公开(公告)号：WO9940067A2

公开(公告)日：1999-08-12

申请号：PCT/EP9900852

申请日：1999-02-05

Applicant: DUPHAR INT RES ,  HARTOG JACOBUS A J ,  VISSER GERBEN M ,  STEEN BARTHOLOMEUS J VAN ,  TULP MARTINUS T M ,  RONKEN ERIC ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M

Inventor： DEN HARTOG JACOBUS A J ,  VISSER GERBEN M ,  VAN STEEN BARTHOLOMEUS J ,  TULP MARTINUS T M ,  RONKEN ERIC ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M

IPC: A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D413/14 ,  C07D

CPC classification number: C07D413/14

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2 or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

Abstract translation: 本发明涉及一组新颖的苯并异恶唑衍生物，它们是多巴胺D4-受体的有效和选择性拮抗剂。 所述化合物具有通式（I）：其中（R 1）n表示0,1或2个取代基，所述取代基可以相同或不同，选自C 1-3烷基或烷氧基，卤素，三氟甲基，硝基， （C1-2） - 氨基，磺酰基 - （C1-3）烷基或 - 烷氧基，磺酰基三氟甲基，磺酰基氨基和磺酰基单或二烷基（C1-2） - 氨基，X是O，S，NH或 NCH 3，Y代表CH 2或（CH 2）2，（R 2）m代表0,1或2个可与甲基和乙基相同或不同的取代基，或（R 2）m是亚甲基桥或亚乙基 桥基，A是基团-CH 2 - （CRH）p - ，其中R是氢或甲基，p是0或1，B代表2-或3-吲哚基或2-苯并咪唑基，这些基团可以在碳上被1 或C1-C3-烷基或烷氧基，卤素，三氟甲基，硝基，氨基，单或二烷基（C1-2）氨基，磺酰基 - （C1-3）烷基或 - 烷氧基，磺酰基三氟甲基， 磺酰基氨基和磺酰基单或二烷基（C1-2） - 氨基。

公开(公告)号：CA2320120A1

公开(公告)日：1999-08-12

申请号：CA2320120

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： VISSER GERBEN M ,  TULP MARTINUS T M ,  DEN HARTOG JACOBUS A J ,  VAN STEEN BARTHOLOMEUS J ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M ,  RONKEN ERIC

IPC: A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D413/14

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2 or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

公开(公告)号：CA2063314A1

公开(公告)日：1992-09-21

申请号：CA2063314

申请日：1992-03-18

Applicant: DUPHAR INT RES

Inventor： LANGE JOSEPHUS H M ,  TOOROP GERRIT P ,  VAN WIJNGAARDEN INEKE ,  DEN HARTOG JACOBUS A J

IPC: C07D317/64 ,  C07D319/18 ,  C07D405/06 ,  A61K31/36 ,  A61K31/445 ,  A61K31/495

Abstract: DIR 0482 The invention relates to compounds having anti-ischaemic activity, memory enhancing activity and anti-convulsive activity of the formulae 1A and 1B (1A) (1B) wherein -R1 + R2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 13 C-atoms; -Z is methylene optionally substituted with one alkyl group having 1-3 C-atoms, or with one phenylalkyl group with 1-3 C-atoms in the alkyl group, which phenyl group may be substituted with a group (R5)p wherein. R6 is halogen, hydroxy, alkyl or hydroxyalkyl having 1-5 C-atoms, alkoxy having 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O)2-alkyl having 1-3 Catoms, amino, mono- or dialkylamino having 1-3 C-atoms per alkyl group, trifluoromethyl, trifluoromethoxy, a sulphonylamido group SO2NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 C-atoms, the group COOH, SO3H,CONH2, the amidino group or cyano group, and p has the value 0-3; -R3 and R4 independent of each other represent hydrogen, alkyl having 1-10 C-atoms, alkenyl or alkynyl having 3-10 Catoms, cycloalkyi having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or alkynyl group, which groups R3 and R4 may be substituted with a group (R8)p wherein R6 and p have the above mentioned meanings, or wherein R3+R4 together with DIR 0482 the nitrogen atom form a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may contain a second hetero-atom from the group consisting of oxygen, sulphur and nitrogen, which ring may be substituted with a group (R5)p wherein R6 and p have the above mentioned meanings, or with phenylalkyl, heteroarylalkyl, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl having at most 3 C-atoms in the alkyl, alkenyl or alkynyl part, which groups may be substituted with a group (R6)p wherein R6 and p have the above-mentioned meanings, or which ring may be annelated with a phenyl group; -R5 is alkyl having 1-12 C-atoms, alkenyl or alkynyl having 3-12 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl sub-group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl-alkynyl having 3-5 C-atoms in the alkenyl subgroup or alkynyl sub-group, which groups may be substituted with a group (R6)p, wherein R6 and p have the abovementioned meanings, and which alkyl sub-groups, alkenyl sub-groups and alkynyl sub-groups may contain a group -O-, S- or CO, or a pharmacologically acceptable salt thereof

