TWI298020B - Gabapentin analogues for sleep disorders - Google Patents
Gabapentin analogues for sleep disorders Download PDFInfo
- Publication number
- TWI298020B TWI298020B TW090114841A TW90114841A TWI298020B TW I298020 B TWI298020 B TW I298020B TW 090114841 A TW090114841 A TW 090114841A TW 90114841 A TW90114841 A TW 90114841A TW I298020 B TWI298020 B TW I298020B
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- TW
- Taiwan
- Prior art keywords
- aminomethyl
- acetic acid
- cyclopentyl
- methyl
- butyl
- Prior art date
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- 238000011084 recovery Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960004889 salicylic acid Drugs 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
- 238000004513 sizing Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 206010042772 syncope Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000016788 valerian Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Anesthesiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1298020 A7 B7 五、發明説明( 發明背景 如下式化合物 h2n-ch2-c-ch2-coor
(CHA 其中由美國專利案號4,024,175及其分部的美國專利案號 4,087,544中已知&是氫或低碳數烷基基團且η是4、5或6。 所申請的用途是:有效的保護抗胺基硫腸引起的瘦攣;保 護性作用抗心峻(cardiazole)痙攣;大腦疾病、癲癇、暈 厥、運動減退、及顱損傷;以及大腦功能的改善。該化合 物適用於年老患者。該專利經本發明引用。 美國專利申請案09/485,382,申請曰爲2000年2月8曰, 涵蓋下述式I及IA化合物。該申請案提出多種化合物的用 途。該專利經本發明引用。 式I化合物
(CH2)n 其中Ri是氫或低碳數烷基且η是由4至6的整數,及其於醫 藥上可接受的鹽及式II化合物 R4 R3
h2nch—c—CH2COOH
I R2 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1298020 A7 B7 五、發明説明(2 ) 氫、甲基,或羧基;或其個別的鏡像異構物;或其於醫藥 上可接受的鹽,其可用於治療失眠症(美國專利申請案 60/092166,於1998年7月9日申請,經本發明引述)。 發明摘要 本發明是關於治療失眠症的方法,即治療難以入眠或睡 眠形態受干擾以造成睡眠不足的感覺。失眠症是一般性的 症狀,可能是由多種情感性及生理上的異常所引起(默克 手册 Merck Manual,第 16版,第 1445_6 頁)〇 使用本發明的化合物治療失眠症的益處是不會成癮。另 外該化合物在體内的半衰期是適合在夜間作用且隨後在早 晨時即經身體清除而容易清醒。該化合物可與其他試劑共 組以加強睡眠謗導效應。該試劑包括退黑激素、白胺酸、 纈草、百香果、抗組織胺如二苯基胺鹽酸鹽(diphenydramine hydrochloride)或道西胺琥 ίό 酸酯(doxylamine succinate)、苯 幷二苹(benzodiazepines)及非苯幷二苹(nonbenzodiazepines) 的安眠藥。 使用本發明式I及IA化合物的其他優點包括該化合物相 當不具毒性的本質、容易製備、該化合物易於耐受的事 實,以及易於以靜脈注射使用該藥物。以本發明方法治療 的受者是哺乳類,包括人類。 使用在本發明的化合物是如下式I及IA的化合物 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1298020 --—, 五、發明説明(3
