TWI249402B - 2,7-substituted indoles - Google Patents
2,7-substituted indoles Download PDFInfo
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- TWI249402B TWI249402B TW092125197A TW92125197A TWI249402B TW I249402 B TWI249402 B TW I249402B TW 092125197 A TW092125197 A TW 092125197A TW 92125197 A TW92125197 A TW 92125197A TW I249402 B TWI249402 B TW I249402B
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- compound
- alkyl
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- acid
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- 150000002475 indoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 238000000034 method Methods 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- -1 acryl Chemical group 0.000 claims description 61
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 201000010099 disease Diseases 0.000 claims description 29
- 239000002585 base Substances 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 13
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 238000012360 testing method Methods 0.000 claims description 11
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 230000003902 lesion Effects 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 6
- 208000028017 Psychotic disease Diseases 0.000 claims description 5
- 239000000556 agonist Substances 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 208000024827 Alzheimer disease Diseases 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 208000023105 Huntington disease Diseases 0.000 claims description 4
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- 208000018737 Parkinson disease Diseases 0.000 claims description 4
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- 239000000460 chlorine Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 235000020824 obesity Nutrition 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
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- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 235000013405 beer Nutrition 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 231100001014 gastrointestinal tract lesion Toxicity 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 2
- BBEAZDGZMVABIC-UHFFFAOYSA-N 1,1,1,3,3,3-hexachloropropane Chemical group ClC(Cl)(Cl)CC(Cl)(Cl)Cl BBEAZDGZMVABIC-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- SFDJOSRHYKHMOK-UHFFFAOYSA-N nitramide Chemical group N[N+]([O-])=O SFDJOSRHYKHMOK-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 27
- 239000000651 prodrug Substances 0.000 abstract description 4
- 229940002612 prodrug Drugs 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 62
- 238000006243 chemical reaction Methods 0.000 description 31
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 239000000243 solution Substances 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
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- 239000000843 powder Substances 0.000 description 15
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- 150000001412 amines Chemical class 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000003282 alkyl amino group Chemical group 0.000 description 9
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- 239000012044 organic layer Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- C07D401/02—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 two hetero rings
