公开(公告)号：US06194405B1

公开(公告)日：2001-02-27

申请号：US09533625

申请日：2000-03-22

申请人： Pilar Gil-Lopetegui ,  Francisco Javier Fernández-Gadea ,  Theo Frans Meert

发明人： Pilar Gil-Lopetegui ,  Francisco Javier Fernández-Gadea ,  Theo Frans Meert

IPC分类号： A01N4346

CPC分类号： C07D493/04 ,  C07D307/93

摘要： This invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, wherein n is zero to 6; p and q are zero to 4; r is zero to 5; R1 and R2 each independently are hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; halomethylcarbonyl; or R1 and R2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; each R3 and R4 independently are halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, aminosulfonyl, mono- or di(C1-6alkyl)aminosulfonyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; each R5 independently is C1-6alkyl, cyano or halomethyl; X is CR6R7, NR8, O, S, S(═O) or S(═O)2; aryl is optionally substituted phenyl; provided that the compound is other than (±)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]-furan-2-methanamine oxalic acid. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

摘要翻译： 本发明涉及式（I）化合物，N-氧化物形式，其药学上可接受的加成盐和立体异构形式，其中n为0-6; p和q为零至4; r为0〜5; R1和R2各自独立地为氢; 任选取代的C 1-6烷基; C 1-6烷基羰基; 卤代甲基羰基; 或者R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; 每个R 3和R 4独立地是卤素，氰基，羟基，卤代甲基，卤代甲氧基，羧基，硝基，氨基，单或二（C 1-6烷基）氨基，C 1-6烷基羰基氨基，氨基磺酰基，一或二（C 1-6烷基）氨基磺酰基， C 1-6烷基，C 1-6烷氧基，C 1-6烷基羰基，C 1-6烷氧基羰基; 每个R 5独立地是C 1-6烷基，氰基或卤代甲基; X是CR 6 R 7，NR 8，O，S，S（= O）或S（= O）2; 芳基是任选取代的苯基; 条件是该化合物不是（±）-3,3a，8,12b-四氢-N-甲基-2H-二苯并[3,4：6,7] - 环庚并[1,2-b] - 呋喃-2-基 - 草胺草酸。 式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

公开(公告)号：US06288058B1

公开(公告)日：2001-09-11

申请号：US09745517

申请日：2000-12-21

申请人： Pilar Gil-Lopetegui ,  Francisco Javier Fernández-Gadea ,  Theo Frans Meert

发明人： Pilar Gil-Lopetegui ,  Francisco Javier Fernández-Gadea ,  Theo Frans Meert

IPC分类号： A61K63155

CPC分类号： C07D493/04 ,  C07D307/93

摘要： This invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, wherein n is zero to 6; p and q are zero to 4; r is zero to 5; R1 and R2 each independently are hydrogen; optionally substituted C1-6alkyl; C1-6alkylcarbonyl; halomethylcarbonyl; or R1 and R2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; each R3 and R4 independently are halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C1-6alkyl)amino, C1-6alkylcarbonylamino, aminosulfonyl, mono- or di(C1-6alkyl)aminosulfonyl, C1-6alkyl, C1-6alkyloxy, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl; each R5 independently is C1-6alkyl, cyano or halomethyl; X is CR6R7, NR8, O, S, S(═O) or S(═O)2; aryl is optionally substituted phenyl; provided that the compound is other than (±)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]-furan-2-methanamine oxalic acid. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

摘要翻译： 本发明涉及式（I）化合物，N-氧化物形式，其药学上可接受的加成盐和立体异构形式，其中n为0-6; p和q为零至4; r为0〜5; R1和R2各自独立地为氢; 任选取代的C 1-6烷基; C 1-6烷基羰基; 卤代甲基羰基; 或者R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; 每个R 3和R 4独立地是卤素，氰基，羟基，卤代甲基，卤代甲氧基，羧基，硝基，氨基，单或二（C 1-6烷基）氨基，C 1-6烷基羰基氨基，氨基磺酰基，一或二（C 1-6烷基）氨基磺酰基， C 1-6烷基，C 1-6烷氧基，C 1-6烷基羰基，C 1-6烷氧基羰基; 每个R 5独立地是C 1-6烷基，氰基或卤代甲基; X是CR 6 R 7，NR 8，O，S，S（= O）或S（= O）2; 芳基是任选取代的苯基; 条件是该化合物不是（±）-3,3a，8,12b-四氢-N-甲基-2H-二苯并[3,4：6,7] - 环庚并[1,2-b] - 呋喃-2-基 - 草胺草酸。 式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

