cis-[1-(4-isopropylcyclohexyl)piperidin-4-ylidene]phenylamine | 254097-70-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: cis-[1-(4-isopropylcyclohexyl)piperidin-4-ylidene]phenylamine
• CAS: 254097-70-6
• 化学式: C₂₀H₃₀N₂
• 分子量: 298.472
• InChiKey: GXETWWCCWKWBEZ-MSEWRSJXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.07
• 重原子数：
  22.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  15.6
• 氢给体数：
  0.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  cis-[1-(4-isopropylcyclohexyl)piperidin-4-ylidene]phenylamine 在 10percent Pd/C 盐酸 、 lithium aluminium tetrahydride 、 氢气 、 三苯基膦 、 cesium fluoride 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 乙二醇二甲醚 、 乙醚 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 66.5h， 生成 (3'aRS,6'aRS)-1-(cis-4-isopropylcyclohexyl)-5'-(2-hydroxyethyl)-2'-phenylhexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrrole]
  参考文献：
  名称：

  Novel Hexahydrospiro[piperidine-4,1‘-pyrrolo[3,4-c]pyrroles]:  Highly Selective Small-Molecule Nociceptin/Orphanin FQ Receptor Agonists

  摘要：

  Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited H-3-N/OFQ binding to the NOP receptor (K-i = 0.49 nM) but was > 1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTPgammaS binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.

  DOI：

  10.1021/jm0209174
• 作为产物：
  描述：

  1-氨基-4-异丙基环己烷 在 4 A molecular sieve 、 potassium carbonate 作用下， 以 正戊烷 为溶剂， 反应 146.0h， 生成 cis-[1-(4-isopropylcyclohexyl)piperidin-4-ylidene]phenylamine
  参考文献：
  名称：

  Novel Hexahydrospiro[piperidine-4,1‘-pyrrolo[3,4-c]pyrroles]:  Highly Selective Small-Molecule Nociceptin/Orphanin FQ Receptor Agonists

  摘要：

  Novel hexahydrospiro[piperidine-4,1'-pyrrolo[3,4-c]pyrroles that act as potent and selective orphanin FQ/nociceptin (N/OFQ) receptor (NOP) agonists were identified. The best compound, (+)-5a, potently inhibited H-3-N/OFQ binding to the NOP receptor (K-i = 0.49 nM) but was > 1000-fold less potent in binding to MOP, KOP, and DOP opiate receptors. Further, (+)-5a potently stimulated GTPgammaS binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. These results indicate that (+)-5a is a highly selective and potent small-molecule full agonist of the NOP receptor.

  DOI：

  10.1021/jm0209174

文献信息

• DI-OR TRIAZA-SPIRO [4,5] DECANE DERIVATIVES
  申请人：——

  公开号：US20030176701A1

  公开（公告）日：2003-09-18

  The present invention relates to compounds of the general formula 1 wherein R 1 is C 6-10 -cycloalkyl, optionally substituted by lower alkyl or —C(O)O-lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, optionally substituted by lower alkyl; decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl; 2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or octahydro-inden-2-yl; R 2 is hydrogen; lower alkyl; ═O or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; 2 is cyclohexyl or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; X is —CH(OH)—; —C(O)—; —CHR 3 —; —CR 3 ═; —O—; —S—; —CH(COOR 4 )— or —C(COOR 4 )═; Y is —CH 2 —; —CH═; —CH(COOR 4 )—, —C(COOR 4 )═; or —C(CN)—; R 3 is hydrogen or lower alkoxy; R 4 is lower alkyl, cycloalkyl, phenyl, or benzyl and either a or b is optionally an additional bond, and to pharmaceutically acceptable acid addition salts thereof. The compounds are agonists of the orphanin FQ (QFQ) receptor and therefore useful in the treatment of diseases, related to this receptor.

