TWI293254B - The use of selective dopamine d4 receptor agonists for treating sexual dysfunction - Google Patents
The use of selective dopamine d4 receptor agonists for treating sexual dysfunction Download PDFInfo
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- TWI293254B TWI293254B TW090128952A TW90128952A TWI293254B TW I293254 B TWI293254 B TW I293254B TW 090128952 A TW090128952 A TW 090128952A TW 90128952 A TW90128952 A TW 90128952A TW I293254 B TWI293254 B TW I293254B
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- receptor
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- receptor agonist
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
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- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
1293254
:本發明有關選擇性多巴胺〇4受體促效 孩選禮Μ夕m η、η 逐及有關含 組 合物 4㈣促效劑而用以治療性官能障礙之 贫明ΐ京 ,莖遲緩及勃起係由陰莖小體海綿體平滑崎張度加以 =。_該肌肉緊張受複雜之生化事件控制,其又與末梢及中 ^經系統之程度有關。交感神經、較感神經及軀體神婉 下尿道之神經支配整體部分之神經解剖 海綿體緊張。 ^ 、^里勃起為可藉中樞神經系統(CNS)路徑起始之海綿體平 ^肌鬆弛之結果。該等路徑活化末梢神經而神經支配^莖 導致釋出—氧化氮_。NO擴散調節引起陰莖勃起之^ 體平滑肌舒緩。 臨床前證據顯示多巴胺(DA)在哺乳類陰莖勃起中扮演重 要角色。性刺激可藉由感官(性慾)資訊起始達到哺乳類^大 腦皮質。該大腦皮質與邊緣結構如扁桃體以及中腦結構如 腦導管間灰白質(PGA)及丘腦下部有延伸關聯。於丘腦下部 中兩個重要核心為中間、視前葉區域(MPOA)及副心室核(PVN) 。該MPOA及PVN核心在性行為中扮演重要角色,因該等區 域之兩側損害完全消除男性性行為之故。神經支配該ργΝ及 MPOA核之不確定(incert0)_腦丘下部多巴胺激導路徑已與da 试劑之早期勃起效果有關。全身性投與DA受體促效劑如阿 朴嗎啡(5, 6, 6a,7·四氫-6-甲基-4H-二苯并[de5 g]喹啉-1〇, 11-二 -4 _ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1293254 ^ • · A7 B7 五、發明説明(2 ) 醇)、奎朴羅(quinpirole)及(-)3- (3-羥基苯基)-N-丙基哌啶(3- PPP) 於大鼠中促進陰莖勃起’為受鹵基· p定醇(haloperidol)阻斷之 效果,一種中樞DA拮抗劑。由於勃起效果無法藉多哌啶酮 (domperidone)(—種末梢DA#抗劑)阻斷,因此相信DA促效劑 之早期勃起效果在中心受調節(Andersson K及Wagner G.陰莖勃 起之生理學,生理學回顧(1995)75: 191-236 ; deGroat W及Booth A,中樞控制陰莖勃起:於泌尿生殖系統之中樞控制,卷3, (Maggi C編輯)(1993)第 467-524頁,Hardwood學院出版社,Chur, 瑞士;及 Moreland RB,Nakane Μ, Hsieh G 及 Brioni JD,男性勃 起官能障礙之藥理治療之展望,Curr Opinion CPNS Invest Drugs (2000) 2:283-302) 〇 臨床數據亦顯示CNS中DA系統在調節男性性行為中扮演 重要角色如由帕金森氏症病患中L-多巴之性刺激效果及由 阿朴嗎啡於人類中之早期勃起效果可見(Morales A,Geaton J, Johnson B及Admas Μ,口服及局部治療勃起官能障礙:現況 及未來,於北美泌尿臨床(1995)卷22,第879- 886頁;卩&(111^ Nathan H,Auerbach S,Lewis R,Lewand Μ及 Perdok R,阿朴嗎 口非 SL對安慰劑於男性勃起官能障礙(MED)之效果及安全性,泌 尿學(1999) 161-214(摘要 821);及 Dula E,Keating W5 Siami P, Edmonda A, 〇’ Neil J,於勃起官能障礙之男性中以舌下投與 阿朴嗎啡對安慰劑之固定劑量及劑量最適療程之效果及安 全性,泌尿學(2000) 56: 130- 135)。 DA受體屬於藉偶合至細胞内GTP-結合蛋白質而通過細胞 膜發出訊號之蛋白質受體超族群。已鑑定數種G蛋白質(包含 -5- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1293254 * · A7 B7 五、發明説明(3 )