公开(公告)号：US07282508B2

公开(公告)日：2007-10-16

申请号：US10491379

申请日：2002-10-10

申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Antonio Gómez-Sánchez ,  Theo Frans Meert

发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Antonio Gómez-Sánchez ,  Theo Frans Meert

IPC分类号： A61K31/445 ,  C07D401/00

CPC分类号： C07D401/04 ,  C07D401/14 ,  C07D413/14 ,  C07D417/14

摘要： The present invention relates to novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof and the N-oxide forms thereof. In particular are claimed compounds according to Formula (I) in which A═B is C═O or SO2, X is a covalent bond, R1 is alkyloxy, alkyloxyalkyl, Ar or NR9R10, wherein R9 and R10 each independently are hydrogen or Ar; or A═B and R1 together form a benzoxazolyl radical; p is zero, R3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R4 and R5 each are hydrogen. The invention also relates to processes for the preparation of the compounds according to the invention and their use in medicine, in particular as selective non-peptide δ-opioid agonists for use in the treatment of various pain conditions.

摘要翻译： 本发明涉及式（I）的新的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构形式，其互变异构体 及其N-氧化物形式。 特别是根据式（I）的化合物，其中AB是CO或SO 2，X是共价键，R 1是烷氧基，烷氧基烷基，Ar或NR 其中R 9和R 10各自独立地是氢或Ar;其中R 9和R 10各自独立地是氢或Ar; 或A-B和R 1一起形成苯并恶唑基; p为0，R 3为任选被羟基，烷基或烷氧基羰基取代的苄基，R 4和R 5各自为氢。 本发明还涉及根据本发明的化合物的制备方法及其在医学中的用途，特别是用于治疗各种疼痛病症的选择性非肽δ-阿片样物质激动剂。

公开(公告)号：US07390822B2

公开(公告)日：2008-06-24

申请号：US10492778

申请日：2002-10-10

申请人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Paul Joannes Ludovicus Herijgers ,  Theo Frans Meert ,  Antonio Gómez-Sánchez ,  Willem Flameng ,  Marcel J. M. Borgers

发明人： Frans Eduard Janssens ,  Joseph Elisabeth Leenaerts ,  Francisco Javier Fernández-Gadea ,  Paul Joannes Ludovicus Herijgers ,  Theo Frans Meert ,  Antonio Gómez-Sánchez ,  Willem Flameng ,  Marcel J. M. Borgers

IPC分类号： A61K31/445 ,  A61K31/454

CPC分类号： A61K31/454

摘要： The present invention relates to an agent for reducing ischaemic damage to an organ, in particular to a heart and a brain, pharmaceutical compositions comprising said agent and the use of said agent for the treatment of ischaemic diseases to the heart and the brain. The agent comprises a substituted 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivative according to Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the tautomeric forms thereof, the N-oxide forms thereof and the prodrugs thereof. In particular are claimed the compounds according to Formula (I) in which A=B is C═O or SO2, X is a covalent bond, R1 is alkyloxy, alkyloxyalkyl, Ar or NR9R10, wherein R9 and R10 each independently are hydrogen or Ar; or A=B and R1 together form a benzoxazolyl radical; p is zero, R3 is benzyl optionally substituted with hydroxy, alkyl or alkyloxycarbonyl and R4 and R5 each are hydrogen. The use of said agents has important clinical ramifications with regard to the reduction of ischaemic damage to an organ in a mammal, in particular to a heart and/or a brain, the prevention of coronary artery diseases in a mammal by inducing a cardioprotective effect and the treatment and prevention of stroke.

