TW450808B - Use of central cannabinoid receptor antagonists for the preparation of drugs - Google Patents
Use of central cannabinoid receptor antagonists for the preparation of drugs Download PDFInfo
- Publication number
- TW450808B TW450808B TW087101128A TW87101128A TW450808B TW 450808 B TW450808 B TW 450808B TW 087101128 A TW087101128 A TW 087101128A TW 87101128 A TW87101128 A TW 87101128A TW 450808 B TW450808 B TW 450808B
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- pharmaceutically acceptable
- pharmaceutical composition
- effective amount
- solvate
- acceptable salt
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
450808 鍾濟部中央標準局負工消費合作社印裝 A7 B7 五、發明説明（1 ) 本發明係關於一種中央類大麻酚受體或稱爲CB:受體括 抗劑之新穎用途。 本發明更特別關於以CB!受體拮抗劑製備可用於治療慾 望障礙藥劑之用途。可用治療慾望陣礙藥劑之目的是調節 食用慾望’特別是希望食用糖、碳水化合物、酒糈或藥 物，和通常較想食用會刺激食慾的成份。 本敘述及本專利申請書中，據了解慾望障礙之意義爲： -與一種物質’而五特別是物質之濫用和/或對物質產生 依賴性有關之障礙， -飲食行爲障礙，特別是該些容易引起超重，不論其原 因，例如饑餓症、對糖有慾望和非胰岛素依賴性糖尿病之 障礙。 據了解物質的意義爲會引起慾望之成份，例如糖、碳水 化合物、酒精或藥物。 本發明因此也闞於以CBi受體拮抗劑製備可用於治療饑俄 症和肥胖，包括與第II型糖尿病（非胰島素依賴性糖尿病）有關 的肥胖，或更常見由於病人超重引起之任何疾病，及治療藥物濫 用或藥物依賴性之藥劑的用途。 四氫大麻酚或Δ 9-THC是由印度大麻草（Cannabis sativa)萃取出來的主要活性成份（Tuner，1985, in Marijuana, M., ED. Harvey, DY, IRL Press, Oxford) ° 類大麻酚的效果是由於特異性受體對G蛋白質偶合的交 互作用有高度親和力造成。目前記載的受體有兩種型態： 主要存在於中樞神經系統的CBi受體（Devane等人，分子藥 本紙張尺廋適用中國國家標準（CNS) A4规格（210X297公釐） (請先閱讀背面之注^K項#-填寫本頁) . • I— 450808 A7 B7 經濟部中央標準局貝工消費合作社印製 五、發明説明（2 ) 理學，1988, M，605-613)，和存在於免疫系統的CB2受體 (Nye等人，藥理學和實驗治療學雜誌，，”1985, 234.784-791 ; Kaminski 等人 1992，分子藥理學，U, 736-742 : Munro等人，自然，1993. 365.61-65)。由於合成配位禮， 例如CP 55,94〇(藥理實驗治療學雜誌，1988. 247. 1046-1051)和WIN 55212-2(藥理實驗治療學雜誌，I"3, 264, 1352-1363)的發展，以及由更近期之選擇性CBi受體拮抗劑 SR 141716 A(M, Rinaldi-Carmona 等人，FEBS Lett·，1994, 11立，240-244)的發現，因此能了解這些受體的特性。 對類大麻酚受體有親和性之年合物族群已記載於一些專 利或專利申請書中，特別是歐洲專利申請書EP-576 357， 其中敘述了吡唑衍生物，和專利申請書WO 96/02248，其 中特別敘述了苯并呋喃衍生物。 更特別的是，式（I) ·