Gs、Gq及Gi),其可引起特異之細胞内事件(Milligan G及Rees S, 嵌合體G蛋白質:其於藥物發現之潛力利用,藥理科學趨勢 (1999)20: 118- 124)。 有5種已知DA受體其分為兩類·· Dr類及Dr類。該D!-類受 體包含〇丨及D5。D2-類受體包含D2、D3及D4 (Missale C5 Robinson S5 Jaber M及Caron Μ,多巴胺受體:由結構自功能,生理學 回顧(1998)78: 189-225)。該Dr類家族受體亞型經Gs偶合且可活 化腺甞酸酯環酶。該Dr類家族受體亞型經偶合且其增加 細胞内鈣量及抑制腺茹酸酯環酶。 該Dr類家族成員為可活化腺甞酸酯環酶之Gs-偶合之受體 。經mRNA表現及免疫組織化學研究兩者,D!受體為CNS中最 豐富且最廣泛分布之DA受體(Vallone D5 Picetti R及Boireli E, 多巴胺受體結構及功能,神經科學生物行為回顧(2000) 24: 125- 132)。於紋狀體、核伏狀體及嗅結節以及邊緣系統中 發現丘腦下部及丘腦。該D]受體表現已報導於心臟及腎臟中 ,及儘管該等末梢D]受體仍不清楚,但其在控制血液動力變 數所扮演之角色已經證實。該D5受體雖然比D!受體具有對 DA之更高親和性,但其極少分布於CNS中而無在CNS外部無 表現之證據。
Dr類家族成員為可抑制腺甞酸酯環酶及增加細胞内鈣量 之Q偶合之受體。D2受體為最豐富之Dr類受體且位於腦部 區域如紋狀體及黑質且於末梢區域如心臟、垂體腺及腎臟。 D3受體大量見於腹面紋狀體/核伏狀體區域、嗅結節、樹枝 狀腦迴及紋狀皮層中之以明顯集團分布之卡勒哈氏島中 -6- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1293254 A7 B7 五、發明説明( (Suzuki M5 Hurd Y,Sokoloff P,Schwartz J及 Sedwall G,D3 多巴胺受體 mRNA於人類腦中廣泛表現,Brain Res (1998) 779: 58- 74)。 D4受體表現以藉就地RNA雜化及免疫組織學研究而見於文 獻。近來,研究顯示D4在腦丘下部之entorhinal皮質、側中隔 核、海馬及内部視前葉區域表現最高(Primus R,Thurkauf A, Xu J5 Yevich E,Mcinemey S,Shaw K,Tallman J及 Gallagher D,於 大鼠及人類腦中藉使用新穎d4受體-選擇性配位體[3h]ngd 94-1之多巴胺D4結合位置之分布及特徵化,J Pharmacol Exp Ther (1997) 282: 1020-1027)。D4分布與D2於腦中分布不同,因D2 受體於紋狀體區域最豐富。D4受體於腦丘下部之MPOA中之 表現對加速陰莖勃起具重要性,鑒於腦丘下部於皮質及脊 柱路徑間整合區域扮演之角色。D4受體於其他CNS區域、丘 腦、丘腦下及脊柱中之參與作用未被排除。 兩種化合物·· N-{[4-(2-氰苯基)-1-哌畊基]甲基}_3_甲基 苯甲醯胺及5-氟_ 2- { [ 4- (2-吡啶基)-1-哌畊基]甲基} - 1H- W哚 近來已描述為選擇性多巴胺D4受體促效劑(Glase SA,Akunne H,Georgic L,Hellner T5 MacKenzie R,Manley P,Pugsley T及 Wise L,醫藥化學期刊(1997) 40: 1771-1772 ;及 Zom SH,Jackson E, Johnson C,Lewis J5 Fliri A, Soc Neurosci Abstr 23:685 (1997))。然而, 對D4選擇性促效劑之化合物並未鑑定特定之治療利用性。 本發明鑑定出為D4促效劑之可用以治療哺乳類性官能幛 礙之治療用途。更詳言之,為選擇性多巴胺D4受體促效劑之 化合物可用以治療性官能障礙包含(但不限於)男性勃起官能 障礙(MED)。多巴胺受體已知可調節數種其他生理反應如嘔 75003-960627.doc - 7 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1293254
==液動力效果…卜選擇性D4促效劑轉選擇性促效 劑具有之優點為選擇灿促效劑可減少哺乳類之唱吐及/或 血液動力效果。 發明概述 主要具體例中,本發明有關-種治療性官能障礙之方法, 包括投與治療有效量之多巴胺^受體促效劑或其醫藥可接 ,性鹽或其前藥,其中該化合物不為阿朴嗎啡(5从7_四 虱-6-甲基-4H-二苯并[de,g]膣啉-l〇5ll_二醇)。 、本發明另-具體例係有關一種治療男性性官能障礙之方 法、,該性官能障礙包含(但不限於)勃起官能障礙及早洩,該 万法包括投與治療有效量之多巴胺α受體促效劑或其醫藥 可接受性鹽或其前藥。. 本發月另具體例係有關一種治療女性性官能障礙之方 法,該性官能障礙包含(但*限於)女性性高潮缺乏、陰蒂勃 2不全、陰道充血、性感不快及陰道痙攣,該方法包括投與 治療有效量之多巴胺A受體促效劑或其醫藥可接受性鹽或 其前藥。 發明詳細說明 本文所有參考文獻均併於本文供參考。 王要具體例中,本發明有關一種治療性官能障礙之方法, 包括投與治療有效量之多巴胺D4受體促效劑或其醫藥可接 ^性鹽或其前藥,其中該化合物不為阿朴嗎啡(5, 6, 6a,7-四 虱4甲基-4H-二苯并[de5g]璧啉_ 10, n_二醇)。本發明有關 一種治療男性性官能障礙之方法,該性官能障礙包含(但不 A 齡(21GX297公釐) 1293254
T万、)勃起I能障礙及早洩,該方法包括投與治療有效量之 多巴胺A受體促效劑或其醫藥可接受性鹽或其前藥。本發明 有關種冶療女性性官能障礙之方法,該性官能障礙包 含(但不限於)女性性高潮缺乏、陰蒂勃起不全、陰道充血、 性感不快及陰道痙攣,該方法包括投與治療有效量之多巴 胺受體促效劑或其醫藥可接受性鹽或其前藥。 另一具體例中,本發明有關一種治療性官能障礙之方法, 2括投與治療有效量之多巴胺^受體促效劑或其醫藥可接 受性鹽或其前藥。本發明有關一種治療男性性官能障礙之 万法,該性官能障礙包含(但不限於)勃起官能障礙及早洩, ,方法包括投與治療有效量之多巴料受體促效劑或其醫 藥可接受性鹽或其前藥。本發明又有關一種治療女性性官 能障礙,方法,該性官能障礙包含(但不限於)女性性高潮缺 乏陰蒂勃起不全、陰道充血、性感不快及陰道痙攣,該方 法包括投與治療有效量之多巴胺D4受體促效劑或其醫藥可 接受性鹽或其前藥。 、本發明較佳具體例係有關一種治療男性勃起官能障礙之 万法,菘万法包括投與治療有效量之多巴胺d4受體促效劑或 其醫藥可接受性鹽或其前藥。. —需了解本發明範目内,選擇性乡巴胺03受體促效劑或其醫 藥可接受性鹽或前藥亦可用以治療性官能障礙。 本發明另一具體例係有關一種治療男性性官能障礙之方 法,該方法包括投與治療有效量之Ν_{[4·(2-氰苯基卜^哌喷 基]甲基卜3-甲基苯甲醯胺或其醫藥可接受性鹽或其前藥。 75003-960627.doc _ 9 · 本紙張尺度適用中國國家標準(C]SJS) Α4規格(210X297公潑) 一 " 1293254 • * A7