- C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
I 1249402 玖、發明說明: 【發明所屬之技術領域】 本發明係有關2,7-經取代之吲哚與相關之組合物、其用為 醫療劑之用途及其製備方法。 【先前技術】 神經遞質5-羥基色胺(5-HT)作為腦中主要調節性神經遞 質之作用係透過許多稱為5_HT1、5-HT2、5-HT3、5-HT4、 5-HT5、5_HT6與5-HT7之受體家族所媒介。基於腦中高量之 5-HT6受體!nRNA可知,5_HT6受體可能在中樞神經系統病 變之病理學及治療法中扮演某種角色。特定言之,已判別 出5-HT6選擇性配位體有用於治療某些CNS病變之潛力, 如:巴金森氏症、亨丁頓氏症、焦慮症、抑鬱症、燥鬱症、 精神病、癲癇、強迫觀念與強迫行為性病變、偏頭痛、阿 茲海默氏症(加強認知記憶力)、睡眠障礙、進食異常如:厭 食症與貪食症、恐慌症、專注力缺乏過動異常(ADHD)、專 注力缺乏異常(ADD)、自毒品脫瘾如:古柯鹼、酒精、尼古 丁與苯并二吖呼,精神***症、及與脊柱創傷與/或頭部傷 害如:腦積水有關之病變。此等化合物應亦可用於治療某 些胃腸道(GI)病變,如:腸功能異常。參見例如:B.L. Roth 等人之Pharmacol. Exp. Ther·,1994, 268, p. 1403-14120、D.R.
Sibley等人之Mol. Pharmacol.,1993, 43, 320-327、A.J· Sleight 等人之 Neurotransmission,1995,11,1_5與 A.J· Sleight 等人之 Serotonin ID Research Alert,1997, 2(3),115-8。5-HT6擴抗劑 已被認為可作為適用於治療肥胖症之化合物。參見例如: 87762 -6 - 1249402
Bentley等人之Br. J. Pharmac· 1999,Suppl 126; Bently等人之 Psychopharmacol· 1997,Suppl A64: 255; Wooley等人之 Neuropharmacology 2001,41: 210-129;與 WO 02/098878 o 雖然已揭示一些5-HT6調節劑,但仍需要可用於調節 5-HT6之化合物。 【發明内容】 本發明一項目的為⑴如下式化合物:
或其醫藥上可接受之鹽, 其中 η為0、1或2 ; ρ為1或2 ; R1為可視需要經取代之芳基或可視需要經取代之雜芳基; R2為可視需要經取代之雜環基; R3為氫、烷基或-C(=0)-R5,其中R5為烷基、烷氧基、芳基, 或芳氧基;且 各R4分別獨立為氫、羥基、氰基、烷基、烷氧基、硫烷基、 烷硫基、_基、自烷基、羥烷基、硝基、烷氧羰基、烷羰 基、燒基續醯基、芳基續醯基、鹵燒橫酿基、胺基、燒胺 基、二烷胺基、烷基(芳基)胺基、烷胺基羰基、烷羰基胺基、 烷羰基(烷胺基)、烷胺磺醯基、烷基磺醯基胺基或亞甲二氧 87762 1249402 基氫、烷基、烷氧基、自基、或自烷基。 本發明另一個目的為: (ϋ)如⑴之化合物, 其中 η為2 ;
Rl為可視需要經取代之芳基; R2為可視需要經取代之雜環基; R3為氫且 R4為氫。 (111)如(11)之化合物,其中R2為六氫吡畊基或六氫吡啶-4-基’其可視需要經燒基取代。 (iv) 如(iii)之化合物,其中R2為六氫吡畊基、4_甲基六氫 吡畊-1-基、N-甲基六氫吡啶_4_基或六氫吡啶基。 (v) 如(ii)之化合物’其中Ri為可视需要經取代之苯基或可 視需要經取代之嘧吩基。 (vi) 如(v)之化合物,其中Ri為嘧吩|基或苯基,其可視需 要經烷基、南基或函烷基取代。 (vii) 如(vi)之化合物,其中Ri為笨基、2,3_二氯笨基、2•氣 苯基、2·三氟甲基苯基、3-溴苯基。 (viii) 如(ii)之化合物,其為: 2-苯績酿基-7_六氫p比_ -1-基丨嗓, 2_苯續酿基-7_(4_甲基-六氫p比p井-1-基)-1Η-β丨嗓, 2-(2,3-二氯-苯績酿基)-7_六氫外-1-基-1Η-Μ丨噪, 2-(2,3·二氯-苯磺醯基)_7-(4-甲基-六氫吡畊-1·基嗓, 87762 -8 - 1249402 2-(2-氟-苯磺酿基)·7_六氫吡畊小基-⑴—丨哚, 2_苯續酿基-7-六氫吡啶-4_基-1Η•吲哚, 苯磺醯基甲基·六氫吡啶-4_基)-1Η_<哚, 7_(4_甲基-六氫吡畊“·基)-2-(2-三氟甲基-苯磺醯基兴丨仏吲 嗓, 7_六氫吡畊-1-基-2_(2-三氟甲基·苯磺醯基)-1Η_吲哚, 2·(3-漠-苯磺酿基)_7-(4-甲基六氫吡”井小基)_1Η_吲哚, 2-(3_漢-苯橫醯基)-7-六氫吡畊小基嗓。 (lx) 一種製備如下式2-經取代之吲哚之方法:
其中 11為 〇、1或 2 ; ρ為1或2 ;
Rl為可视需要經取代之芳基或可視需要經取代之雜芳基; R為可視需要經取代之雜環基; R為氧、奴基或-C(=〇)-R5,其中R5為燒基、燒氧基、芳基, 或芳氧基;且 各R4分別獨立為氫、羥基、氰基、烷基、烷氧基、硫烷基、 故碗基、齒基、由烷基、羥烷基、硝基、烷氧羰基、烷羰 基、燒基績酿基、芳基績醯基、由燒續醯基、胺基、燒胺 基、一燒胺基、说基(芳基)胺基、燒胺基羰基、燒羰基胺基、 87762 1249402 烷羰基(烷胺基)、烷胺磺醯基、烷基磺醯基胺基或亞甲二氧 基氫、概基、燒氧基、_基、或齒燒基; 該方法包括由如下式經取代之吲哚:
R2· 、R3. 其中R2’為可視需要經取代之雜環基,可視需要使用保護基 保護;R3’為烷基或-C(=0)-R5,各R4'分別獨立為氫、羥基、 氰基、烷基、烷氧基、硫烷基、烷硫基、由基、函烷基、 經燒基、硝基、燒氧羰基、跪羰基、燒基績酿基、芳基續 醯基、由烷磺醯基、胺基、烷胺基、二烷胺基、烷基(芳基) 胺基、烷胺基羰基、烷羰基胺基、烷羰基(烷胺基)、燒胺磺 醯基、烷基磺醯基胺基或亞甲二氧基氫、烷基、烷氧基、 鹵基、或ί烷基,可視需要使用保護基保護, (a) 使用驗產生脫除質子之β丨嗓;及 (b) 由脫除質子之吲哚與如下式磺酸化劑接觸: y-scvr1,其中γ為鹵離子,或與如式·· W-s-s-r1二硫化劑 接觸,產生如下式之2-經取代之#丨嗓:
其中取代基之定義如上述, 87762 -10 - 1249402 (C)可視需要使用氧化劑氧化硫;及 (d)可視需要脫除保護基,產生如式ι2-經取代之%令。 (X)如(ix)之方法,其中γ為氟。 (xi) —種組合物,其包含·· ⑷醫療有效量之⑴至(viii)之式!化合物;及 (b)醫藥上可接受之載劑。 (xii) —種以一種或多種⑴至(viii)之化合物於製造醫藥, 供/口療或預防可利用5HT6促效劑減輕之疾病上之用途。 (xiii) 如(xii)之用途,其中該疾病包括⑶仏病變。 (XIV)如(xl11)之用途,其中該疾病包括精神病、精神*** 症、燥鬱症、神經病變、記憶障礙、專注力缺乏異常、 金森氏症、肌萎縮性侧索硬化、阿茲海默氏症與亨丁頓 症0 (XV)如(XH)之用途,其中該疾病包括胃腸道病變。 (xvi)如(xii)之用途,其中該疾病包括肥胖。 【實施方式】 除非另有說明’否則本申請案(包括說明書與申請專利 圍)中所使用之名詞定義如下。應注意,本說明書與附綠: 申請專利範圍所使用之,,一"、"一個"與"該”包括複數形^ 除非另有說明。 一種化合物或受體位置之活性之化 π促效劑π指可加強另 合物。 :燒基"指單價直鏈或分支之飽和煙部份基圏,其僅由与 與氫原子組成,具有】至12個碳原子,以m個較佳。燒屬 87762 • 11 - 1249402 5例包括(但不限於):甲基、乙基、丙基、異丙基、異丁基、 弟丁基弟一丁基、戊基、正己基、辛基、十二燒基, 等等。 烷氧基’,指如式_〇Ra部份基團,其中Ra為如本文中定義之 燒基。 ’’擷抗劑’’指可降低或防止另一種化合物或受體位置之作 用之化合物。 ”方基”指由單環或雙環之芳香系環組成之單價環狀芳香 炫邵份基團。該芳基可視需要經1、2或3個(較佳為1或2個) 取代基取代,其中各取代基分別獨立為羥基、氰基、烷基、 k乳基、硫燒基、卣基、鹵燒基、經燒基、硝基、燒氧談 基、燒羰基、烷基磺醯基、芳基磺醯基、鹵烷磺醯基、胺 基、燒胺基、二烷胺基、烷基(芳基)胺基、烷胺基羰基、烷 羧基胺基、烷羰基(烷胺基)、烷胺磺醯基、烷基磺醯基胺基 或亞甲二氧基,除非另有說明。較佳取代為烷基、烷氧基、 鹵基、或函烷基。芳基部份基團實例包括(但不限於):可視 需要經取代之苯基與可視需要經取代之莕基,等等。 ”芳氧基”指如式-〇Rb之部份基團,其中Rb為如本文中定 義之芳基。 ”環烷基”指由單環或雙環組成之單價飽和碳環部份基 團。該環烷基可視需要經一個或多個取代基取代,其中各 取代基分別獨立為羥基、烷基、烷氧基、函基、鹵烷基、 胺基、單烷胺基或二烷胺基,除非另有說明。環烷基部份 基團實例包括(但不限於):環丙基、環丁基、環戊基、環己 87762 -12- 1249402 基、壤庚基’等等。 Π疾病”指任何疾病、病症、症候或症狀。 齒基自離子與,齒素,,在本文中可交換使用,且指取 代基氟、氯、溴或碘,較佳為氟或溴。 ”齒烷基”指如本文中定義之烷基中一個或多個氫已被相 同或相異函素置換。卣燒基實例包括-CH2C1、-CH2CF3、 -CH2CC13、全氟坑基(例如:_CF3),等等。 雜万基指5至12個環原子之單價單環、雙環或三環芳香 系邵份基團,其中包含!、2、3或4個選自N、〇或3中之環 雜原子,其餘環原子為碳。#芳基環可視需要分別獨立經 一個或多個取代基取代,較佳為經丨或〗個取代基取代,該 取代基係選自··經基、氰基、燒基、燒氧基、硫燒基、烷 硫基、齒基、_烷基、羥烷基、硝基、烷氧羰基、烷羰基、 燒基%醯基、芳基磺醯基、卣烷磺醯基、胺基、烷胺基、 一烷胺基、烷基(芳基)胺基、烷胺基羰基、烷羰基胺基、烷 援基(坑胺基)、烷胺磺醯基、烷基磺醯基胺基或亞甲二氧 基’除非另有說明。較佳取代基為烷基、烷氧基、卣烷基 或函基。更明確言之,雜芳基包括(但不限於)吡啶基、呋喃 基、硫苯基、嘍唑基、異嘧唑基、***基、咪唑基、異噚 峻基、晚咯基、吡唑基、嘧啶基、苯并呋喃基、異苯并呋 喃基、苯并嘍唑基、苯并異嘍唑基、苯并***基、钊哚基、 異4卜木基、苯并$唾基、p奎琳基、異”奎琳基、苯并咪峻基、 苯并異嘮唑基、苯并硫苯基、二苯并呋喃基與苯并二吖呼 -2-酮-5-基,等等。 87762 -13- 1249402 ’’雜環基’’指由1至3個環組成之單價飽和部份基團,其中 包含1、2或3個選自Ν、0或S中之雜原子。雜環基環可视需 要分別獨立經一個或多個取代基取代,較佳為經1或2個取 代基取代,該取代基係選自:羥基、氰基、烷基、烷氧基、 礙烷基、烷硫基、函基、函烷基、羥烷基、硝基、烷氧羰 基、烷羰基、烷基磺醯基、芳基磺醯基、鹵烷磺醯基、胺 基、烷胺基、二烷胺基、烷基(芳基)胺基、烷胺基羰基、烷 羰基胺基、燒羰基(烷胺基)、烷胺磺醯基、烷基磺醯基胺基 或亞甲二氧基,除非另有說明。較佳取代基為烷基、烷氧 基、鹵烷基、或由基。更明確言之,雜環基一詞包括(但不 限於):嗎啉基、六氫吡畊基、六氫吡啶基、吡咯啶基、四 氫吱喃基、吖哩基,等等。 ”脫離基”指在合成有機化學中,與其字義有關之基團, 亦即可於取代反應之條件下被置換之原子或基團。咸了 解,特疋之脫離基依反應條件而定,包括依該脫離基所附 接之原子而足。例如:續醯基化合物之脫離基包括(但不限 於)鹵素、磺酸根,等等。 绸即劑”指可與標的物交互反應之分子。該交互反應包 括(但不限於):如本文中定義之促效劑、擷抗劑,等等。 ’’可視需要”指隨後所說明之事件或條件不一定會發生且 该說明包括發生孩事件或條件及不發生該事件或條件之情 況。 惰性有機溶劑”或”惰性溶劑”指該溶劑於相關說明之反 應條件下呈惰性,包括例如:苯、甲苯、乙腈、四氫呋喃、 87762 -14- 1249402 n,n-二甲基甲醯胺、氯仿、二氯甲烷、- —氟乙烷、***、 乙酸乙酯、丙酮、甲基乙基酮、甲醇、广舲 ^ 乙知、丙醇、異丙 每、第三丁醇、二吟垸、㈣,等等。除非另有說明,否 則本發明反應中所使用之溶劑為惰性溶劑。 ’’醫藥上可接受”指其適合製備之醫藥組合物通常為安 全、無毒且沒有生物上或其他方面不期望之性質,且包括 獸醫學及人類醫學可接受使用者。 化合物之”醫藥上可接受之鹽”指如本文中定義之醫藥上 可接受者,其具有所需之母化合物之醫藥性質。此等鹽類 包括: 1 / 與無機酸形成之酸加成鹽,此等酸如··鹽酸、氫溴酸、 硫酸、硝酸、磷酸,等等;或與有機酸形成之酸加成鹽, 此等酸如:乙酸、苯磺酸、苯甲酸、樟腦磺酸、擰檬酸、 乙磺酸、冨馬酸、葡庚酸、葡糖酸、麩胺酸、乙醇酸、羥 基莕甲酸、2-羥基乙磺酸、乳酸、馬來酸、蘋果酸、丙二 酸、扁桃酸、甲磺酸、黏康酸、2-苯磺酸、丙酸、水楊酸、 琥珀酸、酒石酸、對甲笨磺酸、三氟乙酸、三甲基乙酸, 等等,或 當母化合物中含有酸性質子時,其被金屬離子置換(例 如:驗金屬離子、鹼土金屬離子或鋁離子)形成鹽;或與有 機或换機驗配位形成鹽類。可接受之有機鹼包括二乙醇 胺、乙醇胺、N·甲基葡糖胺、三乙醇胺、三甲醇胺基甲烷, 等等。可接受之無機鹼包括氫氧化鋁、氫氧化鈣、氫氧化 鉀、碳酸鈉與氫氧化鈉。 87762 -15- 1249402 較佳之醫藥上可接受之鹽類為與乙酸、鹽酸、硫酸、甲 磺酸、馬來酸、磷酸、酒石酸、檸檬酸、鈉、鉀、鈣、鋅、 與鎂形成之鹽類。 咸了解,所有提及之醫藥上可接受之鹽包括該相同酸加 成鹽之如本又所疋義之溶劑加成型(溶合物)或結晶型(多晶 型)。 "前藥指化合物之醫藥用不活化型,其必須由個體接受 投藥後,在活體内代謝,例如··經生物液體或酵素代謝, 形成化合物之醫藥活性型,以產生所需之醫藥效果。前藥 可於吸收前、吸收期間或吸收後代謝,或在特定位置代謝。 雖然許多化合物之代謝作用主要發生在肝中,但幾乎所有 其他組織與器官(尤指肺部)均可進行程度不一之代謝作 用。可利用化合物之前藥型於例如··改善生體可用率、改 善個體之接受性,如:遮蔽或降低不宜人之特性,如··苦 味或腸胃刺激性、改善溶解性(如:經靜脈内投藥用時),提 供長效或延緩釋出或傳送、改善調配方便性、或提供定點 傳送化合物。本文所提及之化合物包括化合物之前藥型。 ’’保護基"指可在多官能基化合物中選擇性封阻一個反應 性位置之基團,以便於一般與其合成化學有關之另一個未 受保護之位置上選擇性進行化學反應。本發明某些製程依 賴保護基來封阻反應物中反應性氮與/或氧原子。例如:,,胺 基保護基”與”氮保護基,,名詞在本文中可交換使用,且指彼 等可於合成期間保護氮原子對抗不期望之反應之有機基 團。氮保護基實例包括(但不限於)三氟乙醯基、乙醯胺基、 87762 •16· 1249402 苯甲基(Bn)、苯甲氧羰基(甲酯基CBZ)、對甲氧苯甲氧羰 基、對硝基苯甲氧羰基、第三丁氧羰基(BOC),等等。同樣 地’ 11起基保護基π指彼等在合成過程中保護經基之氧原子 對抗不期望之反應之基團。輕基保護基之實例包括(但不限 於)··苯甲基、矽烷基、四氫吡喃基、酯,等等。