其中R至R14如前述所定義。 本發明化合物及其於醫藥上可接受的鹽及該化合物 驅藥可用於治療失眠症及無法入睡症。 則 發明詳述 使用在本發明的化合物及其於醫藥上可接受的鹽如 及IA所定義 工
裝
η
線 或其於醫藥上可接受的鹽,其中: R是氫或低碳數烷基; R1至R14分別選自氫、由1至6個碳原子的直鏈或分支烷 基、苯基、苯甲基、氟、氣、溴、羥基、羥基甲基、 胺基、胺基甲基、主氟甲基、-C02H、-C02R15、 -CH2C02H、-CH2C02R15、-OR15,其中的 R15是由 1至 6 -6- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公董) 1298020
個碳原子的直鏈或分支烷基、苯基,或苯甲基,且R1 至R8不同時爲氫。 較佳的本發明化合物是如式I化合物其中R1至R14係選自 氫、甲基、乙基、丙基、異丙基、直鏈或分支丁基、苯基 或苯甲基。 更佳的化合物是如式I化合物其中Rl至Ri4係選自氫、甲 基、乙基,或苯甲基。 最佳的化合物係選自: (1 α,3從,4α)-(1-胺基甲基-3,4_二甲基-環戊基)_乙酸; (1 α,3 α,4 α)_(1-胺基甲基_3,4_二乙基-環戊基)_乙酸; (1 α,3 α,4α)-(1_胺基甲基-3,4_二異丙基·環戊基)-乙酸; [1S_(1從,3 α,4“)]·(ΐ-胺基甲基·3_乙基_4_甲基-環戊基卜乙 酸; [1R-(1 α,3從,4以)]_(1_胺基甲基_3_乙基·4_甲基·環戊基)-乙 酸; [1S-(1 α,3 α,4α)]-(1•胺基甲基-3-異丙基·4·甲基-環戊基)-乙酸; [1R-(1 α,3 α,4α)]-(1-胺基甲基_3-異丙基-4 -甲基-環戊基)- 乙酸; [1S-(1 α,3 α,4α)]-(1-胺基甲基-3-乙基_4_異丙基-環戊基)-乙酸; [1R_(1 α,3 “,4以)]_(1_胺基甲基-3-乙基-4-異丙基-環戊基)-乙酸; [1S-(1 α,3 α,4π)]-(1-胺基甲基-3-第三丁基·4·甲基-環戊 7- |本紙張尺度適用中國國家標準&NS) Α4規格(210X 297公釐) 1298020 A7 B7 五、發明説明(5 ) 基)-乙酸; [1R_(1從,3“,4沒)]-(卜胺基甲基小第三丁基·4_甲基環戊 基)_乙酸; [1S-(1從,3 “,4沒)]-(1-胺基甲基第三丁基-4_乙基-環戊 基)-乙酸; [1R_(1々,3 α,4以)]-(1-胺基甲基-3-第三丁基·4·乙基-環戊 基)-乙酸; [1S-(1 α,3 α,4以)]-(1-胺基甲基-3-第三丁基異丙基-環 戊基)-乙酸; [1R_<1 α,3 α,4以)]-(1·胺基甲基-3-第三丁基-4_異丙基-壤 戊基)-乙酸; 胺基甲基-3,4-二第三丁基-環戊基)-乙 酸; [1S-丨1π,3π,4α)]"·(1-胺基甲基-3 -甲基-4 -苯基-緣戊基)-乙 酸; [1尺-(1“,3以,4<^)]-(1-胺基甲基_3-甲基-4-苯基-環戊基)-乙 酸; [1S-0 α,3 “,4以)]-(1-胺基甲基_3_苯甲基_4_甲基-環戊基)-乙酸; [1R-(1 α,3 α,4江)]-(1·胺基甲基-3-苯甲基_4·甲基·環戊基)"* 乙酸; (1S-順Η卜胺基甲基·3_甲基·環戊基)_乙酸; (1S-順)-(1-胺基甲基-乙基-環戊基)*乙酸’ (1S-順Η1-胺基甲基·3_異丙基·環戊基)-乙酸; -8- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(6 ) (1S-順)-(1•胺基甲基-3-第三丁基-環戊基)-乙酸; (1S-順H1-胺基甲基_3_苯基-環戊基)-乙酸; (1S-順)-(1-胺基甲基-3-苯甲基-環戊基)-乙酸; (1R-順)-(1·胺基甲基-3-甲基-環戊基乙酸; (1R-順)·(1-胺基甲基_3_乙基-環戊基)_乙酸; (1R_順)-(1_胺基甲基-3-異丙基-環戊基)_乙酸; (1R-順)-(1-胺基甲基-3-第三丁基·環戊基)_乙酸; (1R-順)-(1-胺基甲基-3_苯基-環戊基)_乙酸; (1R-順)-(1-胺基甲基-3_苯甲基-環戊基)_乙酸; (S)-(l-胺基甲基-3,3-二甲基·環戊基)·乙酸; (S)-(l-胺基甲基_3,3·二乙基-環戊基)_乙酸; (1-胺基甲基-3,3,4,4·四甲基·環戊基)-乙酸; (1·胺基甲基-3,3,4,4_四乙基-環戊基)-乙酸; (1“,3/?,4;5)-(1-胺基甲基-3,4-二甲基-環戊基)-乙酸’· (1以,3卢,4/?)-(1-胺基甲基-3,4-二乙基-環戊基)-乙酸; (1從,3yS,4/?)