摘要翻译： 本发明涉及用于减轻对器官特别是心脏和脑的缺血性损伤的药剂，包含所述药物的药物组合物和所述药物用于治疗心脏和脑部的缺血性疾病的用途。 该试剂包含根据式（I）的取代的4-苯基-4- [1H-咪唑-2-基] - 哌啶衍生物，其药学上可接受的酸或碱加成盐，其立体化学异构形式，其互变异构形式， 其N-氧化物形式及其前药。 特别要求保护的是根据式（I）的化合物，其中A = B是CO或SO 2，X是共价键，R 1是烷氧基，烷氧基烷基， Ar或NR 9 R 10，其中R 9和R 10各自独立地为氢或Ar; 或A = B和R 1一起形成苯并恶唑基; p为0，R 3为任选被羟基，烷基或烷氧基羰基取代的苄基，R 4和R 5各自为氢。 所述试剂的使用对于减少对哺乳动物，特别是心脏和/或脑的器官的缺血损伤，通过诱导心脏保护作用来预防哺乳动物的冠状动脉疾病，具有重要的临床后果，以及 治疗和预防中风。

公开(公告)号：US6057441A

公开(公告)日：2000-05-02

申请号：US155840

申请日：1998-10-06

申请人： Pilar Gil-Lopetegui ,  Francisco Javier Fernandez-Gadea ,  Theo Frans Meert

发明人： Pilar Gil-Lopetegui ,  Francisco Javier Fernandez-Gadea ,  Theo Frans Meert

IPC分类号： A61K31/00 ,  A61K31/34 ,  A61K31/343 ,  A61K31/4025 ,  A61K31/4035 ,  A61K31/443 ,  A61K31/445 ,  A61K31/4465 ,  A61K31/4523 ,  A61K31/4525 ,  A61K31/495 ,  A61K31/496 ,  A61K31/535 ,  A61K31/5375 ,  A61K31/5377 ,  A61K31/55 ,  A61P1/00 ,  A61P1/14 ,  A61P9/00 ,  A61P9/02 ,  A61P25/06 ,  A61P25/18 ,  A61P25/22 ,  A61P25/24 ,  A61P25/30 ,  C07D307/93 ,  C07D405/02 ,  C07D405/06 ,  C07D491/048 ,  C07D493/04 ,  C07D493/10 ,  C07D495/04 ,  C07D223/14 ,  C07D211/08 ,  C07D313/00 ,  C07D337/12 ,  C07D405/00

CPC分类号： C07D493/04 ,  C07D307/93

摘要： This invention concerns the compounds of formula (I), ##STR1## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereoisomeric forms thereof, wherein n is zero to 6; p and q are zero to 4; r is zero to 5; R.sup.1 and R.sup.2 each independently are hydrogen; optionally substituted C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; halomethylcarbonyl; or R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; each R.sup.3 and R.sup.4 independently are halo, cyano, hydroxy, halomethyl, halomethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6 alkyl)aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl; each R.sup.5 independently is C.sub.1-6 alkyl, cyano or halomethyl; X is CR.sup.6 R.sup.7, NR.sup.8, O, S, S(.dbd.O) or S(.dbd.O).sub.2 ; aryl is optionally substituted phenyl; provided that the compound is other than (.+-.)-3,3a,8,12b-tetrahydro-N-methyl-2H-dibenzo[3,4:6,7]-cyclohepta[1,2-b]-furan-2-methanamine oxalic acid. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

摘要翻译： PCT No.PCT / EP97 / 01829 Sec。 371 1998年10月6日第 102（e）日期1998年10月6日PCT 1997年4月9日PCT公布。 公开号WO97 / 38991 日期1997年10月23日本发明涉及式（I）化合物，N-氧化物形式，其药学上可接受的加成盐及其立体异构形式，其中n为0-6; p和q为零至4; r为0〜5; R1和R2各自独立地为氢; 任选取代的C 1-6烷基; C 1-6烷基羰基; 卤代甲基羰基; 或者R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; 每个R 3和R 4独立地是卤素，氰基，羟基，卤代甲基，卤代甲氧基，羧基，硝基，氨基，单或二（C 1-6烷基）氨基，C 1-6烷基羰基氨基，氨基磺酰基，一或二（C 1-6烷基）氨基磺酰基， C 1-6烷基，C 1-6烷氧基，C 1-6烷基羰基，C 1-6烷氧基羰基; 每个R 5独立地是C 1-6烷基，氰基或卤代甲基; X是CR 6 R 7，NR 8，O，S，S（= O）或S（= O）2; 芳基是任选取代的苯基; 条件是该化合物不是（+/-） - 3,3a，8,12b-四氢-N-甲基-2H-二苯并[3,4：6,7] - 环庚并[1,2-b]呋喃 -2-甲胺草酸。 式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