  本发明涉及一般式1的化合物， 其中， R1是C6-10环烷基，可选地被较低烷基或-C（O）O-较低烷基取代； 十氢萘-1-基；十氢萘-2-基；吲哚-1-基或吲哚-2-基，可选地被较低烷基取代； 十氢-萜烯-2-基； 双环[6.2.0]癸-9-基； 萘并环[1]苯-1-基； 2,3-二氢-1H-菲-1-基； 2,3,3a,4,5,6-六氢-1H-菲-1-基或八氢-茚-2-基； R2是氢；较低烷基；═O或苯基，可选地被较低烷基，卤素或烷氧基取代； 2是环己基或苯基，可选地被较低烷基，卤素或烷氧基取代； X是—CH（OH）—；—C（O）—；—CHR3—；—CR3═；—O—；—S—；—CH（COOR4）—或—C（COOR4）═； Y是—CH2—；—CH═；—CH（COOR4）—，—C（COOR4）═；或—C（CN）—； R3是氢或较低烷氧基； R4是较低烷基，环烷基，苯基或苯甲基； a或b是可选的额外键，以及其药学上可接受的酸盐。 这些化合物是孤儿受体FQ（QFQ）激动剂，因此在与该受体相关的疾病的治疗中有用。
• Spiro[piperidine-4,1'-pyrrolo [3,4-C] pyrrole]derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US06075034A1

  公开（公告）日：2000-06-13

  The present invention relates to compounds of the general formula wherein R.sup.1 is C.sub.5-12 -cycloalkyl, optionally substituted by lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, optionally substituted by lower alkyl; decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl; bicyclo[3.3.1]non-9-yl; 2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl; octahydro-inden-2-yl; 1,2,3,4-tetrahydro-naphthalen-1-yl; 1,2,3,4-tetrahydro-naphthalen-2-yl; naphthalen-lower alkyl-1-yl; naphthalen-lower alkyl-2-yl; acenaphthen-1-yl; and 5-isopropyl-2-methyl-bicyclo[3.1.0]hex-3-yl; R.sup.2, R.sup.3 are hydrogen; hydroxy; lower alkyl; .dbd.O; or phenyl, optionally substituted by lower allyl, halogen or alkoxy; R.sup.4 is hydrogen; lower alkyl; --(CH.sub.2).sub.n CH(OH)CF.sub.3 ; --(CH.sub.2).sub.n C.sub.3-6 -cycloalkyl; phenyl; benzyl; tetrahydrofuran-3-yl; --(CH.sub.2).sub.n OCH.sub.2 C.sub.6 H.sub.5 ; --(CH.sub.2).sub.n morpholinyl; 3-methyl-oxetan-3-yl-methyl; --(CH.sub.2).sub.n CH.sub.2 OH; --S(O).sub.2 -lower alkyl; --C(O)-lower alkyl; --C(O)CF.sub.3 ; --C(O)(CH.sub.2).sub.n OCH.sub.3 ; --(CH.sub.2).sub.n C(O)N(lower alkyl).sub.2 ; --S(O).sub.2 heteroaryl; --C(O)heteroaryl; --S(O).sub.2 -phenyl; --S(O).sub.2 --N(lower alkyl).sub.2 ; --C(O)--C.sub.3-6 -cycloalkyl; --C(O)O-phenyl; or --C(O)O-lower alkyl: R.sup.5 is hydrogen; halogen; lower alkyl; trifluoromethyl or lower alkoxy; n is 0-3; and to pharmaceutically acceptable acid addition salts thereof The compounds of formula I and their salts are useful as in the treatment of psychiatric, neurological and physiological disorders.