之N-六氫叱吡啶-5-(4-氣苯基）rl-(2,4-二氣苯基）-4-甲基吡唑-3-羧基醯胺，也稱爲SR 141716，其醫藥上可接 受的鹽和其溶劑化物係敘述於歐洲專利申請書EP-656 354 中，做爲CB!中央受體拮抗劑之用。 -5 - 本紙張尺度適用中國國家梯準（CNS ) A4規格（210X297公釐） 請 先 閲 背 ft 之 注
I t 450808 A7 B7 五、發明説明（3 ) SR 141716 A 是 SR 141716 的鹽酸鹽。 已知d-9-四氫大麻酚，其國際非專有名稱爲索麻酚，係 用於治療食慾不振，特別是患有AIDS(疼痛徵狀處理雜 誌，1995,尬(2)，8947)或癌症的病人（緩和看護雜誌， 1994,尬(1)，14-18)。 也記載了中央類大麻酚受體拮抗劑SR 141716和其鹽， 能用於治療食慾障礙，特別是做爲減食慾劑，和用於治療 與使用會影響心志之物質有關的障礙。 傳統的減食慾劑會使降低食慾，其通常與待食用的食物 無關8 目前已意外地發現CBi受體拮抗劑會選擇性地在闞於會 引起食慾之物質的食用行爲障礙上有特異性質。 因此施予CBi受體拮抗劑能調節想要食用非必需食物增 目的慾望，例如過多糖、過多碳水化合物，酒精或藥物。 事實上’動物實驗已顯示一種新行爲：動物不再會有正 常情況發現例如糖或酒精成份的愉悦，而自然表現出對其 慾望。此種缺乏慾望本身也會明顯地表現在預先以已知會 增加食慾之神經肽’例如神經肽Y(NPY)處理的動物上。 經濟部中央楳準局舅工消费合作社印裂 根據本發明，其一方面係關於以CB!受體拮抗劑製備可 用於治療慾望障礙藥劑的用途上。 適合本發明目的之CB!受體拮抗劑，特別是式（π)化合 物 -6 - 本紙張尺度適用中國國家樣準（CNS ) A4規格（2丨Οχ刊7公羞） 450808 Α7 Β7 五、發明説明（4 )
鋰濟部中央揉準局男工消费合作社印装 其中 -Ri是氫，氟，羥基，（CVCs)烷氧基，（Ci-C：；)烷氧基，羥 基（C1-C5)坡氧基，-NRioRii基’氰基，（Ci-bs)坑確酸基， (C1 - C 5)娱•亞確随基； -R2和Κ·3是（C1-C4)坑基喊與其鍵結的氮原子一起形成飽和 或未飽和5-至10·員雜環基，其未被取代或者被（CpCs)烷 基或（C〗-C3)烷氧基未取代或多取代；/ -R4 ’ ’ R<S，.Κ·7，厌8和尺9备獨立爲氣，鹵素或三氟 甲基，而如果是氟，R4，. R5，Κ·6，Κ·7，厌8和/或 R9也能是氟甲基，但前提是至少其中一個取代基R4或R7 不是氫；及 -Rig和R"各獨立爲氮或（C]-C5)燒基，或者Rio和Rii與 其鍵結的氮原子一起形成選自吡咯啶-1 -基，六氫吡啶-卜 j 基，嗎啉-4-基和六氫吡基之雜環基，其未被取代或 可被（CVC4)烷基取代，或其鹽及其溶劑化物。 本發明更特別關於以N-六氫吡啶-5-(4·氣苯基）-1-(2,4-二氣苯基）-4-甲基吡唑·3-羧醸胺，其醫藥上可接受的鹽和 其溶劑化物製備可用於治療慾望障礙藥劑之用途上。 -7- ^紙張尺度遙用中國國家揉準（CNS ) Α4規格（210X297公釐） <請先聞讀背面之注意事項再填寫本頁) 450808 A7 B7 五、發明説明（5 ) 根據本發明，CBi受體拮抗劑也能與另一種活性要素聯 合用來製備可用於治療慾望障礙，特別是法療飲食行爲障 礙之藥劑·，也能使用一種含有CB,受體拮抗劑與調節代謝 障礙之化合物，尤其是jS3-腎上腺發生之受體激動劑，下 文稱爲3激動劑之醫藥組合物。 因此本發明也關於含有CB!受體拮抗劑與代謝障礙調節 劑，例如降低血脂、hypolydemic或解脂之醫藥組合物。 本發明更特別關於含有CBi受體拮抗劑與A激動劑之醫藥 組合物。 根據本發明之用途的激動劑爲式（III)化合物 <請先聞讀背面之注意事項再填寫本I) 0H,
訂 其中： -X是氫，鹵素，三氟曱基或（c!-c4)烷基；和 -R是氫未被或可被羧基或其中烷氧基是（Ci-Ce)的烷氧羰 鲤濟部中央揉準局舅工消费合作杜印製 基取代之甲基， t 及其醫藥上可接受之鹽，於EP 0 211 721和EP 0 303 546 中指出，係做爲解腸痙攣劑之用。. 在式（ΠΙ)化合物中，以下化合物： *2-[(7-羥基-1，2,3,4-四氫莕-2-基）胺基]-1-苯基乙醇： *2-[(7-羥基-1，2,3,4-四氳萘-2-基）胺基]-1.(3-氣苯基）乙 -8- 本紙張尺度適用中國國家梂準（CNS)A4規格（210X297公釐） ^§0 808 Α7 Β7 五、發明説明（β 醇； 伞 2·[(7-乙氧羰基甲氧基·12,3,4_四氩莕_2基）胺基】 (3·氣苯基）乙醇； . 孝 鋰濟部中央標準局員工消费合作社印衷 2·[(7_乙氧羰基甲氧基d，2,3,4·四氳茶·2基）胺基苯 基乙醇； *(lR，2’RS)-2.[(7_輕基·12,34_四氧茶_2_基）胺基】」·苯 基乙醇； *(lS’2’RS)-2-[(7,基四氫茶_2基）胺基】“苯 基乙醇； *( + )-(lR)-2-[(7_羥基-丨，2,3,4·四氫荅_2基）胺基苯 基乙醇； *( + )-(18)-2-[(7-羥基-1，2,3,4-四氫蓁_2_基）胺基]_1_苯 基乙醇； *(-)-(1尺)-2-[(7-羥基_1，2,3,4-四氫蓁_2-基）胺基]-1-苯 基乙醇； *(-)-(13)-2-[(7-羥基-1，2,3,4-四氫茬-2-基）胺基]-1-苯基 乙醇； *N-[(2S)-7-乙氧羥基甲氧基四氫荅_2-基]_ (2R)-2-(3·氣苯基）·2-羥基乙胺；和 *N-[(2R)_7·乙氧羥基甲氧基·ι，2,3,4-四氫莕-2·基]-(2R)-2-(3-氣苯基）·2-獲基乙胺， 及其醫藥上可接受的鹽特別有效。 N-[(2S)-7-甲氧羥基甲氧基_l,2,3,4-四氫莕-2-基]_ (2R)-2-(3-氣苯基）·2-羥基乙胺（SR 58611)其醫藥上可接 9- 本紙張尺度逋用中固國家榡準（CNS > A4規格（210X297公釐） (請先閱讀背面之注f項再填寫本I) 訂 t
4 50 8 08 A7 B7 五、發明説明（7 ) (請先閲讀背面之注意事項再填寫本頁) 受的鹽非常特別有效，尤其是其里酸里，SR 58611 A。 根據本發明能使用的其它/? 3激動劑爲式（fv)化合物
OX， Y Z A-CH-CH2-N-CH-(CH2)n.WH^^R' (IV) R" 其中： •η 是 1，2 或 3 ; -Α是苯幷吱喃-2-基或是未被取代或可被一個或兩個鹵原 子或（C〖-C4)烷基或三氟甲基取代的苯基； •R·是： -氫； -(Ci-Ce)燒基； 經濟部中夬棣準局貝工消費合作社印« -選自以下基團之官能基：羥基；（CrCe)烷氧基；（c2-C6) 鏈烯氧基；（C2-C6)块氧基；（C3-C8)環烷氧基，·（C3-C8)環 烷基烷氧基；苄氧基；苯氧基；氫硫基；（(^-<：6)烷 硫基；（C2-C6)鍵締硫基；（C2-C6)決硫基；（C3-C8)環娱1硫 基；（C3-C8)環燒基（Ci-Cs)坑疏基；字硫基；苯硫基；（Ci_ C6)燒亞續酿基；（C2-C6)鍵亞確磁基；（C3-C8)環淀亞續酿 ί