公开(公告)号：DK1054885T3

公开(公告)日：2007-10-15

申请号：DK99914450

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： DEN HARTOG JACOBUS A J ,  VAN STEEN BARTHOLOMEUS J ,  TULP MARTINUS T M ,  RONKEN ERIC ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M ,  VISSER GERBEN M

IPC: C07D413/14 ,  A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2, or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

公开(公告)号：PT1054885E

公开(公告)日：2007-10-03

申请号：PT99914450

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： HARTOG JACOBUS A J DEN ,  VISSER GERBEN M ,  STEEN BARTHOLOMEUS J VAN ,  RONKEN ERIC ,  LANGE JOSEPHUS H M ,  TULP MARTINUS T M ,  KRUSE CORNELIS G

IPC: C07D413/14 ,  A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00

公开(公告)号：CA2320120C

公开(公告)日：2009-08-11

申请号：CA2320120

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： VISSER GERBEN M ,  DEN HARTOG JACOBUS A J ,  LANGE JOSEPHUS H M ,  TULP MARTINUS T M ,  VAN STEEN BARTHOLOMEUS J ,  RONKEN ERIC ,  KRUSE CORNELIS G

IPC: C07D413/14 ,  A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1- 2)- amino, X is O, S, NH or NCH3, Y represents CH2 or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different , from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen o r methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1- 3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

公开(公告)号：DE69936572T2

公开(公告)日：2008-06-19

申请号：DE69936572

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： DEN HARTOG JACOBUS A J ,  VISSER GERBEN M ,  VAN STEEN BARTHOLOMEUS J ,  TULP MARTINUS T ,  RONKEN ERIC ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M

IPC: C07D413/14 ,  A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2, or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

公开(公告)号：AU3327399A

公开(公告)日：1999-08-23

申请号：AU3327399

申请日：1999-02-05

Applicant: DUPHAR INT RES

Inventor： HARTOG JACOBUS A J DEN ,  VISSER GERBEN M ,  STEEN BARTHOLOMEUS J VAN ,  TULP MARTINUS T M ,  RONKEN ERIC ,  KRUSE CORNELIS G ,  LANGE JOSEPHUS H M

IPC: A61K31/445 ,  A61K31/454 ,  A61K31/55 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D413/14

Abstract: The present invention relates to a group of novel benzisoxazole derivatives which are potent and selective antagonists of the dopamine D4-receptor. The compounds have general formula (I) wherein (R1)n represents 0, 1, or 2 substituents, which can be the same or different, from the group C1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino mono- or dialkyl (C1-2)-amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino, X is O, S, NH or NCH3, Y represents CH2, or (CH2)2, (R2)m represents 0, 1, or 2 substituents, which can be the same or different, from the group methyl and ethyl, or (R2)m is a methylene bridge or ethylene bridge, A is a group -CH2-(CRH)p- wherein R is hydrogen or methyl and p is 0 or 1, and B represents 2- or 3-indolyl or 2-benzimidazolyl, which groups may be substituted at carbon with 1 or 2 substituents from the group C-1-3-alkyl or alkoxy, halogen, trifluoromethyl, nitro, amino, mono- or dialkyl (C1-2)amino, sulfonyl-(C1-3)alkyl or -alkoxy, sulfonyl trifluoromethyl, sulfonyl amino, and sulfonyl mono- or dialkyl (C1-2)-amino.

