CN106414439A - 作为食欲素受体拮抗剂的哌啶衍生物 - Google Patents
作为食欲素受体拮抗剂的哌啶衍生物 Download PDFInfo
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- CN106414439A CN106414439A CN201580012396.4A CN201580012396A CN106414439A CN 106414439 A CN106414439 A CN 106414439A CN 201580012396 A CN201580012396 A CN 201580012396A CN 106414439 A CN106414439 A CN 106414439A
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- unsubstituted
- alkane
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- hetero atom
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- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 208000020351 pituitary gland basophil adenoma Diseases 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 208000030153 prolactin-producing pituitary gland adenoma Diseases 0.000 description 1
- 230000001107 psychogenic effect Effects 0.000 description 1
- 150000003214 pyranose derivatives Chemical class 0.000 description 1
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 201000002859 sleep apnea Diseases 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- DAJSVUQLFFJUSX-UHFFFAOYSA-M sodium;dodecane-1-sulfonate Chemical compound [Na+].CCCCCCCCCCCCS([O-])(=O)=O DAJSVUQLFFJUSX-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000005985 stomach dysfunction Effects 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000018553 tannin Nutrition 0.000 description 1
- 239000001648 tannin Substances 0.000 description 1
- 229920001864 tannin Polymers 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical group C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
Description
Claims (22)
- 式(I)所示化合物或其药学上可接受的盐,其中,A选自任选被取代的3~12元环烃基或杂环烃基或环烃杂基,所述环烃基或杂环烃基或环烃杂基可以单环、联环、螺环、并环或稠环形式存在,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;B选自C(=O)、S(=O)或S(=O)2;X选自任选被取代的(CH2)r1(U)r2(CH2)r3,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;r1、r3分别独立地选自0、1或2,r2选自0或1,r1、r2和r3同时为0表示X为仅起连接作用的单键;U选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基的数目在化学上可稳定实现的前提下是任意的;D、L分别独立地选自任选被取代的CH2,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;T选自C或者仅起连接作用的单键,当T选自单键时R2、R3不存在;M选自C(Y)(R1a),此时Q选自C(R1b)(R1c),或者,M选自C(R1b)(R1c),此时Q选自C(Y)(R1a);Y选自-(CH2)r4(G)r5(CH2)r6-Y1,Y1选自-O-E或式(Y2)所示结构,G选自卤代或羟代或胺代或未被取代的CH2、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、S(=O)、S(=O)2、C(=O)或C(=S),取代基的数目在化学上可稳定实现的前提下是任意的;r4、r6分别独立地选自0、1或2,r5选自0或1,r4、r5和r6同时为0表示相应结构为仅起连接作用的单键;E选自任选被取代的5~6元环烃基或杂环基,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g选自任选被取代的CH2、CH、NH、或选自N、O、S、S(=O)、S(=O)2、C(=O)或C(=S),且Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g至少一项为任选被取代的CH、CH2或NH,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;代表单键或双键;R1a、R1b、R1c、R2、R3分别独立地选自H、F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的,或者任选地R2、R3连接成环;和该化合物或其药学上可接受的盐包含一个或多个手性中心。