公开(公告)号：WO03037891A8

公开(公告)日：2003-09-04

申请号：PCT/EP0212077

申请日：2002-10-29

Applicant: JANSSEN PHARMACEUTICA NV ,  FREYNE EDDY JEAN EDGARD ,  BUIJNSTERS PETER JACOBUS JOHAN ,  WILLEMS MARC ,  EMBRECHTS WERNER CONSTANT JOHA ,  LOVE CHRISTOPHER JOHN ,  JANSSEN PAUL ADRIAAN JAN ,  LEWI PAULUS JOANNES ,  HEERES JAN ,  DE JONGE MARC RENE ,  KOYMANS LUCIEN MARIA HENRICUS ,  VINKERS HENDRIK MAARTEN ,  VAN AKEN KOEN JEANNE ALFONS ,  DIELS GASTON STANISLAS MARCELL

Inventor： FREYNE EDDY JEAN EDGARD ,  BUIJNSTERS PETER JACOBUS JOHAN ,  WILLEMS MARC ,  EMBRECHTS WERNER CONSTANT JOHA ,  LOVE CHRISTOPHER JOHN ,  JANSSEN PAUL ADRIAAN JAN ,  LEWI PAULUS JOANNES ,  HEERES JAN ,  DE JONGE MARC RENE ,  KOYMANS LUCIEN MARIA HENRICUS ,  VINKERS HENDRIK MAARTEN ,  VAN AKEN KOEN JEANNE ALFONS ,  DIELS GASTON STANISLAS MARCELL

IPC: A61K31/435 ,  A61K31/4406 ,  A61K31/50 ,  A61K31/501 ,  A61K31/505 ,  A61K31/506 ,  A61K31/5377 ,  A61P3/10 ,  A61P17/00 ,  A61P21/04 ,  A61P25/00 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/24 ,  A61P25/28 ,  A61P29/00 ,  A61P31/18 ,  A61P35/00 ,  A61P35/02 ,  C07D213/53 ,  C07D213/74 ,  C07D239/42 ,  C07D239/48 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D417/12

CPC classification number: C07D213/74 ,  C07D239/42 ,  C07D239/48 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D417/12

Abstract: This invention concerns a compound of formula (I), a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A is a 6-membered heterocycle; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl; optionally substituted C1-6alkyloxy C1-6alkylcarbonyl; X is a direct bond or a linker atom or group; Z is a direct bond or a linker atom or group; R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, a carbocycle or a heterocycle, each of said groups may optionally be substituted; R3 is hydrogen; hydroxy; halo; optionally substituted C1-6alkyl or C1-6alkenyl or C2-6alkynyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C1-6alkyl)amino; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; polyhaloC1-6alkylthio; R21; R21-C1-6alkyl; R21-O-; R21-S-; R21-C(=0)-; R21-S(=0)p-; R7-S =O R7-S(=O)p-NH-; R21-S(=O)p-NH-; R7-C(=0)-; -NHC(=0)H; -C(=O)NHNH2; R7-C(=O)-NH-; R21-C(=O)-NH-; -C(=NH)R7; -C(=NH)R21; R° is an optionally substituted heterocycle provided that -X-R2 and/or R3 is other than hydrogen;their use, pharmaceutical compositions comprising them and processes for their preparation.