-(l-胺基甲基_3,4·二異丙基-環戊基)·乙酸; [lR-(la,3/?,4y5)]-(l_胺基甲基·3_乙基-4·甲基·環戊基)-乙 酸; [18-(1(^,3/?,4/?)]-(1_胺基曱基-3-乙基-4-甲基-環戊基)-乙 酸; [111-(1(^,3;9,4;5〇]-(1-胺基甲基"<3-異丙基">4-甲基"<環戊基)- 乙酸; [1S-C1 α,3/?,4/?)]_0_胺基甲基·3_異丙基_4·甲基-環戊基)-乙酸; -9 - 1298020 A7 _B7 五、發明説明(7 ) tlR气1 胺基甲基_3_乙基_4·異丙基·環戊基)_ 乙酸; [1S-(1以,3/3,4/?)l·(L·胺基甲基-3-乙基-4-異丙基-環戊基)- 乙酸; [;11^1^3卢,4/?)]-(1-胺基甲基_3-第三丁基_4-甲基-環戊 基)-乙酸; [1S_(1 π,3 y5,4A)]-(卜胺基甲基第三丁基-4-甲基-環戊 基)-乙酸; [111-(1(^,3/?,40)]-(1_胺基甲基-3-第三丁基-4-乙基_環戊 基)乙酸; [18-(1“,3;5,4;3)]-(1-胺基甲基-3-第三丁基-4-乙基-環戊 基)-乙酸; [1R-(1 α,3 ,4 Θ )]-(1_胺基甲基_3·第三丁基-4-異丙基-環 戊基)_乙酸; [18-(1從,3;3,4;3)]-(1_胺基甲基-3-第三丁基-4_異丙基-環 戊基)-乙酸; (1從,3 ,4卢)-(卜胺基甲基_3,4_二第三丁基·環戊基)-乙 酸; [1化-(1“,3/?,4>5)]-(1-胺基甲基-3-甲基-4-苯基_環戊基)-乙 酸; [1S-(1以,3/?,4/?)]-(1-胺基甲基-3-甲基-4-苯基_環戊基)-乙 酸; [1R-(1 ^^3/?,4/?)l·ll-胺基甲基-3苯甲基_4·甲基-環戊基)- 乙酸; -10- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(8 ) [1S-(1 α,3/?,4y5)]-(l_胺基甲基-3_苯甲基_4_甲基-環戊基)-乙酸; (1R-反)-(1 -胺基甲基_ 3 _甲基_ J募戊基)_乙酸; (1R -反)-(1 •胺基甲基-3 乙基-壤戊基)_乙酸; (1R-反)-(1-胺基甲基-3-異丙基·環戊基)_乙酸; (1R-反)-(1 _胺基甲基-3-第二丁基·環戊基)乙酸; (1R-反)-(1-胺基甲基·3·苯基幕戊基)-乙酸; (1R-反)-(1 -胺基甲基-3 _苯甲基-ί幕戊基)-乙酸; (1S -反)-(1 •胺基甲基_ 3 _甲基-壤戊基)-乙酸; (1S -反)·( 1 -胺基甲基_ 3 -乙基-ί幕戊基)-乙酸; (1S·反)-(1-胺基甲基-3_異丙基·緣戊基)-乙酸; (1S_反)-(1•胺基甲基-3·第二丁基-環戊基)-乙酸; (1S -反)-(1-胺基甲基-3 -苯基-¾戊基)-乙酸; (1S-反)-(1 -胺基甲基-3-苯甲基-J募戊基)_乙酸; (R)-( 1 胺基甲基-3,3_二甲基·環戊基)_乙酸; (R)-(l -胺基甲基_3,3-二乙基幕戊基)-乙酸; 順-(1•胺基甲基-3-甲基·環丁基)-乙酸; 順-(1-胺基甲基-3-乙基-環丁基)-乙酸; 順-(1-胺基甲基-3-異丙基-環丁基)·乙酸; 順-(1-胺基甲基_3_第二丁基-環丁基)-乙酸; 順-(1-胺基甲基-3-苯基-環丁基)-乙酸; 順-(1-胺基甲基_3_苯甲基-環丁基)_乙酸; 反-(1-胺基甲基_3_甲基·環丁基)_乙酸; 反_(1_胺基甲基-3-乙基·環丁基)-乙酸; -11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1298020 A7 __B7______ 五、發明説明(9 ) 反-(1-胺基甲基-3-異丙基-環丁基)·乙酸; 反-(1-胺基甲基-3·第三丁基·環丁基)-乙酸; 反- (1-胺基甲基-3_苯基·環丁基)-乙酸; 反-(1-胺基甲基-3-苯甲基-環丁基)-乙酸; 順-(1-胺基甲基-3-乙基-3_甲基-環丁基)-乙酸; 順-(1-胺基甲基_3_異丙基-3·甲基-環丁基)_乙酸; 順-(1-胺基甲基-3-第三丁基-3-甲基-環丁基)_乙酸; 順-(1-胺基甲基-3-甲基-3-苯基-環丁基)-乙酸; 順-(1-胺基甲基-3·苯甲基-3-甲基-環丁基)_乙酸; 反-(1-胺基甲基-3-乙基-3-甲基-環丁基)-乙酸; 反-(1-胺基甲基-3-異丙基_3_甲基-環丁基)_乙酸; 反-(1-胺基甲基-3·第三丁基-3-甲基-環丁基)_乙酸; 反-(1-胺基甲基-3-甲基-3-苯基-環丁基)-乙酸; 反-(1·胺基甲基-3-苯甲基_3-甲基-環丁基)_乙酸; 順-(1-胺基甲基-3-乙基-3-異丙基-環丁基)_乙酸; 順·( 1 -胺基甲基-3 -第二丁基· 3 -乙基-ί尽丁基)-乙缸’ 順-(1 •胺基甲基-3-乙基-3-苯基-環丁基)-乙酸; 順-(1 ·胺基甲基-3 -苯甲基_ 3 -乙基-稼丁基)-乙叙’ 反-(1 _胺基甲基-3 -乙基-3 -異丙基·壤丁基)-乙酸’ 反-(1-胺基甲基·3-第三丁基-3-乙基-環丁基)_乙酸; 反-(1 -胺基甲基-3 -乙基-3 -苯基-壤丁基)-乙酸’ 反-(1 •胺基甲基-3_苯甲基_3_乙基-環丁基)_乙酸; 順-(1-胺基甲基-3-第三丁基-3-異丙基-環丁基)_乙酸; 順-(1-胺基甲基_3_異丙基-3-苯基-環丁基)·乙酸; -12- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1298020 A7 B7 ^_ 五、發明説明(10 ) 反-(1-胺基甲基-3-苯甲基·3-異丙基-環丁基)·乙酸; 順-(1-胺基甲基-3-第三丁基_3·苯基·環丁基)_乙酸; 反-(1-胺基甲基-3_苯甲基-3_第三丁基-環丁基)-乙酸; 反-(1-胺基甲基-3-第三丁基-3·異丙基-環丁基)_乙酸; 反-(1-胺基甲基-3-異丙基-3-苯基-環丁基)-乙酸; 順-(1-胺基甲基-3-苯甲基-3-異丙基-環丁基)_乙酸; 反-(1-胺基甲基_3_第三丁基_3_苯基-環丁基)·乙酸; 順-(1-胺基甲基·3·苯甲基-3-第三丁基-環丁基)_乙酸; (1_胺基甲基-3,3_二甲基-環丁基)-乙酸; (1-胺基甲基_3,3_二乙基-環丁基)-乙酸; (1_胺基甲基_3,3_二異丙基-環丁基)-乙酸; (1_胺基甲基·3,3_二第三丁基-環丁基)-乙酸; (1·胺基甲基-3,3_二苯基-環丁基)-乙酸; (1·胺基甲基-3,3·二苯甲基·環丁基)-乙酸; (1-胺基甲基·2,2,4,4_四甲基環丁基)_乙酸; (1_胺基甲基-2,2,3,3,4,4-六甲基_環丁基)-乙酸; (R) -(l-胺基甲基-2,2-二甲基環丁基)_乙酸; (S) _(l-胺基甲基-2,2-二甲基·環丁基)_乙酸; (1R-順)-(1_胺基甲基-2-甲基·環丁基)-乙酸; [1R-(1 α,2 α,3 α)]_(1_胺基甲基·2,3-二甲基·環 丁基)·乙 酸; (1從,2泛,4α)_(1·胺基甲基·2,4·二甲基環丁基)_乙酸; [1R_(1 α,2 a,3 >9 )]-(1·胺基甲基·2,3-二甲基環 丁基)-乙 酸; -13- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(11 ) (1從,2從,4/?)-(1_胺基甲基_2,4_二甲基環丁基)-乙酸; (1S-反)-(1_胺基甲基-2-甲基·環丁基)-乙酸; [1S_(1 ,3 /?)]_〇胺基甲基-2,3-二甲基-環丁基)_ 乙 酸; (1 a,2y5,4y5)-(l·胺基甲基·2,4_二甲基-環丁基)-乙酸; [1S-(1 α,2Θ,3 π)]-(1·胺基甲基-2,3-二甲基-環丁基)_ 乙 酸; (1〜20,44-(1_胺基甲基_2,4-二甲基-環丁基)-乙酸; (1R_反)-(1-胺基甲基-2-甲基·環丁基)_乙酸; [1R_(1 α,2 Θ,3卢)]-(1·胺基甲基-2,3-二甲基-環丁基)-乙 酸; [1R-(1〜2/?,4 0)]-(1-胺基甲基-2-乙基-4_甲基-環丁基)-乙 酸; [1R-(1 π,2/?,3 α)]-(1_胺基甲.基·2,3-二甲基-環丁基 l· 乙 酸; (1 π,2/?,4從)-(1_胺基甲基-2,4-二甲基-環丁基)-乙酸; (1S-順)-(1-胺基甲基-2-甲基-環丁基)-乙酸; [1S-(1從,2以,3從)]-(1_胺基甲基_2,3_二甲基-環丁基)乙 酸; [1S-(1 α,2 π,3 α)]-(1-胺基甲基 _2,4_ 二甲基-環丁基)_ 乙 酸; [1S-(1 α,2 Α,3 〇0]_(1_胺基甲基·2,3-二甲基-環丁基)_ 乙 酸; (1從,2“,40)-(1_胺基甲基-2,4-二甲基-環丁基)-乙酸; -14- 本紙張尺度適用中國國家標準(CNS) Α4規格(210X 297公釐) 1298020 A7 B7 五、發明説明(12 ) (3S,4S)-(1-胺基甲基_3,4·二甲基-環戊基)·乙酸; (3R,4R)-(1-胺基甲基-3,4·二甲基-環戊基)-乙酸; (3R,4R)-(1-胺基甲基·3,4-二乙基環戊基)-乙酸; (3S,4S)-(1·胺基甲基-3,4·二異丙基-環戊基)-乙酸; (3R,4R)-(1-胺基甲基-3,4_二異丙基-環戊基)-乙酸; (3S,4S)-(1-胺基甲基_3,4·二第三丁基-環戊基)-乙酸; (3R,4R)-(1-胺基甲基-3,4-二第三丁基-環戊基)-乙酸; (3S,4S)-(1-胺基甲基-3,4-二苯基·環戊基)·乙酸; (3R,4R)-(1-胺基甲基·3,4·二苯基-環戊基)-乙酸; (3S,4SH1·胺基甲基_3,4·二苯曱基-環戊基)-乙酸; (3R,4R)-(1-胺基甲基-3,4·二苯甲基·環戊基)·乙酸; [1S-(1 α,3 α,4/3)]-(1-胺基曱基·3-甲基-4_乙基·環戊基)-乙 酸; [1R-(1〜3卢,4“)]-(1_胺基甲基-3_甲基-4-乙基_環戊基)_乙 酸; [1R_(1 <^,3以,4/?)]