基；（C3-C8)環虎續睹基；（C3-Cg)環燒基（C!-C6)烷續斑 基；芊磺醯基；苯磺醯基；氰基；碲基；未被或可被一個 或兩個選自（CVC6)烷基、（c2-c6)鏈烯基、（C2-C6)炔基、 (c3-c8)環烷基、（C3-C8)環烷基（C^-Ce)烷基；苄基和苯基 之相同或不同基取代的胺基；羧基；其中烷氧基是（Ci-CJ -10- 本紙張尺度適用中國躅家揉準（CNS ) A4規格（210X297公釐） 450808 A7 B7 五、發明説明（8 ) 的烷氧羰基；（CrCJ鏈烯氧羰基：（C2_C6)炔氧羰基；（c3· C8)環烷氧羰基；（C3-C8)環烷基（C]-C：6)烷氧羰基；苄氧羰 基；苯氧羰基；和胺基上未被或被一個或兩個選自（crc6) 烷基、（c2-c6)鏈晞基、（c2-c6)炔基、（c3-c8)環烷基、（c3-C8)環烷基（CrCd烷基、芊基和苯基之相同或不同基取代 的胺基甲醯基； -Rnl基選自以下基團：被一種官能基取代的（Cj-Ce)烷 基；被一種官能基取代的（C2- C(S)鍵缔基；被一種官能基取 代的（c2-c6)炔基；在苯基上被（CrCJ坑基或被一種官能 基取代的苯基（CrCJ烷基；在苯基上被（CpCe)烷基或被一 種官能基取代的苯基（C2-C6)鏈埽基；在苯基上被（Ci-Cs)烷 基或被一種官能基取代的苯基（C2-C6)炔基；在苯基上被 (C^Ce)烷基或被一種官能基取代的苄基；和未被或被（(：「 C6)烷基或一種官能基取代的苯基，該官能基如上述定義； -0-R1 2，S-R2，SO-R2 或 S02-Rin 基’其中 Rni 如 上述定義； 經濟部中央標準局貝工消費合作社印製 (請先W讀背面之注意事項再填寫本頁) -NRniR〇基，其中R2如上述定義；而且R〇是氫或如上 述R2之定義，或R2和RG與其鍵結的氮一起形成選自吡 洛唉，六氫p比症和嗎#基的基囷； -COOR2基或基CO-SR2，其中R2如上述定義； -CONR2基R0基，其中R2如上述定義；而且R0是氣或 如上述R2之定義’或R2和1^與其鍵結的氮一起形成選 自吡咯啶，六氫吡啶和嗎啉基的基圈；或 -SOjNRmR0基，其中R2如上述定義；而且R〇是氫或如 1 - 2 本紙張尺度適用中國B家橾準{ CNS ) A4规格（210xw?公着） 450808 A7 B7 五、發明説明（9 ) 上述R111之定義，或R111和RQ與其鍵結的氮''一起形成選自 11比洛咬，六氫比唉和嗎琳基的基團； 广 -Rln是氫；鹵素；（c^cd烷基；如上述定義之一種官能 基；OR111基，R111如上述定義；COOR111基’ R111如上 述定義，或CONR1UR0基，其中R111如上述定義；而且R〇 是氫或如上述R111之定義，或R1"和R。與其鍵結的氮—起 形成選自P比嘻淀，六氫P比峻和嗎0林基的基困； -W是直接鍵結或氧原子； -X'是氫，（CVC6)烷基或（CVC6)烷羰基； γ是氫或Α·-(：Η(ΟΗ)-(：Η2-基，A·除了苯幷吱喃-2·基外與 Α相同、；或 . -X’和γ視情況被其中烷氧基是（Cl_C6)的烷氧羰基取代， 一起形成亞甲基；視情況被含氧基取代的亞乙基；或1,3-亞丙基；及 Z是氩或（q-Ce)坑.基， . 和其醫藥上可接受的鹽，於EP 0 255 il5中指出，其係做 爲解腸痙攣劑之用》 根據本發明也能使用的其它/? 3激動劑爲式（V)化合物 (請先閲讀背面之注項再填寫本頁) 經濟部中央樣準局負工消費合作社印製 0Η
ch-ch2-nh-ch