習此相關 技藝之人士咸了解如何選用容易脫除且有能力抗拒接續反 應之基團。 π溶合物”指含有化學計量或非化學計量溶劑之溶劑加成 型。有些化合物可捕捉固定莫耳比例之溶劑分子形成晶體 狀態’因而形成溶合物。若溶劑為水時,則所形成之溶合 物為水合物,當溶劑為醇時,所形成之溶合物為醇合物。 水合物係由一個或多個水分子與其中一種物質組合形成, 其中水保留其分子態η2〇,此組合可形成一種或多種水合 物。 ”個體’’指哺乳動物與非哺乳動物。哺乳動物指哺乳動物 綱之任何成員,包括(但不限於)人類;非人類靈長類如:黑 Μ獲與其他類人猿及猴子屬;農場動物如:牛、馬、綿羊、 山羊與豬;家畜動物如:兔子、狗與貓;實驗室動物包括 嘆齒類如,大老鼠、小白鼠與天竺鼠;等等。非哺乳動物 實例包括(但不限於)鳥類,等等。”個體”一詞不代表特定年 齡或性別。 π醫療有效量”指該化合物之用量當投與個體供治療疾病 時,足以治療該疾病。”醫療有效量”將依化合物、所治療 之疾病、該治療疾病之嚴重性、該個體之年齡與相對健康 87762 •17- 1249402 狀況、投藥之途徑與型式、參與之醫師或獸醫之判斷、及 其他因素等而定。 當代號中提及"彼等如上述定義”與”如本文中定義,,時,包 括该等代號之廣義定義及若出現之任何較佳、更佳及最佳 定義。 疾病之,’治療,,或”處理”包括·· (0預防疾病,亦即使可能暴露到該疾病或有發生該疾 病傾向,但尚未經歷或出現該疾病症狀之個體不要發展出 该疾病臨床症狀。 (11)抑制疾病,亦即遏止該疾病或其臨床症狀發展,或 ㈣舒解疾病’亦即暫時或永久性消除該疾病或其臨床 症狀。 化學反應中所提及之,,處理”、,,接觸,,及"反應,,係指於適當 條件下添加或混合兩或多種試劑,以產生指定與,或所需 之產物咸了解,產生指定與/或所需之產物之反應不一定 =初所添加之兩種試劑組合直接產生,亦即,混合物中 可此產生一種或多種中間物,其最終才形成該指定與/或所 需之產物。 ^ ^本申請案所採用之命名法係依據AUTONOMtm 0係種Beilstein Institute之電腦化系統,以產生IUPAC 系統命名法。 本發明—方面提供如下式化合物: 87762 1249402
其醫藥上可接受之鹽或其前藥, 其中 η為0、1或2 ; η為2較佳; ρ為1或2,ρ為1較佳; R1為芳基或雜芳基; R2為雜環基; R3為氫、燒基或-C(=0)-R5,其中R5為烷基、烷氧基、芳 基或芳氧基;且 各R4分別獨立為氫、羥基、氰基、烷基、烷氧基、硫烷 基、烷硫基、鹵基、南烷基、羥烷基、硝基、烷氧羰基、 说羰基、烷基磺醯基、芳基磺醯基、函烷磺醯基、胺基、 烷胺基、二烷胺基、烷基(芳基)胺基、烷胺基羰基、烷羰基 胺基、烷羰基(烷胺基)、烷胺磺醯基、烷基磺醯基胺基或亞 甲二氧基;R4為氫、烷基、烷氧基、鹵基、或鹵烷基較佳。 咸了解’本發明範圍不僅包括可能出現之多種異構物, 亦包括該異構物可能形成之多種混合物。此外,本發明之 範圍亦包括式I化合物之溶合物與鹽類。 較佳者,R1為嘧吩基或笨基,其可視需要經一個或多個 選自下列各物組成之群中之取代基取代:烷基、燒氧基、 87762 -19- 1249402 鹵基、鹵燒基、_S〇yRa、_NRaRb、_NRb-C( = 〇)-Ra,其中 Ra 為烷基或芳基,Rb為氫或燒基,及其混合物。更佳者,R1 為嘍吩-2-基、苯基、2,夂二氯苯基、2_氟苯基、2_甲基苯基、 2-二氟甲基苯基或3-漠苯基。 較佳者’ R2為可视需要經取代之六氫p比啤基或六氫?比淀 基。更佳者’ R2為可视需要經取代之六氫说_ 基或六氫 叶匕淀-4-基。亦更佳者,R2為六氫吡畊-;[-基、仁甲基六氫吡 井1基3,5_一甲基六氫p比π井-1 -基、N-甲基六氫p比淀-4-基 或六氯说嗓-4-基。—項特定具體實施例中,以2為4_甲基六 氫吡畊_1-基。 較佳者,R3為氫或甲基。 較佳者,R4為氫。 此外,本文中說明之較佳基團之組合將形成其他較佳具 體實施例。例如·· ~项特別佳具體實施例中,R1為苯基,n 為2,R2為六氫基,R3為氫或甲基,且R4為氫。依此 万式,多種較佳化合物均包括在本發明範園内。 有些代表性式I化合物示於下表丨中: 表1·代表性式I化合物: 87762 •20- 1249402 # 名稱 結構式 M+H 實例 1 2-苯績醯基-7-六氫吡啡 〔N〕hCI hN 342 1 2 2-苯績醯基;(4-甲基-六 氫吡畊小基)_m-啕哚 (^fo 0 HC, 1 356 2 3 2-(2,3-二氯-苯績酿基)-7· 六氫p比p井-1-基-1H-4卜朵 N H Cl Cl CP HC, H 410 1 4 2-(2,3-二氯-苯續酿基)-7-(4_甲基·六氫p比呼_ 1 -基)-1H-巧丨哚 N Cl Cl 9 HC, 424 2 5 2-(2-氟-苯磺醯基)-7-六氫 吡畊-1-基-1H-吲哚 〔n〕二 Nh 360 1 6 2-苯續醯基·7·六氫p比淀-4-基·1Η-吲哚 LnJ hci H 339 3 7 2-苯磺醯基-7-(1-甲基-六氫0比淀-4_基)_1!1-<嗓 Wi-o kNJ HCI 1 355 4 87762 -21 - 1249402 # 名稱 結構式 Μ+Η 實例 8 7·(4_甲基-六氫吡__1-基> 2_(2_三氟甲基-苯續醯基 1Η-啕哚 W-1-P F3C 1 424 4 9 7-六氫ρ比_小基_2·(2_ 三氟甲基"苯續S蠢基)-1Η-啕哚 0 F3C Η 410 ! 3 10 2·(3-溴-苯磺醯基)-7-(4-甲基-六氫叶卜井_1·基-1H- 片1噪 N Br Ο ΐ 435 4 11 2-(3_溴-苯橫醯基)-7_六氫 吡畊-基-1H-巧丨哚 — Ν ΰΓ Ο 421 1 3 ί ; 本發明另一方面提供〜種組合物,其包含醫療有效量之 式I化合物及醫藥上可接受之載劑。 本發明另一方面提供一種治療個體之CNS疾病之方 法’其包括對該個體投予醫療有效量之式j化合物。較佳者 該疾病包括精神病、精神***症、燥鬱症、神經病變、記 憶障礙、專注力缺乏異常、巴金森氏症、肌萎縮性侧索硬 化、阿茲海默氏症與亨丁頓氏症。 87762 -22- 1249402 本發明另一方面提供一種治療個體之胃腸道病變之方 法,其包括對該個體投予醫療有效量之式I化合物。 本發明另一方面提供一種治療個體肥胖之方法,其包括 對該個體投予醫療有效量之式I化合物。 本發明另一方面提供一種製造式I化合物之方法。 本發明化合物可依下文所示及說明之合成反應圖闡述之 多種方法製備。 製備此等化合物所使用之起始物與試劑通常可自商品供 應商取得,如:Aldrich Chemical Co.,或可採用習此相關 技藝之人士已知之方法,依參考文獻中所示之方法製備, 如:Fieser and Fieserfs Reagents for Organic Synthesis, Wiley & Sons: New York,1991,Volumes 1-15; Rodd’s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals ;及 Organic Reactions,Wiley & Sons:New York,1991,Volumes 1-40。下列合成反應圖僅 供說明合成本發明化合物之一些方法,及在本申請案所含 揭示内容中對此等合成反應圖可進行之多種不同修正及對 習此相關技藝之人士提供之建議。 合成反應圖之起始物與中間物若需要時,可依一般技術 單離及純化,其包括(但不限於):過濾、蒸餾、結晶、層析, 等等。此等物質之特性可採用一般方式判別,包括物理常 數與光譜數據。 除非另有說明,否則本文所述之反應最好在惰性蒙氣 下,於常壓下,反應溫度為約-78°C至約150°C之範圍下, 87762 -23- 1249402 更佳為約Ot:至約125〇C下,最佳且適宜在約室溫(或常溫) 下進行,例如:約20°C下。 一項具體實施例中,式I化合物之製法為由如下式經取代 之吲哚進行脫質子反應:
其係與鹼反應,添加如式:Y-SOyR1磺酸化劑,其中R1、 R與R如本文中定義,R3為燒基或{(=〇)15,其中R5如本 文中定義,Y為脫離基,以函離子較佳,以氟離子更佳。咸 了解,當R2與/或R4具有一個或多個酸性質子(相對於所使用 之鹼)時,應使用適當保護基保護。保護此等酸性質子之保 護基係習此相關技藝之人士習知者,且依該酸性質子之性 質而定,例如:依其是否為胺基質子或羥基質子,等等而 定。 鹼之強度應足以主要脫除啕哚環系之2_位置上質子。此 等鹼係習此相關技藝之人士習知者,包括有機金屬化合 物,如:有機鋰,例如:第三丁基鋰’及格林納試劑(Gdgnard reagents),例如:第三丁基鎂卣化物。通常,脫質子反應係 於約〇 c或以下溫度進行,較佳為約_4(rc或以下溫度,更 佳為約-7〇°C或以下溫度。典型之脫質子反應係於約_75β(:下 進行。 合適之磺酸化劑包括芳基磺醯基_化物,例如:芳基磺 87762 -24- 1249402 醯基氟化物。芳基磺醯基氟化物很容易由相應之芳基磺醯 基氯化物經氟離子來源處理’如:氟化钾或其他合適金屬 氟化物。芳基磺醯基氯化物轉化成其相應氟化衍生物之反 應主要涉及芳基磺醯基氯化物與氟化鉀,於惰性有機溶劑 中(如:1,4-二哼烷)之反應。該反應通常於回流條件下進行 約1至約48小時,典型約24小時。通常,於反應中使用過量 氟化鉀,以後在水洗過程中即可排除。所得之芳基磺醯基 氟化物典型地不再進行任何純化即可使用。 或者,式I化合物之製法亦可由脫除質子之峋哚基與如 式:R^-S-S-R1二硫化物試劑反應,產生如下式之硫醚:
其中p、R1、R2、R3與R4如本文中定義。典型地,添加二 硫化物試劑至脫除質子之吲哚中,於相同溫度下添加鹼。 然後於該溫度下攪拌反應混合物數分鐘至數小時,典型為 約1至2小時,使之慢慢回升至室溫。 式III硫醚化合物可使用氧化劑氧化,形成相應之亞砜與/ 或砜。合適之氧化劑包括間氯過苯甲酸(MCpBA)、過碘酸 鹽、過氧單硫酸鉀(〇xone®),及習此相關技藝之人士已知 之其他硫氧化劑。例如:硫醚Iu可與MCpBA反應,其係由 兩種試劑於約01下,於惰性溶劑中組合,如:二氯甲烷, 並於罜溫下攪拌混合物數小時。過量之MCpB A典型地經由 水性溶液,較佳為鹼水溶液洗滌而脫除。氮原子之任何不 87762 -25- 1249402 期望之氧化反應可經由膦化合物(如:三苯基膦)中止粗產物 之反應而減少。 當R1或R2基團含有保護基或當R3'為保護基時,此等保護 基可在合成後採用習此相關技藝之人士已知之一般反應條 件脫除。參見例如:Protective Groups in Organic Synthesis, 第 3版,T.W. Greene and P.G.M. Wuts,John Wiley & Sons, New York,1999,其揭示内容已以引用之方式完全併入本文 中 〇 有關製備式I化合物之更詳細内容已說明於實例中。 本發明化合物具有選擇性5-HT6受體親和性,適用於治療 某些CN S病變,如:巴金森氏症、亨丁頓氏症、焦慮症、 抑鬱症、燥鬱症、精神病、癲癇、強迫觀念與強迫行為性 病變、偏頭痛、阿茲海默氏症(加強認知記憶力)、睡眠障礙、 進食異常如:厭食症與貪食症、恐慌症、專注力缺乏過動 異常(ADHD)、專注力缺乏異常(ADD)、自毒品脫癮如:古 柯鹼、酒精、尼古丁與苯并二吖呼,精神***症、及與脊 柱創傷與/或頭部傷害如:腦積水有關之病變。此外,本發 明化合物亦可用於治療某些胃腸道(GI)病變,如:腸功能異 常。 本發明化合物之藥理學可採用相關技藝已知之方式測 定。以放射性配位體結合性分析法及功能性分析法測定試 驗化合物於5-HT6受體之親和性之活體外技術說明於實例 6-8 中。 本發明包括醫藥組合物,其包含至少一種本發明化合 87762 •26- 1249402 物,或其個異構物、異構物之消旋或非消旋混合物或其醫 藥上可接受之鹽或溶合物,及至少一種醫藥上可接受之載 劑與可視需要選用之其他醫療劑與/或預防性成分。 通常,本發明化合物將依類似用途之藥劑所採用之任何 可接受之投藥模式投予醫療有效量。合適劑量範圍典型為 每天1-500 mg,以每天1_1〇〇 mg較佳,以每天13〇 mg最佳, 依多種因素而定,如··所處理之疾病嚴重性、患者之年齡 與相對健康狀況、所使用化合物之藥效、投藥途徑與形式、 該投藥法之適應症、及所參與之醫師之偏好與經驗。處理 此等疾病之習此相關技藝之人士不需太多試驗即可依據其 個人知識及本申睛案之揭示内容來決定本發明化合物針對 特別疾病之醫療有效量。 通常,本發明化合物將以醫藥調配物形式投藥,包括彼 等適合經口(包括經頰内與舌下)、直腸、鼻内、局部、肺部、 ***或非經腸式(包括經肌内、動脈内、椎管内、皮下與靜 脈内)投藥,或呈適合吸入或吹入之投藥形式。較佳投藥方 式通承為使用合:!:之每日劑量療程經口投藥,該療程可依 據病症程度調整。 本發明化合物可與-種或多種常用辅劑、載劑或稀釋濟 共同形成醫藥組合物或單位劑型。該醫藥組合物或單位濟 土可匕;I比例之_般成分,含或不含其他活性化合糸 或活性成分’ JL單位劑型可配合所需使用之每日劑量車 圍’包含任何合適有效量之活性成分。所使用之醫藥組‘ 物可主口虹,如·錠劑或填充膠囊、半固體、粉劑、持与 87762 -27- 1249402 釋出性調配物、或液體如:溶液、懸浮液、乳液、酏劑、 或口服用之填充膠囊;或呈直腸或***投藥用之塞劑;或 呈非經腸式投藥用之無菌注射液。合適之代表性單位劑型 為包含約1毫克活性成分之調配物,或更廣義而言,為每錠 約0.01至約100毫克。 本發明化合物可調配成多種經口投藥劑型。該醫藥組合 物與劑型可包含本發明化合物或其醫藥上可接受之鹽作為 活性成分。醫藥上可接受之載劑可呈固體或液體。固體型 製劑包括粉劑、錠劑、丸劑、膠囊、扁囊劑、塞劑與勻散 性粒劑。固體載劑可為一種或多種亦可作為稀釋劑、調味 劑、溶解劑、潤滑劑、懸浮劑、結合劑、防腐劑、錠劑崩 解劑或包埋材料之物質。粉劑中之載劑通常為與細碎活性 成分形成混合物之細碎固體。錠劑中之活性成分通常與具 有必要之結合能力之載劑,依適當比例混合,並壓製成所 需形狀與大小。粉劑與錠劑最好包含約!至約7〇%活性化合 物。合適載劑包括(但不限於)碳酸鎂、硬脂酸鎂、滑石、糖、 乳糖、果膠、糊精、澱粉、明膠、黃耆膠、甲基纖維素、 羧甲基纖維素鈉、低熔點蠟、可可奶油,等等。,,製劑,,一 詞包括活性化合物與作為載劑之包埋材料之調配物,所形 成膠囊中之活性成分(含或不含載劑)則被與之組合之載劑 包圍。同樣地’亦包括爲囊劑與***錠。鍵劑、粉劑、膠 囊、丸劑、扁囊劑與***錠為適合經口投藥之固體劑型。 其他適合經口投藥之劑型包括液體劑型,包括乳液、糖 漿、酏劑、水溶液、水性懸浮液,或固體劑型,其係供於 87762 -28- 1249402 臨用前方製成液體劑型。乳液可製成溶液,例如:水性聚 乙二醇溶液,或可包含例如,如··卵磷脂、單油酸山梨糖 醇酐酿或金合歡膠。水溶液之製法可由活性成分溶於水 中,添加合適著色劑、調味劑、安定劑與增稠劑。水性懸 浮液之製法為由細碎之活性成分勻散於含有黏性物質 (如:天然或合成膠、樹脂、甲基纖維素、羧甲基纖維素鈉 及其他習知之懸浮劑)之水中。