-(1-胺基甲基-3-甲基-4_乙基-環戊基)-乙 酸; [lS_(la,3A,4a)]-(l-胺基甲基_3_甲基-4-乙基-環戊基)_乙 酸; [1S-(1 α,3 α,4θ)]-(1-胺基甲基-3-甲基-4-異丙基-環戊基)-乙酸; [1化_(1以,3;9,4“)]-(1_胺基甲基-3_甲基-4_異丙基-環戊基)- 乙酸; [1R_(1泛,3從,4;5)]-(1·胺基甲基-3-甲基-4-異丙基-環戊基)- -15- 本紙張尺度適财_轉準(CNS) A4規格(21G x 297公羡) 1298020 A7 B7 五、發明説明(13 乙酸; [1S_(;1 α^3y5,4/?)l·l卜胺基甲基-3-甲基·4-異丙基-環戊基h 乙酸; [1S_(1 胺基甲基_3_甲基-4-第三丁基-環戊 基)_乙酸; [lR-(la 3/?〆汉)卜(1-胺基甲基-3_甲基_4_第三丁基-環戊 基)_乙酸; [1R-(1 α,3 胺基甲基_3_甲基-4-第三丁基-環戊 基;l·乙酸; [1S_(1 α,3 A,4汉胺基甲基-3_甲基第三丁基-環戊 基)_乙酸; [18-(1^3泛,4卢)]-(1-胺基甲基-3-甲基-4-苯基-環戊基)-乙 酸; 3 0 4戊)]-(1-胺基甲基_3·甲基-4-苯基環戊基)乙 酸; [1R_〇 胺基甲基-3·甲基-4_苯基-環戊基)-乙 酸; [1S彳1“ 3/5 卜胺基甲基-甲基-4-本基·環戊基)-乙 酸; [1S-(;1 (卜胺基甲基·3-苯甲基-心甲基-環戊基)_ 乙酸; [1R-(1 a,3y5,^)]^1-胺基甲基苯甲基4-甲基-環戊基)-乙酸; [1仏-(1“,3從,4々)]-(1-胺基甲基-3-苯甲基-4-甲基-環戊基)- -16- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱) 1298020 A7 B7 五、發明説明(14 ) 乙酸; [18_纟1以,3;5,4以)]-(1-胺基甲基-3-苯甲基-4_甲基-環戊基)- 乙酸; [1S-(1 α,3 胺基甲基乙基異丙基·環戊基)- 乙酸; 3/?,4從)]-(1-胺基甲基"%乙基-4-異丙基·環戊基)- 乙酸; f 1R_(1 π 3沒,4/^)]-(1-胺基甲基·3·乙基-4-異丙基-環戊基)-乙酸; [1S-(1 π,3 /?,4α)]·(1-胺基甲基-3-乙基-4-異丙基-環戊基) 乙酸; [1S-(1 π,3沈,4/?)]-(1_胺基甲基-3·第三丁基-4-乙基-環戊 基)-乙酸; [1R_(1 π,3 y5,4沈)]_(1_胺基甲基-3-第三丁基·4_乙基-環戊 基)_乙酸; [1R-(1 α,3 π,4/?)]_(1_胺基甲基_3_第三丁基_4_乙基-環戊 基)_乙酸; [lS-(la,3y5,4以)]_(1_胺基甲基-3-第三丁基·4_乙基-環戊 基)-乙酸; [1S-(1以,3從,4;5)]-(1_胺基甲基-3-乙基-4_苯基-環戊基)-乙 酸; [1R-(1以,3 /?,4以)]_(1_胺基甲基-3 -乙基_4_苯基-環戊基)-乙 酸; [1R-(1 α,3 α,4 /?)]·(1·胺基甲基-3-乙基-4-苯基-環戊基)乙 17· 本紙張尺度適用中國國家標準(CNS) Α4規格(210χ 297公釐) 裝 訂
1298020 A7 _ B7 ____— 五、發明説明(15 ) 酸; [1S-(1〜3;5,4以)]-(1-胺基甲基_3-乙基-4_苯基-環戊基)-乙 酸; [1S-(1從,3 _胺基甲基-3-苯甲基-4-乙基-環戊基卜 乙酸; [1R-(1 從,3/?,4π)]_(レ胺基甲基_3-苯甲基-4_乙基-環戊基)-乙酸; [1R-(1 α,3 α,4/?)]-(1-胺基甲基-3-苯甲基·4-乙基-環戊基)_ 乙酸; [1S-(1 π,3/?,4π)]-(l-胺基甲基-3-苯甲基-4-乙基-環戊基)· 乙酸; [1S_(1從,3從,4 0)]-(1-胺基甲基-3-第三丁基_4_異丙基-環 戊基)_乙酸; [1R-(1 α,3/?,4 α)]-(1·胺基甲基_3_第三丁基-4-異丙基-環 戊基)-乙酸; [1R-(1 α,3 π,4Α)]-(1-胺基甲基-3-第三丁基_4_異丙基-環 戊基)-乙酸; 以,3 Θ,4沈)]·^1 —胺基甲基-第三丁基異丙基-環 戊基)-乙酸; [1S-(1 α,3 “,4/?)]