7 、、本發明另-具體例係有關一種治療女性性官能障礙之方 法,孩万法包括投與治療有效量之乂{[4♦氯苯基十井基] 甲基卜3-甲基苯甲醯胺或其醫藥可接受性鹽或其前藥。 本發明另-具體㈣—種治療録勃起f能障礙之 万法,孩方法包括投與治療有效量之叫吵氨苯舒ι十井 基]甲基卜3_甲基苯甲醯胺或其醫藥可接受性鹽或其前藥。 本發明另-具體例係有關—種治療男性性官能障礙之方 1,該方法包括投與治療有效量之5_氟列4似咬基 畊基]甲基}-1沁吲哚或其醫藥可接受性鹽或其前藥。 、本發明另一具體例係有關一種治療女性性官能障礙之方 法泛方法包括投與治療有效量之5_氟列4分比咬基)]_哌 口井基]甲基}]印<嗓或其醫藥可接受性鹽或其前藥。 、本發明另-具體例係有關—種治療男性勃起官能障礙之 方法泫方法包括投與治療有效量之&氟啶基)_ ι 味味基]甲基卜1Η斗朵或其醫藥可接受性鹽或其前藥。 本發明另一具體例中’該選擇性多巴胺D4受體促效劑為具 有下列作用之化合物:a)對多巴胺A受體之&值之選擇性至 少為對多巴胺D2受體之&之3倍;b)在本文所述之乡巴胺〇4受 體之貫能藥理模型任_種中可作為促效劑。 本發明另一具體例中,該選擇性多巴胺D4受體促效劑為具 有下列作用之化合物:a)對多巴胺认受體之&值之選擇性至 ^為對多巴胺D2受體之以25倍;b)在本文所述之乡巴胺D4 又to足έ能藥理模型任一種中可作為促效劑。 本發明另一具體例中,該選擇性多巴胺d4受體促效劑為具 75003-96Q627.doc ---______ _ _ 10 · 本紙張尺度適财關轉%CNS)鐵格(ϋ7公董)----- 1293254 A7
有下列作用之化合物:a)#々 丨、么料夕、η / )對夕巴胺〇4受體之Ki值之選擇性至 少為對多巴胺d2受體之κ 受體之官能藥理模_ —種中倍;W在本文所述之多巴胺D4 種中可作為促效劑。 本發明另一具體例中, 有下列作用之化合物:_^擇性多巴胺D4受體促效劑為具 少為對多巴贱受體之^^胺A受體之Ki值之選擇性至 受體之官能藥理”+ 在本文所述之多巴胺D4 種中可作為促效劑。 =:另一具體例中,該選擇性多巴胺D4受體促 t::用之化合物:a)對多巴_豊之Ki值之選擇性至 2對夕巴胺D2受體之Ki之·倍;触本文所述之多 文體q«理模餘—種中可作域效劑。 方^ ^具例中,該選擇性多巴胺D4受體促效劑為具 有^ :用之化合物:鱗多巴胺Μ體之Kl值之選擇性至 ^對夕巴胺D2受體之&之細倍;b)在本文所述之多巴 受理模型任―㈣可作為促效劑。 务月另、Uj中’該選擇性多巴胺A受體促效劑為具 ^ #Μ用义化。物· &)對多巴胺D4受體之Ki值之選擇性至 2對多巴贱受體之Ki之轉;b)在本文所述之多巴 ⑼^能藥㈣㈣—種中可作為促效劑。 本叙月另具例中,孩選擇性多巴胺D4受體促效劑為具 下列作用(化u物.a)對多巴胺〇4受體之Ki值之選擇性至 少^多巴胺D2受體之…㈣倍;b)在本文所述之多巴_ 受骨豆之賞能藥理模型任-種中可作為促效劑。 教月另纟把例係有關一種治療哺乳類性官能障礙之
本紙張尺度適财®國豕標準(CNS) A4規格(g 297公釐) 1293254
五、發明説明( G胺二需此治療之哺乳類投與治療有效量之選擇性 效劑不引起明_吐 又性鹽或前藥,其中該促 法本=:需―:!例係有關一種治療男性性官能一 巴胺Da〜療之哺乳類投與治療有效量之選擇性多 ==或其醫藥可接受性鹽或前藥,其中該促效 法本IS::具體例係有關一種治療女性性官能障礙之方 巴胺D與触:此々療《哺乳類投與治療有效量之選擇性多 ^不引起明顯嘔吐。 古、本 a t例係有關一種治療男性勃起官能障礙之 括對而此/口療之哺乳類投與治療有效量之選擇性 受體促效劑或其醫藥可接受性鹽或前藥,其二 效W不引起明顯嘔吐。 _ I月另*體例係有關一種用以治療性官能障礙之醫 ,、W樂可接受性鹽或前藥及醫藥可接受性載體。 本叙明另一具體例係有關一種用以治療男性性官能障礙 ,醫藥組合物,包括治療有效量之選擇性多巴胺啦體促效 劑或其醫討接受性鹽或《及醫討接受性載體。 、明另一具體例係有關一種用以治療女性性官能障礙 木組合物,包括治療有效量之選擇性多巴胺仏受體促效 劑或其醫藥可接受性鹽或前藥及醫藥可接受性載體。 1293254 • . A7 B7 五、發明説明(10 ) 本發明另一具體例係有關一種用以治療男性勃起官能障 礙之醫藥組合物,包括治療有效量之選擇性多巴胺D4受體促 效劑或其醫藥可接受性鹽或前藥及醫藥可接受性載體。 本文所用之“選擇性”代表與多巴胺促效劑對D4受體與對 D2受體比較之選擇性。 ㈠阿朴嗎啡已知為多巴胺促效劑(Altar, C等人,Mol Pharmacol (1988) 33 ⑹ 690-695 ; Moellar,HG等人,Psychopharmacology (Berlin) (1987) 91 (1) 50-55 ;及 Fray,PJ 等人,Psychopharmacology (Berlin) (1980) 69 (3) 253-259),其對多巴胺 D4受體 Kf 4 nM對多巴 胺E>2受體KfO· 7-24 nM而顯示對多巴胺D4受體並無選擇性 (Vallone D等人,神經科學及生物行為回顧(2000) 24, 125-132)。 多巴胺類促效劑如阿朴嗎啡缺乏選擇性有助於解釋與該 等藥劑有關之副作用如嘔吐及暈厥。使用選擇性D4促效劑代 表對治療CNS調節之障礙之明顯優點,因為選擇性D4促效劑 促進陰莖勃起而不引起副作用如嘔吐及暈厥。本文所用之 “明顯嘔吐,,代表臨床人口中嘔吐反應為20%或以上。較好, 臨床人口之p區吐反應小於10%。更好臨床人口之呕吐反應小 於5% 〇 • 多巴胺D2及多巴胺D4結合分析 表1說明之用以測定結合親和性(κ〇之多巴胺〇2及d4結合分 析係依據本技藝已知之標準程序進行且概述於本文。示於 表1之結合數據由法國Cerep,86600 Celle L’ Evescault進行。 簡言之’在多巴胺〇2及1)4受體之受體結合分析係於表現重 組人類亞型之細胞株所得之細胞膜中進行。