TW202034920A - 用於治療睡眠呼吸中止之α2-腎上腺素受體亞型C(α-2C)拮抗劑 - Google Patents
用於治療睡眠呼吸中止之α2-腎上腺素受體亞型C(α-2C)拮抗劑 Download PDFInfo
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- TW202034920A TW202034920A TW108134163A TW108134163A TW202034920A TW 202034920 A TW202034920 A TW 202034920A TW 108134163 A TW108134163 A TW 108134163A TW 108134163 A TW108134163 A TW 108134163A TW 202034920 A TW202034920 A TW 202034920A
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- methyl
- dihydrobenzo
- oct
- alkyl
- phenyl
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Abstract
本發明係關於用於治療及/或預防與睡眠有關之呼吸疾病、較佳是阻塞性及中樞性睡眠呼吸中止及打鼾之方法中的α2-腎上腺素受體亞型C(α-2C)拮抗劑,特別是式(I)之芳基哌
Description
阻塞性睡眠呼吸中止(OSA)為與睡眠有關之呼吸疾病,其特徵在於上呼吸道阻塞重複發作。當吸氣時,兩個相反力的交互作用可確保上呼吸道通暢。上呼吸道肌肉的擴張作用抵消了管腔內負壓,而使管腔收縮。橫膈膜肌及其他輔助呼吸肌的主動收縮在氣道中產生負壓,從而構成呼吸的驅動力。上呼吸道的穩定性實質上係取決於上呼吸道擴張肌之協調及收縮特性。
由於一些上呼吸道擴張肌之活動降低,於OSA之上呼吸道塌陷被認為是在睡眠開始時發生的,結果無法保持於解剖構造上脆弱的氣道開放。然而,一些上呼吸道擴張肌,包括頦舌肌,其為上呼吸道擴張肌中最重要的且其乃由舌下神經來支配,可回應呼吸刺激而提高睡眠過程中之活性,從而可能抵消一些睡眠開始時之變化。據觀察,OSA患者具有無呼吸中止的區間,於其
間,該頦舌肌肌肉活動與具有經常性阻塞性呼吸中止之睡眠相比較時僅較高25-40%(Jordan AS,White DP,Lo YL et al.,Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea.Sleep 2009,32(3):361-8)。去甲腎上腺素係舌下運動神經元活力中最強的神經調節劑之一(Horner R.L.Neuromodulation of hypoglossal motoneurons during sleep.Respir Physiol Neurobiol 2008,164(1-2):179-196)。據信,下降之去甲腎上腺素能驅動可導致睡眠依賴性之舌下運動神經元興奮性降低,從而導致上呼吸道擴張肌之活力降低,尤其是舌肌肌肉之活力降低。
α2C腎上腺素受體係調節中樞去甲腎上腺素能神經元釋放去甲腎上腺素,其等係參與去甲腎上腺素突觸前反饋抑制作用之自身受體(Hein L.et al,Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999,402(6758):181-184)。藉由α2c腎上腺素受體拮抗作用而增加舌下神經運動神經元的活性可穩定該上呼吸道並保護其等免於塌陷及閉塞。再者,亦可藉由穩定上呼吸道之機制來抑制打鼾。
於單純打鼾時,上呼吸道則無阻塞。由於上呼吸道縮小了,所吸入及呼出之空氣的流速提高。此與鬆弛之肌肉一起導致氣流中口腔及咽喉中之軟組織拍打。此種輕微振動產生了典型的鼾聲。
阻塞性打鼾(上呼吸道阻力徵候群、嚴重打鼾、呼吸不足徵候群)係由於上呼吸道在睡眠中反復局部阻塞所引起。此導致氣道阻力增加且因而增加了胸腔內壓力明顯波動時的呼吸功。由於其等係於OSA完全氣道阻塞所導致,吸氣過程中胸腔負壓的發展可因此達到一數值。對於心臟,循環及睡眠品質的病理生理影響與阻塞性睡眠呼吸中止者相同。發病機制可能與OSA者相同。阻塞性打鼾通常是OSA的先驅(Hollandt J.H.et al.,Upper airway resistance syndrome(UARS)-obstructive snoring.HNO 2000,48(8):628-634)。
中樞性睡眠呼吸中止(CSA)係由於腦功能紊亂或呼吸調節功能受損而導致。CSA之特點為於睡眠時缺乏呼吸之驅動力,導致通風不足或缺乏通風,以及氣體交換不良之反復區間。CSA有幾種表現形式。這些包括高海拔誘發之週期性呼吸、特發性CSA(ICSA)、麻醉藥引起之中樞性呼吸中止、肥胖症之低通氣徵候群(OHS)及Cheyne-Stokes呼吸(CSB)。儘管各類型之CSA中所涉及的精確沉澱機制可能會有很大差異,但睡眠期間不穩定的通氣驅動為主要的潛在特徵(Eckert D.J.et al.,Central sleep apnea:Pathophysiology and treatment.Chest 2007,131(2):595-607)。
US 2018/0235934 A1係說明使用可促進舌下運動神經元興奮性之試劑來治療例如阻塞性睡眠呼吸中止之疾病的方法。作為促進舌下運動神經元興奮性之試劑,係描述中樞腎上腺神經元之脫抑劑及/或興奮劑。於某些具體例中,該中樞去甲腎上腺素能神經元之脫抑劑為α2-腎上腺素受體拮抗劑,如育亨賓(yohimbine)或α2-腎上腺素受體亞型A(α-2A)拮抗劑或α2-腎上腺素受體亞型C(α-2C)拮抗劑。該α2-腎上腺素受體拮抗劑係選自包括下列者:阿替美唑(Atipamezole)、MK-912、RS-79948、RX 821002、[3H]2-甲氧基-亞達唑散(idazoxan)及JP-1302。