公开(公告)号：US20080070924A1

公开(公告)日：2008-03-20

申请号：US10560482

申请日：2004-06-07

申请人： Frans Eduard Janssens ,  Francois Maria Sommen ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck ,  Theo Frans Meert

发明人： Frans Eduard Janssens ,  Francois Maria Sommen ,  Joseph Elisabeth Leenaerts ,  Yves Emiel Maria Van Roosbroeck ,  Theo Frans Meert

IPC分类号： A61K31/496 ,  A61P25/04

CPC分类号： A61K31/4468 ,  A61K31/485 ,  A61K31/496 ,  A61K2300/00

摘要： This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and 1-(1,2-disubstituted piperidinyl)-4-substituted piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity the use of said formulation for the manufacture of a medicament for the prevention and/or treatment of emesis, pain and/or nociception, in particular in acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments and the use of an NK1-receptor antagonist for the manufacture of a medicament for the prevention and/or treatment of respiratory depression and tolerance in opioid-based treatments of pain.The pharmaceutical formulations according to the invention comprise NK1-antagonists according to the general Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1.The pharmaceutical composition according to the invention reduces to a large extent a number of unwanted side-effects associated with opioid analgesics, in particular respiratory depression and tolerance, thereby increasing the total tolerability of said opioids in pain treatment.

摘要翻译： 本发明涉及用于基于阿片样物质治疗疼痛和/或伤害感受的新型制剂，其包含阿片样镇痛药和具有神经激肽拮抗活性的1-（1,2-二取代哌啶基）-4-取代的哌嗪衍生物，特别是NK < 所述制剂用于制备用于预防和/或治疗呕吐，疼痛和/或伤害感受的药物，特别是在急性和慢性疼痛治疗中，特别是在炎性，术后， 急诊室（ER），突破性，神经病理性和癌症疼痛治疗，以及使用NK1受体拮抗剂制备用于预防和/或治疗阿片样物质的呼吸抑制和耐受性的药物 的治疗疼痛。 根据本发明的药物制剂包含根据通式（I）的NK 1 - 拮抗剂，其药学上可接受的酸或碱加成盐，其立体化学异构形式，其N-氧化物形式和 其中所有取代基如权利要求1中所定义。根据本发明的药物组合物在很大程度上降低了与阿片类镇痛药相关的许多不想要的副作用，特别是呼吸抑制和耐受性，从而增加了 所述阿片类药物在疼痛治疗中。

公开(公告)号：US5773433A

公开(公告)日：1998-06-30

申请号：US817989

申请日：1997-04-25

申请人： Francisco Javier Fernandez-Gadea ,  Victor Karel Sipido ,  Jose Ignacio Andres-Gil ,  Theo Frans Meert

发明人： Francisco Javier Fernandez-Gadea ,  Victor Karel Sipido ,  Jose Ignacio Andres-Gil ,  Theo Frans Meert

IPC分类号： A61K31/535 ,  A61K31/55 ,  A61K31/553 ,  A61K31/554 ,  A61P9/00 ,  A61P25/00 ,  A61P25/18 ,  A61P25/24 ,  A61P25/26 ,  C07D261/20 ,  C07D267/16 ,  C07D498/04 ,  C07D513/04

CPC分类号： C07D513/04

摘要： This invention concerns the compounds of formula (I), the pharmaceutically acceptable salts and stereoisomeric forms thereof, and also the N-oxide forms thereof. ##STR1## wherein: R.sup.1 and R.sup.2 each independently are hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkylcarbonyl; trihalomethylcarbonyl; C.sub.1-6 alkyl substituted with hydroxy, C.sub.1-6 alkyloxy, carboxyl, C.sub.1-6 alkylcarbonyloxy, C.sub.1-6 alkyloxycarbonyl or aryl; or R.sup.1 and R.sup.2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle; R.sup.3 to R.sup.10 each independently are hydrogen, halo, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkylcarbonylamino, aminosulfonyl, mono- or di(C.sub.1-6 alkyl)-aminosulfonyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylcarbonyl, C.sub.1-6 alkyloxycarbonyl; R.sup.11 is hydrogen, C.sub.1-6 alkyl, or trifluoromethyl; R.sup.12 is hydrogen, C.sub.1-6 alkyl, cyano, or trifluoromethyl; n is zero to 6; and X is O, S, S(.dbd.O) or S(.dbd.O).sub.2. The compounds of formula (I) may be used as therapeutic agents in the treatment or the prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

