkyl group containing 3 to 7 carbon atoms or (c) R1 and R2 together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring of formula II
in which R8 represents H or an alkyl group containing 1 to 3 carbon atoms and B represents an alkylene group of 2 to 4 carbon atoms optionally interrupted by oxygen, sulphur, sulphinyl or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms or the substituents on two adjacent carbon atoms of the alkylene group form a benzene ring or B represents an alkenylene group of 3 carbon atoms; R3 is a straight or branched alkyl group containing 1 to 7 carbon atoms or a cycloalkyl group containing 3 to 7 carbon atoms or a group of formula III
in which R4 and R'4, which are the same or different, are H or an alkyl group containing 1 to 4 carbon atoms; in which R5 is H or a straight or branched aliphatic group of 1 to 4 carbon atoms, said aliphatic group being optionally substituted by methoxy; in which R6 is (a) H, (b) a straight or branched aliphatic group of 1 to 6 carbon atoms optionally substituted by hydroxy or an acylated derivative thereof, by an alkoxy group containing 1 to 3 carbon atoms, by an alkylthio group containing 1 to 3 carbon atoms, by an optionally alkylated amino group, by a carbocyclic group containing 3 to 7 carbon atoms or by cyano or (c) a cycloalkyl ring containing 3 to 7 carbon atoms; or the group R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV
in which R6 is as hereinbefore defined, Rg and R10, which are the same or different, are H or an alkyl group of 1 to 4 carbon atoms optionally substituted by methoxy, and D is an oxyethylene group in which the oxygen atom is bonded to the carbon atom carrying the groups R9 and R10 or an alkylene group of 2 to 5 carbon atoms optionally substituted by one or more alkyl groups of 1 to 3 carbon atoms; or the group R3 and the group R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V
in which R6 is as hereinbefore described, in which R11 is H or an alkyl group containing 1 or 2 carbon atoms, and E is an alkylene group of 2 to 4 carbon atoms optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI
in which G is an alkylene group of 4 or 5 carbon atoms optionally interrupted by oxygen, sulphur or nitrogen optionally substituted by an alkyl group containing 1 to 3 carbon atoms, said alkylene group being optionally substituted by one or more alkyl groups containing 1 to 3 carbon atoms; and R7 represents H or one or more optional substituents selected from halo, alkyl groups containing 1 to 4 carbon atoms optionally substituted by methylthio, alkoxy groups containing 1 to 3 carbon atoms, alkylthio groups containing 1 to 3 carbon atoms, alkylsulphinyl groups containing 1 to 3 carbon atoms, alkylsulphonyl groups containing 1 to 3 carbon atoms, alkoxycarbonyl groups containing a total of 2 or 3 carbon atoms, trifluoromethyl or cyano.
2. Compounds of formula I as claimed in claim 1 in which n = 0, R1 and R2, which are the same or different, are selected from (a) alkyl groups of 1 to 3 carbon atoms optionally substituted by methoxy (b) allyl groups or (c) cyclohexyl groups.
3. Compounds of formula I as claimed in claim 2 in which R1 and R2 are both alkyl, allyl or 2-methoxyethyl or R1 is methyl and R2 is 2-methoxyethyl or cyclohexyl.
4. Compouds of formula I as claimed in claim 2 in which the group NR1R2 is dimethylamino, diethyl-amino, diallylamino, (2-methoxyethyl)methylamino, cyclohexylmethylamino or bis(2-methoxyethyl)amino.
5. Compounds of formula I as claimed in claim 1 in which n = 0, the group NR1 R2 is a heterocyclic ring represented by formula II, R8 represents H or methyl and B represents a group selected from -(CH2)2-, -CHMeCH2-, o-phenylene, -(CH2)3-, -CH2CHMeCH2-, (cm2)4 ' -CH2OCH2-, -CHMeOCHMe-, -CH2SCH2-, -CH2S(O)CH2-, -CH2NMeCH2- or -CH=CHCH2-.
6. Compounds of formula I as claimed in claim 5 in which the group NR1 R2 is 1-pyrrolidinyl, 2-methyl-l- pyrrolidinyl, piperidino, 4-methyl-piperidino, 1-hexa- hydroazepinyl, morpholino, 2,6-dimethylmorpholino, thiamorpholino, thiamorpholino-1 -oxide, 2-isoindolinyl, 4-methyl-1 -piperazinyl or 1-(1 ,2,5,6-tetrahydro)-pyridyl.
