公开(公告)号：JPH11147871A

公开(公告)日：1999-06-02

申请号：JP25910598

申请日：1998-08-31

Applicant: DUPHAR INT RES

Inventor： FEENSTRA ROELOF W ,  VISSER GERBEN M ,  KRUSE CORNELIS G ,  TULP MARTINUS T M ,  LONG STEPHEN K

IPC: C07D215/06 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61P25/18 ,  A61P43/00 ,  C07D209/08 ,  C07D209/34 ,  C07D215/14 ,  C07D215/38 ,  C07D223/16 ,  C07D263/58 ,  C07D265/36 ,  C07D279/16 ,  C07D401/04 ,  C07D401/12 ,  C07D409/12

Abstract: PROBLEM TO BE SOLVED: To obtain a new piperazine compound exhibiting high affinity for both dopamine D2 and serotonin 5-HT A receptors and useful for treating schizophrenia and other psychopathy. SOLUTION: The compound of formula I R1 is H or fluoro; R' is H or a 1-4C alkyl; R2 is H, a 1-4C alkyl or oxo; or R1 and R2 together form a bond; R" is H or a 1-4C alkyl; the dotted line is a single or double bond; (p) is 0-2; Y is C, O, N or S; Y is N or C; R3 and R4 are each H or a 1-4C alkyl; (n) is 1 or 2; Q is CH2 -C(R5 ,R6 )-Z-R7 [R5 and R6 are each H or the like; Z is C(R8 ,R9 )-0 (R8 and R9 are H or the like) or the like; R7 is a cyclic group or the like]}, for example, a compound of formula II, is obtained from a compound of formula III as a starting raw material by a known method.

公开(公告)号：JPH11302279A

公开(公告)日：1999-11-02

申请号：JP28357898

申请日：1998-09-21

Applicant: DUPHAR INT RES

Inventor： TULP MARTINUS T M ,  LONG STEPHEN K ,  DEN HARTOG JACOBUS A J ,  FEENSTRA ROELOF W ,  KRUSE CORNELIS G

IPC: C07D411/12 ,  A61K31/00 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14 ,  C07D411/14 ,  C07D413/04 ,  C07D413/12 ,  C07D413/14

Abstract: PROBLEM TO BE SOLVED: To provide the subject compounds having an affinity for dopamine D2 and D4 receptors, without showing a noted preference for one over the other, also having an affinity for serotonin 5-HT1a , and useful for treatment of mental diseases, e.g. schizophrenia. SOLUTION: The compounds are shown by formula I [A is a 5- to 7-membered heterocyclic group having 1 to 3 hetero atoms selected from the group consisting of O, N and S; R1 is H or fluoro; R2 is a 1-4C alkyl, oxo or the like; (p) is 0 to 2; Z is C or N; broken line is a single bond when Z is N and single or double bond when Z is C; R3 and R4 are each H or a 1-4C alkyl; (n) is 1 or 2; R5 is a 2-, 3- or 4-pyridyl substituted with Y at the meta site for methylene cross-linking; and Y is phenyl or furanyl] and salts thereof, e.g. a compound shown by formula II. The compound shown by formula I is obtained by reacting a compound shown by formula III with a compound shown by the formula; R5 -CH2 -X (X is an eliminable group).

公开(公告)号：CA2350137C

公开(公告)日：2008-04-22

申请号：CA2350137

申请日：1999-11-10

Applicant: DUPHAR INT RES

Inventor： LONG STEPHEN K ,  MOS JOHANNES ,  VAN DER HEIJDEN JOHANNES A M ,  FEENSTRA ROELOF W ,  VISSER GERBEN M ,  KRUSE CORNELIS G ,  VAN SCHARRENBURG GUSTAAF J M ,  TOOROP ANNE G ,  TOOROP GERRIT

IPC: C07D413/04 ,  A61K31/40 ,  A61K31/4164 ,  A61K31/42 ,  A61K31/425 ,  A61K31/4439 ,  A61K31/454 ,  A61K31/496 ,  A61P25/00 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D209/34 ,  C07D235/26 ,  C07D263/58 ,  C07D277/68 ,  C07D401/04 ,  C07D417/04

Abstract: The invention relates to novel compound of the general formula (I) : wherein: S1 represents H, a halogen atom, OH, CN, NH2, CF3, OCF3, SCF3 C1-3-alkyl, C1-3-alkoxy, or mono- or di-C1-3-alkyl- substituted-amino; ---Z represents =C or -N; R1 and R2, independently, represent H or C1-3-alkyl; or R1 and R2 together from a C2-3-bridge; R4 represents H or C1-3-alkyl; and Q represents: (i) methyl, or (ii) ethyl or cyclopropylmethyl optionally substituted with one or more F; or a salt or prodrug thereof. It has been found that these compounds have both partial dopamine D2-receptor agonism and partial serotonin 5-HT1A-receptor agonism mediated activities.