Abstract translation: 本发明涉及式（I）化合物，N-氧化物，药学上可接受的加成盐，季胺及其立体化学异构形式，其中环A为6-元杂环; R1是氢; 芳基; 甲酰基; C1-6烷基; 任选取代的C 1-6烷基; C1-6alkyloxycarbonyl; 任选取代的C 1-6烷氧基C 1-6烷基羰基; X是直接键或连接原子或基团; Z是直接键或连接原子或基团; R 2是氢，C 1-10烷基，C 2-10烯基，C 2-10炔基，碳环或杂环，所述基团中的每一个可任选被取代; R3是氢; 羟基; 光环; 任选取代的C 1-6烷基或C 1-6烯基或C 2-6炔基; C1-6烷; C 1-6烷; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy; 羧基; 氰基; 硝基; 氨基; 单或二（C 1-6烷基）氨基; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; polyhaloC1-6alkylthio; R21; R21-C 1-6烷基; R21-O-; R21-S-; R21-C（= O） - ; R21-S（= O）p - ; R7-S = O R7-S（= O）p-NH-; R21-S（= O）P-NH-; R7-C（= O） - ; -NHC（= O）H; -C（= O）NHNH 2; R7-C（= O）-NH-; R21-C（= O）-NH-; -C（= NH）R 7; -C（= NH）R 21; R°是任选取代的杂环，条件是-X-R 2和/或R 3不是氢;它们的用途，包含它们的药物组合物及其制备方法。

公开(公告)号：EP0206415A2

公开(公告)日：1986-12-30

申请号：EP86201048

申请日：1986-06-17

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： JANSSENS FRANS EDUARD ,  DIELS GASTON STANISLAS MARCELL

IPC: C07D211/58 ,  A61K31/4188 ,  A61K31/4523 ,  A61K31/52 ,  A61P37/08 ,  A61P43/00 ,  C07D333/00 ,  C07D401/06 ,  C07D401/12 ,  C07D405/12 ,  C07D405/14 ,  C07D409/06 ,  C07D473/00 ,  C07D473/30 ,  C07D473/40 ,  C07D498/04 ,  C07D513/04 ,  C07D519/00

CPC classification number: C07D473/30 ,  C07D473/00 ,  C07D473/40

Abstract: Novel (4-piperidinylmethyl and hetero)purines of formula … … wherein -A =A -A =A - is -N=CH-N=CH- or -CH=N-CH=N- and L is a radical L -CrH2r-T-CsH2s- or … … the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.

Abstract translation: 其中-A 1 = A 2 -A 3 = A 4是-N = CH-N = CH-或 - （CH 2） CH = N-CH = N-，L是自由基L 1 -Cr H 2r-T-C c H 2 ......或其药学上可接受的酸加成盐及其可能的立体化学异构形式，该化合物是抗过敏剂 ; 含有作为活性成分的化合物的药物组合物和制备所述化合物和药物组合物的方法。

公开(公告)号：EA009217B1

公开(公告)日：2007-12-28

申请号：EA200500616

申请日：2003-10-07

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： JANSSEN FRANS EDUARD ,  SOMMEN FRANCOIS MARIA ,  DE BOECK BENOIT CHRISTIAN ALBE ,  LEENAERTS JOSEPH ELISABETH ,  VAN ROOSBROECK YVES EMIEL MARIA ,  DIELS GASTON STANISLAS MARCELL

IPC: C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04

Abstract: Данноеизобретениеотноситсяк замещеннымпроизводным 1,4-дипиперидин-4-илпиперазина, которыеявляютсяантагонистаминейрокининов, вчастностиантагонистами NK-рецепторов, кихполучению, композициям, содержащимуказанныесоединения, атакжек применениюихв качествелекарственныхсредств, вчастности, длялечениярвоты, состояниятревоги, депрессии, панкреатитаи IBS (синдромраздраженногокишечника). Соединенияданногоизобретениямогутбытьпредставленыобщейформулой (I), включающейтакжеихфармацевтическиприемлемыекислотно- илиосновно-аддитивныесоли, ихстереохимическиизомерныеформы, их N-оксиднуюформуи ихпролекарства, гдевсезаместителипринимаютзначения, определенныев формулеизобретения. Сучетомихспособностипротивостоятьвоздействиямнейрокининовпутемблокированиянейрокининовыхрецепторови, вособенности, антагонизированиявоздействиявещества P черезблокирование NK-рецептора, соединенияданногоизобретенияявляютсяполезнымив качествелекарственныхсредств, особеннодляпрофилактикии терапевтическоголечениянейрокинин-опосредованныхсостояний, такихкак, например, расстройстваЦНС, вчастностидепрессия, состояниятревоги, расстройства, связанныесострессом, бессонница, расстройствапознавательнойспособности, расстройстваличности, шизоаффективныерасстройства, расстройствапитания, нейродегенеративныезаболевания, наркологическиерасстройства, нарушениянастроения, сексуальнаядисфункция, больи другиесвязанныес ЦНСсостояния; воспаление; аллергическиереакции; рвота; желудочно-кишечныерасстройства, вчастностисиндромраздраженногокишечника (IBS); поражениякожи;