—G (V) 其中： -12- 本紙張尺度適用中國固家棣率（CNS >A4題（210X297公釐 450808 A7 B7 五、發明説明（1〇 ) -E是氫，（(VC4)烷基，（CVCU)烷氧基，苯基’硝基，鹵 原予或三氟甲基； -L是氫，（CVC4)烷基，（CVC4)烷氧基，苯基’硝基，鹵 原子；或 -E 和 L —起形成-CH=CH-CH=CH-或-CH2-CH2-CH2-CH2-; 和 -G是氫，氣原子，羥基或0G’基，其中σ是（CVCU)烷基，其 係未被取代或可被輕基，（CVC4)燒氧基，（C1-C4)燒氧凝基， 羧基或（c3-c7)環烷基取代；（c3-c7)環烷基：或（c2-c4)烷酿 基。 和其醫藥上可接受的鹽，於EP 0 255 415中指出，其係做爲 解腸痙攣劑之用。 在式（V)化合物，：N-[(2R)-(6-羥基-1，2,3,4-四氫莕-2· 基）甲基]-(2R)_2·羥基-2·(3 -氣苯基）乙胺（SR 59104)， 1^-[(21〇-(7-甲氧基-1，2,3,4-四氫莕-2-基）甲基】-(211)-2-羥基-2-(3-氣苯基）乙胺（SR 59119)和其醫藥上可接受的鹽 是特別有效的化合物。 經濟部中央榡準局負工消费合作社印裂 (請先閲讀背面之注意事項再填寫本頁) 根據本發明其它有效的/3 3激動劑有EP 23385中所载之 化合物BRL 35135 ; US 5 061 727中所載之化合物CL 316243 ; EP 218440 中所載之化合物 AZ 002 ; US 5 321 036中所載之化合物BMS 187257 ; EP 473 285中所載之化 合物 ZD 7114 ; Am. J. Clin. Nutr.，1992，1^(1，Suppl.)， 249S_251S中所載之化合物RO 40-2148 ;和以下專利/專利 申請書所載之產物：WO 96/35671，WO 96/35670， -13- 本紙張尺度追用中國躅家標準（CNS ) A4規格（2丨0X297公釐） 450808 A7 B7 五、發明说明（11 ) WO 96/16038，WO 96/04233，WO 95/33724， WO 95/29159，EP 659737，WO 95/04047，EP 516349， EP 473285，EP 23385，EP 21636，EP 7205， JP 08198866，JP 08157470，WO 96/16938， EP 714883，WO 96/04234，US 5 488 064， US 5 482 971，US 5 491 134，WO 95/29159 » WO 95/33724，ZA 9409874，WO 95/29903， US 5 461 163，WO 95/25104，EP 659737， JP 07112958，WO 95/8527，WO 95/07284， JP 07025756，WO 95/03289，WO 95/04047， WO 95/01 1 70，WO 94/29290，US 5 373 020， JP 06293664，WO 94/12166 和 US5 451 677。 關於用途爲藥劑時，〇丑1受體拮抗劑化合物本身或與卢3 激動劑聯合，必須配製成醫藥组合物。 本發明之醫藥组合物以口服、舌下、皮下、肌肉下、靜 脈内、經皮膚、局部或直腸投藥時，活性要素本身或與其 它活性要素，能與傳統醫藥載劑一起混合後，以單位形式 對動物和人類投藥。投藥之適當單位形式包括口服形式， 例如藥片、凝膠膠囊，粉末，口服顆粒和溶液或懸浮液， 舌下和頰劑形式投藥，噴霧器，植入體、皮下、肌肉内、 靜脈内、鼻腔内或眼眶内的形式和直腸形式投藥。 本發明之醫藥組合物中，一種或多種活性要素通常以劑 量單位配製。