公开(公告)号：DZ2613A1

公开(公告)日：2003-03-01

申请号：DZ980223

申请日：1998-09-22

Applicant: DUPHAR INT RES

Inventor： FEENSTRA ROELOF W ,  HARTOQ DEN JACOBUSA A J ,  KRUSE CORNELIS G

IPC: C07D411/12 ,  A61K31/00 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14 ,  C07D411/14 ,  C07D413/04 ,  C07D413/12 ,  C07D413/14 ,  C07D295/12

Abstract: The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties. It has been found that compounds of the formula (a) wherein A represents a heterocyclic group of 5-7 ring atoms wherein 1 - 3 heteroatoms from the group O, N and S are present, R1 is hydrogen or fluoro, R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2, Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Zis carbon, R3 and R4 independently are hydrogen or C1-4-alkyl, n has the value 1 or 2, R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q, Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl, R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3 and salts thereof, show affinities for both the dopamine D2-, D3-, D4- receptors and the serotonin 5-HT1A receptor.

公开(公告)号：BR9803497A

公开(公告)日：2000-05-02

申请号：BR9803497

申请日：1998-09-21

Applicant: DUPHAR INT RES

Inventor： TULP MARTINUS T M ,  LONG STEPHEN K ,  DEN HARTOG JACOBUS A J ,  FEENSTRA ROELOF W ,  KRUSE CORNELIS G

IPC: C07D411/12 ,  A61K31/00 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14 ,  C07D411/14 ,  C07D413/04 ,  C07D413/12 ,  C07D413/14 ,  C07D401/10 ,  C07D403/10 ,  C07D405/10 ,  C07D409/10 ,  C07D411/10 ,  C07D413/10

Abstract: The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties. It has been found that compounds of the formula (a) wherein A represents a heterocyclic group of 5-7 ring atoms wherein 1 - 3 heteroatoms from the group O, N and S are present, R1 is hydrogen or fluoro, R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2, Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Zis carbon, R3 and R4 independently are hydrogen or C1-4-alkyl, n has the value 1 or 2, R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q, Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl, R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3 and salts thereof, show affinities for both the dopamine D2-, D3-, D4- receptors and the serotonin 5-HT1A receptor.

公开(公告)号：NO984380L

公开(公告)日：1999-03-25

申请号：NO984380

申请日：1998-09-21

Applicant: DUPHAR INT RES

Inventor： FEENSTRA ROELOF W ,  HARTOG JACOBUS A J DEN ,  KRUSE CORNELIS G ,  TULP MARTINUS T M ,  LONG STEPHEN K

IPC: C07D411/12 ,  A61K31/00 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14 ,  C07D411/14 ,  C07D413/04 ,  C07D413/12 ,  C07D413/14

Abstract: The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties. It has been found that compounds of the formula (a) wherein A represents a heterocyclic group of 5-7 ring atoms wherein 1 - 3 heteroatoms from the group O, N and S are present, R1 is hydrogen or fluoro, R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2, Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Zis carbon, R3 and R4 independently are hydrogen or C1-4-alkyl, n has the value 1 or 2, R5 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q, Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl, R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3 and salts thereof, show affinities for both the dopamine D2-, D3-, D4- receptors and the serotonin 5-HT1A receptor.

