TWI252105B - 5HT2C receptor modulators - Google Patents

5HT2C receptor modulators Download PDF

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TWI252105B
TWI252105B TW092108353A TW92108353A TWI252105B TW I252105 B TWI252105 B TW I252105B TW 092108353 A TW092108353 A TW 092108353A TW 92108353 A TW92108353 A TW 92108353A TW I252105 B TWI252105 B TW I252105B
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tetrahydro
compound
methyl
group
benzoazepine
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TW092108353A
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TW200400037A (en
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Jeffrey Smith
Brain Smith
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Arena Pharm Inc
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Description

丄仏丄05 16.如印求項15之化合物，其中&係選自下列各物組成之群 中.笨碳基、吱喃基、η比洛基、„比D坐基與咪吐基。 如請求項！之化合物，其中r4為全鹵烷基。 如請求項17之化合物，其中R4gcF3。 19·如D月求項1之化合物，其中尺4為_〇r5。 20.如請求項19之化合物，其中Rs為甲基、乙基、正丙基、 異丙基或烯丙基。 • 21.如凊求項2〇之化合物其中R5為曱基或烯丙基。 22. 如凊求項化合物，其中1為5員雜芳基，其具有至多 2個選自〇、]^與s中雜原子，且該雜芳基可視需要經1或2 個選自_素與C丨_8烷基之取代基取代。 23. 如請求項22之化合物’其中&係選自下列各物組成之群 中·苯硫基、呋喃基、D比咯基、吼唑基與咪唑基，其可 視需要經1或2個選自鹵素或甲基之取代基取代。 24. 如凊求項！之化合物，其中h為苯基，其可視需要經至 • 多兩個選自下列之取代基取代：Cm烷基、鹵素盥烷氧 基。 25·如請求項丄之化合物，其中心與尺4與其附著之原子形成 -0-CH=c(CH3)-。 如。月求項1之化合物，其中R3為鹵素與I為_〇R5，其中 R5為C〗_8烧基。 27. 如請求項1之化合物，其中h為氣與I為_〇R5，其中I 為Ci_8燒基。 28. 如請求項1之化合物，其中&為溴與&為_〇R5 ,其中r 102035-981007.d〇c 為Cl-8烷基。 29 l Λ .如請求項1之化合物，其中&為碘與1為_〇汉5，其中R5 為Ci-8烷基。 .如請求項1之化合物，其中R3為鹵素與心為曱氧基。 h如請求項！之化合物’其中&為鹵素與尺4為烯丙氧基。 二如請求項1之化合物，其中： R2為曱基、乙基、異丙基或CH2OH ;或心與尺“形成_ CH2-CH2-; R3為鹵素或5-員雜芳基’其具有至多2個選自〇、^^與s 中雜原子，且具有至多2個選自鹵素與Ci 8烷基之取代 基； 汉4為Η、烧氧基、5-員雜芳基，其具有至多2個選自 〇、Ν與S中雜原子，且具有至多2個選自鹵素與ci8烷基 之取代基’或為苯基，其可視需要經至多兩個選自下列 之取代基取代：C]·8燒基、齒素與统氧基； 或尺3及R4與其附著之原子形成-〇-CH=C(CH3)-;及 R6為Η或曱基； 或其醫藥上可接受之鹽、溶合物或水合物。 33.如請求項丨之化合物，其中·· R2為甲基、乙基、異丙基或CH2OH ;或R2與R2a形成- ch2-ch2-; R3為氯 '漠或蛾； R·4為Η或烧氧基；及 R6為Η或曱基； I02035-981007.doc 或其醫藥上可接受之鹽、溶合物或水合物。 34·如請求項1之化合物，其中：