公开(公告)号：AU6305790A

公开(公告)日：1991-03-28

申请号：AU6305790

申请日：1990-09-21

Applicant: DUPHAR INT RES

Inventor： WITIAK DONALD T ,  WIJNGAARDEN INEKE VAN ,  NAIR RAGHUNATHAN V ,  LANGE JOSEPHUS H M ,  HARTOG JACOBUS A J DEN

IPC: A61K31/357 ,  A61K31/36 ,  A61K31/443 ,  A61K31/445 ,  A61K31/495 ,  A61K31/535 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  C07C217/58 ,  C07D295/096 ,  C07D317/64 ,  C07D319/18 ,  C07D321/10 ,  C07D405/06 ,  A61K31/335 ,  A61K31/44 ,  A61K31/47

公开(公告)号：CA2025731A1

公开(公告)日：1991-03-23

申请号：CA2025731

申请日：1990-09-19

Applicant: DUPHAR INT RES

Inventor： WITIAK DONALD T ,  VAN WIJNGAARDEN INEKE ,  NAIR RAGHUNATHAN V ,  LANGE JOSEPHUS H M ,  DEN HARTOG JACOBUS A J

IPC: A61K31/357 ,  A61K31/36 ,  A61K31/443 ,  A61K31/445 ,  A61K31/495 ,  A61K31/535 ,  A61P9/00 ,  A61P9/08 ,  A61P9/10 ,  C07C217/58 ,  C07D295/096 ,  C07D317/64 ,  C07D319/18 ,  C07D321/10 ,  C07D405/06 ,  C07D317/46 ,  A61K31/335 ,  A61K31/395 ,  C07D405/10 ,  C07D413/10

Abstract: DIR 0444 The invention relates to compounds having anti-ischaemic activity of the formula (1) wherein: -R1 + R2 together form an alkylene group having 1-3 C-atoms which may be substituted with one or more alkyl group(s) having 1-3 C-atoms; -Z is methylene optionally substituted with one or two alkyl group(s) having 1-3 C-atoms, or with one phenyl group or phenylalkyl group with 1-3 C-atoms in the alkyl group, which phenyl groups may be substituted with a group (R6)p wherein R6 is halogen, hydroxyl alkyl or hydroxyalkyl having 1-5 C-atoms, alkoxy having 1-3 C-atoms, S-alkyl, S(O)-alkyl or S(O)2-alkyl having 1-3 C-atoms, amino, mono- or dialkylamino having 1-3 Catoms per alkyl group, trifluoromethyl, trifluoromethoxy, a sulphonylamido group SO2NHR or a carbalkoxy group COOR wherein R is alkyl having 1-4 Catoms, the group COOH, SO3H,COHN2, the amidino group or cyano group, and p has the value 0-3; -R3 and R4 independent of each other represent hydrogen, alkyl having 1-10 C-atoms, alkenyl or alkynyl having 310 C-atoms, cycloalkyl having 3-8 C atoms, cycloalkylalkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 Catoms in the alkyl group, phenylalkenyl, heteroarylalkenyl, phenylalkynyl or heteroaryl-alkynyl group having 3-5 C-atoms in the alkenyl group or alkynyl DIR 0444 group, which groups R3 and R4 may be substituted with a group (R6)p wherein R6 and p have the above mentioned meanings, or wherein R3+R4 together with the nitrogen atom form a saturated or unsaturated heterocyclic group of 5-7 ring atoms, which may contain a second hetero-atom from the group consisting of oxygen, sulphur and nitrogen, which ring may be substituted with a group (R6)p wherein R6 and p have the above mentioned meanings, or with phenylalkyl, phenylalkenyl, thienylalkenyl, pyridinylalkenyl, phenylalkynyl, thienylalkynyl or pyridinylalXynyl having at most 3 C-atoms in the alkyl, alkenyl or alkynyl part, which groups may be substituted with a group (R6)p wherein R6 and p have the above-mentioned meanings, or which ring may be annelated with a phenyl group: -R5 is alkyl having 1-12 C-atoms, alkenyl or alkynyl having 3-12 C-atoms, cycloalkyl having 3-8 C-atoms, cycloalkyl-alkyl having 3-8 ring atoms and 1-5 C-atoms in the alkyl group, phenylalkyl or heteroaryl-alkyl having 1-5 C-atoms in the alkyl sub-group, phenylalkenyl, heteroaryl-alkenyl, phenylalkynyl or heteroaryl alkynyl having 3-5 C atoms in the alkenyl sub-group or alkynyl sub-group, which groups may be substituted with a group (R6)p, wherein R6 and p have the above-mentioned meanings, and which alkyl subgroups, alkenyl sub-groups and alkynyl sub-groups may contain a group -O-, -S- or CO, or a pharmacologically acceptable salt thereof.