對D2受體分析而 -13- 本紙張尺度適财_家標準(CNS) Μ規格(21()><297公董) 1293254 、 . . A7 B7 五、發明説明(u) 言,轉染之A9L細胞之細胞膜以[3H]-史拜酮(spiperone)(0· 3 nM) 培育60分鐘,使用(+)- 丁克嗎(butaclamol)(10 μΜ)以定義非特異 結合(Grandy等人,Proc Natl Acad Sci USA (1989) 86: 9762-9766)。對 D4受體分析而言,轉染之CHO細胞之細胞膜以[3H]-史拜酮 (spiperone)(0.5 nM)培育 60分鐘,使用(+)- 丁克嗎(butaclamol)(10 μΜ)以定義非特異結合(Van Tol等人,Nature (1992) 358: 149-152) 。特異結合定義為總結合與非特異結合之差。使用Cheng-Prusoff程式測定Ki值並列於表1 〇 支巴胺D9及D4受體之結合數攄 表1數據證明N-{ [4-(2-氰苯基)·1-哌嗜基]甲基卜3-甲基苯 甲醯胺及5-氟-2-{[4-(2-吡啶基)-1-哌畊基]甲基}-1Η-啕哚對 多巴胺D4受體之選擇性比多巴胺!)2受體大100倍以上。 表1 化合物 Ki (nM) d2 d4 阿朴嗎啡 32 1.5 N-{[4-(2-氰苯基)小哌畊基1甲基甲基苯甲醯胺 >1000 10 5_氟-2][4_(2-吡啶基VI-旅畊基]甲基}-1Η-吲哚 >1000 2.6 心{[4-(2-氰苯基)_1_哌啩基]甲基卜3_甲基苯甲醯胺對多 巴胺D4受體Ki=8.7 nM而對多巴胺D2受體Ki=3740 nM顯示對多 巴胺D4選擇性> 400倍(Glase,SA等人,醫藥化學期刊(1997) 40, 1771· 1772 ;及 Chicv C等人,Mol Pharmacol (1994) 45,51-60)。 5-氟-2- { [4-(2-吡啶基)-μ哌畊基]甲基} _ 1Η-喇哚對多巴 胺D4受體Kf=6.0 nM與對多巴胺〇2受體相較顯示對多巴胺〇4選 -14- 75003-960627.doc 本紙張尺度適用中國國家標準⑴&印A4規格(21〇 χ 297公釐) 1293254 . ‘ A7 ______B7__ 五、發明説明( ) 12 擇性 > 1〇〇倍(Z〇m SH等人,Soc Neurosci Abstr 23:685 (1997))。 本文所用“促效劑,,代表與受體相互反應及引出可觀察之 生化反應之化學實質。該反應相對於已知促效劑標準測量。 例如’多巴胺D4受體促效劑代表與多巴胺〇4受體相互反應及 引出可觀察之生化反應之化學實質。該反應相對於全促效 劑如多巴胺或奎朴羅所測量。 多巴胺受體促效作用之測定可藉下述三種分析之任一 種建立。在下述三種分析任一種中,與多巴胺或奎朴羅作為 100%促效標準相較,在多巴胺d4受體顯示最小25%促效作用 之化合物可視為本發明範圍内之促效劑。促效作用值係以 至少二次獨立觀察之平均值。較好,意欲在本發明範圍内之 D4促效劑與多巴胺及奎朴羅標準相較將顯示4〇%或以上之促 效作用。 體促效作用之官能性藥理楛刮 L_L 胸#分析 多巴胺D4受體於以人類多巴胺d4受體轉染之CHO pro- 5細 胞中之促效活化作用將刺激絲狀分裂。該反應藉測量[3H]胸 嘗之細胞攝取及比較對全促效劑如奎朴羅(定義為1〇〇%)之反 應而測定。N-{[4-(2-氰苯基)-1-哌喷基]甲基卜3_甲基苯甲醯 胺顯示於[3h]胸甞攝取分析衍生出反應,與驼5()為17 _之奎 朴羅相較衍生出80%反應(Glase,SA等人,醫藥化學期刊(丨997) 40, 1771-1772 ;及 Chio, C等人,Mol Pharmacol (1994) 45, 51-60)。 以人類〇4受體轉染之CHO pro- 5細胞舖於含青黴素(1〇〇 u/ 毫升)及鏈黴素(1〇〇克/毫升)之10%胎牛血清之ΜΕΜ- α之96洞 75003-960627.doc - 15 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
裝 f 1293254 . * A7 ___B7_._ 五、發明説明(η ) 盤中。48小時後,細胞為藉洗滌及維持於不含血清之培養基 中而去除之血清。24小時後,添加載劑、標準品或測試化合 物。18小時後,添加[3H]胸苷(5 μα/洞)歷時2小時,接著添加 胰蛋白酶(100微升〇· 25°/。)歷時1小時,及使用Brandel或其他96-洞細胞收取機藉過濾終止分析。濾液使用LKB-盤計數系統 或其他盤計數系統計算其放射活性。對各測試化合物測定10 點劑量-反應曲線,及自所得曲線計算50%刺激作用所需之 藥物濃度(EC5G)。藉比較各測試化合物之最大效果相對於以 各試驗中奎朴羅最大有效濃度所得之效果而評估固有促效 活性。 2. cAMP分析 該cAMP分析為決定多巴胺D4功能活性之功能分析,其涉 及測量於表現人類D4受體之CHO細胞中forskolin-刺激之cAMP 累積作用。促效劑抑制forskolin-刺激之cAMP累積作用。5-氟-2- { [4-(2-吡啶基)-1-哌哄基]甲基} - 1H-吲哚顯示可抑制 forskolin-刺激之 cAMP 累積作用,EC50= 5· 8 nM (Zorn SH等人, Soc Neurosci Abstr 23: 685 (1997))。 用以測量抑制forskolin-刺激之cAMP累積作用之cAMP分析述 於 Gazi等 X,Arch Pharmapol· 361 (2000) 555-564。細胞於 24」洞盤 中生長至融合及以1毫升Hepes-緩衝之鹽溶液洗滌。細胞接 著以 6 μ(Ζϋ/ 毫升[2-3H]腺嗓呤(23 Ci/ 毫莫耳;Anawa Trading, Wangen,瑞士)在37°C於0. 5毫升相同緩衝液中標記2小時。其 接著以1 ^:升補充有ImM異丁基甲基黃嘌呤之緩衝溶液洗;:條2 次。細胞在forskolin存在或不存在下在37°C培育於1毫升相同 -16- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1293254 A7 B7 五、發明説明(14) 溶液中。15分鐘後’移除培養基及再置於1毫升含cAMP及 ATP(均0.1 nM)之5%三氟乙酸溶液中。