Ri 為 Η ; R2為甲基； R3為氯、、/臭或ρ塞吩； R4為Η、烷氧基、吡唑_3_基或苯基，其中該吡唑基可 视需要具有至多2個選自下列之取代基：鹵素與Cw烷 基且5亥本基可視需要具有一個函素取代基；及 為 Η ; 或其醫藥上可接受之鹽、溶合物或水合物。 •如凊求項1之化合物，其係選自下列各物組成之群中： 8-溴-7-羥基-1-曱基_2,3,4,5-四氫-1Η-3-苯并氮呼； 7·稀丙氧基-8-漠小甲基-2,3,4,5_四氫他_3_苯并氮呼. '苯甲氧基待i-甲基-2,3,4,5_四氫，_3_笨并氮呼’. 乙氧基小甲基·2,3,4,5-四氫_1Η·3_苯并氮呼； 異丙氧基小甲基_2’3,4’5.四氫_出_3_苯并氣呼； Ν-丙基-8-溴-7-甲氧基-1-甲基-2,34STOe 1Τ 〇 · ，，4,5-四虱-1H-3-苯并氮 呼， 7-羥基-8-碘-1-甲基-2,3,4,5-四氯-丨乩3笨并氮呼； 7-烤丙氧基-8-埃小甲基_2,3,4,5_四氫抓3_苯并氮呼； 3,5-二甲基·6,7,8,9_四氫·5Η]_氧雜_7_氮雜環庚茚. 7·烯丙氧基各氯小甲基-2,3’4,5_四氫他3_苯并氮呼； 7-甲氧基-1-甲基-8-(2-嘧吩基）-2,3 4 s , . ，，4,5-四氫-1H-3-苯并氮 呼， 102035-981007.doc 1252105 8-.氰基-7-曱氧基-1-曱基-2,3,4,5-四氫-111-3-苯并氮呼； 8 - >臭-1 -球·丙基-7 -曱氧基-2，3，4，5 -四鼠-1H-3 -本弁氣呼， 8->臭-1-經基曱基-7-甲氧基-2,3,4,5-四風-111-3-苯弁氣 呼； 8 -》臭-1 -異丙基-7 -曱乳基-2，3，4，5 -四氮-1Η - 3 -苯弁氣呼， 8 - >臭-7 -經基-1 -異丙基-2，3，4，5 -四氮-1Η - 3 -苯并氮呼， 7- 烯丙氧基-8-溴-1-異丙基-2,3,4,5-四氫-1Η-3-苯并氮 呼；
8- 溴-7-曱氧基-1,4-二曱基-2,3,4,5-四氫-111-3-苯并氮呼； 7-稀丙氧基-8->臭-1,4-二甲基-2,3,4,5 -四鼠-1Η-3-苯弁氮 呼； 7-(2-甲基-2Η-吡唑-3-基）-1-曱基-2,3,4,5-四氫-1^1-3-苯并 氮呼； 7-(4-溴-2-甲基-2H-吡唑-3-基）-1-曱基-2,3,4,5-四氫-1H-3-苯并氮呼；
7-(3-氯苯基）-1-曱基-2,3,4,5-四氫-111-3-苯并氮呼； 7- (2-氣苯基）-1-曱基-2,3,4,5-四氫-111-3-苯并氮呼； 8- 氣-1-羥基-2,3,4,5-四氫-1^1-3-苯并氮呼； 8->臭-1-曱基-2,3,4,5-四鼠-11'1-3-苯弁氮呼， 8-氟-1-曱基-2,3,4,5-四氫-11^3-苯并氮呼； 7-氟-1-曱基-2,3,4,5-四氫-111-3-苯并氮呼； 7,8-二氯-1-曱基-2,3,4,5-四氫-1H-3-苯并氮呼； ^[-曱基-8-氣-1-甲基-2,3,4,5-四氫-111-3-苯并氮呼； 1-曱基-7-三氟曱氧基-2,3,4,5-四氫-出-3-苯并氮呼； 102035-981007.doc -6 - 8-碘-1-曱基-7-三氟甲氧基-2,3,4,5-四氫-111-3-苯并氮 呼； N-丙基-8-碘-7-曱氧基-1-甲基-2,3,4,5-四氫-1H-3-苯并氮 呼； 1-乙基-8-碘-7-甲氧基-2,3,4,5-四氫-1^1-3-苯并氮呼； 7-(3-甲氧基苯基）-1-甲基-2,3,4,5-四氫-1H-3-苯并氮呼； 7-(2,6-二氟苯基）-1-甲基-2,3,4,5-四氫-1H-3-苯并氮呼； 7-(2-氟苯基）-8-氯-1-甲基-2,3,4,5-四氳-111-3-苯并氮呼； 7-(2-三氟曱基苯基）-1-甲基-2,3,4,5-四氫-1H-3-苯并氮 呼； 7-(3-三氟甲基苯基）-1-曱基-2,3,4,5-四氫-1H-3-苯并氮 呼； 7- (4-三氟曱基苯基）-1-甲基-2,3,4,5-四氫-1H-3-苯并氮 呼； 8- (2-氣苯基）-1-甲基-2,3,4,5-四氫-1H-3-苯并氮呼； 與8-溴-1-曱氧基甲基-7-曱氧基-2,3,4,5-四氫-1H-3-苯并 氮呼； 或其醫藥上可接受之鹽、溶合物或水合物。 