固體劑型包括溶液、懸浮 液、與乳液,其中除了活性成分外,尚包含著色劑、調味 劑、安定劑、緩衝劑、人工與天然甜味劑、勻散劑、增稠 劑、溶解劑,等等。 本發明化合物可調配成非經腸式投藥用(例如:注射,例 如·大丸劑注射或連續輸液)且可含在安瓶、預填充之針 筒、小體積輸液中形成單位劑型或可含在多劑量容器中, 並添加防腐劑。組合物可於油性或水性媒劑中形成懸浮 液、溶液或乳液,例如:於水性聚乙二醇中形成溶液。油 性或非水性載劑、稀釋劑、溶劑、或媒劑實例包括丙二醇、 聚乙二醇、植物油(例如:橄欖油),與注射用有機酯類(例 士 ’由酸乙酉曰),且可包含调配劑如:防腐劑、濕化劑、乳 化劑或懸浮劑、安定劑與/或勻散劑。或者,活性成分可呈 粉末形式,其可由無菌固體經過無菌單離法製得或由溶液 經冷凍乾燥法製得,使用前方與合適媒劑再組成,例如: 使用播囷、無熱原水再組成。 本發明化合物可調配成局部投藥至表皮上之油膏、乳霜 或洗液,或呈穿皮式貼劑。油膏與乳霜可使用例如··水性 87762 -29- 1249402 或油性基質’添加合適增稠劑與/或膠凝劑調配。洗液可使 用水性或油性基質調配,且通常亦包含一種或多種乳化 劑、安定劑、勻散劑、懸浮劑、增稠劑或著色劑。適合局 邵投藥至口中之調配物包括***錠,其係於有調味之基質 中包含活性劑,該基質通常為蔗糖與金合歡膠或黃耆膠; 糖衣錠係於惰性基質中包含活性成分,該基質為如:明膠 與甘油或蔗糖與金合歡膠;且漱口水係於合適之液態載劑 中包含活性成分。 本發明化合物可調配成塞劑投藥。首先熔解低熔點蠟, 如:脂肪酸甘油酯或可可奶油之混合物,然後均勻分散活 ^生成刀,例如·加以攪拌。熔化之均勻混合物再倒至合宜 大小之模型中,使之冷卻,及固化。 發月化口物可调配成***投藥用。子宮托、衛生棉條、 礼相凝膠膏劑、泡沐劑或嘴劑中除了活性成分外,尚 包含相關技藝已知之適當載劑。 本發明化合物可調配成鼻内投藥用。可依-般方式直接 t用溶液或懸浮液至鼻腔中,例如··使用滴藥器、吸管或 嘴配物可呈單劑量型或多劑量型。滴藥器或吸管 < ^劑量型可由患者施用預定適當#曲積之a涂七# p 成。若使用噴霧器時,可使4;\洛液或懸洋液達 本發月化5物可調配物成氣霧劑投藥,特定言之 呼吸道上,包私絲鲁七一 朱主 如:5微米或以 。化合物之粒子大小通常為例 計編.T。此寺粒子大小可依相關技藝已知之方式 例如.微粉化。活性成分可裝在含有合適推進刺(如 87762 -30 - 1249402 氯氟碳化物(CFC),例如匕氯二氟甲垸、三氯氣甲燒或二 氯四氟乙烷)或二氧化碳或其他合適氣體之加壓罐中。氣霧 劑宜亦包含界面活性劑如:印嶙脂。藥物之劑量可利用定 量閥控制。或者’活性成分可呈乾粉狀,例如:化合物於 合適粉末基質(如:乳糖、澱粉、澱粉衍生物如:羥丙基甲 基纖維素與聚乙烯峨錢酮(PVP))中之粉末混合物。粉末 載劑將於鼻腔中形成凝膠。粉末組合物可呈單位劑型,例 如:明膠或發泡包之膠囊或卡管,然後經由吸藥器投予粉 若需要時’調配物可使用適合持續釋出或控制活性成分 釋出投藥之腸溶性包衣製備。例如:本發明化合物可於穿 皮式或皮下藥物傳送裝置中調配。當需要持續釋出化合物 及當極需要患者適應療程時,此等傳送I统較有利。穿皮 式傳送系統中之化合物經常附著在黏貼皮膚之固態擔體 上。所需之化合物亦可與渗透加強劑組合m職(1· 十二燒基氮雜環舰·2·酮)。持續釋出之傳送系統係經由手 術或注射嵌入皮下層。皮下植入物則將化合物包埋在液體 可溶性膜中’例如:秒膠,或生物可降解之聚合物,例如: 聚乳酸。 酱藥製劑最好呈單位劑型。此等形式之製劑細分成含有 適量活性成分之單位劑量。單位劑型可包裝成製劑,該包 裝中則包含分開劑量之製劑,如:包裝錠劑、膠囊,及含 在小瓶或安瓶中之粉劑。此外,單位劑型亦可為膠囊、鍵 劑、扁囊劑或***錠本身,或可以適當數量之其中任-種 87762 -31- 1249402 形成包裝形式。 其他合適之醫藥載劑與其調配物說明於Remington: The
Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company,第 19 版,Easton, Pennsylvania。含有本發明化合物之代表性醫藥調配物說明 於實例6-12中。 實例 下列製法與實例將使習此相關技藝之人士更詳細了解及 操作本發明。此等實例不應視為本發明之限制範圍,其僅 供說明及代表用。 實例1 本實例說明採用下文所示合成反應圖製備式I化合物之 方法: 2 _苯磺醯基-7 六氫吡啡-1 -基_ 1K哚之製法
1-1 1-2 1-3 1-4 1 步騾1 於室溫下,在含啕哚1-1 (1.22 g,4.0 mmol)之 THF (40 mL) 溶液中依序添加二碳酸二-第三丁酯(1.3 g,6.1 mmol)與 DMAP (56 mg,0·46 mmol)。反應混合物於室溫與氮氣流下 攪拌3小時後,真空濃縮。所得殘質分溶於乙酸乙酯(50 mL) 87762 -32- 1249402 與飽和碳酸氫鋼水溶液(50 mL)之間。有機層經飽和碳酸氛 鈉水溶液(2 X 25 mL)、鹽水(25 mL)依序洗滌。有機層脫水 (MgS04),過濾與濃縮,產生透明油狀物。該油狀物經矽膠 層析,以己烷/乙酸乙酯(23:1)溶離,產生1.5 g (93%) boc-六氫峨p井boc_4卜朵1 _2,為白色固體。(Μ+Η)+=402·2。 步騾2 於惰性蒙氣下,在_75°C之含雙-boc-<哚1-2 (500 mg,1.25 mmol)之 THF (25 mL)溶液中慢慢添加 t-BuLi (1.47 mL,2.5 mmol)。攪拌反應混合物30分鐘,此時添加二苯基二硫化物 (340 mg,1 ·63 mmol)。攪拌反應1.5小時後,使之回升至室 溫(45分鐘)。反應混合物經飽和氯化銨溶液(55 mL)中止反 應,以乙酸乙酯(3 X 20 mL)萃取。合併之乙酸乙酯層經鹽 水(25 mL)洗滌,脫水(MgS04),過濾與濃縮,產生黃色油 狀物。該油狀物經矽膠層析,以己烷/乙酸乙酯(23:1)溶離, 產生440 mg (69%) 2-苯基硫醚-7-六氫吡啡-1-基啕哚1-3。 步驟3與4 於0°C下,在含化合物1-3 (440 mg,0.86 mmol)之二氯甲 燒(40 mL)溶液中添加 MCPBA (745 mg,3.02 mmol)。使反應 回升至室溫,攪拌5小時,此時添加三苯基膦(271 mg,1.03 mmol)。於室溫下攪拌反應混合物一夜。反應混合物分溶於 水(50 mL)與二氯甲烷(50 mL)之間。有機層經1M氫氧化鈉(3 x35 mL)與鹽水(35 mL)洗滌。有機層脫水(MgS04),過濾與 濃縮。所得油狀物經矽膠層析,以己烷/乙酸乙酯(17:3)溶 離,產生 160 mg (34%)產物 4-4。M+H=542。 87762 -33 - 1249402 步驟5 取含化合物1 _4 (160 mg,0·3 mmol)之異丙醇(15 mL)與濃 HC1 (4 mL)溶液回流1小時。反應混合物濃縮,所得粉末與 異丙醇(10 mL)及醚(20 mL)磨製。過濾後,產生表1之化合 物 1,為白色固體(90 mg,89%)。M+H=342。 同樣地,依上述相同方式合成上表1之化合物3與5: 2-(2,3-二氯-苯績醯基)_7-六氫咐;_-1-基-111-4丨嗓與2-(2-氟-苯磺醯基)_7_六氫吡畊-1-基·1Η-吲哚。 實例2 本實例說明表1中化合物2之製法。 2-苯磺醯基-7-(4-甲基-六氫吡畊-1-基)-1Η-峭哚