  本发明涉及一般式化合物，其中R.sup.1为C.sub.5-12-环烷基，可选地被低碳烷基取代;十氢萘-1-基;十氢萘-2-基;茚-1-基或茚-2-基，可选地被低碳烷基取代;十氢萜烯-2-基;双环[6.2.0]癸-9-基;芴-1-基;双环[3.3.1]壬-9-基;2,3-二氢-1H-苯并-1-基;2,3,3a,4,5,6-六氢-1H-苯并-1-基;八氢茚-2-基;1,2,3,4-四氢萘-1-基;1,2,3,4-四氢萘-2-基;萘-低碳烷基-1-基;萘-低碳烷基-2-基;芴-1-基;和5-异丙基-2-甲基-双环[3.1.0]己-3-基; R.sup.2，R.sup.3为氢;羟基;低碳烷基; .dbd.O;或苯基，可选地被低烯丙基，卤素或烷氧基取代;R.sup.4为氢;低碳烷基;--(CH.sub.2).sub.n CH(OH)CF.sub.3;--(CH.sub.2).sub.n C.sub.3-6-环烷基;苯基;苄基;四氢呋喃-3-基;--(CH.sub.2).sub.n OCH.sub.2 C.sub.6 H.sub.5;--(CH.sub.2).sub.n 嘧啶基;3-甲基-噁唑-3-基-甲基;--(CH.sub.2).sub.n CH.sub.2 OH;--S(O).sub.2-低碳烷基;--C(O)-低碳烷基;--C(O)CF.sub.3;--C(O)(CH.sub.2).sub.n OCH.sub.3;--(CH.sub.2).sub.n C(O)N(低碳烷基).sub.2;--S(O).sub.2杂环芳基;--C(O)杂环芳基;--S(O).sub.2-苯基;--S(O).sub.2--N(低碳烷基).sub.2;--C(O)--C.sub.3-6-环烷基;--C(O)O-苯基;或--C(O)O-低碳烷基: R.sup.5为氢;卤素;低碳烷基;三氟甲基或低碳基氧基; n为0-3;以及其药学上可接受的酸加盐。公式I的化合物及其盐在治疗精神病学、神经学和生理学疾病中有用。
• Di-or triaza-spiro [4,5] decane derivatives
  申请人：Hoffman-La Roche Inc.

  公开号：US06642247B2

  公开（公告）日：2003-11-04

  The present invention relates to compounds of the general formula wherein R1 is C6-10-cycloalkyl, optionally substituted by lower alkyl or —C(O)O-lower alkyl; decahydro-naphthalen-1-yl; decahydro-naphthalen-2-yl; indan-1-yl or indan-2-yl, optionally substituted by lower alkyl; decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; acenaphthen-1-yl; 2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl or octahydro-inden-2-yl; R2 is hydrogen; lower alkyl; ═O or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; is cyclohexyl or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; X is —CH(OH)—; —C(O)—; —CHR3—; —CR3═; —O—; —S—; —CH(COOR4)— or C(COOR4)═; Y is —CH2—; —CH═; —CH(COOR4)—, —C(COOR4)═; or —C(CN)—; R3 is hydrogen or lower alkoxy; R4 is lower alkyl, cycloalkyl, phenyl, or benzyl and either a or b is optionally an additional bond, and to pharmaceutically acceptable acid addition salts thereof. The compounds are agonists of the orphanin FQ (QFQ) receptor and therefore useful in the treatment of diseases, related to this receptor.

  本发明涉及一般式化合物，其中R1是C6-10环烷基，可选地被较低烷基或—C（O）O-较低烷基取代；十氢萘-1-基；十氢萘-2-基；吲哚-1-基或吲哚-2-基，可选地被较低烷基取代；十氢萘并2-基；双环[6.2.0]癸-9-基；芴-1-基；2,3-二氢-1H-苯并-1-基；2,3,3a,4,5,6-六氢-1H-苯并-1-基或八氢-茚-2-基；R2是氢；较低烷基；═O或苯基，可选地被较低烷基，卤素或烷氧基取代；是环己基或苯基，可选地被较低烷基，卤素或烷氧基取代；X是—CH（OH）—；—C（O）—；—CHR3—；—CR3═；—O—；—S—；—CH（COOR4）—或C（COOR4)═；Y是—CH2—；—CH═；—CH（COOR4）—，—C（COOR4)═；或—C（CN）—；R3是氢或较低烷氧基；R4是较低烷基，环烷基，苯基或苄基，a或b中的任意一个可选地是额外的键，以及其药物可接受的酸盐。这些化合物是孤儿FQ（QFQ）受体的激动剂，因此在与该受体相关的疾病的治疗中有用。
• Diaza-spiro[3,5] nonane derivatives
  申请人：Hoffmann-La Roche Inc.