在4°C歷時30分鐘後, 三氟乙酸萃取液直接在Dowex AG-50W-X4及氧化鋁管拄上依 序進行層析。以[3H]cAMP/([3H]cAMP+[3H]ATP)之比例而計算 cAMP形成。 3.螢光成像盤讀取機(FLIPR)分析 該FLIPR分析為可在表現人類D4受體且以Gq()5蛋白質嵌合體 共轉染肢HEK293細胞中進行。G_蛋白質嵌合體之表現^使〇4 受體活化後之細胞内鈣變化。藉由將穩定轉染*^DrSEK293 日舍)° 細胞舖於96洞盤各洞中。細胞培育直至達融合(約48小’。 自盤移開培養基及添加含螢光鈣偵測染料Flou-4A # $ & 細胞在室溫培育1小時。細胞接著以磷酸鹽緩衝之令^ # 滌3次及添加150微升PBS。欲測試化合物於96-洞盤τ ^ Μ微扑化 含細胞之盤置於螢光盤讀取機(FLIPR)及藉同時添加. k 丨耆螢光 合物溶液至所有洞中而開始反應。以1秒間隔取樣測 訊號共60秒。衍生自10 μΜ多巴胺之訊號使用作為1〇0°° ν 合物劑量·反應曲線公稱化而測定相對於多巴胺之# #其 比。分析劑量反應曲線以決定EC5G (nM)。队{[4-(2-氣f > 1-哌畊基]甲基}-3-甲基苯甲醯胺及5-氟-2-{[4-(2_邮 1- 哌畊基]甲基} - 1H-啕哚之數據示於表A。表A之數膠\ ,免5-氟一 N-{ [4· (2-氰苯基)-i-哌p井基]甲基卜3-甲基苯甲婊脒 2- {[4-(2-吡啶基)-1_哌畊基]甲基1H-啕哚為促效劑。
75003-960627.doc - 17 - 本紙張尺度適用中國國家標準(CIsjS) A4規格(210 X 297公釐) 1293254 A7 B7 五、發明説明(
表A η ec5〇 (nM) 最大 反應 N-{ [4-(2-氰苯基)小哌畊基]甲基卜3-曱基苯甲醯胺 12 5.6 68% 5-氟-2-{[4-(2-吡啶基)小哌畊基]甲基}-1Η-吲哚 4 32 46% 大鼠陰莖勃起模型 使用威斯達鼠作為體内研究陰莖勃起之主要動物模型。 所有實驗於具有紅光之擴散照射測試室中在9·Ό0 AM至3:00 PM 間進行。大鼠與以稱重及開始實驗前適應該測試室60分鐘。 皮下藥物注射後大鼠置於個別透明蘢(20x30x30公分)中。藥 物投藥後60分鐘期間内直接觀察並記錄陰莖勃起數量。記錄 展現一次或以上勃起之動物數並以發生百分比示於表2-4。 大鼠中阿朴嗎啡謗發之陰莖勃起 (L)-抗壞血酸之食鹽水(1毫克/毫升)使用作為載劑。每劑 量使用32隻動物。表2數據顯示阿朴嗎啡在劑量0. 01微莫耳/ 公斤至0.3微莫耳/公斤謗發明顯之陰莖勃起促進作用。或然 率或有意義量以P對載劑加以表示。“P”為統計學測試之或 然率或有意義量。 表2 劑量微莫耳/公斤 發生率(%) Ρ 載劑 22 0. 003 28 0.01 56 <0.01 0.03 69 <0.001 0.1 92 <0.001 0.3 66 <0.001 1.0 25 75003-960627.doc - 18 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1293254
甲基蒎甲醯胺於士I 土誘發陰莕勃杂 b(l)-抗壞血酸之食鹽水(1毫克/毫升)使用作為載劑。每劑 y使用14隻大藏。在導致大鼠陰莖勃起發生率之劑量 微莫耳/公斤之阿朴嗎啡作為陽性對照組。表3數據證明沁 { [4 (2氯苯基)_ μ味畊基]甲基卜3_甲基苯甲醯胺在微莫 耳/么斤至1. 0微莫耳/公斤間之劑量於大鼠中謗發明顯之陰 莖勃起。或然率或有意義量以ρ對載劑加以表示。 阿朴嗎啡OKI) 86 <0. 001 ~' 0.03 42 0.1 71 <0.01 —^' 0.3 79 <0.01 ~ 1.0 68 <0.05 比淀基哌畊基1曱基!-1Η-吲哚於大鼠中$ 發陰莖勃刼 (L)-抗壞血酸之食鹽水(1毫克/毫升)使用作為載劑。每劑 I使用10隻大鼠。在導致大鼠陰莖勃起9〇%發生率之劑量〇. j 微莫耳/公斤之阿朴嗎啡作4陽性對照組。表4數據證明5-氟-2-{[4-(2-吡啶基)-μ哌畊基]甲基哚在1〇微莫耳/ 公斤至3. 0微莫耳/公斤間之劑量於大鼠中謗發明顯之陰莖勃 起。或然率或有意義量以ρ對載劑加以表示。 -19- 75003-960627.doc 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1293254
。雄性費兹白鼬(體重1(Μ·5公斤)實驗前禁食隔夜。動物個 於觀察€中接著皮下投與藥物及在注射後90分鐘内觀 奈藥物诱發〈噁心及嘔吐。噁心之特徵為拍擊、張嘴、後退 、埋頭及強烈異常修飾行為"g吐—般藉該等行為漸進且特 被為胸部異常收縮,其與唱吐或反胃有關。記錄謗發至呕吐 之白鼬數目並以發生率(%)表現於表孓7。 太鼠中阿朴嗎啡謙發之嘔吐 使用食鹽水作為載劑。每劑量使用6至12隻動物。表5數據 證明所有劑量中阿朴嗎啡謗發嘔吐。或然率或有意義量以p 對載劑加以表示。 劑量微莫耳/公斤 發生率(%) Ρ 載劑 ' 0 0· 1 32 <0.05 0.3 82 <0.001 1.0 48 <0.01 3.0 32 <0.05 10.0 32 <0.05 -20- 本紙張尺度適用中國國家標準(CNS) A#規格(21〇χ 297公釐) 1293254
纽 4- (2-氰苯_基)· μ 味喷 f誘發之喉吐 使用3%二甲基亞砜之食鹽水作為载劑。每劑量使用6至12 隻動物。在導致大鼠陰莖勃起83%發生率之劑量〇·3微莫耳/ 公斤之阿朴嗎啡在表6中作為陽性對照組。Ν- {[心(2_氰苯 基)-1-哌畊基]甲基卜3-甲基苯甲醯胺在任何劑量未謗發嘔 吐。或然率或有意義量以p對載劑加以表示。 表6 劑量微莫耳/公斤 ~ ------ 發生率(%) p 載劑 0 阿朴嗎啡(0. 3) 83 <0.001 0.1 0 0.3 0 --- 1.0 0 3.0 0 2- {「4·—(2〇比淀某V 1-咪唔基·[甲某1H_吲哚於大鼠中辩 發之喉吐 使用1%二甲基亞砜之食鹽水作為載劑。每劑量使用6至12 隻動物。在導致大鼠陰莖勃起83%發生率之劑量〇. 3微莫耳/ 公斤之阿朴嗎啡在表7中作為陽性對照組❶5_氟-2-{ [4-(2-吡 啶基)-1-哌p井基]甲基} - 1H〃引哚在任何劑量未謗發嘔吐。或 然率或有意義量以p對載劑加以表示。 -21 - 75003-960627.doc 本紙張尺度適用中國國家標準(C&S) A4規格(210X 297公釐) 191293254 五、發明説明( 劑微莫耳/公斤 載劑 :朴嗎啡(0. 3) 1.0 3.0 0