摘要翻译： PCT No.PCT / EP95 / 04197 Sec。 371日期1997年04月25日 102（e）日期1997年4月25日PCT提交1995年10月25日PCT公布。 WO96 / 14321 PCT出版物 日期1996年5月17日本发明涉及式（I）化合物，其药学上可接受的盐和立体异构形式，以及其N-氧化物形式。 （I）其中：R1和R2各自独立地为氢; C 1-6烷基; C 1-6烷基羰基; 三卤代甲基羰基 被羟基，C 1-6烷氧基，羧基，C 1-6烷基羰基氧基，C 1-6烷氧基羰基或芳基取代的C 1-6烷基; 或者R 1和R 2与它们所连接的氮原子一起可以形成吗啉基环或任选取代的杂环; R3至R10各自独立地为氢，卤素，氰基，羟基，三氟甲基，三氟甲氧基，羧基，硝基，氨基，单或二（C1-6烷基）氨基，C1-6烷基羰基氨基，氨基磺酰基，单或二（C1-6烷基） 氨基磺酰基，C 1-6烷基，C 1-6烷氧基，C 1-6烷基羰基，C 1-6烷氧基羰基; R 11是氢，C 1-6烷基或三氟甲基; R 12是氢，C 1-6烷基，氰基或三氟甲基; n为0〜6; X为O，S，S（= O）或S（= O）2）。 式（I）化合物可用作治疗或预防CNS障碍，心血管疾病或胃肠道疾病的治疗剂。

公开(公告)号：US20080213275A1

公开(公告)日：2008-09-04

申请号：US11875429

申请日：2007-10-19

申请人： Eddy Jean Edgard FREYNE ,  Michel Marie Francois Janicot ,  Theo Frans Meert ,  Timothy Pietro Suren Perera

发明人： Eddy Jean Edgard FREYNE ,  Michel Marie Francois Janicot ,  Theo Frans Meert ,  Timothy Pietro Suren Perera

IPC分类号： A61K39/395 ,  A61K31/519 ,  A61K31/4985 ,  A61P35/00 ,  A61K31/704

CPC分类号： A61K31/4985 ,  A61K31/519 ,  A61K31/704 ,  A61K45/06 ,  A61K2300/00

摘要： The present invention is concerned with the finding that the macrocyclic quinazoline derivative 4,6-ethanediylidenepyrimido[4,5-b][6,1,12]benzoxadiazacyclo-pentadecine, 17-bromo-8,9,10,11,12,13,14,19-octahydro-20-methoxy-13-methyl-, described as compound 22 in PCT publication WO2004/105765, is useful in the manufacture of a medicament for the treatment or prevention of bone cancers and methods for killing bone cancer cells, including osteosarcomas, chondrosarcomas, myeloma bone disease and osteolytic bone metastases from other primary sites. It accordingly provides methods for treating, preventing, delaying or mitigating bone cancer, or for preventing and treating of bone loss associated with cancer metastases.

摘要翻译： 本发明涉及大环喹唑啉衍生物4,6-乙二亚甲基嘧啶并[4,5-b] [6,1,12]苯并恶二氮杂环十五碳烯，17-溴-8,9,10,11,12， 在PCT公开WO2004 / 105765中描述为化合物22的13,14,19-八氢-20-甲氧基-13-甲基可用于制备用于治疗或预防骨癌的药物和用于杀死骨癌的方法 细胞，包括骨肉瘤，软骨肉瘤，骨髓瘤骨病和其他原发部位的骨溶解性骨转移。 因此，它提供了治疗，预防，延缓或减轻骨癌或预防和治疗与癌症转移相关的骨丢失的方法。

公开(公告)号：US06403589B1

公开(公告)日：2002-06-11

申请号：US09446140

申请日：1999-12-15

申请人： Theo Frans Meert ,  Herman Van Belle

发明人： Theo Frans Meert ,  Herman Van Belle

IPC分类号： A61K3150

CPC分类号： C07D295/15 ,  A61K31/496 ,  C07D213/38

摘要： This invention concerns the use of nucleoside transport inhibitors, more particularly compounds of formula an N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein R1 is C1-4alkyl, aminocarbonyl or mono- or di(C1-4alkyl)aminocarbonyl, Ar is a phenyl or pyridinyl derivative and L is a radical of formula wherein Ar1 is a phenyl derivative; Ar2 is a phenyl or pyridinyl derivative; and Alk is C1-4alkanediyl; for the manufacture of a medicine for the treatment of warm-blooded animals suffering from pain.