α2C腎上腺素受體係隸屬於G-蛋白質偶合受體家族。除了不同的α1-腎上腺素受體,存在有三種不同的A2-腎上腺素受體亞型(α2A、α2B及α2C)。其等在受到內源兒茶酚胺(腎上腺素,去甲腎上腺素)刺激後,參與不同組織中數種不同生理作用之介導,來自突觸或經由血液。α2腎上腺素受體扮演重要的生理角色,主要係在心血管系統及在中樞神經系統。α2A-及α2C-腎上腺素受體為在中樞神經系統中參與去甲腎上腺素之突觸前反饋抑制的主要自動受體。去甲腎上腺素於該α2C-腎上腺素受體上之效價及親和力較於α2A-腎上腺素受體上者為高。該α2C-腎上腺素受體係以低內生性去甲腎上腺素濃度來抑制去
甲腎上腺素之釋放,而α2A-腎上腺素受體係以高內生性去甲腎上腺素濃度來抑制去甲腎上腺素之釋放(Uys M.M.et al.Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition,Depression,and Schizophrenia-New Developments and Future Perspective.Frontiers in Psychiatry 2017,Aug 14;8:144.doi:10.3389/fpsyt.2017.00144.eCollection 2017)。
芳基哌作為α2-腎上腺素受體亞型C(α-2C)拮抗劑以及其等之製備方法及其作為醫藥品之用途已知於WO 2010/058060 A1,其中該化合物係揭示有用於治療疾病,例如,壓力所傳播之疾病、帕金森氏症、抑鬱症、精神分裂症、注意缺陷多動障礙、創傷後應激障礙、強迫症、Tourette's徵候群、眼瞼痙攣或其他局灶性肌張力障礙、顳葉癲癇伴精神病、藥物性精神病、亨丁頓氏症、性激素濃度起伏引起之疾病、恐慌症、阿茨海默氏症或輕度認知障礙。其等並無揭示這些化合物於治療與睡眠有關之呼吸疾病、較佳為阻塞性及中樞性睡眠呼吸中止及打鼾之用途。
目前OSA患者之黃金標準治療是持續性呼吸道正壓治療(CPAP)。藉由氣流渦輪泵夾板產生的正氣流壓力打開了上呼吸道,逆轉所有可能導致咽部塌陷的原因,因而避免呼吸不足、呼吸中止及睡眠不足。不幸的,長期以來,所有OSA患者中多達50%不耐受CPAP(M.Kohler,D.Smith,V.Tippett et al.,Thorax 2010 65(9):829-32:Predictors of long-term compliance with continuous positive airway pressure)。因此,仍需尋找有效的治療劑以治療及/或預防與睡眠有關之呼吸疾病,如阻塞性睡眠呼吸中止。因此,本發明之目的在於提供有效的治療劑以治療及/或預防與睡眠有關之呼吸疾病,例如,阻塞性睡眠呼吸中止、中樞性睡眠呼吸中止及打鼾。
本發明係關於式(I)化合物
於一可能之式I化合物亞族中,X為O。
於其他可能之式I化合物亞族中,A、B、D及E為C。
於另一可能之式I化合物亞族中,A為N;且B、D及E為C。
於其他可能之式I化合物亞族中,n為1。
於其他可能之式I化合物亞族中,n為2。
於另一可能之式I化合物亞族中,X 為O、S或CH2;Z 為-[CH2]n-;A 為C或N;B、D及E為C;R1 為H、鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為1或2。
於本發明之其他具體例中
X 為O;Z 為-[CH2]n-;A 為C或N;B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為1或2。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A、B、D及E為C;R1 為(C1-C6)烷基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H或鹵素;R3 為H;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為1或2。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A 為N;B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H或鹵素;R3 為H;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為1或2。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A 為N;B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;R5 在每次出現時係獨立為H或(C1-C6)烷基;
m 為0;且n 為1。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A 為N;B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為2。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A、B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;
R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為1。