公开(公告)号：NO20070878L

公开(公告)日：2007-02-16

申请号：NO20070878

申请日：2007-02-16

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： LOMMEN GUY ROSALIA EUGENE VAN ,  DIELS GASTON STANISLAS MARCELL ,  CIK MIROSLAV

IPC: C07D211/16 ,  C07D211/40 ,  C07D211/96 ,  C07D401/04 ,  C07D413/06 ,  C07D417/12

Abstract: the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is 0, 1 or 2; R 2 represents hydroxy; -X- represents C 2-4 alkynyl, C 1-12 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula wherein; -X 1 - represents C 1-12 alkyl, phenyl or a divalent radical selected from the group consisting of -X 2 - represents C 1-12 alkyl, C 1-4 alkyloxyC 1-4 alkyl, phenyl or a divalent radical of formula -X 3 - represents phenyl or a divalent radical selected from the group consisting of R 1 independently represents hydrogen, C 1-4 alkyl, C 1-4 alkyloxy-, Ar 1 , Ar 2 -carbonyl, Het 1 -C 1-4 alkyl, Het 2 , NR 3 R 4 -C 1-4 alkyl, Ar 3 -C 1-4 alkyloxy- or Het 4 -oxy-; R 3 and R 4 each independently represents hydrogen, C 1-4 alkyl, C 1-4 alkyloxy-, or Het 3 ; Het 1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl, thiazolyl, pyridinyl, or thiadiazolyl wherein said Het 1 is optionally substituted with one or where possible two or more substituents selected from the group consisting of hydroxy, halo, C 1-4 alkyloxycarbonyl-, C 1-4 alkyl-, C 1-4 alkyloxy- and C 1-4 alkyloxy-substituted with halo; in particular Het 1 represents a heterocycle selected from indolyl or pyridinyl; Het 2 represents a heterocycle selected from indolyl, benzisoxazolyl or oxodiazolyl wherein said Het 2 is optionally substituted with one or where possible two or more substituents selected from the group consisting of hydroxy, halo, C 1-6 alkyl- and C 1-4 alkyloxy-; Het 3 represents a heterocycle selected from benzimidazolyl, benzisoxazolyl or benzthiazolyl wherein said Het 3 is optionally substituted with one or where possible two or more substituents selected from the group consisting of hydroxy, halo, C 1-6 alkyl- and C 1-4 alkyloxy-; in particular Het 3 represents benzthiazolyl substituted with C 1-4 alkyloxy-; Het 4 represents a heterocycle selected from benzimidazolyl, benzisoxazolyl or benzthiazolyl wherein said Het 4 is optionally substituted with one or where possible two or more substituents selected from the group consisting of hydroxy, halo, C 1-6 alkyl- and C 1-4 alkyloxy-; in particular Het 4 represents benzthiazolyl; Ar 1 represents phenyl optionally substituted with halo, C 1-4 alkyl or C 1-4 alkyl substituted with one, two or three halo substituents; Ar 2 represents phenyl optionally substituted with halo, C 1-4 alkyl or C 1-4 alkyl substituted with one, two or three halo substituents; in particular Ar 2 represents phenyl substituted with halo or trifluromethyl; Ar 3 represents phenyl optionally substituted with halo, C 1-4 alkyl or C 1-4 alkyloxy-.