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中A选自式(A1)或(A2)所示结构单元:其中,Z1、Z2、Z3、Z4、Z5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、或C1-6烷代或C3-8环烷代或未被取代的C(=O)NH或NH、C=N、N、O、S、S(=O)、S(=O)2、C(=O)O、C(=O)或C(=S),取代基的数目在化学上可稳定实现的前提下是任意的;V1、V2、V3、V4、V5分别独立地选自卤代或羟代或胺代或未被取代的CH或CH2、C1-6烷代或C3-8环烷代或未被取代的C(=O)NH或NH、C=N、C、N、O、S、S(=O)、S(=O)2、C(=O)O、C(=O)或C(=S),且V1-5至少一项为C或N,取代基的数目在化学上可稳定实现的前提下是任意的;代表单键或双键;R4、R6分别独立地选自H、F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;R5、R7分别独立地选自任选被取代的5~6元环烃基或杂环基,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的;n4选自0、1、2、3、4;和n6选自0、1、2、3。
- 根据权利要求2所述的化合物或其药学上可接受的盐,其中结构单元选自苯基或吡啶基,选自呋喃基、噻吩基或噻唑基。
- 根据权利要求2或3所述的化合物或其药学上可接受的盐,其中式(A2)选自式(A21)所示结构:式中,V1、V2、V3、V4、V5、R6、R7、n6如权利要求2中所定义。
- 根据权利要求4所述的化合物或其药学上可接受的盐,其中A选自式(A22)所示结构单元:其中,R6、R7如权利要求2中所定义;n6a选自0、1或2。
- 根据权利要求2、3、4或5所述的化合物或其药学上可接受的盐,其中所述R5或R7中5~6元环烃基或杂环基分别独立地选自苯基、吡啶基、呋喃基、噻吩基、噻唑基、嘧啶基、吡唑基、1,2,3-三唑基或1,2,5-三唑基。
- 根据权利要求1、2、3、4或5所述的化合物或其药学上可接受的盐,其中所述A选自:
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中式(Y2)选自式(Y21)所示结构:式中,Y2a、Y2b、Y2c、Y2d、Y2e、Y2f、Y2g如权利要求1中所定义。
- 根据权利要求8所述的化合物或其药学上可接受的盐,其中式(Y21)选自任选被取代的式(Y22)所示结构:其中,取代基选自F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
- 根据权利要求9所述的化合物或其药学上可接受的盐,其中Y选自任选被取代的
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中Y选自-CH2-O-E或-O-E,其中,E如权利要求1中所定义。
- 根据权利要求1或11所述的化合物或其药学上可接受的盐,其中E选自式(Ea)所示结构单元:其中,E1、E2、E3、E4分别独立地选自卤代或羟代或胺代或未被取代的CH、N;和R8、R9分别独立地选自H、F、Cl、Br、I、CN、=O、=S、OH、SH、NH2、卤代或羟代或胺代或未被取代的C1-6烷基或杂烷基或烷杂基或杂烷杂基、卤代或羟代或胺代或未被取代的C3-8环基或杂环基或环杂基或杂环杂基,杂原子或杂原子团分别独立地选自C1-6烷代或C3-8环烷代或未被取代的C(=O)NH、C(=O)O、C1-6烷代或C3-8环烷代或未被取代的NH、O、S、C1-6烷代或C3-8环烷代或未被取代的C=NH、C=O、C=S、S(=O)和/或S(=O)2,取代基、杂原子或杂原子团的数目在化学上可稳定实现的前提下是任意的。
- 根据权利要求12所述的化合物或其药学上可接受的盐,其中将结构单元限定为苯基或者吡啶基,或将其替换为噻吩基或呋喃基。
- 根据权利要求12所述的化合物或其药学上可接受的盐,其中Y选自:
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中U、X、G分别独立地选自NH或N-C1-6烷基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R1a、R1b、R1c分别独立地选自H、甲基或氟。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R2、R3分别独立地选自H、甲基、氟或环丙基。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其中R2、R3连接成3~8元环烷基;具体地,R2、R3连接成环丙基。
- 根据权利要求1~18任意一项所述的化合物或其药学上可接受的盐,其中C1-6烷基选自甲基、乙基、丙基、丁基、戊基、己基,其中所述丙基、丁基、戊基、己基任选地环化或部分环化。
- 根据权利要求1所述的化合物或其药学上可接受的盐,其具有如下结构:
- 一种药物组合物,包括治疗有效量的根据权利要求1~20任意一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载体。
- 根据权利要求1~20任意一项所述的化合物或其药学上可接受的盐或根据权利要求21所述的药物组合物在制备治疗失眠、慢性阻塞性肺病、阻塞性睡眠呼吸暂停、嗜睡、焦虑、强迫、恐慌、尼古丁依赖或饮食混乱障碍的药物中的应用。
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