於本發明之其他具體例中X 為O;Z 為-[CH2]n-;A、B、D及E為C;R1 為鹵素、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-或呋喃基;R2 為H、鹵素、(C1-C6)烷基或羥基(C1-C6)烷基;R3 為H、(C1-C6)烷基或苯基;R5 在每次出現時係獨立為H或(C1-C6)烷基;m 為0;且n 為2。
於較佳具體例中,本發明係關於選自包括下列之式(I)化合物:2-(4-((2,3-二氫苯并[b][1,4]二辛(dioxin)-2-基)甲基)哌-1-基)苯甲酸甲酯、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲醇、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苄腈、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲胺、1-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)-N-甲基甲胺、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(乙氧基甲基)苯基)哌、2-(2-(4-((2,3-二氫苯并[b][14]二辛-2-基)甲基)哌-1-基)苯基)丙-2-醇、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基
甲基)吡啶-2-基)哌、(S)-(2-(4-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-哌-1-基)吡啶-3-基)甲醇、(S)-(2-(4-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-哌-1-基)吡啶-3-基)甲醇HCl、(S)-1-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌HCI、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-((2-氟乙氧基)甲基)吡啶-2-基)哌、1-(2,3-二氯苯基)-4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)吡啶-3-基)甲醇、(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)吡啶-3-基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(R)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌、(1-((2,3-二氫苯并[b][1,4]氧硫雜環己二烯(oxathiin)-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、1-(色滿-2-基甲基)-4-(2-(甲氧基甲基)苯基)哌、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-6-氟苯基)甲醇、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-3-氟苯基)甲醇、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-5-氟苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-丙基苯基)哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(三氟甲氧基)苯基)哌、(S)-1-(聯苯基-3-基)-4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(呋喃-2-基)苯基)哌、(S)-乙基-2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯甲酸酯,(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-o-甲苯基哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-m-甲苯基哌、(S)-(3-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-4-甲基苯基)甲醇、(S)-(3-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-
基)苯基)甲醇、(S)-2-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)乙醇、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷(diazepan)-1-基)苯甲酸甲酯、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)苯基)甲醇、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)菸腈、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)菸醯胺、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)吡啶-3-基)甲醇或(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)吡啶-3-基)甲醇以及其等之鹽類,溶劑合物,及該鹽類之溶劑合物,以用於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
