公开(公告)号：US20090187032A1

公开(公告)日：2009-07-23

申请号：US12303160

申请日：2007-05-18

申请人： Lajosne Dancsi ,  Gyorgy Visky ,  Zoltan Tuba ,  Janos Csorgei ,  Csaba Molnar ,  Endrene Magyari

发明人： Lajosne Dancsi ,  Gyorgy Visky ,  Zoltan Tuba ,  Janos Csorgei ,  Csaba Molnar ,  Endrene Magyari

IPC分类号： C07J3/00 ,  C07D317/72

CPC分类号： C07J21/006 ,  C07J31/006 ,  C07J41/0083 ,  C07J71/001

摘要： The present invention relates to a new industrial process for the synthesis of solvate-free 17α-acetoxy-11β-[4-(N,N-dimethyl-amino)-phenyl]-19-norpregna-4,9-diene-3,20-dione [CDB-2914] of formula (I) which is a strong antiprogestogene and antiglucocorticoid agent. The invention also relates to compounds of formula (VII) and (VIII) used as intermediates in the process.The process according to the invention is the following:i) 3-(ethylene-dioxy)-estra-5(10),9(11)-diene-17-one of formula (X) is reacted with potassium acetilyde formed in situ in dry tetrahydrofuran by known method,ii) the obtained 3-(ethylene-dioxy)-17α-ethynyl-17β-hydroxy-estra-5(10),9(11)-diene of formula (IX) is reacted with phenylsulfenyl chloride in dichloromethane in the presence of triethylamine and acetic acid,iii) the obtained isomeric mixture of 3-(ethylene-dioxy)-21-(phenyl-sulfinyl)-19-norpregna-5(10),9(11),17(20),20-tetraene of formula (VIII) is reacted first with sodium methoxide in methanol, then with trimethyl phosphite,iv) the obtained 3-(ethylene-dioxy)-17α-hydroxy-20-methoxy-19-norpregna-5(10),9(11),20-triene of formula (VII) is reacted with hydrogen chloride in methanol, thenv) the obtained 3-(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene-20-one of formula (VI) is reacted with ethylene glycol in dichloromethane in the presence of trimethyl orthoformate and p-toluenesulfonic acid by known method,vi) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-19-norpregna-5(10),9(11)-diene of formula (V) is reacted with hydrogen peroxide in a mixture of pyridine and dichloromethane in the presence of hexachloroacetone by known method,vii) the obtained 3,3,20,20-bis(ethylene-dioxy)-17α-hydroxy-5,10-epoxy-19-norpregn-9(11)-ene of formula (IV), containing approximately a 1:1 mixture of 5α,10α- and 5β,10β-epoxides, is isolated from the solution and reacted with a Grignard reagent obtained from 4-bromo-N,N-dimethyl-aniline in tetrahydrofuran in the presence of copper(I) chloride catalyst without separation of the isomers by known method,viii) the obtained 3,3,20,20-bis(ethylene-dioxy)-5α,17α-dihydroxy-11β-[4-(N,N-dimethylamino)-phenyl]-19-norpregn-9(11)-ene of formula (III) is reacted with potassium hydrogensulfate in water by known method,ix) the obtained 11β-[4-(N,N-dimethylamino)-phenyl]-17α-hydroxy-19-norpregn-4,9-diene-3,20-dione of formula (II) is acetylated with acetic anhydride in the presence of perchloric acid by known method, finallyx) the solvate-free compound of formula (I) is liberated from the obtained solvate containing compound of formula (I) in a 1:1 mixture of ethanol and water at 70° C.

公开(公告)号：US5082835A

公开(公告)日：1992-01-21

申请号：US491683

申请日：1990-03-09

申请人： Csaba Molnar ,  Gyorgy Hajos ,  Laszlo Szporny ,  Jozsef Toth ,  Arpad Kiraly ,  Anna Boor nee Mezei ,  Janos Csorgei ,  Kristina Szekely ,  Lilla Forgacs ,  Gyorgy Fekete ,  Bulcsu Herenyi ,  Sandor Holly ,  Jozsef Szunyog

发明人： Csaba Molnar ,  Gyorgy Hajos ,  Laszlo Szporny ,  Jozsef Toth ,  Arpad Kiraly ,  Anna Boor nee Mezei ,  Janos Csorgei ,  Kristina Szekely ,  Lilla Forgacs ,  Gyorgy Fekete ,  Bulcsu Herenyi ,  Sandor Holly ,  Jozsef Szunyog

IPC分类号： A61K31/57 ,  A61P29/00 ,  C07J5/00 ,  C07J13/00

CPC分类号： C07J5/0092 ,  C07J13/005

摘要： The invention relates to antiinflammatory compounds of the formula (I), ##STR1## wherein A stands for hydrogen, hydroxyl or trifluoroacetoxy group;X stands for hydrogen or halogen with the proviso that if A is hydrogen, then X also means hydrogen;R stands for hydrogen, benzoyl or C.sub.1-8 alkanoyl group; and represents a single or double bond between two adjacent carbon atoms,as well as pharmaceutical compositions containing these compounds and a process for their preparation.