-(1-胺基甲基-3-異丙基-4_苯基-環戊基)-乙酸; [111-(1“,3>5,4從)]-(卜胺基甲基_3-異丙基-4-苯基-環戊基)- 乙酸; [1R-(1以,3從,4/?)]-(1_胺基甲基-3-異丙基_4-苯基-環戊基)- -18- L本紙張尺度適财规格(21Q x 297公羞) 1298020 A7 B7 _ 五、發明説明(16 ) 乙酸; [1S-(1 α,3卢,4 π)]-(1-胺基甲基_3_異丙基·4·苯基-環戊基)-乙酸; [1S-(1 α,3 α,4;5)]·(1·胺基甲基_3_苯甲基-4-異丙基-環戊 基)-乙酸; [lR-(la,3 y3,4a)]-(1-胺基甲基_3_苯甲基-4-異丙基-環戊 基)-乙酸; [1R-(1仪,3以,4 0)]-(1-胺基甲基-3-苯甲基-4·異丙基·環戊 基)-乙酸; [1S-(1 α,3/?,4 π)]-(1-胺基甲基-3-苯甲基-4-異丙基-環戊 基)-乙酸; [1S-(1 α,3 α,4θ)]·(1_胺基甲基_3_第三丁基_4_苯基-環戊 基)-乙酸; [111_(1<^,3>5,4(^)]-(1-胺基甲基_3-第三丁基-4-苯基-環戊 基)-乙酸; [1R-(1 α,3從,4 0)]-(1-胺基甲基_3_第三丁基_4_苯基-環戊 基)-乙酸; [lS-(la,3y9,4a)]-(l_胺基甲基·3_第三丁基_4_苯基-環戊 基)-乙酸; [1R-(1 π,3 π,4/?)]_(1_胺基甲基_3_苯甲基_4_第三丁基-環 戊基)-乙酸; [1S-(1 π,3 /?,4α)]-(1-胺基甲基-3-苯甲基·4·第三丁基摹 戊基乙酸; [1S-(1從,3從,4Θ)]-(1-胺基甲基-3_苯甲基·4_第三丁基-環 -19- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1298020 A7 B7
五、發明説明(17 ) 戊基)-乙酸; [m-(1 d 胺基甲基-3-苯甲基·4·第三丁基·環 戊基乙酸; 胺基甲基苯甲基苯基環戊基)· 乙酸; [1R-(1 ^314^)]-(卜胺基甲基·3·苯甲基苯基-環戊基> 乙酸; (卜胺基甲基_3_苯甲基·4-苯基-環戊基)_ 乙酸; [1S-(1 π,3 /?,4以)]-(卜胺基甲基苯甲基-4_本基衣戊基) 乙酸; (1R-順)-(1-胺基甲基-2·甲基環戊基)-乙酸; (1S·順)-(1-胺基甲基-2·甲基·環戊基)-乙酸; (1R-反)-(1-胺基甲基_2·甲基·環戊基)_乙酸; (1S-反H1-胺基甲基-2-甲基-環戊基)-乙酸; (R) -(l-胺基甲基-2,2-二甲基環戊基)乙酸; (S) -(l-胺基甲基二甲基-環戊基)_乙酸; (1-胺基甲基-m5·四甲基_環戊基)-乙酸; (1〜2/3,5/?)-(1_胺基甲基-2,5-二甲基-環戊基)-乙酸; (2R,5R)-(1_胺基甲基_2,5_二甲基環戊基)-乙酸; (2S,5S)-(卜胺基甲基_2,5_二甲基-環戊基)-乙酸; (1從,2以,5從)_(1·胺基甲基·2,5-二甲基-環戊基)_乙酸; [1R-(1 α,2以,3 α)]·(1·胺基甲基·2,3-二甲基-環戊基)-乙 酸; -20- 本紙張尺度適财目目家鮮(CNS) Α4規格(膨297公釐) 裝 訂
1298020 A7 B7 五、發明説明(18 ) [1R-(1 α,2卢,3 α)]_(1_胺基甲基_2,3·二甲基-環戊基)-乙 酸; [1R_(1 α,2α,3卢)]-(1-胺基甲基-2,3·二甲基-環戊基)-乙 酸; [1R-(1 0,3卢)]-(1·胺基甲基·2,3·二甲基環戊基)-乙 酸; [1S-(1 α,2 α,3 α)]-(1·胺基甲基-2,3·二甲基-環戊基)-乙 酸; [1S_(1 α,2 0,3 α)]·(1-胺基甲基_2,3_二甲基·環戊基)-乙 酸; [1S_(1 α,2 α,3 θ)]_(1-胺基甲基·2,3_二甲基-環戊基)乙 酸; [1S-(1 α,2/?,3 /?)]_〇_胺基甲基-2,3-二甲基-環戊基)-乙 酸; [1R-(1 α,2 α,4 α)]·(1_胺基甲基-2,4_二甲基-J募戊基)-乙 酸; [1S-(1 α,2 α,4 α)]_(1_胺基甲基-2,4-二甲基-環戊基)-乙 酸; [1R-(1 α,2α,4/?)]·(1·胺基甲基-2,4-二甲基-環戊基)-乙 酸; [1S-(1 α,2 α,4卢)]-(1·胺基甲基·2,4·二甲基-環戊基)-乙 酸; [1R_(1 α,2/?,4 α)]_(1-胺基甲基_2,4_二甲基環戊基)·乙 酸; -21 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(19 ) [1S_(1 ,4 ^ΟΜ1-胺基甲基_2,4_二甲基-環戊基)_乙 酸; [1β-(1 “,20,4/?)]