於更佳之具體例中,本發明係關於選自包括下列之式(I)化合物:(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(R)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-6-氟苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(呋喃-2-基)苯基)哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-o-甲苯基哌、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)苯甲酸甲酯、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌以及其等之鹽類,溶劑合物,及該鹽類之溶劑合物,以用於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
於本發明之最佳具體例中,該式(I)化合物為(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌或(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-([11C]-甲氧基甲基)吡啶-2-基)哌。
本文中所使用之詞具有以下含義。於下列定義中,"至少一個"之詞係指一個或多個,例如一個。
本文中所使用之"羥基"之詞,係像這樣或作為另一基團之一部份,係指-OH基團。
本文中所使用之"(C1-C6)烷基"之詞,係像這樣或作為另一基團之一部份,係指一直鏈或分支具有1、2、3、4、5或6個碳原子之飽和烴基團。(C1-C6)烷基之代表性實例包括,但非侷限於,甲基、乙基、正-丙基、異-丙基、正-丁基、異-丁基、第二-丁基、第三-丁基、正-戊基、異-戊基、及正-己基。
本文中所使用之"(C1-C6)烷氧基"之詞,係像這樣或作為另一基團之一部份,係指(C1-C6)烷基基團,如本文中所定義,經由氧原子而連接至母分子部份。(C1-C6)烷氧基之代表性實例包括,但非侷限於,甲氧基、乙氧基、正-丙氧基、正-丁氧基、異-丁氧基、第二-丁氧基、第三-丁氧基、2,2-二甲基丙氧基、3-甲基丁氧基、及正-己氧基。
本文中所使用之"鹵"或"鹵素"之詞,係像這樣或作為另一基團之一部份,係指氟、氯、溴或碘。
本文中所使用之"羥基(C1-C6)烷基"之詞,係像這樣或作為另一基團之一部份,係指至少一個羥基基團,如本文中所定義,經由一(C1-C6)烷基基團而連接至母分子部份,如本文中所定義。羥基(C1-C6)烷基之代表性實例包括,但非侷限於,羥基甲基、1-羥基乙基、2-羥基乙基、2,2-二羥基乙基、1-羥基丙基、3-羥基丙基、1-羥基-1-甲基乙基、及1-羥基-1-甲基丙基。
本文中所使用之"(C1-C6)烷氧基(C1-C6)烷基"之詞,係像這樣或作為另一基團之一部份,係指至少一個(C1-C6)烷氧基基團,如本文中所定義,經由一(C1-C6)烷基基團而連接至母分子部份,如本文中所定義。當其等有數個(C1-C6)烷氧基基團時,該(C1-C6)烷氧基基團可相同或不同。
(C1-C6)烷氧基(C1-C6)烷基之代表性實例包括,但非侷限於,甲氧基甲基、乙氧基甲基、丙氧基甲基、2-甲氧基乙基、2-乙氧基乙基、2,2-二甲氧基乙基、1-甲基-2-丙氧基乙基、1-甲氧基-1-甲基乙基、及4-甲氧基丁基。
本文中所使用之"羥基(C1-C6)烷氧基"之詞,係像這樣或作為另一基團之一部份,係指至少一個羥基基團,如本文中所定義,經由一(C1-C6)烷氧基基團而連接至母分子部份,如本文中所定義。羥基(C1-C6)烷氧基之代表性實例包括,但非侷限於,羥基甲氧基、二羥基甲氧基、2-羥基乙氧基、2-羥基丙氧基、3-羥基丙氧基、2-羥基丁氧基、及2-羥基-1-甲基乙氧基。
本文中所使用之"(C1-C6)烷氧基(C1-C6)烷氧基"之詞,係像這樣或作為另一基團之一部份,係指至少一個(C1-C6)烷氧基基團,如本文中所定義,經由(C1-C6)烷氧基基團而連接至母分子部份,如本文中所定義。該(C1-C6)烷氧基基團可相同或不同。(C1-C6)烷氧基(C1-C6)烷氧基之代表性實例包括,但非侷限於,甲氧基甲氧基、丙氧基甲氧基、2-甲氧基乙氧基、2-乙氧基乙氧基、2-丁氧基乙氧基、2,2-二甲氧基乙氧基、1-甲基-2-丙氧基乙氧基、2-甲氧基丙氧基及4-甲氧基丁氧基。
本文中所使用之"鹵(C1-C6)烷氧基"之詞,係像這樣或作為另一基團之一部份,係指至少一個鹵素,如本文中所定義,經由一(C1-C6)烷氧基基團而連接到母體分子部分,如本文中所定義。當其有數個鹵素時,該鹵素可相同或不同。鹵(C1-C6)烷氧基之代表性實例包括,但非侷限於,氟甲氧基、氯甲氧基、二氟甲氧基、三氟甲氧基、2-溴乙氧基、2,2,2-三氯乙氧基、3-溴丙氧基、2-氯丙氧基、及4-氯丁氧基。
本文中使用之"本發明化合物"之表示係指式I化合物。
製藥上可接受之鹽類,如酸加成鹽類,包含有機酸及無機酸兩者,係已知於製藥領域。製藥上可接受之酸加成鹽類的代表性實例包括,但非侷限
於,氯酸鹽、溴酸鹽、硫酸鹽、硝酸鹽、磷酸鹽、磺酸鹽、甲烷磺酸鹽、甲酸鹽、酒石酸鹽、順式丁烯二酸鹽、檸檬酸鹽、苯甲酸鹽、水楊酸鹽、抗壞血酸鹽、醋酸鹽及草酸鹽。