每天投藥之每種劑量單位的CB:受體拮抗劑 包含0.5至1000毫克，以1至500毫克較佳，而最好爲2 -14- 本紙張尺度速用中國國家樓準（CNS ) A4規格（210X297公釐） 面 之 注 2 經濟部中央橾準局負工消费合作社印製 450808 A7 ______B7 五、發明説明（12 ) 至200毫克。 .若一起使用2種活性要素時，劑量單位含有〇5至600毫 克，以1至400毫克較佳，而最好是2至200毫克的CB!受 體拮抗劑化合物；其它的活性要素，特別是点3激動劑則 爲〇·5至600毫克，以2至400毫克較隹，而最好是1〇至 250毫克。 當固態組合物製備成藥片型態時，可以將潮濕劑像十二 烷基硫酸鈉加入微粒化或未經微粒化的活性要素内，而且 全部成份與一種酱藥賦形劑，像二氧化矽、滅：粉、乳糖、 硬脂酸鎂、滑石或其類似物混合。藥片可以塗上廉接，許 多種聚合物或其它遴當的物質，或者也能經處理而具有持 續或延緩活性，使得預定量之活性要素能繼續釋放出來。 藉由混合一種或多種活性要素與稀釋劑，像是甘醇或甘 油酸’而且將所生成的混合物裝入軟或硬凝膠膠囊内，可 以獲得凝膠膠囊形式之製劑。 糖漿或酏劑形式之製劑能含有一種或多種活性要素，與 最好是不含卡洛里的增甜劑，做爲殺菌劑的對氧苯甲酸甲 醋（methlparaben)和對氧苯甲酸甲酯（propyiparaben)，香料 經濟部中央橾隼局負工消费合作社印裝 和適當的增色劑。 在水中會散開的粉末或顆粒能含有一種或多種活性要 素’與分散劑或潮濕劑或與懸浮劑，像聚乙烯吡咯烷網或 以及與増甜劑或味覺調節劑混合。 使用與在直腸溫度下會熔解之結合劑，例如可可亞奶油 或聚乙二醇製備之栓劑能有效地經直腸投藥。 -15- 本*度巾 gjg[家鮮（CNS ) A4^ ( 21QX297公着） 450808 經濟部中央標率局負工消费合作社印策 A7 B7 五、發明説明（13 ) 使用含有藥效上相容的分散劑和/或溶解劑，例如丙二醇 或丁二醇懸浮水溶液、等張鹽水溶'液或可注射之無菌溶液 能有效地非經腸投藥。 因此，可以使用助溶劑，例如醇像乙醇或甘醇像聚乙二 醇或丙二醇，和親水界面活性劑像Tween®80製備靜脈内 注射之水溶液。以三酸甘油酯或甘油醚溶解活性要素能製 備肌肉内注射之油性溶液》 使用多層形式丸劑或輿其中活性要素是溶於酒精性溶液 之儲主能有效地經皮膚投藥。 一種或多種活性要素也能視情況與一種或多種載劑或添 加劑配製成微膠囊或微球狀。 一種或多種活性要素也能以與環糊精，例如“-，卢-或 r -環糊精’ 2 -羥基·丙基環糊精或甲基-々-環糊精形 成複合物的形式存在。 持久釋放形式使用於慢性治療的情況下可以使用植入 體。這些植入體能以油狀懸浮液的形式或溶於等培養基之 微球狀懸浮液的形式製備。 根據本發明的其它方面，CBl受體拮抗劑和代謝陣的調 節劑’尤其是/? 3激動劑，在治療慾望障礙，特別是飲食 行爲障礙時，能同時、依序或經一段時間以上投藥。 本發明因而更關於藉由同時、依序或經一段時間以上投 以受體拮抗劑和代謝障礙的調節劑，尤其是卢3激動 劑’以治療慾望障礙之製劑组，該製劑组中的受體拮 抗劑和代謝障礙的調節劑，尤其是卢3激動劑，是單獨成 -16- 本紙張尺度遙用中國國家橾準（CNS ) A4说格（210X297公着） (請先閎讀背面之注意事項再填寫本頁) 訂 Ψ 0808 -¾ 4 A7 B7 五、發明説明（14 ) 層而且視情況包裝不同》 更特別的是，該製劑組含有N -六氫吡啶- 5·(4 -氣苯基）_ 1-(2,4-二氣苯基）-4 -甲基n比岭-3-叛基酿胺，其醫藥上可 接受一種鹽或其溶劑化物中的一種，和N-[(2 S)-7-乙氧經 基甲氧基-1，2,3,4-四氩荅-2-基】-(2R)-2-(3-氣苯基羥 基乙胺或其醫藥上可接受之鹽的一種。 