公开(公告)号：NZ539848A

公开(公告)日：2006-06-30

申请号：NZ53984803

申请日：2003-10-07

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： JANSSENS FRANS EDUARD ,  SOMMEN FRANCOIS MARIA ,  DE BOECK BENOIT CHRISTIAN ALBE ,  LEENAERTS JOSEPH ELISABETH ,  VAN ROOSBROECK YVES EMIEL MARI ,  DIELS GASTON STANISLAS MARCELL

IPC: C07D20060101 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  A61K31/435 ,  A61P25/00

Abstract: Disclosed are compounds of formula (I) wherein the substituents are defined in the specification. Compounds of formula (I) are useful in the treatment of neurokinin mediated conditions such as emesis, depression, anxiety disorders, pain, pancreatitis, micturition disorders, irritable bowel syndrome (IBS) or overactive bladder.

公开(公告)号：BRPI0410714A

公开(公告)日：2006-06-13

申请号：BRPI0410714

申请日：2004-05-25

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： FREYNE EDDY JEAN EDGARD ,  PERERA TIMOTHY PIETRO SUREN ,  BUIJNSTERS PETER JACOBUS JOHAN ,  WILLEMS MARC ,  DIELS GASTON STANISLAS MARCELL ,  EMBRECHTS WERNER CONSTANT JOHA ,  HOLTE PETER TEN ,  SCHULTZ-FADEMRECHT CARSTEN ,  ROMBOUTS FREDERIK JAN RITA

IPC: A61K31/529 ,  A61P35/00 ,  C07D239/88 ,  C07D239/93 ,  C07D239/94 ,  C07D498/08

Abstract: The present invention concerns the compounds of formula the N -oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein Z represents NH; Y represents -C 3-9 alkyl-, -C 2-9 alkenyl-, -C 3-7 alkyl-CO-NH optionally substituted with amino, mono - or di(C 1-4 alkyl)amino or C 1-4 alkyloxycarbonylamino-, -C 3-7 alkenyl-CO-NH- optionally substituted with amino, mono- or di(C 1- 4 alkyl)amino- or C 1-4 alkyloxycarbonylamino-, C 1-5 alkyl-NR 13 -C 1-5 alkyl-, -C 1-5 alkyl-NR 14 -CO-C 1-5 alkyl-, -C 1-6 alkyl-CO-NH-, -C 1-5 alkyl-CO NR 15 -C 1-5 alkyl-, -C 1-3 alkyl-NH-CO-Het 20 -, -C 1-2 alkyl-CO-Het 21 -CO-, -C 1-2 alkyl-NH-CO-CR 16 R 17 -NH-, -C 1-2 alkyl-CO-NH-CR 18 R 19 -CO-, -C 1-2 alkyl-CO-NR 20 -C 1-3 alkyl-CO-, or -NR 22 -CO-C 1-3 alkyl-NH-; X 1 represents a direct bond, O or-O-C 1-2 alkyl-; X 2 represents a direct bond, -CO-C 1- 2 alkyl-, NR 12 , -NR 12 -C 1-2 alkyl-, -O-N=CH- or -C 1-2 alkyl-; R 1 and R 2 each independently represents hydrogen or halo; R 3 represents hydrogen; R 4 represents hydrogen or C 1-4 alkyloxy; R 12 and R 13 each independently represents hydrogen or C 1-4 alkyl; R 14 and R 15 represents hydrogen; R 16 and R 17 each independently represent hydrogen or C 1-4 alkyl; R 18 and R 19 each independently represent hydrogen or C 1-4 alkyl optionally substituted with phenyl or hydroxy; R 20 and R 21 each independently represent hydrogen or C 1-4 alkyl optionally substituted with C 1-4 alkyloxy; Het 20 , Het 21 and Het 22 each independently represent a heterocycle selected from the group consisting pyrrolidinyl, 2-pyrrolidinonyl or piperidinyl optionally substituted with hydroxy.