P <0.001 於大^」非選擇性及選擇性多巴胺D4受體促效劑 巧1^:、!勃起原效果。然而,選擇性多巴胺A受體促效 ;匕低之唱吐傾向。因此與選擇性多巴胺D,受體促 3 =之勃衫縣轉低之Μ傾向教㈣擇性多巴 女4文體促效劑可用以治療 性勃起官能障礙。 此障礙,包含(但不限於)男 ^又所用〈“醫藥可接受性載體,,意指非毒性惰性固體、 =體或液體填充劑、稀釋劑、包囊物質或任何類型之調配 ^ I作為醫藥可接受載體之有些實例為糖類如乳糖、葡 ^及薦糖’·殿粉如玉米興粉及馬蛉絲粉;纖維素及其衍 普去/甲基纖維素、乙基纖維素及纖維素乙酸自旨;粉末 Κ /膠麥芽糖;明膠;滑石;賦型劑如椰子奶油及栓劑蠟 及二花生油、棉子油、葵花油、芝麻油、橄欖油、玉米油 匕大二油,甘油如丙二醇;酯如油酸乙酯及月桂酸乙酯;瓊 張入^衝^如I氧化錢及氯氧化叙;褐、溪酸;無熱源水;等 =水,林格氏溶液;乙醇;及磷酸鹽緩衝溶液以及其他 母陵可相谷潤滑劑如月桂基硫酸納及硬脂酸鎂,以及著 本紙張
1293254
五、發明説明(21 骨匕,釋劑、溶劑或載劑實例包含水、乙醇、多元醇(丙二 二聚乙二醇、甘油等)、其適宜混合物、植物油(如橄欖油) 、、:王十有機酯如油酸乙酯。使用包衣劑如卵磷脂、在分散 中藉維持所需粒徑及藉使用界面活性劑可維持適當 =等組靖可包含佐劑如保存劑、濕潤劑、乳化劑及分 竑:。可猎各種抗菌及抗真菌劑例如對-羥基苯甲酸酯、氯 了:化m避免微生物作用。亦宜包含等張劑例如糖類 /化鈉♦。使用延缓吸收之藥劑如單硬脂酸鋁及明膠可製 桴延緩吸收之可注射醫藥劑。 、有些例中,為了延長藥物效果,經常需要減緩藥物自皮下 王t《吸收。此可藉利用具不良水溶解度之結晶 i速液體懸浮液而達成。藥物吸收速率视其溶 ,連羊:疋,接讀結晶大小及結晶型而定。或者,非經 腸u又藥』之延緩吸收藉溶解或懸浮藥物於油性載骨 而芫成。 庄 田除了活性化合物以夕卜,·懸浮液可含有懸浮劑例如乙氧化 異硬脂醇、聚氧乙埽山梨糖醇及山梨糖醇㈣、微晶纖維素 、::氧化鋁、膨潤土,旨,脂、黃耆膠、及其混合物:、 右需要’及就更有效分散而言,選擇性多巴胺仏受體促效 ,考併入緩釋或標的輸送系統中如聚合物基質、脂質體及 μ:體。其可藉留住細菌脂濾膜過濾或併入殺菌固體組合 物悲《殺菌劑而殺菌,其在使用前可溶於無菌水或有啦並 他無菌可注射介質中。 一八 -24- 本紙張尺度家_7^_)域格(21GX撕公爱) 22 25- 1293254 發明説明( 上二X巴胺込受體促效劑亦可成微包囊態,若適當心 :二或夕種賦型劑包囊。固體劑型之錠劑、糖衣鍵、膠 粒射製備為包衣及包殼如腸*、料控制之包 衣及醫樂调配技蕺禾知> Α 士 L. _ . —知《包衣。此固體劑型中,活性化合物可 =土广私性稀_如·、乳m㈣合。 務 中,此劑型亦可包括惰性稀釋#j ^ 麻em. 料心夕卜《其他物質,如製錠潤滑 =/、他Μ助劑如硬㈣敍微晶齡素。膠囊、鍵劑及 =例中’孩劑型亦可包括缓衝劑。其可視情況含有霧濁 π可為可僅釋出活性成分之組合物,或較好在某些腸道中 以緩釋万式釋出。可用之包埋組合物實例包含聚合物質及墙。 ,可注射儲袋可藉形成選擇性多巴胺仏受體促效劑微包囊 於生物可降解聚合物如聚乳交酿·聚乙交酿中形成微包囊基 質而製得。視選擇性多巴胺A受體促效劑對聚合物比例及視 所用特疋聚合物性質而定,可控制選擇性多巴胺〜受體促效 劑釋出速率。其他生物可降解聚合物實例包含聚(原㈤及聚 (酸酐)。儲袋可注射調配物亦可藉將藥物捕捉人脂質體或微 乳液(其與體組織可相容)中而製備。 " 可〉王射調配物可藉例如經留置細菌之濾紙過滤或藉由併 入殺菌劑而呈在使用前可於無菌水或其他無菌可注射介Μ 中溶解或分散之無菌固體組成物予以殺菌。 貝 可 >王射製劑例如無菌可注射水性或油性懸浮亦可依據已 知領域使用適宜分散劑或濕潤劑及懸浮劑調配。該無^可 /王射製劑亦可為於非毒性、非經腸道可接受稀釋劑或溶, 中足無菌可注射溶液、懸浮液或乳液,如於I,、丁二醇中之 本紙度適财H a j標準(CNS) Α4規格
五、發明説明( 可用之可接受載劑及溶劑為水、林格氏溶液撕及 ㈣氯化納溶液。此外,無菌之狀油f知上使用作為溶劑 或,介質。就此目的而言,可使用任何品牌固定油包含合 成早-或二甘油S旨。此外,脂肪酸如油酸可用以製備注射劑。 硬脂酸鎂、固體聚乙二醇、月桂基硫酸納及其混合物混合。 膠囊、錠劑及丸劑之例中,劑型亦可包含緩衝劑。 類似型態之固體組合物亦可使用如乳糖或:奶糖以及高 刀子里聚乙一醇等之賦型劑而軟及硬填充之明膠膠囊中作 為填充劑。 口服投藥之固體劑型包含膠囊、錠劑、丸劑、粉劑及顆粒 .此固體劑型中’選擇性多巴胺D4受體促效劑與至少一種 惰性醫藥可接受性賦型劑或載體如檸檬酸鋼或磷酸二每及/ 或a)填充劑或延展劑如澱粉、乳糖、薦糖、葡萄糖、甘露糖 畔切酸;b)黏合劑如羧甲基纖維素、褐藻酸鹽、明膠、聚 乙埽峨❹酮、隸及阿拉伯膠;e)保濕劑如甘油;由崩解 劑如瓊脂-壤月旨'礙酸每、馬鈴薯或樹薯則分、褐藻酸 '某 些碎酸鹽及碳酸納;e)溶液阻滞劑如石壤;把收加速劑如 四級按化合物;g)濕潤劑如_醇及單硬脂酸甘油醋;⑴吸 收劑如高領土及膨潤黏土;及i)潤滑劑如滑石、硬脂酸約、 叙劑、糖衣錠、膠囊、丸劑及顆粒劑之固體劑型可以包衣 及包殼製備,如腸衣及醫藥調配領域已知之其他包衣。其可 視情況含有霧濁劑及亦可為可僅釋出活性成分之組合物, f較好在某些腸道中以緩釋方式釋出。可用之包埋組合物 實例包含聚合物質及蠟。 -26- 本紙張尺度^中國國家標準(CNS) A4規格(210X 297公楚y 1293254 * · A7