公开(公告)号：CA2247734A1

公开(公告)日：1999-03-24

申请号：CA2247734

申请日：1998-09-21

Applicant: DUPHAR INT RES

Inventor： TULP MARTINUS T M ,  LONG STEPHEN K ,  DEN HARTOG JACOBUS A J ,  FEENSTRA ROELOF W ,  KRUSE CORNELIS G

IPC: C07D411/12 ,  A61K31/00 ,  A61K31/44 ,  A61K31/4427 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4545 ,  A61K31/495 ,  A61K31/496 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  C07D401/12 ,  C07D401/14 ,  C07D405/04 ,  C07D405/12 ,  C07D405/14 ,  C07D409/14 ,  C07D411/14 ,  C07D413/04 ,  C07D413/12 ,  C07D413/14 ,  A61K31/47

Abstract: The invention relates to a group of new piperazine and piperidine compounds havi ng interesting pharmacological properties. It has been found that compounds of the formula (a) (see fig. I) wherein - A represents a heterocyclic group of 5-7 ring atoms wherein 1 - 3 hetero atoms from the group O, N and S are present, - R1 is hydrogen or fluoro, - R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2, - Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Zis carbon, - R3 and R4 independently are hydrogen or C1-4-alkyl, - n has the value 1 or 2, - R3 is 2-pyridyl, 3-pyridyl or 4-pyridyl substituted at the meta-position with respect to the methylene bridge with a group Y, and optionally substituted with (R6)q, - Y is phenyl, furanyl or thienyl, which groups may be substituted with 13 substituents of the group hydroxy, halogen, CF3, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl, - R6 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3 and salts thereof.

公开(公告)号：SK133198A3

公开(公告)日：1999-02-11

申请号：SK133198

申请日：1997-03-20

Applicant: DUPHAR INT RES

Inventor： FEENSTRA ROELOF W ,  KRUSE CORNELIS G ,  TULP MARTINUS T M ,  KUIPERS WILMA ,  LONG STEPHEN K

IPC: A61K31/00 ,  A61K31/34 ,  A61K31/343 ,  A61K31/357 ,  A61K31/42 ,  A61K31/423 ,  A61K31/44 ,  A61K31/495 ,  A61K31/496 ,  A61K31/535 ,  A61K31/55 ,  A61K31/551 ,  A61K31/5513 ,  A61P25/04 ,  A61P43/00 ,  C07D209/08 ,  C07D215/12 ,  C07D215/38 ,  C07D263/58 ,  C07D265/36 ,  C07D307/79 ,  C07D311/18 ,  C07D317/66 ,  C07D319/08 ,  C07D319/14 ,  C07D319/18 ,  C07D321/10 ,  C07D327/06 ,  C07D333/54 ,  C07D401/04 ,  C07D403/04 ,  C07D405/04 ,  C07D405/14 ,  C07D407/10 ,  C07D407/12 ,  C07D409/04 ,  C07D409/10 ,  C07D409/12 ,  C07D411/04 ,  C07D413/04 ,  C07D413/10 ,  C07D413/12 ,  C07D409/14 ,  A61K31/435

Abstract: The invention relates to a group of new piperazine and piperidine compounds having interesting pharmacological properties. It has been found that compounds of formula (a) wherein A represents a heterocyclic group of 5-7 ring atoms wherein 1-3 heteroatoms from the group O, N and S are present; R1 is hydrogen or fluoro; R2 is C1-4-alkyl, C1-4-alkoxy or an oxo group, and p is 0, 1 or 2; Z represents carbon or nitrogen, and the dotted line is a single bond when Z is nitrogen, and a single or double bond when Z is carbon; R3 and R4 independently are hydrogen or C1-4-alkyl; n has the value 1 or 2; R5 is halogen, hydroxy, C1-4-alkoxy or C1-4-alkyl, and q is 0, 1, 2 or 3; Y is phenyl, furanyl or thienyl, which groups may be substituted with 1-3 substituents of the group hydroxy, halogen, C1-4-alkoxy, C1-4-alkyl, cyano, aminocarbonyl, mono- or di-C1-4-alkylaminocarbonyl; and salts thereof show high affinity for both the dopamine D2 and serotonin 5-HT1A receptors.

公开(公告)号：CZ299774B6

公开(公告)日：2008-11-19

申请号：CZ20011657

申请日：1999-11-10

Applicant: DUPHAR INT RES

Inventor： FEENSTRA ROELOF W ,  VAN DER HEIJDEN JOHANNES A M ,  MOS JOHANNES ,  LONG STEPHEN K ,  VISSER GERBEN M ,  KRUSE CORNELIS G ,  VAN SCHARRENBURG GUSTAAF J M ,  TOOROP GERRIT P