在含表1中化合物1(參見上述實例1)(340 mg,1.04 mmol) 之THF (50 mL)溶液中添加甲 (37%,0.4 mL,5·2 mmol)後, 添加三乙醯氧基氫硼化鈉(330 mg,1.56 mmol)。於室溫下 攪拌反應混合物24小時。混合物分溶於乙酸乙酯(50 mL)與 水(50 mL)之間。乙酸酿層經鹽水洗ί條,脫水(MgS〇4),濃 縮,產生白色固體。固體溶於醚(3〇 mL)中,以過量1M HC1 之醚溶液處理。收集白色沉澱,乾燥,產生純產物(表1之 化合物2)。 同樣地,依上述相同方式合成表1之化合物4 : 2-(2,3-二 87762 -34- 1249402 氯-苯磺醯基)-7-(4-甲基-六氫吡啡-1-基)_ι η-吲哚。 實例3 此實例說明表1之化合物6之製法:2-苯磺醯基-7-六氫吡 淀-4-基丨嗓。
步驟1 取含7-溴巧哚(1.25g,6.4 mmol)之THF (15 mL)溶液於氬 氣下冷卻至_70°C ’以20分鐘時間添加n_BuLi(9.6mL,19.2 mmol)。使反應混合物於冰浴中回升至-5°C,於此溫度下攪 拌30分鐘。混合物冷卻至-70 °C,以15分鐘時間添加含 N-Boc-六氫口比淀酮(2.5g,12.8 mmol)之 THF (10 mL)溶液。 反應於-70°C下攪拌45分鐘後,回升至室溫。加水(1〇 mL) 中止反應,分溶於水(25 mL)與乙酸乙酯(50 mL)之間。有機 層經水(15 mL)與鹽水(30 mL)洗藤後,脫水(MgS04),過濾, 與濃縮。殘留之褐色油狀物經層析,以丙酮:己烷(1:4)溶 離,產生1·17 g (收率58%) 4-羥基-4-(1Η_吲哚-7_基)-六氫吡 啶_1_羧酸第三丁酯XVI。 87762 -35- 1249402 步驟2 取4-羥基-4-(1Η-吲哚-7_基)_六氫吡啶-1_羧酸第三丁酯 XVI (1.17 g,3.7 mmol)與吡啶(20 mL)及磷醯氯(0.7 mL,7.4 mmol)於室溫與於氮蒙氣下合併,攪拌一夜。反應分溶於乙 酸乙酯(55 mL)與水(55 mL)之間。乙酸乙酯層經水(2X30 mL) 與鹽水(55 mL)洗滌後,脫水(MgS04),過濾與濃縮,產生(700 mg,64%) 4·(1Η-4 丨哚-7-基)_3,6_ 二氫-2H-吡啶 _1-羧酸第三 丁酯 XVII。 步騾3 取含4-(1Η-β丨哚-7-基)-3,6-二氫-2Η-吡啶-1_羧酸第三丁酯 XVII (700 mg,2.3 mmol)與 10% Pd/C (70 mg)之乙醇(75 mL) 混合物於氫蒙氣下,於帕爾振靈器上,於50 psi下振盪:一 夜。反應混合物經蓋上玻璃濾器之寅氏鹽填料過濾。濾液 濃縮,產生(680 mg,95%) 4_(1Η-β|哚-7-基)_六氫吡啶-1-羧酸第三丁酯XVIII。 步驟4 於室溫下,在含4-(1Η-蜊哚-7-基)-六氫吡啶_1_羧酸第三 丁酯 XVIII (360 mg,1.2 mmol)之 THF (30 mL)溶液中添加二 碳酸二第三丁酯(262 mg,1.2 mmol)後,添加觸媒量DMAP (5.6 mg,0.046 mmol·)。反應混合物於室溫與於氮蒙氣下攪 拌24小時,此時汽提反應混合物。所得殘質分溶於乙酸乙 酉旨(50 mL)與飽和碳酸氫納(50 mL)之間。有機層經飽和碳酸 氮鈉(2 X 25 mL)及鹽水(25 mL)洗滌。有機層脫水(MgS04), 過濾與濃縮,產生透明油狀物。此油狀物經矽膠層析,以 87762 -36- 1249402 己烷/乙酸乙酯(23:1)溶離,產生400 mg (83%) 7-(1-第三丁氧 羰基-六氫吡啶-4-基)-吲哚·1-羧酸第三丁酯XIX。 步騾5 在-75°C之含7-(1-第三丁氧羰基-六氫吡啶-4-基)_吲哚-b 羧酸第三丁酯 XIX (440 mg,1 ·0 mmol)之 THF (20 mL)溶液中 慢慢添加t-BuLi (1.2 mL,2·0 mmol)。反應混合物於_75°C下 攪拌45分鐘,添加苯磺醯基氟化物(0.2 mL,1.6 mmol,參 見下文中實例4)。反應攪拌2.5小時,此時離開冷卻槽,使 反應回升至室溫。添加飽和氯化铵溶液(25 mL)中止反應, 以乙酸乙酿(3 X 20 mL)萃取。合併之乙酸乙酯層經鹽水(25 mL)洗滌,脫水(MgSCU),過濾與汽提後,產生黃色油狀物。 此油狀物經矽膠層析,以己燒/乙酸乙酯(4:1)溶離,產生(330 mg,60%)產物2-苯磺醯基-7-(l-第三丁氧羰基_六氫吡啶_4-基)-啕哚-1-羧酸第三丁酯XX。 步騾6 取2-苯績酿基-7-(1-第三丁氧羰基·六氫p比淀基)-吲嗓 -1-羧酸第三丁酯XX (330 mg,0.61 mmol)溶於1M HC1之乙 醇溶液(30 mL)中,加溫至回流。2.5小時後,冷卻反應混合 物至室溫,添加醚(30 mL)。收集白色沉澱,產生21〇 mg (91%) 產物2-苯確g蠢基-7-六氫ρ比咬-4_基)-1 丨嗓XXI。 同樣地’依相同方式合成上述表1之化合物9與η : 7-六 氫吡畊-1-基-2-(2-三氟甲基-苯磺醯基)_1H-T7?|哚與2_(3-溴_ 苯磺醯基)_7_六氫吡畊小基-1H-吲哚。 實例4 87762 -37- 1249402 本實例說明苯磺醯基氟化物之製法。
二噚烷 KF,回流
4 添加氟化4甲(99%)(12 g,216 mmol)至含苯績醯氯(51 mmol) 之1,4_二$燒(35 mL)溶液中。反應混合物回流24小時後, 冷卻至室溫,倒至冰水(200 mL)中。以氯仿(3 X 50 mL)萃取 冰水。合併之氯仿層脫水(MgS04),過濾與濃縮,產生苯磺 酿基氟化物(4)。 實例5 本實例說明表1之化合物7之製法:2-苯磺醯基甲基_ 穴氣p比- 4 _基) 1Η - β | 口朵
一次添加全量三乙醯氧氫硼化鈉(110 mg,0.52 mmol)至 惰性蒙氣下,含2·苯磺醯基-7_六氫吡啶-4_基)-1H-啕哚XXI (130 mg,〇·34 mmol,參見上述實例 3)與甲醛(30%)(0.14 mL, 1·7 mmol)之THF (20 mL)溶液中。反應攪拌24小時後真空濃 縮。殘質分溶於1 M氫氧化鈉(25 mL)與乙酸乙酯(25 mL)之 間。水層經乙酸乙酯(2 X 15 mL)萃取。合併之有機層脫水 (MgSCU),過濾,添加HC1之醚溶液至濾液中。收集沉澱, 87762 -38- 1249402 產生130 mg (98%) 2·苯磺醯基-7-(1-甲基-六氫吡啶-4-基)-1H-W丨哚XXIII,為白色粉末。 同樣地,依上述相同方式合成表1化合物8與10 : 7-(4-甲 基-六氫吡畊-1-基)-2-(2-三氟甲基·苯磺醯基)-1Η-啕哚與 2-(3溪·苯橫酿基)-7-(4 -甲基-7T氯ρ比口井-丨-基丨卩朵。 實例6 本實例說明式I化合物之活體外放射性配位體結合性試 驗。 本發明化合物之活體外結合活性測定法如下。於衍生自 安定表現重組人類5-HT6受體之HEK293細胞之細胞膜中測 定競爭性結合[3H] LSD之配位體親和性,進行兩重覆。 所有測定法均於含 50 mM Tris-HCl,10 mM MgS04,〇·5 mM EDTA,1 mM抗壞血酸,pH 7.4,37°C下,250微升反應 體積之分析緩衝液中進行。分析試管包含[3H] LSD (5 nM) (競爭性配位體)與膜,於振盪水浴中,於37°C下培養60分 鐘,使用Packard 96孔細胞收集器過滤至Packard GF-B分析 板上(先浸泡〇·3% PEI),以冰冷之50 mM Tris-HCl洗滌3 次。採用Packard TopCount測定結合之[3H]LSD,以每分鐘 之放射活性數表示。 