根據本發明其它方面，另係關於一種治療愁望障礙的方 法，特別是治療飲食行爲障礙的方法，其包含對需要此種 治療的病人投予（治療的）有效量如上定義之031受體拮抗 劑。該CBi受體拮抗劑能有助於與代謝障礙的調節劑，尤 其是如上述定義之/5 3激動劑一起使用。尤其，CB〗受雜 拮抗劑和代謝障礙的調節劑能同時、依序或經一段時間以 上投藥。 1號試驗：SR 141716 A對於老鼠在攝取蔗糖溶液上的效 果 本實驗係根據W. C. Lynch等人，生理行爲，1993, U, 877-880 進行。 經濟部中央標準局貞工消t合作社印敢 (請先閲讀背面之注f項再填寫本頁) 重190至210克的Sprague-Dawley公鼠在正常光照循環 下（從早上7點至晚上7點）隨意地飲用水。 在6天内，早上11點和下午3點間，取出食物和水瓶， 而且給予老鼠5%蔗糖溶液供其飲用。 取出飲用低於3克蔗糖溶液之老鼠。 在第7天時根據以下步驟進行試驗： 早上9點： 取出食物， -17- 本紙張X度適用中國國家標半（CNS > A4規格（2IOX297公釐） 450808 經濟部中央標準局貝工消費合作社印掣 A7 B7 五、發明説明（15 ) 早上10點：口服投予SR 141716 A， 早上11點=T0 :將秤重過的蔗糖溶液倒入瓶内，το + 1小 時，Τ0 + 2小時，Τ0 + 3小時，Τ0 + 4 小時：由瓶重測量食用的蔗糖量。 表1 治療 老鼠數目 以克表示食用的蔗糖量 po 1小時 2小時 3小時 4小時 賦形劑 8 11.33 17.74 22.50 28.34 2毫升/公斤 ±2.50 土 4.00 ±4.83 ±5.01 SR 141716 A 6 5.18 9.18 12.49 16.10 0.3毫克/公斤 土 1.61 土 2.12 ±4.47 ±3.95 SR 141716 A 6 3.27* 3.16** 5.65* 7.43** 1毫克/公斤 土 1.40 土 1.40 ±2.23 ±2.81 SR 141716 A 6 2.95* 5.41* 6.96* 8.58** 毫克/公斤 ±1.20 ±1.33 ±2.15 ±2.92 *P<0,05 ; ，Dunnett 試驗 由表1報告之結果可見投予0.3毫克/公斤或以上劑量之 sr 141716 A相當能減少糖水溶液的食用。 2號試驗：SR141716A對於老鼠在消耗蔗糖溶液上的效 果 C 57 BL 6公鼠（iffa_credo)在抵達當天於相反的循環下 (夜間由早上10點至晚上10點）分開置於裝有2瓶水的動 物飼養室内。一週後，以裝有10%酒精溶液的瓶子置換其 中一瓶水進行6小時試驗，每天，倒入酒精瓶的30分鐘 前，以SR 141716 A皮下處理老鼠。在6小時後測量食用 -18- 本紙張尺度邊用中國國家榇準（CNS > 規格（2丨0X297公釐） {請先閲讀背面之注項再填寫本頁) 訂 f 450808 A7 B7 五、發明説明（16 ) 之酒精和水的量。重復此試驗4天。 表2 以 SR141716A 處理 毫克/公斤皮下 老鼠數目 以克表示 在第4天 食用的酒精量 以克表示 食用的水量 賦形劑 20 1.9 ± 0.1 1.1 ± 0.1 0.1 10 1_4 士 0.2 1.1 ± 0.3 0.3 10 1.3 ± 0.2 1.1 土 0.3 1 10 1.1 ± 0.2" 1.3 ± 0‘1 3 10 1.0 土 0.2** 1.6 土 0,3 ****p<0.01，Dunnett 試驗 結果顯示經處理的動物其酒精食用量明顯減少；未處理 的動物爲1.9 ± 〇 1克，而接受3毫克/公斤SP 14 1 716 A 的動物爲1.0 士0.2 ;水的食用量呈平行增加：由1.1 ± 0.1至 1-6 ± 0.3 克。 實施例1含有1毫克081受體拮抗劑之凝膠膠囊 經濟部中央揉準局貝工消费合作社印製 SR 141716微粒 1.00毫克 玉米澱粉 51·00毫克 乳糖單水合物 103.33毫克