IPC: C07D401/04 ,  A61K31/40 ,  A61K31/4164 ,  A61K31/42 ,  A61K31/423 ,  A61K31/425 ,  A61K31/4427 ,  A61K31/4439 ,  A61K31/496 ,  A61P25/00 ,  A61P25/16 ,  A61P25/22 ,  A61P25/24 ,  A61P25/28 ,  A61P43/00 ,  C07D209/34 ,  C07D211/68 ,  C07D235/26 ,  C07D241/04 ,  C07D263/58 ,  C07D277/68 ,  C07D413/04 ,  C07D417/04

Abstract: Deriváty piperazinu a piperidinu vzorce I, kde S.sub.1.n. je vodík, halogen C.sub.1-3.n.alkyl, CN, CF.sub.3.n., OCF.sub.3.n., SCF.sub.3.n., C.sub.1-3.n.alkoxy, aminoskupina nebo aminoskupina substituovaná mono- nebo di-C.sub.1-3.n.alkylem, nebo hydroxyl; X je NR.sub.3.n., S, CH.sub.2.n., O, SO neboSO.sub.2.n., kde R.sub.3.n. je H nebo C.sub.1-3.n.alkyl; ...Z je H nebo C.sub.1-3.n.alkyl nebo R.sub.1.n. a R.sub.2.n. mohou spolecne tvorit mustek obsahující 2 až 3 atomy uhlíku; R.sub.4.n. je vodíknebo C.sub.1-3.n.alkyl; Q je methyl, ethyl, ethylsubstituovaný jedním nebo více fluory, cyklopropylmethyl, poprípade substituovaný jedním nebo více fluory a jejich soli. Mají aktivitu zprostredkovanou jak cástecným agonismem vuci receptoru dopaminuD.sub.2.n., tak cástecným agonismem vuci receptoru serotoninu 5-HT.sub.1A.n.. Jejich použití pri lécbe CNS, úzkosti, deprese a Parkinsonovy choroby.

公开(公告)号：CA2246126C

公开(公告)日：2006-10-31

申请号：CA2246126

申请日：1998-08-28

Applicant: DUPHAR INT RES

Inventor： TULP MARTINUS T M ,  FEENSTRA ROELOF W ,  LONG STEPHEN K ,  KRUSE CORNELIS G ,  VISSER GERBEN M

IPC: C07D215/06 ,  C07D263/58 ,  A61K31/435 ,  A61K31/495 ,  A61K31/496 ,  A61K31/535 ,  A61K31/54 ,  A61K31/55 ,  A61P25/18 ,  A61P43/00 ,  C07D209/08 ,  C07D209/34 ,  C07D215/12 ,  C07D215/14 ,  C07D215/227 ,  C07D215/38 ,  C07D223/16 ,  C07D265/36 ,  C07D279/16 ,  C07D401/04 ,  C07D401/12 ,  C07D409/12 ,  C07D413/12 ,  C07D417/04

Abstract: The invention relates to a group of novel piperazine and piperidine derivatives having interesting pharmacological properties. The compounds have the general formula (a) (see formula I) wherein - R1 is hydrogen or fluoro, - R' is H or C1-4-alkyl, R2 is H, C1-4-alkyl or an oxo group, or R' and R2 together represent a bon d, - R" is H or C1-4-alkyl , and the dotted lines can represent a single or double bond; - p has the value 0-2, - Y represents C, O, N or S, - T represent N or C, - R3 and R4 independently are hydrogen or C1-4-alkyl, - n has the value 1 or 2, - Q is a group of the formula -CH2-C(R5R6)-Z-R7 wherein R5 and R6 represent H or C1-7alkyl, C1-3-alkylphenyl, Z represents -C(R6R9)-O-, -C(R8R9)-C(=O)-, - C(R8R9)-C (=NOR10)-, -NH-C(=O)- or -O-CH2-, wherein R8 - R10 represent H or C1-4-alkyl , and R7 is a 5- or 6-membered cyclic group, aromatic group or hetero-aromatic group, or the 1- or 2-adamantyl group, which group R7 can be substituted with O-C1-4-alkyl , CN, halogen or C-1-4-alkyl, with the proviso that R 7 cannot be 1-alkylcycloalkyl, and that compounds wherein Z is the group-NH-C(=0)- and R5=R6=H, T is nitrogen, and the bicylic group is 1,4- benzoxazin-8-yl, quinoxalin-5-yl, quinolin-5-yl, indol-4-yl, benzoxazol-7-yl, benzimidazol-4- yl, benzothiazol-7-yl are not included,and salts thereof. These compounds have high affinity for both the dopamine D2 receptors and serotonine 5-HT1A receptors.