公开(公告)号：CO5640038A2

公开(公告)日：2006-05-31

申请号：CO05119403

申请日：2005-11-24

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： JEAN EDGARD FREYNE EDDY ,  PERERA TIMOTHY PIETYRO SUREN ,  BUIJNSTERS PETER JACOBUS JOHANNES ANTONIUS ,  WILLEMS MARC ,  DIELS GASTON STANISLAS MARCELL ,  EMBRECHTS WERNER CONSTANT JOHAN ,  TEN HOLTE PETER ,  ROMBOUTS FREDERICK JAN RITA ,  SCHULTZ FADEMRECHT CARSTEN

IPC: A61K31/529 ,  A61P35/00 ,  C07D239/88 ,  C07D239/93 ,  C07D239/94 ,  C07D498/08

Abstract: 1.- Un compuesto que posee la fórmulalas formas N-óxidos, las sales de adición aceptables para uso farmacéutico y las formas estereoquímicamente isómeras del mismo, donde:Z representa O, CH2, NH o S; en particular Z representa NH;Y representa -alquilo C3-C9-, -alquenilo C3-C9-, -alquinilo C3-C9-, -alquilo C3-C7-CO-NH- sustituido en forma optativa con amino, mono- o di(alquil C1-4)amino o alquiloxicarbonilamino C1-4-, -alquenil-C3-7-CO-NH- opcionalmente sustituido con amino, mono- o di(alquil C1-4)amino o alquiloxicarbonilamino C1-4-, -alquinil-C3-7-CO-NH- opcionalmente sustituido con amino, mono- o di(alquil C1-4)amino o alquiloxicarbonilamino C1-4-, -alquiloxi-C1-5- alquilo C1-5-, -alquil-C1-5-NR13-alquilo C1-5, -alquil-C1-5-NR14-CO-alquilo C1-5, -alquil-C1-5-CO-NR15-alquilo C1-5-, -alquil-C1-6-CO-NH-, -alquil-C1-6-NH-CO-, -aIquil-C1-3-NH-CS-Het20-, -alquil-C1-3-NH-CO-Het20-, -alquil-C1-2-CO-Het21-CO-, -Het22-CH2-CO-NH-alquilo C1-3-, -CO-NH-alquilo C1-6-, -NH-CO-alquilo C1-6-, -CO-alquilo C1-7, -alquil-C1-7-CO-, -alquil-C1-6-CO-alquilo C1-6-, -alquil-C1-2-NH-CO-CR16R17-NH-, -alquil-C1-2-CO-NH-CR18R19-CO-, -alquil-C1-2-CO-NR20-alquil-C1-3-CO-, -alquil-C1-2-NR21-CH2-CO-NH-alquilo C1-3- o -NR22-CO-alquil-C1-3-NH-;X1 representa una unión directa, O, -O-alquil-C1-2-, CO, -CO-alquilo C1-2-, NR11, -NR11-alquilo C1-2-, -CH2-, -O-N=CH- o -alquilo C1-2-;X2 representa una unión directa, O, -O-alquilo C1-2-, CO, -CO-alquilo C1-2-, NR12, -NR12-alquilo C1-2-, -CH2-, -O-N=CH- o -alquilo C1-2-;R1 representa hidrógeno, ciano, halo, hidroxi, formilo, alcoxi C1-6-, alquilo C1-6-, halo-fenil-carbonilamino-, alcoxi C1-6- sustituido con halo, ...

公开(公告)号：IS8077A

公开(公告)日：2005-10-14

申请号：IS8077

申请日：2005-10-14

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： FREYNE EDDY JEAN EDGARD ,  PERERA TIMOTHY PIETRO SUREN ,  ROMBOUTS FREDERIK JAN RITA ,  BUIJNSTERS PETER JACOBUS JOHAN ,  WILLEMS MARC ,  DIELS GASTON STANISLAS MARCELL ,  EMBRECHTS WERNER CONSTANT JOHA ,  HOLTE PETER TEN ,  SCHULTZ-FADEMRECHT CARSTEN