摘要翻译： 本发明涉及使用核苷转运抑制剂，更特别的是N-氧化型式的化合物，其药学上可接受的酸加成盐或其立体化学异构形式，其中R 1是C 1-4烷基，氨基羰基或单或二（C 1-4烷基 ）氨基羰基，Ar是苯基或吡啶基衍生物，L是脯氨酸的基团Ar1是苯基衍生物; Ar2是苯基或吡啶基衍生物; Alk是C1-4烷二基; 用于制造用于治疗患有疼痛的温血动物的药物。

公开(公告)号：US20060128721A1

公开(公告)日：2006-06-15

申请号：US10560476

申请日：2004-06-07

申请人： Frans Janssens ,  Francois Sommen ,  Benoit Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts ,  Yves Emiel, Maria Van Roosbroeck ,  Theo Frans Meert

发明人： Frans Janssens ,  Francois Sommen ,  Benoit Christian Albert Ghislain De Boeck ,  Joseph Elisabeth Leenaerts ,  Yves Emiel, Maria Van Roosbroeck ,  Theo Frans Meert

IPC分类号： A61K31/496

CPC分类号： A61K45/06 ,  A61K31/496 ,  A61K31/551 ,  A61K2300/00

摘要： This invention concerns novel formulations for opioid-based treatments of pain and/or nociception comprising opioid analgesics and 1,4-di-piperidin-4-yl-piperazine derivatives having neurokinin antagonistic activity, in particular NK1 antagonistic activity, the use of said formulation for the manufacture of a medicament for the prevention and/or treatment of emesis, pain and/or nociception, in particular in opioid-based acute and chronic pain treatments, more in particular in inflammatory, post-operative, emergency room (ER), breakthrough, neuropathic and cancer pain treatments and the use of an NK1-receptor antagonist for the manufacture of a medicament for the prevention and/or treatment of respiratory depression in opioid-based treatments of pain. The pharmaceutical formulations according to the invention comprise a pharmaceutically acceptable carrier and, as active ingredients, a therapeutically effective amount of an opioid analgesic and NK1-antagonists according to the general Formula (I) the pharmaceutically acceptable acid or base addition salts thereof, the stereochemically isomeric forms thereof, the N-oxide form thereof and prodrugs thereof, wherein all substituents are defined as in claim 1. The pharmaceutical composition according to the invention reduces to a large extent a number of unwanted side-effects associated with opioid analgesics, in particular emesis, respiratory depression and tolerance, thereby increasing the total tolerability of said opioids in pain treatment.

摘要翻译： 本发明涉及用于基于阿片样物质治疗疼痛和/或伤害感受的新制剂，其包含具有神经激肽拮抗活性的阿片类镇痛药和1,4-二哌啶-4-基 - 哌嗪衍生物，特别是NK1 拮抗活性，所述制剂用于制备用于预防和/或治疗呕吐，疼痛和/或伤害感受，特别是基于阿片样物质的急性和慢性疼痛治疗的药物的用途，特别是在炎性， 手术，急诊室（ER），突破性，神经病理性和癌症疼痛治疗，以及使用NK 1受体拮抗剂制备用于预防和/或治疗阿片样物质中呼吸抑制的药物 的治疗疼痛。 根据本发明的药物制剂包含药学上可接受的载体，并且作为活性成分，具有治疗有效量的根据通式（I）的药学上可接受的酸的阿片样物质止痛剂和NK 1拮抗剂 或其碱加成盐，其立体化学异构形式，其N-氧化物形式和其前药，其中所有取代基如权利要求1中所定义。根据本发明的药物组合物在很大程度上降低了多个不需要的副产物， 与阿片类止痛药相关的作用，特别是呕吐，呼吸抑制和耐受性，从而增加所述阿片类药物在疼痛治疗中的总耐受性。