RU1797610C - Способ получени (2-морфолинофенил)гуанидинов или их фармацевтически приемлемых солей - Google Patents

Способ получени (2-морфолинофенил)гуанидинов или их фармацевтически приемлемых солей

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RU1797610C
RU1797610C SU904831862A SU4831862A RU1797610C RU 1797610 C RU1797610 C RU 1797610C SU 904831862 A SU904831862 A SU 904831862A SU 4831862 A SU4831862 A SU 4831862A RU 1797610 C RU1797610 C RU 1797610C
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morpholinophenyl
optionally substituted
guanidines
pharmaceutically acceptable
preparing
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SU904831862A
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English (en)
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Гопалан Баласубраманьян
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Дзе Бутс Компани ПЛС
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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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    • C07D401/00—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
    • C07D401/02—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
    • 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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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Description

и получают З-метил-2-морфолинофенилизо- тиоцианат в виде красного масла.
Взаимодействием З-метил-2-морфоли- нофенилизотиоцианата (8 г) в этаноле (5 мл) с насыщенным раствором аммиака в этаноле (60 мл) при комнатной температуре в течение 4 ч получают 1-(3-метил-2-морфолинофенил}- тиомочевину (точка плавлени  178-179°С).
1 Смесь 1-(3-метил-2-морфолинофенил)- тиомочевины (6 г), суспендированной в воде (40 мл), тригидрата ацетата свинца (9 г) в воде (40 мл), гидроокиси кали  (13,5 г) в воде (35 мл) нагревают при 90-95°С 1 ч и получают М-(3 метил-2-морфолинофенил}-цианамид (точка плавлени  Т37-138°С), который перекристаллизовывают из этилацетата.
Способом, аналогичным описанному в примере 1, (3-метил-2-морфолинофенил)- цианамид (2,5 г) в этаноле (8 мл) и 33% эта- нрловый раствор диметиламина (3,5 мл) нагревают с обратным холодильником 1 ч. Добавл ют дополнительное количество 33% этанолового раствора диметиламина (3,5 мл), смесь нагревают с обратным холодильником еще 1 ч и получают 1,2-диметил- 2-(3- метил-2-морфолинофенил)-гуанидин (точка плавлени  100°С), который перекристаллизовывают из гексана и перевод т в его монофумаратную соль (точка плавлени  180°С), которую перекристэллизовывают из смеси м.етанол-эфир в отношении 1:1..
П р и м е р 18. Взаимодействием 4-ме- токси-2-морфолиноанилина (4,7 г) И тиофос- тена (2,9 г) б.диоксане (25 мл) и воде (75 мл) в течение 30 мин при 0°С и 3 ч при комнатной температуре получают остаток, который экстрагируют дихлорметаном и получают 4- метокси-2-морфолинофенилизотиоцианат в виде масла.
Взаимодействием 4-метокси-2-морфо- линофенилизотиоцианата (4,1 г)с насыщенным раствором аммиака в этаноле (30 мл) в течение 24 часов при комнатной температуре получают 1-(4-метокси-2-морфолинофе- нил)-ти:омочевину (т.пл, 175°С).
Смесь 1-(4-метокси-2-морфолинофе- нил)-тиомочевины (3,8 г), суспендированной в воде (26 мл), тригидрата ацетата свинца (5,7 г) в воде (26 мл) и гидроокиси кали  (8,4 г) в воде (24 мл) нагревают при 90-95°С в течение 30 мин и получают М-(4-метокси-2- морфолинофенил)-цианамид.
Смесь М-(4-метокси-2-морфолинофе- нил)-цианамида(1,9 г) и 33% раствора диметиламина в этаноле (2,5 мл) нагревают с обратным холодильником 15 мин и получали 1,1 -диметил-2-(4-метокси-2-морфолинофе - н.ил)-гуанидин (точка плавлени  135°С), который перекристаллизовывают из гексана.
П р и м е р 19. Хлорид натри  (5,6 г), хлорид меди (1) (0,2 г) и дигидрат хлорида меди (2) (0,34 г) добавл ют к раствору карбоната натри  3,75 г) в воде (25 мл). Смесь
5 охлаждают до 20°С и в течение 15 мин добавл ют раствор М-(2-морфолинофенил)-ти- омочевины (6 г) в дихлорметана (45 мл). Температуру повышают до 40°С и поддерживают на этом уровне 4,5 ч. Добавл ют
0 воду (100 мл) и дихлорметан (200 мл) и смесь перемешивают 10 минут. Органический слой отдел ют и водный слой промывают дихлорметаном. Объединенный органический слой промывают рассолом и сушат.
5 Удалением растворител  получают остаток, который перемешивают с 20 % - ным раствором гидроокиси натри  (100 мл), нагревают на паровой бане и затем фильтруют. Фильтрат промывают эфиром, подкисл ют
0 до рН 4 уксусной кислотой и экстрагируют дихлорметаном. Экстракт промывают рассолом , сушат, растЁоритель удал ют и полученный остаток очищают хроматографией на колонке кремнезема, которую элюируют ,
5 гексаном с последовательно увеличивающимис  добавлени ми (до.30%) этилацетата дл  повышени  пол рности. Получают N-(2- морфолинофенил)-цианамид (т.пл.175- 176°С).
0 Смесь 1М-(2-морфолинофенил)-цианами- да (1,5 г) и 33% этанолового раствора диметиламина (12 мл) нагревают с обратным холодильником 4 ч. После удалени  растворител  получают остаток, к которому добав5 л ют дихлорметан (100 мл) и рассол (50 мл). Смесь перемешивают 5 мин, органический слой отдел ют и сушат. После удалени  растворител  получают 1,1-диметил-2-(2-мор- фолинофенил)-гуанидин (точка плавлени 
0 144-145°С), который перекристаллизовывают из гексана.
Гипогликемическую активность соединений формулы 1: примеров 1-19 подтверждали следующим . Крыс массой
5 150-200 г фиксировали на 18 ч и затем подкожно инъецировали глюкозу (800 мг/ 4 мл/кг) с последующим пероральным введением дозы соединени , прилежащего испытани м (х мг в 4 или 5 мл 2 % агара/кг) Через
0 2 и 4 ч отбирали кровь из глазницы и глюкозу плазмы оценивали на анализаторе глюкозы Бекмана с использованием специфического метода окислени  глюкозы. Затем рассчитывали процентное снижение глюкозы
5 плазмы в сравнении с контрольными животными , которые не получали испытываемого соединени , но получали только 2%-ный го- могенат агара. Соединени  обладают гипо- гликемической активностью в этом тесте, если они показывали 15% или более снижеФ о р м у л а и з о б р е т е н и   Способ получени  (2-морфолинофенил)- гуанидинов формулы
,ыО
где Вз имеет указанные значени , при температуре кипени  реакционной смеси в течение времени, достаточного дл  завершени  реакции,с выделением целевого продукта в свободном виде в виде фармацевтически приемлемой соли.
Т а б л и ц а 1
Me - СНз
111797610 12
Т а б л и ц а 2 Глюкозонормализующее действие (2-морфолинофенил) - гуанидинов
SU904831862A 1989-02-16 1990-12-03 Способ получени (2-морфолинофенил)гуанидинов или их фармацевтически приемлемых солей RU1797610C (ru)