IPC: A61K31/529 ,  A61P35/00 ,  C07D239/88 ,  C07D239/93 ,  C07D239/94 ,  C07D498/08

公开(公告)号：NO20052192D0

公开(公告)日：2005-05-04

申请号：NO20052192

申请日：2005-05-04

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： DIELS GASTON STANISLAS MARCELL ,  ROOSBROECK YVES EMIEL MARIA VA ,  JANSSENS FRANS EDUARD ,  LEENAERTS JOSEPH ELISABETH ,  SOMMEN FRANCOIS MARIA ,  BOECK BENOIT CHRISTIAN ALBERT

IPC: C07D20060101 ,  C07D211/58 ,  C07D401/14 ,  C07D405/14 ,  C07D409/14 ,  C07D413/14 ,  C07D417/14 ,  C07D471/04 ,  C07D

公开(公告)号：PL369259A1

公开(公告)日：2005-04-18

申请号：PL36925902

申请日：2002-10-29

Applicant: JANSSEN PHARMACEUTICA NV

Inventor： FREYNE EDDY JEAN EDGARD ,  BUIJNSTERS PETER JACOBUS JOHAN ,  WILLEMS MARC ,  EMBRECHTS WERNER CONSTANT JOHA ,  LOVE CHRISTOPHER JOHN ,  JANSSEN PAUL ADRIAAN JAN ,  LEWI PAULUS JOANNES ,  HEERES JAN ,  DE JONGE MARC RENE ,  KOYMANS LUCIEN MARIA HENRICUS ,  VINKERS HENDRIK MAARTEN ,  VAN AKEN KOEN JEANNE ALFONS ,  DIELS GASTON STANISLAS MARCELL

IPC: A61K31/435 ,  A61K31/4406 ,  A61K31/50 ,  A61K31/501 ,  A61K31/505 ,  A61K31/506 ,  A61K31/5377 ,  A61P3/10 ,  A61P17/00 ,  A61P21/04 ,  A61P25/00 ,  A61P25/04 ,  A61P25/16 ,  A61P25/18 ,  A61P25/24 ,  A61P25/28 ,  A61P29/00 ,  A61P31/18 ,  A61P35/00 ,  A61P35/02 ,  C07D213/53 ,  C07D213/74 ,  C07D239/42 ,  C07D239/48 ,  C07D401/04 ,  C07D401/12 ,  C07D403/04 ,  C07D403/12 ,  C07D405/12 ,  C07D409/12 ,  C07D417/12

Abstract: This invention concerns a compound of formula a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein ring A is a 6-membered heterocycle; R1 is hydrogen; aryl; formyl; C1-6alkylcarbonyl; optionally substituted C1-6alkyl; C1-6alkyloxycarbonyl; optionally substituted C1-6alkyloxyC1-6alkylcarbonyl; X is a direct bond or a linker atom or group; Z is a direct bond or a linker atom or group; R2 is hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, a carbocycle or a heterocycle, each of said groups may optionally be substituted; R3 is hydrogen; hydroxy; halo; optionally substituted C1-6alkyl or C2-6alkenyl or C2-6alkynyl; C1-6alkyloxy; C1-6alkylthio; C1-6alkyloxycarbonyl; C1-6alkylcarbonyloxy; carboxyl; cyano; nitro; amino; mono- or di(C1-6alkyl)amino; polyhaloC1-6alkyl; polyhaloC1-6alkyloxy; polyhaloC1-6alkylthio; R21; R21-C1-6alkyl; R21-O-; R21-S-; R21-C(-O)-; R21-S(-O)p-; R7-S(-O)p-; R7-S(-O)p-NH-; R21-S(-O)p-NH-; R7-C(-O)-; -NHC(-O)H; -C(-O)NHNH2; R7-C(-O)-NH-; R21-C(-O)-NH-; -C(-NH)R7-C(-NH)R21; R4 is an optionally substituted heterocycle provided that -X-R2 and/or R3 is other than hydrogen; their use, pharmaceutical compositions comprising them and processes for their preparation.