7. Compounds of formula I as claimed in claim 1 in which n = 1 and the group NR1R2 is morpholino or thiamorpholino.
8. Compounds of formula I as claimed in claim 1 in which R3 is methyl, ethyl, propyl, isopropyl, butyl t-butyl, pentyl, cyclohexyl, amino, methylamino, dimethylamino or ethylamino.
9. Compounds of formula I as claimed in claim 1 in which R5 is H, methyl, ethyl or methoxyethyl.
10. Compounds of formula I as claimed in claim 1 in which R6 is H or a straight or branched alkyl group containing 1 to 5 carbon atoms optionally substituted by hydroxy, by an acylated derivative of hydroxy, by methoxy, by methylthio, by dimethylamino, by phenyl or by cyano, R6 is a straight or branched alkylene group containing 3 to 6 carbon atoms or R6 is a cycloalkyl group containing 5 or 6 carbon atoms.
11. Compounds of formula I as claimed in claim 10 in which R6 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methylpropyl, 2 ,3-dihydroxypropyl, 2-acetyloxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, 2-methylthioethyl, 2-dimethylaminoethyl, benzyl or 2-phenylethyl 2-cyanoethyl, allyl, 2-methylallyl, cyclopentyl or cyclohexyl.
12. Compounds of formula I as claimed in claim 1 in which the group -N=C(R3)NR5R6 is:acetamidino, N-methylacetamidino, N,N-dimethylacetamidino, N,N-diethylacetamidino, N- (2 -acetyloxyethyl) acetamidino, N-butylacetamidino, N-pentylacetamidino, N-methylpropionamidino, N,N-dimethylpropionamidino N-ethylpropionamidino, butyramidino, N-methylbutyramidino, N,N-dimethylbutyramidino, N-ethylbutyramidino, isobutyranidino, N-methylisobutyramidino, N,N-dimethylisobutyramidino, valeramidino, N-methylvaleramidino, 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-butylguanidino, N-ethyl-N-methylguanidino, N,N-diethylguanidino, N,N'-diethylguanidino, N,N',N'-trimethylguanidino, 1,1,3,3-tetramethylguanidino, N-ethyl-N'-methylguanidino, 1-ethyl-1,3,3-trimethylguanidino, 1-butyl-1,3,3-trimethylguanidino, N-methyl-N-propylguanidino, N-butyl-N-methylguanidino, N-sec-butyl-N' -methylguanidino, N-tert-butyl-N'-methylguanidino, N-isobutyl-N'-methylguanidino, N-butyl-N' -methylguanidino, N-butyl-N'-ethylguanidino, N-methyl-N'-pentylguanidino, N-cyclopentyl-N'-methylguanidino, N-(2-methoxyethyl)guanidino, N-(2-methoxyethyl)-N-methylguanidino, N- (2 -methoxyethyl) -N' -methylguanidino, N-ethyl-N-(2-methoxyethyl)guanidino, N,N-bis(2-methoxyethyl)guanidino, N-methyl-N-(2-methylthioethyl)guanidino, N-allyl-N-methylguanidino, N-allyl-N'-methylguanidino, 1-allyl-1,3,3-trimethylguanidino, N,N-diallylguanidino,
13.Compounds of formula I as claimed in claim 1 in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula IV, R9 and R1o, which are the same or different, are H or alkyl groups containing 1 to 3 carbon atoms optionally substituted by methoxy, D is selected from -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH2CMe2 - or -O(CH2)2- and the group R6 is H, methyl, ethyl, isopropyl, cyclohexyl, 2-cyanoethyl, 2-acetoxyethyl or 2-methoxyethyl.
14. Compounds of formula I as claimed in claim 13 in which formula IV represents:2-pyrrolidinylidene, 1-methyl-2-pyrrolidinylidene, 3-methyl-2-pyrrolidinylidene, 1-ethyl-2-pyrrolidinylidene, l-isopropyl-2-pyrrolidinylidene, 1-cyclohexyl-2-pyrrolidinylidene, 1- (2-methoxyethyl) -2-pyrrolidinylidene, 1,3-dimethyl-2-pyrrolidinylidene, 5,5-dimethyl-2-pyrrolidinylidene, 1,3,3-trimethyl-2-pyrrolidinylidene, 1,5,5-trimethyl-2-pyrrolidinylidene, 3-isopropyl-1 -methyl-2-pyrrolidinylidene, 1 -ethyl-3,3-dimethyl-2-pyrrolidinylidene, 3 ,3-diethyl-1 -methyl-2-pyrrolidinylidene, 2-piperidinylidene, 1-methyl-2-piperidinylidene, 1,3-dimethylpiperidinylidene, 1 -ethyl-2-piperidinylidene, 1-isopropyl-2-piperidinylidene, 1 - (2-cyanoethyl) -2-piperidinylidene, 1-(2-acetoxyethyl)-2-piperidinylidene, 3-(2-methoxyethyl)-1-methyl-2-piperidinylidene, 2-hexahydroazepinylidene, l-methyl-2-hexahydroazepinylidene, 2-octahydroazocinylidene or 3-morpholinylidene.