液口 =樂《液體劑型包含醫藥可接受性乳液、微乳液、溶 劑以二:液甘草劑。除了選擇性多巴胺⑽體促效 ^甘…可含有苯領域慣用之惰性稀釋劑,例如 =Γι溶解劑及乳化劑如乙醇、異丙醇、碳酸乙酿 甲基甲醯胺、油類(尤其:帛二 μ 兹广/八 化生油玉米油、胚芽油、 ㈣見油、錄油及芝麻油)、甘油 '四氫吱喃醇、聚乙二於 及山梨糖醇酐之脂肪酸酯及其混合物。 于 除”青性稀釋劑以外,口服组合物亦可包含佐劑如濕潤 训、乳化劑、甜味劑 '矯味劑及香味劑。 本發明化合物之局部或經皮投藥劑型包含軟膏、糊膏、乳 霜、乳膠、凝膠、溶液、噴霧劑、吸人劑或貼劑。活性成分 tt ^ ^ ^ ^ ^ ^ ^ 保存劑或緩衝劑混合。眼用調配劑、耳滴劑、眼軟膏、粉劑 及溶液亦可為本發明之範圍。 除了選擇性多巴胺D4受體促效劑以外,該軟膏、糊膏、乳 相及喊膠可含有賦型劑如動物及植物脂肪、油、蠟、石蠟、 澱粉、黃耆膠、纖維素衍生物、聚乙二醇、矽氧、膨潤土、 石夕酸、滑石及氧化鋅或其混合物。 除了選擇性多巴胺D4受體促效劑以外,該粉劑及噴霧劑可含 有賦型劑如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺粉 末或遠等物質之混合物。糖漿又可含有慣用推進劑如氯氟烴。 ^ 選擇性多巴胺〇4受體促效劑可以衍生自無機或有機酸之 醫藥可接受性鹽型態使用。“醫藥可接受性鹽,,意指在合理 -27 -本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1293254
醫藥判斷範圍内適用於與人類或低等動物接觸而無毒性、 刺激性、過敏反應等且具有合理之效益/危險性比例者。醫 某可接焚性鹽為本技藝悉知。例如μ. Berge等人描述於醫 藥科學期刊1977,66:1之醫藥可接受性鹽。該鹽可就此於本 發明化合物最後單離及純化期間製備或另外使游離鹼官能 基Μ適^有機I反應而製備。代表性酸加成鹽包含(但不限 於)乙鉍鹽、己一酸鹽、褐藻酸鹽、檸檬酸鹽、天門冬胺酸 鹽、苯曱酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、 樟腦磺酸鹽、二葡糖酸鹽、甘油基磷酸鹽、半硫酸鹽、庚酸 鹽、己酸鹽、冨馬酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽、2_ 羥基乙烷磺酸鹽、乳酸鹽、馬來酸鹽、甲烷磺酸鹽、菸驗酸 鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果酸鹽、過硫酸鹽 、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、琥珀酸鹽 、酒石酸鹽、硫氰酸鹽、磷酸鹽、榖胺酸鹽、碳酸氫鹽、對-甲苯績酸鹽及十一碳燒酸鹽。 醫樂可接文性-藥”或“前藥”意指在合理醫藥判斷範圍 内適用於與人類或低等動物接觸而無毒性、刺激性、過敏反 應等且具有合理之效益/危險性比例且對其用途有效之選擇 性多巴胺D4受體促效劑之該等前藥。〗選擇性多巴胺a受體促 效劑之前藥可於體内藉例如血液中水解而轉化成選擇性多 巴胺A受體促效劑。整個討論見於τ·扭卯啪及ν·撤皿之 A.C.S研討會系列之新穎輸送系統之前藥,卷14,及
Roche編輯之藥物設計之生物可逆載體,美國醫藥協會及派 拉蒙出版社(1987)彳 -28-本紙張尺度適用中國國家標準(CNS) A4規格(210X297公I) 1293254 A7 B7 五、發明説明(26 本發明醫藥組合物中活性成分之確實劑量可變只要獲得 可有效達成特定病患、組合物及投藥模式所需之治療反應 之選擇性多巴胺卬受體促效劑即可。該選擇之劑量將視特定 化合物活性、投藥路徑、欲治療病況嚴重性及欲治療病患病 況及先㈤醫藥史而定。然而,熟知本技藝者可在開始時使用 比達到所需治療效果低之選擇性多巴胺A受體促效劑而逐 漸增加劑量直至達到所需效果。 本發明有關一種選擇性多巴胺仏受體促效劑以化學合成 或藉體内生物轉化形成選擇性多巴胺〜受體促效劑。 使用於上述或其他治療時,可以純態或以醫藥可接受性 •1或岫樂形式使用治療有效量之選擇性多巴胺受體促效 $。或者,選擇性多巴胺A受體促效劑可以含所欲之選擇性 多巴胺D4受體促效劑與一或多種醫藥可接受賦型劑組合之 醫藥組合物使用。“治療有效量,,之本發明化合物意指在可 應用至任何醫藥治療之合理效益/危險性比值下之足量選擇 性多巴胺D4受體促效劑以抑制性t能障礙。然㈣了解選擇 1*生夕巴D4爻體促效劑及其組合物之總日劑量將可由醫師 在合理醫藥判斷範圍内分為數次使用。對任何特定病患之 特定治療-效果劑量將視'各種因素而^,包含欲治療之二官 能障礙及性官能障礙之嚴重性;所用之特定選擇性多巴胺A 受體促效劑活性;所用特定條件;病患年齡、體重、一般健 康狀況、性別及飲食;投藥時間、投藥路徑、及所用特定選 擇性多巴胺d4受體促效劑之分泌速率;治療時程;用以^ 或共同與所用選擇性多巴胺受體促效劑投藥之藥物;及: -29-:297公釐) 1293254 A7 B7 五、發明説明(27 ) 藥領域悉知之因素。例如熟知本技藝者可在開始時使用比 達到所需治療效果低之選擇性多巴胺D4受體促效劑而逐漸 增加劑量直至達到所需效果。 投與至人類或低等動物之選擇性多巴胺D4受體促效劑總 曰劑量可自約0.001至約30毫克/公斤/天之範圍。就口服投藥 目的而言,更佳之劑量可在約0.01至約10毫克/公斤/天之範 圍。若需要,有效日劑量就投藥目的可分成多次劑量;結果 ,單一劑量組合物可含有此量或其次分多次劑量而構成該 日劑量。 £ 75003-960627.doc - 30- 本紙張尺度適用中國國家標準(Ciis) A4規格(210 X 297公釐)
Claims (1)
12 93 2^0128952號專利申請案 ’中文·申請專利範圍替換本(96年6月、 申請專利範園 其係用作製備用於治療哺乳類性 、 猎由向需要該治療之哺乳類投予 :、糸 ^ . •有效罝之該樂劑, -中“夕巴胺d4受體促效劑對〇4受體擇 受體之卿性至少m €㈣為對D2 :別或其醫藥可接受性鹽係用作製備用於治療 4· 性性官能障礙之藥劑,其係藉由向需要該治療之哺乳 類投予治療有效量之該藥劑,其中該多巴胺I受體促效 劑對d4_之選擇性㈣D2受體之選擇性至少⑽倍, 3·如申請專利II圍第!項之用途,其中該多巴胺〜受體促 效劑或其醫藥可接受性鹽係用作製備用於治療哺乳類中 女^性官_礙之藥劑,其係藉由向需要該治療之哺乳 類才又予冶療有效量之該藥劑,其中該多巴胺d 4受體促效 劑對受體之選擇性為對〇2受體之選擇性至少ι〇〇倍。 一種多巴胺D4受體促效劑或其醫藥可接受性鹽之用途, 其係用作製備用於治療哺乳類中男性勃起官能障礙之藥 劑,其係藉由向需要該治療之哺乳類投予治療有效量之 為藥劑’其中該多巴胺D4受體促效劑對D4受體之選擇 性為對D2受體之選擇性至少ι〇〇倍。 5·如申請專利範圍第1至4項中任一項之用途,其中該選擇 性多巴胺受體促效劑對D4受體之選擇性為對D2受體 之選擇性的200倍。