根據本發明所指定之水合物或溶劑合物,如同那些呈固體或液體型態之式(I)化合物形式,係形成一分子化合物或藉由與水進行水合或與溶劑分子進行配位形成複合物。水合物之實例為倍半水合物、單水合物、二水合物或三水合物。同樣的,根據本發明之化合物之鹽類的水合物或溶劑合物亦為適用。
製藥上可接受之酯類,如果適當,可藉由已知方法使用製藥上可接受之酸來製備,其在藥物學領域上屬習用且保留了游離形式之藥理特性。這些酯類之非限制性實例包括脂族酯類或芳族醇類。製藥上可接受之酯類之代表性實例包括,但非侷限於,甲基、乙基、正-丙基、異-丙基、正-丁基、異-丁基、第二-丁基、第三-丁基、及苄基酯。
本發明於其範圍內包括所有可能的幾何異構體,如該化合物以及所有可能的光學異構體的Z及E異構體(順式及反式異構體),如該化合物之非對映異構體及對映異構體。此外,本發明於其範圍內包括個別異構體及其任何混合物兩者,如消旋混合物。該個別異構體得自該起始物質之相關異構體型式或其等可於製備出最終化合物之後根據習用之分離方法來分離。由其混合物中分離光學異構體,如對映異構體時,可使用常用之解析方法,如分步結晶法。
該式(I)化合物,其等之製備及其等作為α2C拮抗劑以治療周邊或中樞神經系統之疾病或狀況之作用大致係揭示於WO-A 2010/058060且尤其是該特定之化合物係本發明所描述之明確部分,且因此合併於本文中作為參考。
本文中所使用之有效量之詞係指式(I)化合物有效於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之量。
本發明進一步係關於式(I)化合物於製備用來治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之醫藥品的用途。
本發明之另一目的在於含有一種或多種式(I)化合物與一種或多種其他活性化合物之組合於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中的用途。
本發明之另一目的為包含至少一種式(I)化合物合併一種或多種惰性無毒性製藥上適合之賦形劑的製藥組成物,其係用於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
本發明進一步係關於製藥組成物,其包含含有一種或多種其他活性化合物合併一種或多種惰性無毒性製藥上適合之賦形劑之組合,其係用於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
本發明亦關於治療及/或預防與睡眠有關之呼吸疾病的方法,其係藉由將治療有效量之至少一種式(I)化合物或包含至少一種式(I)化合物合併惰性無毒性製藥上可接受之添加劑之醫藥品予以全身性及/或局部性給藥。
本發明之另一目的為含有一種或多種式(I)化合物與一種或多種其他活性化合物之組合,其係用於治療及/或預防與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
根據本發明之式(I)之芳基哌可單獨使用或,如果需要,合併有一種或多種其他製藥活性物質,前題為此合併不會導致不想要的及不可接受的
副作用。適用於治療與睡眠有關之呼吸疾病,宜為阻塞性及中樞性睡眠呼吸中止及打鼾之目的之組合的較佳實例,包括:
‧呼吸興奮劑如,舉例說明且優先為,茶鹼、多沙普崙(doxapram)、尼克乙醯胺(nikethamide)或咖啡因;
‧精神興奮劑如,舉例說明且優先為,莫達非尼(modafinil)或阿莫達非尼(armodafinil);
‧安非他命及安非他命衍生物如,舉例說明且優先為,安非他命、甲安非他命或哌醋甲酯;
‧血清素再攝取抑制劑如,舉例說明且優先為,氟西汀(fluoxetine)、帕羅西汀(paroxetine)、西酞普蘭(citalopram)、依他普崙(escitalopram)、舍曲林(sertraline)、氟伏沙明(fluvoxamine)或曲唑酮(trazodone);
‧血清素前體如,舉例說明且優先為,L-色胺酸(tryptophan);
‧選擇性血清素去甲腎上腺素再攝取抑制劑如,舉例說明且優先為,文拉法辛(venlafaxine)或度洛西汀(duloxetine);
‧去甲腎上腺素能及特定之血清素能抗抑鬱藥如,舉例說明且優先為,米氮平(mirtazapine);
‧選擇性去甲腎上腺素再攝取抑制劑如,舉例說明且優先為,瑞波西汀(reboxetine)或阿托西汀(atomoxetine);
‧三環類抗抑鬱藥如,舉例說明且優先為,阿米替林(amitriptyline)、普魯替林(protriptyline)、多塞平(doxepine)、曲米帕明(trimipramine)、丙咪嗪(imipramine)、氯米帕明(clomipramine)或地昔帕明(desipramine);
‧毒蕈鹼受體拮抗劑,舉例說明且優先為奧昔布寧(oxybutynin);
‧GABA激動劑如,舉例說明且優先為,巴氯芬(baclofen);
‧糖皮質激素如,舉例說明且優先為,氟替卡松(fluticasone)、布地奈德(budesonide)、倍氯米松(beclometasone)、莫米松(mometasone)、替考特醇(tixocortol)或曲安西龍(triamcinolone);
‧大麻素受體激動劑;
‧碳酸酐酶抑制劑如,舉例說明且優先為,乙醯唑胺(acetazolamide)、甲唑醯胺(methazolamide)或雙氯芬醯胺(diclofenamide);
‧膽鹼酯酶抑制劑如,舉例說明且優先為,新斯的明(neostigmine)、吡啶斯的明(pyridostigmine)、毒扁豆鹼多奈哌齊(physostigmine donepezil)、加蘭他敏(galantamine)或利凡斯的明(rivastigmine);