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GB898903592A GB8903592D0 (en) 1989-02-16 1989-02-16 Therapeutic agents

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SU894742813A RU1826969C (ru) 1989-02-16 1989-12-29 Способ получени амидинов или их фармацевтически приемлемых солей
SU904831862A RU1797610C (ru) 1989-02-16 1990-12-03 Способ получени (2-морфолинофенил)гуанидинов или их фармацевтически приемлемых солей
SU925011043A RU2052452C1 (ru) 1989-02-16 1992-02-27 Амидиновые производные бензола и их фармацевтически приемлемые соли

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GB9418912D0 (en) * 1994-09-20 1994-11-09 Fisons Corp Pharmaceutically active compounds
AU4176396A (en) * 1994-12-08 1996-06-26 Knoll Aktiengesellschaft Use of substituted phenylamidine and phenylguanidine compounds for the treatment of cerebral and cardiac ischaemia, convulsion and sickle cell anaemia
TW397812B (en) * 1995-02-11 2000-07-11 Astra Ab Bicyclic isothiourea derivatives useful in therapy
AU2978197A (en) * 1996-06-04 1998-01-05 Chugai Seiyaku Kabushiki Kaisha Substituted benzenes having nos inhibitory effects
US6756389B2 (en) * 1996-08-09 2004-06-29 Cambridge Neuroscience, Inc. Pharmaceutically active compounds and methods of use
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