3 6.如請求項1之化合物，其係選自下列各物組成之群中： 8-溴-7-曱氧基-1-曱基-2,3,4,5-四氫-1H-3-苯并氮呼； 8-氯-7-甲氧基-1-甲基-2,3,4,5-四氫-111-3-苯并氮呼； 8-碘-7-曱氧基-卜甲基-2,3,4,5-四氫-1H-3-苯并氮呼； N-曱基-8-溴-7-曱氧基-1-甲基-2,3,4,5-四氫-1H-3-苯并氮 呼； 102035-981007.doc 8 、、鱼 -/、’-1-乙基-7-甲氧基_2,3,4,5_四氫_111_3_苯并氮呼； 8_氣乙基-7·甲氧基-2,3,4,5-四氫-1H-3-苯并氮呼； 8 — 1 -y _ 卜乙基-7-曱氧基_2,3,4,5_四氫_1H_3_笨并氮呼； 7·甲氣基-1-甲基_8_三氟曱基_2,3,4,5_四氫_1113_苯并氮 呼； 與7_甲氧基-1·甲基_8_五氟乙基_2,3,4,5_四氫· 1H3笨并 氮呼； 或其醫藥上可接受之鹽、溶合物或水合物。 月東項1之化合物，其係選自下列各物組成之群中： 8 /臭-1-曱基-2,3,4,5-四氫-1H-3-苯并氮呼； 8碘甲基-2,3,4,5-四氫·1H_3_苯并氮呼； 8 —氟甲基-1-乙基_2,3,4,5_四氫_1H3_苯并氮呼； 8 /臭-1-乙基-2,3,4,5-四氫_111_3_苯并氮呼； 8碘丨'乙基_2,3,4,5-四氫_1H_3_苯并氮呼； 7’8 —氣-1·甲基_2,3,4,5_四氫_1H_3_苯并氮呼；
7’8 —氯-i_乙基·2 3 4,5_四氫_1H3_苯并氮呼； 8氯氟小曱基_2,3,4,5-四氫_1士3_苯并氮呼； 與8氯-7-氟-1-乙基_2,3,4,5-四氫-111-3-苯并氮呼； 邊藥上可接受之鹽、溶合物或水合物。 如明求項37之化合物，其為R對映異構物。 "月求項37之化合物，其為s對映異構物。 仇如=求们之化合物，其為8_氣小甲基.2 3 4 5四氮A 苯并氮呼；或其醫藥上可接受之鹽、溶合物或水 物0 102035-981007.doc ⑷2105 4 1.如請求項40之化合物’其為R對映異構物。 42.如請求項40之化合物，其為S對映異構物。 43‘如請求化合物，其為8_三氟甲基_丨_甲基4 氫-1Η-3-苯并氮呼；或其醫藥上可接受之/~2’3,4，^四 水合物β 氣、容合物或 44. 45. 46. 如請求項43之化合物，其為R對映異構物。 如請求項43之化合物，其為S對映異構物。
如請求項1之化合物，其為8_氯_丨_乙基_2,3,4 $卜 3_苯并氮呼；或其醫藥上可接受之鹽、’溶合：氣娘 物。 物或水合 47·如請求項46之化合物，其為R對映異構物。 48. 如請求項46之化合物，其為s對映異構物。 49. -種調節5HT2C-受體之醫藥組合物，其包含 8中任一項之化合物及醫藥 ，項1至 文之載劑或職形劑。 川·如清求項49之醫藥組合 效劑。 ”中錢合物為該受體之促 5 1. —種治療選自中樞神經系統 <疾病，中樞神經系統受 、'^血目疾病’月腸疾病：尿崩症與睡眠呼吸暫停 醫藥組合物，其包含如請求項1至48中任-項之化合 物’與醫藥上可接受之載劑錢形劑。 。 52.如請求項51之醫藥組合物，其中財枢神經系統疾病係 選自下列組成之群中：抑鬱症、非典型抑t症、躁鬱 疒…、慮#強迫觀念與強迫行為異常、社交恐懼症或 恐慌症 '睡眠失常 '性功能障礙、精神病、精神分裂 l02035-981007.doc :頭痛及其他與頭部疼痛或其他疼痛有關之病症、 常；升高、癲癇、人格異常、與老化相關之行為里 A癡呆相關之行為異常、精神官能症、童年精神異 二攻擊性、與老化相關之記憶失常、慢性疲勞症候 :=酒精上應、肥胖症、貪食症、神經性厭食症 53. =項51之醫藥組合物，其中該中抱神經系統疾病為 54. 如請求項51之醫藥組合物’其中該中樞神經系統受損係 傷、中風、神經變性疾病或毒性或感染性CNS疾病 如吻求項54之醫藥組合物，其中該毒性或感染性cns疾 病為腦炎或腦膜炎。 