15. Compounds of formula I as claimed in claim 1 in which the groups R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a heterocyclic ring of formula V, E is -CH2CH2-, -CMe2CH2-, -CHMeCHMe-, -(CH2)3-, CHMeCH2 - or -(CH2) R11 is H, methyl or ethyl and R6 is H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, allyl, 2-methylallyl, 2-hydroxyethyl, 2-acetoxyethyl, 2-benzoyloxyethyl, 2-methoxyethyl, cyclohexyl, benzyl, phenethyl, 3 -hydroxypropyl, 2-hydroxypropyl, 2 -hydroxy2-methylpropyl, 2-hydroxybutyl, 2 ,3-dihydroxypropyl or 2-dimethylaminoethyl.
16. Compounds of formula I as claimed in claim 15 in which formula V represents:2-imidazolidinylidene, 1-methyl-2-imidazolidinylidene, 4-methyl-2-imidazolidinylidene, 4,4-dimethyl-2-imidazolidinylidene, 4,5-dimethyl-2-imidazolidinylidene, 1-ethyl-2-imidazolidinylidene, 1 -propyl-2-imidazolidinylidene, 1-isopropyl-2-imidazolidinylidene, 1-(n-butyl)-2-imidazolidinylidene, 1-isobutyl-2-imidazolidinylidene, 1-pentyl-2-imidazolidinylidene, 1-allyl-2-imidazolidinylidene, 1-(2-methylallyl)-2-imidazolidinylidene, 1- (2-hydroxyethyl) -2-imidazolidinylidene, 1-(2-hydroxyethyl)-3-methyl-2-imidazolidinylidene, 1-(2-acetoxyethyl)-2-imidazolidinylidene, 1-(2-benzoyloxyethyl)-2-imidazolidinylidene, 1-(2-benzoyloxyethyl)-3-methyl-2-imidazolidinylidene, 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-diethyl-2-imidazolidinylidene, 1 -ethyl-3-methyl-2-imidazolidinylidene, 1-butyl-3-methyl-2-imidazolidinylidene, 1-isopropyl-4,4-dimethyl-2-imidazolidinylidene, 1-methyl-2-perhydropyrimidinylidene or 1,3-diazacycloheptane.
17. Compounds of formula I as claimed in claim 1 in which R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI and G represents a group selected from -(CH2)4-, -(CH2)5-, -(CH2)2O(CH2)2-, -(CH2)2S(CH2)2-, -(CH2)2NMe(CH2)2-, -(CH2)2CHMe(CH2)2- or -CH2CHMeOCHMeCH2-.
18. Compounds of formula I as claimed in claim 17 in which the group NR5R6 is 1-pyrrolidinyl, piperidino, 4-methylpiperidino, morpholino, 2,6-dimethylmorpholino, thiamorpholino or 4-methyl-i -piperazinyl.
19. Compounds of formula I as claimed in claim 17 in which the group -N=C(R3)NR5R6 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, 1 ,i -dimethyl-3 ,3-pentamethyleneguanidino.
20. Compounds of formula I as claimed in claim 1 in which R7 represents H or one or more substituents selected from fluoro, chloro, methyl, ethyl, isobutyl, methylthio-methyl, methoxy, dimethoxy, methoxycarbonyl, methylthio, methylsulphinyl, methylsulphonyl, trifluoromethyl or cyano.
21. Compounds of formula I as claimed in claim 1 in which n = 0, -NR1R2 is morpholino, thiamorpholino, piperidino or 1-pyrrolidinyl, R3 is -NH2, R5 is an aliphatic group containing 1 to 4 carbon atoms R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy or methylthio or R5 and R6 together with the nitrogen atom to which they are attached form a heterocyclic ring of formula VI and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
22. Compounds of formula I as claimed in claim 21 in which R5 is methyl, ethyl or allyl, R6 is methyl, ethyl, allyl, methoxyethyl or methylthioethyl or the group -NR5R6 is morpholino or thiamorpholino and R7 is H, fluoro, chloro, methyl, ethyl, methylthiomethyl or methylthio.