公开(公告)号：US5053404A

公开(公告)日：1991-10-01

申请号：US491682

申请日：1990-03-09

申请人： Csaba Molnar ,  Gyorgy Hajos ,  Laszlo Szporny ,  Jozsef Toth ,  Arpad Kiraly ,  Anna Boor nee Mezei ,  Janos Csorgei ,  Kristina Szekely ,  Lilla Forgacs ,  Gyorgy Fekete ,  Bulcsu Herenyi ,  Sandor Holly ,  Jozsef Szunyog

发明人： Csaba Molnar ,  Gyorgy Hajos ,  Laszlo Szporny ,  Jozsef Toth ,  Arpad Kiraly ,  Anna Boor nee Mezei ,  Janos Csorgei ,  Kristina Szekely ,  Lilla Forgacs ,  Gyorgy Fekete ,  Bulcsu Herenyi ,  Sandor Holly ,  Jozsef Szunyog

IPC分类号： A61K31/58 ,  A61P29/00 ,  C07J7/00 ,  C07J71/00

CPC分类号： C07J71/0031 ,  C07J7/008

摘要： The invention relates to antiinflammatory compounds of the formula (I), ##STR1## wherein A stands for hydrogen or hydroxyl group;X stands for hydrogen or halogen with the proviso that if A is hydrogen, then X also means hydrogen;R stands for hydrogen, benzoyl or C.sub.1-8 alkanoyl group;R.sup.1 and R.sup.2, which are the same or different, stand for hydrogen or a C.sub.1-4 alkyl group; or one of R.sup.1 and R.sup.2 is hydrogen and the other is phenyl group; or R.sup.1 and R.sup.2 together form a C.sub.4-5 alkylene group;means a single or double bond between two adjacent carbon atoms,as well as pharmaceutical compositions containing these compounds and a process for their preparation.

公开(公告)号：US4456601A

公开(公告)日：1984-06-26

申请号：US434335

申请日：1982-10-14

申请人： Jozsef Toth ,  Gyorgy Hajos ,  Gyorgy Fekete ,  Istvan Horvath ,  Laszlo Szporny ,  Anna Boor nee Mezei ,  Peter Aranyi ,  Aniko Naray ,  Sandor Gorog ,  Sandor Holly ,  Csaba Molnar

发明人： Jozsef Toth ,  Gyorgy Hajos ,  Gyorgy Fekete ,  Istvan Horvath ,  Laszlo Szporny ,  Anna Boor nee Mezei ,  Peter Aranyi ,  Aniko Naray ,  Sandor Gorog ,  Sandor Holly ,  Csaba Molnar

IPC分类号： C07J5/00 ,  A61K31/58 ,  A61P29/00 ,  C07J71/00 ,  A61K31/56

CPC分类号： C07J71/0031

摘要： New .DELTA..sup.1,3,5 -3-chloro-pregnane derivatives of the general formula (I), ##STR1## wherein X is hydrogen atom, acetyl group or a chloroacetyl group, andY and Z represent hydrogen atom or a halogen atom, with the proviso that at least one of them is other than hydrogen,are prepared by reacting a .DELTA..sup.1,4 -3-oxo-pregnane derivative of the general formula (II), ##STR2## wherein X' is acetyl group or a chloroacetyl group and Y and Z are as defined above, with a chloromethyleneiminium salt of the general formula (III), ##STR3## wherein A.sup.(-) is a salt-forming anion, in an aprotic solvent in the presence of a tertiary base, and, if desired, subjecting the resulting product to hydrolysis.The compounds of the general formula (I) exert antiphlogistic effects and can be used in the therapy for the treatment of inflammations.

摘要翻译： 通式（I），其中X是氢原子，乙酰基或氯代乙酰基的新的具有通式（I）的1,3,5-三氯 - 孕烷衍生物，Y和Z代表氢原子或 卤素原子，条件是它们中的至少一个不是氢，通过使通式（II）的DELTA 1,4-3-氧代 - 孕烷衍生物，其中X' 与乙酰基或氯乙酰基，Y和Z如上所定义，与通式（III）的氯亚甲基亚胺鎓盐，其中A（ - ）是形成盐的阴离子，在非质子传递溶剂 在叔碱存在下，如果需要，使所得产物水解。 通式（I）的化合物发挥消炎作用，可用于治疗炎症的治疗。