‧食慾抑制劑如,舉例說明且優先為,西布曲明(sibutramin)、托吡酯(opiramate)、芬特明(phentermine)、脂肪酶抑制劑(lipase inhibitors)或大麻素(cannabinoid)受體拮抗劑;
‧鹽皮質激素受體拮抗劑。
本發明之較佳目的為一種或多種式(I)化合物與一種或多種選自下列組成的群組之毒蕈鹼受體拮抗劑,鹽皮質激素受體拮抗劑,利尿劑,皮質類固醇之其他活性化合物的組合,其係用於治療及/或預防與睡眠有關之呼吸疾病、較佳為阻塞性及中樞性睡眠呼吸中止及打鼾之方法中。
於本發明之較佳具體例中,本發明之化合物係與毒蕈鹼受體拮抗劑,舉例說明且優先為奧昔布寧(oxybutynin)合併給藥。
於本發明之較佳具體例中,本發明之該化合物係與鹽皮質激素受體拮抗劑,舉例說明且優先為螺內酯(spironolactone)、依普利農(eplerenone)或芬尼酮(finerenone)合併給藥。
於本發明之較佳具體例中,本發明之化合物係與利尿劑,舉例說明且優先為呋塞米(furosemide)、布美他尼(bumetanide)、托拉塞米(torsemide)、苯氟甲醯肼(bendroflumethiazide)、氯噻嗪(chlorothiazide)、氫氯噻嗪(hydrochlorothiazide)、氫氟甲肼(hydroflumethiazide)、甲噻嗪(methyclothiazide)、聚噻嗪(polythiazide)、三氯噻嗪(trichlormethiazide)、氯噻酮(chlorthalidone)、吲達帕胺(indapamide)、美托拉唑(metolazone)、喹硫唑(quinethazone)、乙醯唑胺(acetazolamide)、二氯苯甲醯胺(dichlorphenamide)、甲唑醯胺(methazolamide)、甘油、異山梨醇、甘露醇、阿米洛利(amiloride)或氨苯蝶啶(triamterene)合併給藥。
於本發明之較佳具體例中,本發明之化合物係與皮質類固醇,舉例說明且優先為潑尼松(prednisone)、潑尼松龍(prednisolone)、甲基潑尼松龍(methylprednisolone)、曲安西龍(triamcinolone)、地塞米松(dexamethasone)、倍他米松(betamethasone)、倍氯米松(beclomethasone)、氟尼縮松(flunisolide)、布地奈德(budesonide)或氟替卡松(fluticasone)合併給藥。
‧氣道正壓通氣裝置如,舉例說明且優先為,CPAP(持續氣道正壓)裝置、BiPAP(雙水平氣道正壓)裝置及IPPV(間歇正壓通氣)裝置;
‧神經下垂之神經刺激器;
‧口腔內助劑如,舉例說明且優先為,突出牙套;
‧鼻用一次性瓣膜;
‧鼻支架。
根據本發明之式(I)之芳基哌可全身性及/或局部性作用。為此目的,其等可依適當的方式給藥,例如藉由口服、腸胃外、經肺、肺內(吸入性)、經鼻、鼻內、咽部、經舌、舌下、經頰、經直腸、經真皮、經皮下、經結膜或經耳途徑,或作為植入物或支架。
發明之另一目的為包含式(I)化合物之製藥組成物,其係藉由口服、腸胃外、經肺、肺內(吸入性)、經鼻、鼻內、咽部、經舌、舌下、經頰、經直腸、經真皮、經皮下、經結膜或經耳途徑,或作為植入物或支架而供全身性及/或局部性給藥。較佳之給藥為經口途徑。
於此等給藥途徑時,根據本發明之化合物可依適當之給藥型式來給藥。
於口服給藥時,適當的給藥型式係根據現有技術狀態,快速及/或以改良的方式作用而釋離根據本發明之化合物,其以結晶及/或非結晶及/或溶解形式含有根據本發明之化合物,例如為錠劑(未包埋或包埋錠劑,例如具有抗胃液或延遲溶解或不溶性塗層,其等控制了根據本發明化合物之釋離),可在口腔中迅速崩解之錠劑、或薄膜/薄片、薄膜/凍乾物、膠囊(例如硬或軟明膠膠囊)、糖衣片、顆粒、小球、粉末、乳劑、懸浮液、氣溶膠或溶液。
非經腸胃給藥可省略吸收步驟(如靜脈內、動脈內、心內、脊髓內或腰內給藥)或涉及吸收(如肌肉內、皮下、皮內、經皮或腹膜內給藥)而進行。非經腸胃給藥之適當給藥型式包括溶液、懸浮液、乳液、凍乾物或無菌粉末型式之注射及灌輸製劑。
於其他給藥途徑時,適合的為,例如吸入配劑(包括粉末吸入器及霧化器)、鼻滴劑、溶液或噴霧劑,經舌、舌下或經頰給藥之錠劑、錠劑、薄膜/薄片或膠囊、栓劑、口服或眼科製劑、陰道膠囊、水性懸浮液(乳液、搖勻式
混合物)、親脂性懸浮劑、藥膏、乳膏、透皮治療系統(如貼布)、牛奶、糊劑、泡沫、塵粉、植入物或支架。
較佳為口服或非經腸胃給藥,特別為口服及靜脈注射給藥。
根據本發明之化合物可轉化為給定之給藥型式。此可藉由本身已知之方法與惰性無毒性製藥上適合之添加劑予以掺合而進行。此等添加劑包括載體(例如微晶纖維素、乳糖、甘露醇)、溶劑(如液態聚乙二醇)、乳化劑及分散劑或潤濕劑(例如十二烷基硫酸鈉、聚氧山梨糖醇油酸酯)、黏合劑(例如聚乙烯吡咯烷酮)、合成及天然聚合物(例如白蛋白)、穩定劑(如抗氧化劑,例如抗壞血酸)、著色劑(如無機染劑,如例如氧化鐵)及風味劑或氣味矯正劑。
通常,為了達到於非經腸胃給藥中所產生之效果,發現給予約0.001至10mg/kg,較佳為約0.01至1mg/kg體重之藥量為有利的。於口服給藥時,該劑量為約0.01至100mg/kg,較佳為約0.01至20mg/kg,且尤其較佳為0.1至15mg/kg體重。
儘管如此,有時仍必須偏離上述數量,亦即取決於體重,給藥途徑,對活性物質之個別反應,製劑的性質以及給藥發生的時間或間隔。因此,在某些情況下,其以少於上述最小數量來進行管理即足已,而於其他情況時,則須超過所定之上限。於大劑量之給藥情況時,最好將其等劃分為數個整日個別給藥。
下列實施例係闡明本發明。本發明非侷限於這些實例。
實例
A.實驗方法
本發明化合物之有利藥理特性可藉由以下方法來確定。