-(1-胺基甲基-2,4-二甲基_環戊基)-乙 酸; 及 [is-(l π,2/?,4/?)]-(1·胺基甲基-2,4-二甲基-環戊基)-乙 酸; 特別適用於失眠症及相關病症的試劑是(3S,4S)-(1-胺基 甲基-3,4-二甲基-環戊基)_乙酸。 同時,特別適用於失眠症及相關病症的試劑是(3S,5R)-3-胺基甲基-5-甲基-辛酸。 名詞”低碳數烷基”係指由1至4個碳原子的直鏈或分支基 團。 名詞’’烷基’'係指由1至6個碳原子的直鏈或分支基團,其 中包括甲基、乙基、丙基、正丙基、異丙基、丁基、2-丁 基、第三丁基、戊基,除非特別提及,但不以此爲限。 苯甲基及苯基基團可以爲未經取代或經由1至3個取代基 所取代,其選自羥基、羧基、碳基烷氧基、_素、CF3、 硝基、烷基,及烷氧基。以卣素爲佳。 因爲胺基酸是兩性、藥理上可接受的鹽,當R是氫時, 可爲適當的無機或有機酸的鹽,例如鹽酸、硫酸、磷酸、 醋酸、草酸、乳酸、檸檬酸、蘋果酸、水揚酸、丙二丁 酸、馬來酸、琥珀酸、甲磺酸,及抗壞血酸。經由相應的 氫氧化物或碳酸酯,可生成帶有鹼金屬或鹼土金屬的鹽, ____ -22- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1298020 A7
如鈉、鉀、鎂,或鈣。四級銨鹽可製備自例如,四甲基銨 離子。可利用已知的方法將胺基酸的羧基進行酯化。 本發明的特定化合物可以非媒合物形態或以媒合物形能 存在,包括水合物形態。一般而言,媒合物形態,包括= 合物形態是與非媒合物形態相當,而且意圖包括在本發明 範圍中。 本發明的特定化合物具有一個或多個不對稱碳中心,而 且每一個中心均可以R(D)或S(L)結構存在。本發明包括所 有的鏡像物及表異構物(epimeric)以及其適當的混合物。 本實驗使用重量爲25〇至36〇克的Sprague_Dawley公老 鼠。將老鼠於23 ± 1°C的室溫下以12:12小時的光照/黑暗循 環(於0900照光)飼養。在實驗中以自由攝取水及食物。將 EEG記錄用的不鏽鋼珠寶螺絲放置在前額及顱頂的皮質 内。將EMG電極植入背側的頸肌肉中。 記錄及分析在恢復期後(至少1星期),將老鼠移至睡眠 記錄籠中。在記錄籠中,老鼠可不受限的移動。連接電極 的繫繩將引導至電子的轉軸。來自轉軸的引線將被牽引至 鄰近房間至用來記錄EEG及EMG活性的Grass Model No. 7D 複寫器。在離線的10秒期間訂定不睡的失眠狀況、非快速 -眼部·移動睡眠(NREMS),以及快速-眼部-移動睡眠 (REMS) 〇每小時計算每次失眠狀態所花費的時間且計算 注射後12個小時期間的總數。在啓動老鼠的光照/黑暗周 -23- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(21 ) 期之光照期之前以PO方式施用藥物或載體。每一隻老鼠 都接受到載體及一藥物劑量。 結果 在注射後12小時的期間,以3、10及30毫克/公斤重的劑 量以PO施用的(3S,4S)-1-胺基甲基-3,4-二甲基-環戊基)-乙 酸(化合物1)及以1、3及20毫克/公斤重的劑量以PO施用的 (3S,5R)-3-胺基甲基-5-甲基-辛酸(化合物2)可顯著的提高老 鼠的NREMS(分別於表1及表2)。在老鼠中增加NREMS睡眠 是在人類中做爲睡眠引導試劑所顯現的典型效果。 (Meltzer L.T.及Serpa K.A.,老鼠的催眠效果評估:對睡眠 清醒周期的影響,藥物發展研究1^8 ; 14:151-159 ; Depoortere H. et al·,催眠藥:藥理-EEG方法的臨床價値, 神經生理學 1986 ; 16: 157-162)。 表1·化合物1提高老鼠的NREMS睡眠(N=8/處理) 注射後12小時的NREMS之 總分鐘數(平均土 SEM) 化合物1(毫克/公斤重P0) 載體 藥物 3 370 + 11 401+8* 10 383 土8 409 + 12* 30 371土14 424 士 6* * PS0.05對載體(配對試驗) -24- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1298020 A7 B7 五、發明説明(22 ) 表2·化合物2提南老鼠的NREMS睡眠(N=8/處理) 注射後12小時的NREMS之 總分鐘數(平均+SEM、 化合物2(毫克/公斤重PO) 載體 藥物 1 409±8 432±8* 3 406±9 451 ±9* 20 412±6 481+6* PS0.05對載體(配對試驗) 本發明化合物可利用多種口服及非經腸道方式的劑型經 製備及投藥。本發明化合物可利用注射方式投藥,即以靜 脈内、肌肉内、皮内、皮下、十二指腸内或腹膜内注射。 