取濃度-結合性數據代入4-參數之對數公式中,定量結合 位置上[3H]LSD之置換量: 減性=底線值Bmax~卷座直—-1 其中Hill為Hill斜率,[配位體]為競爭性放射性配位體濃 87762 -39· 1249402 度’ ICm為放射性配位體產生最大專一結合性之一半值時之 放射性配位體濃度。專一結合性空窗為Bmax與底線參數值 之間之差異。 實例7 採用實例6之過程,測試式I化合物,並發現其係選擇性 5 -HT6擴抗劑。代表性活性示於表2。 表2放射性配位體結合性數據 # 名稱 pKi 3 2-(2,3 -一氣-冬績s盛基)-7•六氯p比p井-1-基· 1H-W 嗓 9.7 5 2-(2-氟-苯磺醯基)-7-六氫吡畊-1-基-1H-峭哚 9.3 8 (4-甲基·六氫吡畊-1·基)_2-(2-三氟甲基-苯磺 醯基]哚 9.5 9 六氫吡畊-1·基-2-(2-三氟甲基-苯磺醯基)-iH- 9.5 10 2-(3-溴-苯磺醯基)-7-(4-甲基-六氫吡畊-1-基) 1H_旧哚 9.6 本發明化合物之認知力加強性質可於動物之認知力模式 中測定:物體認知力模式。採用4個月大之雄性Wistar大老 鼠(荷蘭Charles River公司)。每天製備化合物,溶於生理食 鹽水中,測試三種劑量。總是在T1前60分鐘經i p投藥(注 87762 -40- 1249402 射體積1 mL/kg)。注射化合物後30分鐘,注射莨菪驗 (Scopolamine)氫溴酸鹽。由24隻大老鼠分成兩組同等試驗 組,進行兩種試驗。隨機進行劑量試驗之順序。採用雙盲 法進行試驗。所有大老藏均接受一種劑量條件處理一次。 依Ennaceur,A” Delacour,J·,1988,A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav. Brain Res. 31,47-59說明之方法進行物體認知力試 驗。 雖然本發明已參考其明確具體實施例加以說明,但習此 相關技藝之人士咸了解,可在不偏離本發明精神與範圍下 進行多種變化及改用同等物替代。此外,可配合特定情況、 材料、物質之組成、製程、製程步驟、本發明之主題精神 及範圍進行許多修飾。所有此等修飾均在附錄之申請專利 範圍内。 87762 -41 -
Claims (1)
- Ι249^)&125197號專利申請案 中文申請專利範圍替換本(94年10月) 拾、申請專利範園: •’ I; 1.…一種如下式化合物,或其醫藥上可接受之鹽’ 其中 η為〇、1或2 ; Ρ為1或2 ; R1為可視需要經取代之芳基; R2為可視需要經取代之雜環基; R為氫或垸基; 各r4分別獨立為氫、羥基、氰基、烷基、烷氧基、硫 烷基、烷硫基、鹵基、烷基、羥烷基、硝基、胺基、 燒胺基、二燒胺基、燒基(芳基)胺基; π燒基”本身或與其它基團組合包含高至6個碳原子;及 ^元氧基”包含高至6個碳原子。 2.根據申請專利範圍第1項之化合物, 其中 η為2 ; Rl為可视需要經取代之芳基; R為可視需要經取代之雜環基; R為氫;且 87762-941004.doc 1249402 R為氯。 3.根據申請專利範圍第2項之化合物,其中r2為六氯七井·卜 基或六氫峨淀-4-基,其可視需要經燒基取代。 《根據申請專利範圍第3項之化合物,其中r2為六氯^井.卜 基4-甲基穴氫吡畊_卜基、N_甲基六氫吡啶_4·基或六氫 吡啶基。 根據申明專利範圍第2項之化合物,其中Ri為可視需要經 取代之苯基。 6.根據申請專利範圍第5項之化合物,其中r1為苯基,其可 視需要經烷基、南基或卣烷基取代。 7·根據申請專利範圍第ό項之化合物,其中R!為苯基、2,夂 一氯苯基、2-氟苯基、2-三氟甲基苯基或3_溴苯基。 8·根據申請專利範圍第2項之化合物,其為: 2-表磺酿基-7·六氫p比p井-1-基-He卜朵, 2-苯磺醯基-7-(4-甲基-六氫吡畊-丨哚, 2-〇—氯-苯績酸基)-7-六氫p比呼_1_基_ 丨嗓, 2-(2,3-二氯_苯磺醯基>7-(4-甲基-六氫吡畊_卜基)丨 哚, 2-(2 -氟-苯磺醯基)_7_六氫p比啡-i-基_ΐΗ-β丨嗓, 2·苯磺醯基-7-六氫吡啶·4-基_1H-吲哚, 2-苯績醯基-7-0甲基-六氫吡啶-4-基)-lH-Hh朵, 7-(4-甲基-六氫吡p井-1-基)-2-(2-三氟甲基-苯績醯基)·1Η_ ρ引嗓, 7-穴氣峨啡-1-基-2-(2-三氟甲基-苯績酸基)_1^;-4丨啤, 87762-941004.doc -2- 4 41249402 2-(3-溴-苯磺醯基)_7_(心甲基_六氫吡畊基)_ih_吲哚, 2 (3 /臭表’驗基)-7-六氫17比0井_1_基·1Η-吲嗓。 9· 一種製備如下式2_經取代之⑷哚之方法,,、中n p、r、r2、r3&r4如申請專利範圍第上項所述, 忒方法包括由如下式經取代之4丨嗓:其中R2為可視需要經取代之雜環基,可視需要使用保護 基保濩,R為烷基或保護基<(=0)-R5(其中R5係烷基、烷 氧基、芳基或芳氧基),各R4’如同申請專利範圍第工項中 所載R4 ’但視情況使用保護基保護, (0 使用鹼產生脫除質子之吲哚;及 (11)由脫除質子之吲哚與如下式磺酸化劑接觸: Y-SCVR1,其中γ為鹵離子,或與如式:rLs_S-R1二硫化 劑接觸,產生如下式之2-經取代之4嗓:87762-941004.doc III 1249402 ^ 其中取代基之定義如上述, (in)可視需要使用氧化劑氧化硫;及 (iv)可視需要脫除保護基,產生如幻之I經取代之⑷ 口朵。 10. 根據申請專利範圍第9項之方法,其中γ為氟。 11. -種用s治療或預防利用5ΗΤ6促效劑減輕之疾病狀態之 醫藥組合物,其包含: 0)醫療有效量之根據申請專利範圍第1至8項中任 一項之式I化合物;及 (b)醫藥上可接受之載劑。 12. —種根據申請專利範圍第1至8項中任一項之一種或多種 化合物於製造供治療或預防利用5HT6促效劑減輕之疾病 狀態之藥劑之用途。 13. 根據申請專利範圍第12項之用途,其中該疾病狀態包括 CNS之病變。 14. 根據申請專利範圍第13項之用途’其中該疾病狀態包括 精神病、精神***症、燥參疾、神經病變、記憶障礙、 專注力缺乏異常、巴金森氏病、肌萎縮性侧索硬化、阿 茲海默氏症與亨丁頓氏症。 15. 根據申請專利範圍第12項之用途’其中該疾病狀態包括 胃腸道病變。 16. 根據申請專利範園第12項之用途,其中該疾_狀態包括 肥胖。 87762-941004.doc
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CA2533369C (en) | 2003-07-22 | 2009-07-14 | Arena Pharmaceuticals, Inc. | Diaryl and arylheteroaryl urea derivatives as modulators of the 5-ht2a serotonin receptor useful for the prophylaxis and treatment of disorders related thereto |
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US7629473B2 (en) * | 2005-06-17 | 2009-12-08 | H. Lundbeck A/S | 2-(1H-indolylsulfanyl)-aryl amine derivatives |
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