23. Compounds of formula I as claimed in claim 1 in which n = 0, -NR1R2 is morpholino or thiamorpholino, R3 is a group of formula III in which R4 is an alkyl group containing 1 to 4 carbon atoms and R4, is H, R5 is H, R6 is an aliphatic group containing 1 to 4 carbon atoms optionally substituted by methoxy and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
24. Compounds of formula I as claimed in claim 23 in which R4 is methyl, R4' is H, R5 is H and R6 is methyl, butyl, t-butyl or methoxyethyl.
25. Compounds of formula I as claimed in claim 1 in which n = 0, -NR1R2 is morpholino, thiamorpholino, morpholinomethyl or thiamorpholinomethyl, R3 is an alkyl group of 1 to 4 carbon atoms, R5 and R6 are H and R7 is H, fluoro, methyl, methylthio or methylthiomethyl.
26. Compounds of formula I as claimed in claim 1 selected from: 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 , I -dimethyl-2- (S-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-i -(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-morpholinopheriyl)acetamidine N- (2-morpholinophenyl)pivalamidine and pharmaceutically acceptable salts thereof.
27. Pharmaceutical compositions comprising a therapeutically active amount of a compound of formula I as claimed in any one of the preceding claims in combination with a pharmaceutically acceptable diluent or carrier.
28. The use of compounds of formula I as claimed in any one of claims 1 to 26 as antidiabetic agents.
29. The use of compounds of formula I as claimed in any one of claims 1 to 26 as hypoglycaemic agents.
30. The use of compounds of formula I as claimed in any one of claims 1 to 26 in the manufacture of a medicament for the treatment of diabetes.
31. The use of compounds of formula I as claimed in any one of claims 1 to 26 in the manufacture of a medicament for the treatment of hyperglycaemia.
32. A process for preparing compounds of formula I as claimed in claim 1 comprising the reaction of an aminophenyl compound of formula VII
with an amide or a urea of formula R3. CO .NR5R6 in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulphonyl chloride.
33. A process as claimed in claim 32 for preparing compounds of formula I as claimed in claim 1 wherein the compound of formula VII is reacted with a) a lactam of formula VIII
in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, cyanuric chloride, phosgene, carbon tetrachloride/triphenylphosphine, phosphorus pentachloride or benzenesulphonyl chloride.
b) a compound of formula IX
in which R12 is chloro, -O-POCl2, -O-SOCl, -OCOCl or -OSO2Ph and B is an anion such as halo (e.g. Cl-) or POCK4 c) a compound of formula X
in which R13 is an alkyl group and B is an anion such as fluoroborate or methosulphate.
d) when R6 is H, a ketoxime of formula XI
in the presence of a sulphonyl chloride (for example benzene sulphonyl chloride) or e) a urea of formula XII
in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, phosgene, phosphorus pentachloride or benzenesulphonyl chloride.
34. A process for preparing compounds of formula I as claimed in claim 1 in which R3 and R5 together with the carbon and nitrogen atoms to which they are attached form a ring represented by formula V, said process comprising reaction of a compound of formula XIII
optionally in the form of a salt in which R14 and R15 are H with a diamine of formula XIV R11 NHENHR6 XIV
35. A process for preparing compounds of formula I as claimed in claim 1 in which R3 is a straight or branched alkyl group of 1 to 7 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms and the group NR5R6 is NH2, said process comprising the reaction of a compound of formula VII optionally in the form of a salt with a cyano compound of formula R3CN, optionally in the presence of aluminium chloride.
36. A process for preparing compounds of formula I as claimed in claim 1 in which the group R3 is NH2, said process comprising the reaction of a compound of formula VII optionally in the form of a salt with a cyanamide compound of formula R5R6 NCN.
37. A process for preparing compounds of formula I as claimed in claim 1 in which the group R3 is NH2, said process comprising the reaction of compounds of formula XV
with amines of formula NHR5R6.
38. A process for preparing compounds of formula I as claimed in claim 1 in which R3 is a group of formula III in which R4 is alkyl and R4' is H or alkyl, said process comprising the reaction of a compound of formula XIII in which R14 is the group R4 and R15 is the group R4, with an amine of formula HNR5R6 optionally in the presence of a base or in the presence of potassium hydroxide and lead acetate.
39. A process for preparing compounds of formula I as claimed in claim 1 in which R3 is a group of formula III in which R4 is alkyl and R4, is H and in which R5 is H may be prepared by the reaction of a thiourea of formula XVI
in which R14 is the group R4 and R15 is the group R4, with an amine of formula HNR5R6 optionally in the presence of a base and lead acetate.