同時本發明化合物可利用吸入方式投藥,例如,鼻内吸 入。另外,本發明化合物可利用在皮膚内方式施用。對於 熟知該技藝的人很明顯的是如下的劑型可包含在内做爲活 性組成份’可包括式I或IA化合物或相應的式1或IA化合物 於醫藥上可接受的鹽。 由本發明化合物製備醫藥組合物時,於醫藥上可接受的 載體可爲固體或液體。固體形態的製備物包括粉末、錠 劑、藥片、膠囊、膠囊錠、栓劑及可分散的顆粒。固體載 體可爲一種或多種物質,其可做爲稀釋劑、加味劑、結合 劑、防腐劑、錠劑分散劑或使膠囊化的物料。 對粉末而言,載體是經細分的固體,其與經細分的活性 組成份共組爲混合物。 對錠劑而言,將活性組成份以適當的比率與具有必須的 -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
裝 訂
1298020 A7 B7 五、發明説明(23 ) -- 結合性質之載體相混合並包裝於所需的形狀及尺寸。 較佳的,粉末及錠劑包括由百分之5或1〇至約7〇的活性 組成份。合適的載體是碳酸鎂、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 基甲基纖維素、低溶點壤、可可亞油及其相似者。名詞,, 製備(物Γ意圖包括以製成膠囊物料做爲載體之活性組成 份的調配物’其提供的膠囊之活性組成份,不論帶有或不 帶有其他載體,係經載體包圍而因此與其相關連。同樣也 包括膠囊錠及菱形錠劑。錠劑、粉末、膠囊、藥片、膠囊 錠’及菱形錠劑可用來做爲適合於口服的固體劑型。 對製備栓劑而言,先將低熔點蠟如脂肪酸甘油酯或可可 亞油的混合物加以混合,再藉著攪拌使活性組成份均勻的 仝散。細經熔解的均質化混合物倒入方便大小的模型中, 使冷卻後並使固化。 液體形態的製備物包括溶液、懸浮液,及乳化液,例如 水或水丙二醇溶液。 對於非經腸道液體製備物,其可在水性聚乙二醇溶液的 溶液中調配。 適合口服用途的水性溶液之製備,可將活性組成份溶解 在水中並添加合適的著色劑、加味劑、安定劑及所需的增 厚劑。 適合口服用途的水性懸浮液之製備,可將經細分的活性 組成份與黏性物分散在水中,如天然或合成的膠、樹脂、 甲基纖雉素、複基甲基纖維素納,以及其他已知的懸浮試 -26- ί紙張尺度適财0 B家鮮(_ A4_2igχ 297公爱) 1298020 A7 B7 五、發明説明(24 ) 劑。 同時也包括固體形態的製備物,其意圖在使用前再轉爲 液體製備物供口服使用。該液體形態包括溶液、懸浮液, 及乳化液。除了活性組成份之外,該製備物可包括著色 劑、加味劑、安定劑、緩衝液、人工及天然甜味劑、分散 劑、增厚劑、溶解劑及其相似者。 該醫藥製備物較佳爲單位劑量形態。在該形態下,該製 備物經細分爲包括適當活性組成份數量的單位劑量。該單 位劑型可爲經包裝的製備物,該包裝包含清楚的製備物數 量,如經包裝的錠劑、膠囊,及小管中的粉末或安瓿。同 時,該單位劑型可爲膠囊、錠劑、膠囊錠,或菱形錠劑, 或疋其可爲適當數量的前述任何經包裝形態。 在單位劑量製備物中的活性組成份數量可經變化或根據 特定的應用及活性組成份的效價,經調整由〇· i毫克至1 克。在醫藥用途上,該藥物可每日服用3次,例如以1〇0或 3〇〇毫克的膠囊。若需要的話,該組合物可包含其他相容 的治療試劑。 在治療用途上,使用在本發明方法的化合物的施用是起 始劑量由每曰約〇.01毫克至約1〇〇毫克/公斤重。較佳的每 曰劑量範圍由約〇·01毫克至約1〇〇毫克/公斤重。不過,該 劑量根據患者的需要、欲治療的症狀嚴重性,及所使用的 化合物而有所變化。訂出特定狀態的適當劑量是包括在本 發明的範圍中。—般而言,該治療一開始是以低於該化合 物的最適劑量的少劑量來進行。然後,少量的提高劑量至 __·27_ 尽紙狀跳計® ®家縣 1298020 A7 B7 五、發明説明(25 ) 若需要的話,可 達到該情況下的最適效果。爲方便起見, 將每日的總劑量細分並在當天分數次投服 -28- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
Claims (1)
- 或其醫藥上可接受鹽於製造治療需要該項治療之哺乳動 物之失眠症之藥劑之用途。 2· —種包含(3S,4S)-(1_胺基甲基- 3,4-二曱基-環戊基)_ 乙酸或其醫藥上可接受鹽及醫藥上可接受載劑之醫藥組 合物於製造治療需要該項治療之哺乳動物之失眠症之藥 劑之用途。 3 ·根據申請專利範圍第2項之用途,其中該組合物包含一 活性成份’其中該活性成份為(3S,4S)-(i-胺基甲基_ 3,4 -二甲基-環戊基)_乙酸或其醫藥上可接受鹽。
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2003
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