根據本發明之式(I)化合物於睡眠呼吸中止之治療潛力,已在豬隻阻塞性睡眠呼吸中止(OSA)模式中進行了臨床前評估。
使用負壓,其在經麻醉、自發呼吸之豬隻的上呼吸道可能導致塌陷且因此阻塞(Wirth K.J.et al.,Sleep 36(5)(2013)pp.699-708)。
於模式中係使用German Landrace豬隻。將豬隻麻醉並切開氣管。將兩個管件插入氣管中,一個插入氣管的頭部,另一個插入氣管的尾部。使用連接件,將頭部套管連接到負壓裝置之管子及氣管尾部套管。將氣管尾部套管經由一連接件而另外連接至一具有一開放至大氣之開口的管子,其係提供免費的氣管呼吸,避開了上呼吸道。藉由該等管子之適當的開口及鉗固,呼吸可以從鼻呼吸切換至經由氣管尾部套管呼吸,避開了上呼吸道,且該(隔離的)上呼吸道可連接至負壓裝置,引起吸氣方向之氣流。
在特定的時間點,上呼吸道之塌陷性係讓該豬隻之呼吸經由尾套管並施用負壓-50、-100及-150cm水頭(water head)(cm H2O)至上呼吸道來測試。此造成上呼吸道塌陷,其體現為氣流中斷及管道系統中之壓降。此測試係在該測試藥物給藥之前及在該測試藥物給藥之後的一定時間間隔進行。適當的有效測試物質可在吸氣階段時避免呼吸道塌陷。
於此OSA豬隻模式中,以i.v.大劑量注射1.5mg/kg接著i.v.灌注0.475mg/kg/h系統性施用式(I)((S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲
基)-4-(3-(甲氧基甲基)吡啶-2-基)哌之α2-腎上腺素受體亞型C(α-2C)拮抗劑達4小時而於所有負壓-50、-100及-150cm時抑制上呼吸道塌陷達5小時。
由上述數據,可以推斷出該式(I)α2-腎上腺素受體亞型C(α-2C)拮抗劑適合用來治療與睡眠有關之呼吸疾病,較佳為阻塞性及中樞性睡眠呼吸中止及打鼾。
Claims (11)
- 一種式(I)化合物,其中X 為O、S或CH2;Z 為-[CH2]n-;A、B、D及E獨立為C或N,前題為A、B、D及E中至少3個為C;R1 為H、鹵素、羥基、(C1-C6)烷基、(C1-C6)烷氧基、羥基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、鹵(C1-C6)烷氧基、鹵(C1-C6)烷氧基(C1-C6)烷基、羥基(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基-(C=O)-、CN、(R5)2N-、(R5)2N-(C1-C6)烷基、(R5)2N-(C=O)-、SH-(C1-C6)烷基、羥基(C1-C6)烷基-S-(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基-S-(C1-C6)烷基、羥基(C1-C6)烷基-S(Op)-(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基-S(Op)-(C1-C6)烷基或呋喃基;R2 為H、鹵素、(C1-C6)烷基、(C1-C6)烷氧基或羥基(C1-C6)烷基;R3 為H、鹵素、(C1-C6)烷基或苯基;R4 為鹵素、羥基、(C1-C6)烷基、(C1-C6)烷氧基、CN或(R5)2N-;R5 於每次出現時獨立為H、(C1-C6)烷基或(C1-C6)烷氧基(C1-C6)烷基;m 為0、1或2;n 為1或2;且p 為1或2,以及其等之鹽類、溶劑合物、及該鹽類之溶劑合物,其係使用於治療及/或預防與睡眠有關之呼吸疾病之方法中。
- 根據請求項1之化合物,其中該化合物係選自下列組成之群組:2-(4-((2,3-二氫苯并[b][1,4]二辛(dioxin)-2-基)甲基)哌-1-基)苯甲酸甲酯、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲醇、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苄腈、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲胺、1-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)-N-甲基甲胺、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(乙氧基甲基)苯基)哌、2-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)丙-2-醇、1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌、(S)-(2-(4-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-哌-1-基)吡啶-3-基)甲醇、(S)-(2-(4-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-哌-1-基)吡啶-3-基)甲醇HCl、(S)-1-((7-氟-2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌HCI、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-((2-氟乙氧基)甲基)吡啶-2-基)哌、1-(2,3-二氯苯基)-4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)吡啶-3-基)甲醇、(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)吡啶-3-基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(R)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌、(1-((2,3-二氫苯并[b][1,4]氧硫雜環己二烯(oxathiin)-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、1-(色滿-2-基甲基)-4-(2-(甲氧基甲基)苯基)哌、 (2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-6-氟苯基)甲醇、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-3-氟苯基)甲醇、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-5-氟苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-丙基苯基)哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(三氟甲氧基)苯基)哌、(S)-1-(聯苯基-3-基)-4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(呋喃-2-基)苯基)哌、(S)-乙基-2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯甲酸酯、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-o-甲苯基哌、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-m-甲苯基哌、(S)-(3-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-4-甲基苯基)甲醇、(S)-(3-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)甲醇、(S)-2-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)苯基)乙醇、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷(diazepan)-1-基)苯甲酸甲酯、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)苯基)甲醇、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)菸腈、2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)菸醯胺、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)吡啶-3-基)甲醇或(S)-(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)吡啶-3-基)甲醇。
- 根據請求項1之化合物,其中該化合物係選自下列組成之群組:(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(R)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(甲氧基甲基)苯基)哌、(2-(4-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)哌-1-基)-6-氟苯基)甲醇、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(2-(呋喃-2-基)苯基)哌、 (S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-o-甲苯基哌、2-(4-((2,3-二氫苯并[b][14]二辛-2-基)甲基)-1,4-二氮雜環庚烷-1-基)苯甲酸甲酯、(S)-1-((2,3-二氫苯并[b][1,4]二辛-2-基)甲基)-4-(3-(甲氧基甲基)吡啶-2-基)哌。
- 一種根據請求項1至4之化合物的用途,其中,該與睡眠有關之呼吸疾病為阻塞性及中樞性睡眠呼吸中止及打鼾。
- 一種含有一種或多種式(I)化合物與一種或多種其他活性化合物之組合,其係根據請求項1至5中任一項使用。
- 一種製藥組成物,其係包含至少一種根據請求項1至4中任一項之式(I)化合物合併一種或多種惰性無毒性製藥上適合的賦形劑,其係根據請求項1至4中任一項使用。
- 一種製藥組成物,其係包含根據請求項6之組合合併一種或多種惰性無毒性製藥上適合的賦形劑,其係根據請求項1至5中任一項使用。
- 一種治療及/或預防與睡眠有關之呼吸疾病的方法,其係藉由將治療有效量之至少一種根據請求項1至4中任一項之化合物或包含至少一種根據請求項1至4中任一項之化合物合併惰性無毒性製藥上可接受之添加劑的醫藥品予以全身性及/或局部性給藥。
- 根據請求項9之方法,其中,該醫藥品另外包含至少一種選自下列組成的群組之其他活性化合物:毒蕈鹼受體拮抗劑、鹽皮質激素受體拮抗劑、利尿劑、皮質類固醇。
- 一種醫藥品,其係包含請求項1至4中任一項所定義之式(I)化合物合併一種或多種選自下列組成的群組之其他活性組成份:毒蕈鹼受體拮抗劑、鹽皮質激素受體拮抗劑、利尿劑、皮質類固醇。
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