56.如請求項51之醫藥組合物，其中該心血管疾病為血 塞。 從 5 7 .如凊求項51之醫藥組合物，其中該胃腸疾病為胃腸蠕動 功能障礙。 ^ g _ 、 •種減少哺乳動物食物攝取之醫藥組合物，其包含如靖 长項1至48中任一項之化合物及醫藥上可接受之載劑或 賦形劑。 59·—種誘發哺乳動物飽足感之醫藥組合物，其包含如請求 項1至48中任一項之化合物及醫藥上可接受之載劑或職 形劑。 60. —種控制哺乳動物體重增加之醫藥組合物，其包含如請 102035-981007.doc -10- 1252105 - v 求項1至48中任一項之化合物及醫藥上可接受之載劑或 賦形劑。 61. —種治療肥胖症之醫藥組合物，其包含如請求項1至48 中任一項之化合物及醫藥上可接受之載劑或賦形劑。 62. 如請求項61之醫藥組合物，其係為施用於先前經一步驟 鑑別為需要治療肥胖症之個體。
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US20070060568A1 (en) 2007-03-15
BRPI0309303B1 (pt) 2018-05-29
US20050020573A1 (en) 2005-01-27
TW200400037A (en) 2004-01-01
KR100908166B1 (ko) 2009-07-16
JP2005527579A (ja) 2005-09-15
AU2003221866A1 (en) 2003-10-27
JP4966929B2 (ja) 2012-07-04
EP2374796B1 (en) 2018-02-28
CN101485664A (zh) 2009-07-22
WO2003086306A3 (en) 2004-02-19
US20120135982A1 (en) 2012-05-31
DK1411881T3 (da) 2005-08-29
US20030225057A1 (en) 2003-12-04
US8273734B1 (en) 2012-09-25
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US8575149B2 (en) 2013-11-05
CN1646493A (zh) 2005-07-27
PL211333B1 (pl) 2012-05-31
BR122017023795B1 (pt) 2020-11-24
NZ535381A (en) 2006-07-28
WO2003086306A2 (en) 2003-10-23
ZA200408506B (en) 2006-06-28
CN100486967C (zh) 2009-05-13
US20130217676A1 (en) 2013-08-22
US6953787B2 (en) 2005-10-11
JP4191741B2 (ja) 2008-12-03
CN101486678A (zh) 2009-07-22
JP2013018780A (ja) 2013-01-31
PL231405B1 (pl) 2019-02-28
US8846906B2 (en) 2014-09-30
CN101486678B (zh) 2015-09-09
KR20090007651A (ko) 2009-01-19
KR100908167B1 (ko) 2009-07-16
EP1411881A2 (en) 2004-04-28
US7514422B2 (en) 2009-04-07
CN101486679A (zh) 2009-07-22
JP4155926B2 (ja) 2008-09-24
US20130012495A1 (en) 2013-01-10
JP2009001584A (ja) 2009-01-08
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CA2481723C (en) 2008-02-19

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