40. A process for preparing compounds of formula I as claimed in claim 1 in which R3 is a group of formula III in which R4 is alkyl and R4' is H and in which R5 is H, said process comprising the reaction of a carbodiimide of formula XVII
with an amine of formula H2NR6.
41. A process for preparing compounds of formula I as claimed in claim 1 in which n = 0 and NR1R2 is morpholino, thiamorpholino, 1-pyrrolidinyl or piperidino, said process comprising the reaction of a compound of formula XVII I
with a disubstituted compound of formula XIX K(CH2)2L(CH2)2K XIX in which K is a leaving group and L is -O-, -S-, a direct bond or -CH2- respectively.
GB8929260A 1989-01-02 1989-12-28 Hypoglycaemic amidines and guanidines Expired - Fee Related GB2226562B (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021621A1 (en) * 1993-03-23 1994-09-29 Astra Aktiebolag Guanidine derivatives useful in therapy
EP0805153A1 (en) * 1996-04-30 1997-11-05 Pfizer Inc. Novel muscarinic receptor agonists
WO1998026782A1 (en) * 1996-12-18 1998-06-25 Knoll Aktiengesellschaft Use of 2-(2-morpholinophenyl) guanidine derivatives for the treatment of diabetes complications
US5807886A (en) * 1994-05-07 1998-09-15 Astra Aktiebolag Bicyclic amidine dervatives as inhibitors of nitric oxide synthetase
US5807885A (en) * 1993-08-12 1998-09-15 Astra Aktiebolag Amidine derivatives with nitric oxide synthetase activities
WO2003000659A1 (en) * 2001-06-26 2003-01-03 Nissan Chemical Industries, Ltd. Heterocycloiminophenyl compounds and fungicides and insecticides for agricultural and horticultural use

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN172842B (en) * 1990-05-17 1993-12-11 Boots Pharmaceuticals Limited
AU671071B2 (en) * 1990-08-30 1996-08-15 State of Oregon, acting by and through The Oregon State Board of Higher Education, acting for and on behalf of The Oregon Health Sciences University, Portland, Oregon, and The University of Oregon, Eugene, Oregon, Johnson Hall, Substituted amidines having high binding to the sigma receptor and the use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0233461A2 (en) * 1986-01-13 1987-08-26 American Cyanamid Company 4,5,6-Substituted-2-pyrimidinamines

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0233461A2 (en) * 1986-01-13 1987-08-26 American Cyanamid Company 4,5,6-Substituted-2-pyrimidinamines

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021621A1 (en) * 1993-03-23 1994-09-29 Astra Aktiebolag Guanidine derivatives useful in therapy
US5885985A (en) * 1993-03-23 1999-03-23 Astra Aktiebolag Guanidine derivatives useful in therapy
US5998399A (en) * 1993-03-23 1999-12-07 Astra Aktiebolag Guanidine derivatives useful in therapy as inhibitors of nitric oxide synthetase
US5807885A (en) * 1993-08-12 1998-09-15 Astra Aktiebolag Amidine derivatives with nitric oxide synthetase activities
US6030985A (en) * 1993-08-12 2000-02-29 Astra Aktiebolag Amidine derivatives with nitric oxide synthetase activities
US5807886A (en) * 1994-05-07 1998-09-15 Astra Aktiebolag Bicyclic amidine dervatives as inhibitors of nitric oxide synthetase
US6117898A (en) * 1994-05-07 2000-09-12 Astra Aktiebolag Bicyclic amidine derivatives as inhibitors of nitric oxide synthetase
EP0805153A1 (en) * 1996-04-30 1997-11-05 Pfizer Inc. Novel muscarinic receptor agonists
WO1998026782A1 (en) * 1996-12-18 1998-06-25 Knoll Aktiengesellschaft Use of 2-(2-morpholinophenyl) guanidine derivatives for the treatment of diabetes complications
US6133267A (en) * 1996-12-18 2000-10-17 Knoll Aktiengesellschaft Use of 2-(2-morpholinophenyl) guanidine derivatives for the treatment of diabetes complications
WO2003000659A1 (en) * 2001-06-26 2003-01-03 Nissan Chemical Industries, Ltd. Heterocycloiminophenyl compounds and fungicides and insecticides for agricultural and horticultural use

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Date Code Title Description
727 Application made for amendment of specification (sect. 27/1977)
727A Application for amendment of specification now open to opposition (sect. 27/1977)
727B Case decided by the comptroller ** specification amended (sect. 27/1977)
SP Amendment (slips) printed
732E Amendments to the register in respect of changes of name or changes affecting rights (sect. 32/1977)
PCNP Patent ceased through non-payment of renewal fee

Effective date: 20021228