  公开号：US06113527A1

  公开（公告）日：2000-09-05

  The invention relates to compounds of the general formula ##STR1## wherein R.sup.1 is C.sub.6-12 -cycloalkyl, optionally substituted by lower alkyl or C(O)O lower alkyl, indan-1-yl or indan-2-yl, optionally substituted by lower alkyl; acenaphthen-1-yl; bicyclo[3.3.1]non-9-yl, octahydro-inden-2-yl; 2,3-dihydro-1H-phenalen-1-yl; 2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl, decahydro-azulen-2-yl; bicyclo[6.2.0]dec-9-yl; decahydro-naphthalen-1-yl, decahydro-naphthalen-2-yl; tetrahydro-naphthalen-1-yl, tetrahydro-naphthalen-2-yl or 2-oxo-1,2-diphenyl-ethyl; R.sup.2 is .dbd.O or hydrogen, R.sup.3 is hydrogen, isoindolyl-1,3-dione, lower alkoxy, lower alkyl, amino, benzyloxy, --CH.sub.2 OR.sup.5 or --CH.sub.2 N(R.sup.5).sub.2 ; R.sup.4 is hydrogen or --CH.sub.2 OR.sup.5 ; R.sup.5 is hydrogen or lower alkyl; ##STR2## is cyclohexyl or phenyl, optionally substituted by lower alkyl, halogen or alkoxy; to racemic mixtures and their corresponding enantiomers and or pharmaceutically acceptable acid addition salts thereof. The compounds of the present invention are agonists of the orphamin FQ (OFQ) receptor and therefore useful in the treatment of diseases, related to this receptor.

  本发明涉及一般式化合物##STR1##其中R.sup.1为C.sub.6-12-环烷基，可选地被较低的烷基或C(O)O较低的烷基取代，indan-1-yl或indan-2-yl，可选地被较低的烷基取代；acenaphthen-1-yl；bicyclo[3.3.1]non-9-yl，八氢-2-茚基；2,3-二氢-1H-苯并-1-yl；2,3,3a,4,5,6-六氢-1H-苯并-1-yl，十氢-萜烯-2-yl；bicyclo[6.2.0]dec-9-yl；十氢-萘-1-yl，十氢-萘-2-yl；四氢-萘-1-yl，四氢-萘-2-yl或2-氧代-1,2-二苯基-乙基；R.sup.2为.dbd.O或氢，R.sup.3为氢，异吲哚基-1,3-二酮，较低的烷氧基，较低的烷基，氨基，苄氧基，-CH.sub.2 OR.sup.5或-CH.sub.2N(R.sup.5).sub.2；R.sup.4为氢或-CH.sub.2 OR.sup.5；R.sup.5为氢或较低的烷基；##STR2##为环己基或苯基，可选地被较低的烷基，卤素或烷氧基取代；以及它们对应的外消旋体混合物和其对应的光学异构体或药学上可接受的酸盐。本发明的化合物是orphamin FQ（OFQ）受体的激动剂，因此在治疗与该受体相关的疾病方面有用。
• Spiro(piperidine-4,1'-pyrrolo(3,4-c)pyrrole)
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0963987A2

  公开（公告）日：1999-12-15

  The present invention relates to compounds of the general formula    wherein the substituents are described in the application and to pharmaceutically acceptable acid addition salts thereof. The compound of the invention are useful in the treatment of diseases related to the orphanin FQ (OFQ) receptor, which include psychiatric, neurological and physiological disorders, such as anxiety and stress disorders, depression, trauma, memory loss due to Alzheimer's disease or other dementias, deficits in cognition and leaning, epilepsy and convulsions, acute and/or chronic pain conditions, and symptoms of addictive drug withdrawal, control of water balance, Na+ excretion, arterial blood pressure disorders and metabolic disorders such as obesity.

  本发明涉及通式为 其中的取代基见本申请所述，以及其药学上可接受的酸加成盐。 本发明的化合物可用于治疗与孤儿素 FQ（OFQ）受体有关的疾病，这些疾病包括精神、神经和生理疾病，如焦虑和应激障碍、抑郁症、创伤、阿尔茨海默病或其他痴呆症导致的记忆丧失、认知和精益功能障碍、癫痫和抽搐、急性和/或慢性疼痛病症、成瘾性药物戒断症状、水平衡控制、Na+排泄、动脉血压紊乱和代谢紊乱，如肥胖。