!293254 、申請專利範 園 6·如申請專利範圍第14項中任一項之用途, 性多巴肋4受體促效劑對D4受體之選擇性為對d該 之選擇性的300倍。 2 ^ 7·如申請專利範圍第丄至4項中任一項之用途,其中該選擇 性多巴胺D4受體促效劑對ο)受體之選擇性為對受體 之選擇性的500倍。 8·如申请專利範圍第丨至斗項中任一項之用途’其中該選擇 性多巴胺D4受體促效劑對D4受體之選擇性為對d2受體 之選擇性的1 〇 〇 〇倍。 9·如申請專利範圍第1至4項中任一項之用途,其中該選擇 性多巴胺D4受體促效劑不引起明顯嘔吐。 1〇·如申請專利範圍第丨至4項中任一項之用途,其中該多巴 胺D 4受體促效劑或其醫藥可接受性鹽係與醫藥可接受性 载體組合。 11·如申請專利範圍第2至4項中任一項之用途,其中該選擇 性多巴胺D 4受體促效劑係n - { [ 4 · (2 -氰苯基)· 1 -喊_基] 曱基卜3-曱基苯曱醢胺或其醫藥可接受性鹽。 12.如申請專利範圍第2至4項中任一項之用途,其中該選擇 性多巴胺D4受體促效劑係5 -氟-2-{[4-(2-吡啶基)-1-哌 p井基]曱基} -1 Η -㈣嗓或其醫藥可接受性鹽。 75003-960627.doc -2- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公爱) 裝 玎
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US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
UA78974C2 (en) | 2001-10-20 | 2007-05-10 | Boehringer Ingelheim Pharma | Use of flibanserin for treating disorders of sexual desire |
AU2003231801A1 (en) * | 2002-05-23 | 2003-12-12 | Abbott Laboratories | Acetamides and benzamides that are useful in treating sexual dysfunction |
PL1912650T3 (pl) | 2005-08-03 | 2018-01-31 | Sprout Pharmaceuticals Inc | Zastosowanie flibanseryny w leczeniu otyłości |
WO2007048803A1 (en) | 2005-10-29 | 2007-05-03 | Boehringer Ingelheim International Gmbh | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
US20090312242A1 (en) | 2006-06-30 | 2009-12-17 | Ramiro Castro | Flibanserin for the treatment of urinary incontinence and related diseases |
AR062320A1 (es) | 2006-08-14 | 2008-10-29 | Boehringer Ingelheim Int | Formulaciones de flibanserina y metodo para fabricarlas |
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DE60127712T2 (de) | 2007-12-27 |
BR0110450A (pt) | 2005-02-09 |
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CN1531434A (zh) | 2004-09-22 |
HUP0402358A3 (en) | 2009-08-28 |
HK1059884A1 (en) | 2004-07-23 |
WO2002041894A2 (en) | 2002-05-30 |
UY27031A1 (es) | 2002-07-31 |
KR20030051857A (ko) | 2003-06-25 |
CA2429383A1 (en) | 2002-05-30 |
IL155094A0 (en) | 2003-10-31 |
EP1345608A2 (en) | 2003-09-24 |
CZ20031458A3 (cs) | 2004-02-18 |
AR035600A1 (es) | 2004-06-16 |
JP2004534725A (ja) | 2004-11-18 |
EP1345608B1 (en) | 2007-04-04 |
NO20032304L (no) | 2003-07-15 |
HUP0402358A2 (hu) | 2005-03-29 |
PE20020557A1 (es) | 2002-06-25 |
NO20032304D0 (no) | 2003-05-21 |
AU2002226895B2 (en) | 2006-10-12 |
SK7242003A3 (en) | 2004-01-08 |
PL365890A1 (en) | 2005-01-10 |
ATE358483T1 (de) | 2007-04-15 |
BG107810A (bg) | 2004-02-27 |
ES2284727T3 (es) | 2007-11-16 |
AU2689502A (en) | 2002-06-03 |
WO2002041894A3 (en) | 2002-10-17 |
MXPA03004547A (es) | 2004-03-26 |
NZ525086A (en) | 2006-07-28 |
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