Polyvidone 4.30 毫克 十二烷基硫酸鈉 0. 1 7毫克 交聯的羧曱基纖維素鈉 8.50毫克 -19- 本紙張尺度適用中國國家揉牟（CNS > A4规格（210X2?7公嫠） 4 5Ό 8 0 8 A7 B7 五、發明説明（17 ) 純水：適量供潮濕粒化作用 硬脂酸鎂 1.70毫克 装入170毫克至3號透明白色凝膠醪囊内。 實施例2含有10毫克081受體拮抗劑之凝膠膠囊 1〇.〇殘克 51.00毫克 94.33毫克 4.30毫克 0.17毫克 8.50毫克 經濟部中央棵準局貝工消费合作社印袋 SR 141716 A 微粒 玉米澱粉 乳糖單水合物 Polyvidone 十二烷基硫酸鈉 交聯的羧甲基纖維素鈉 純水：適量供潮濕粒化作用 硬脂酸鎂 1.70毫克 裝入170毫克至3號透明白色凝膠膠囊内。 實施例3含有30毫克CB,受體拮抗劑之凝膠膠囊 SP141716 微粒 30.00 毫克 玉米澱粉 51·00毫克 乳糖單水合物 74.33毫克 Polyvidone 4.30 毫克 十二競> 基硫酸納 0.17毫克 交聯的羧甲基纖維素鈉 8,5〇毫克 純水：適量供潮濕粒化作用 硬脂酸鎂 1.70毫克 裝入170毫克至3號透明白色凝膠膠囊内。 實施例4含有30毫克CBi受體拮抗劑的藥片 20 本紙張尺度適用中國國家揉準（CMS > A4規格（2I0X297公嫠） (請先閲讀背面之注意事項再填寫本頁) 4 60 8 08 A7 B7 五、發明説明（18 ) 經濟部中央揉準局員工消费合作社印裝 SP 141716 微粒 30.00毫克 乳糖單水合物 適量 玉米澱粉 40.00毫克 羥基丙甲基織維素6 cP 5.00毫克 純水：適量供潮濕粒化作用 交聯的羧甲基纖維素鈉 1 0.00毫克 硬脂酸鎂 2.00毫克 完成的藥片内裝有200毫克11 實施例5含有3 0毫克劑量之CB! 受體拮抗劑和2 00毫克 万3激動劑的藥片 SP 141716 微粒 30.00毫克 SP 5861 1 A做爲基質 200.00毫克 乳糖單水合物 適量 Polyvidone 15.00毫克 純水：適量供潮濕粒化作用 交聯的羧甲基纖維素鈉 1 0.00毫克 硬脂酸鎂 5.00毫克 完成的藥片内装有5 00毫克。 實施例6含有10毫克CBi受趙拮抗劑和1〇〇毫克β 3激 動劑的藥片 SP 14 1 716 微粒 10.00毫克 SP 58611 A做爲基質 100.00毫克 玉米;殿粉 30毫克 乳糖單水合物 適量 (請先W讀背面之注意事項再填寫本頁) -21 -本紙張尺度適用、中國國家標準（CNS ) A4说格（2I0X297公釐） A7 經濟部中央梂準局員工消費合作社印裝 五、發明説明（19 ) 羥基丙基甲基纖維素6 cP 純水：適量供潮濕粒化作用 羧甲基澱粉鈉 硬脂酸鎂 完成的藥片内裝有3 00毫克。 B7 5.00毫克 6.00毫克 3.00毫克 (請先閲讀背面之注意事項再填寫本頁) 訂 -22- 本紙張尺度適用中國國家標準（CNS ) 210X297公釐）
Claims (1)
- 經濟部t央樣準局貝工消t合作社印製 '钱發成觀號專利，請案 Jr 圍修正本(9〇年6月）er ^ 、申請專利範圍 •—種經由體拮抗作用而用於治療慾望障礙之醫藥组 合物，其包含有效量之N_六氫吡啶_5_(4·氣苯基卜^ (2,4-二氣苯基）-4-甲基吡唑羧醢胺，或其醫藥上可 接觉的鹽或其溶劑化物，和醫藥上可接受之賦形劑。 2’ 一種經由匚8!受鱧拮抗作用而用於調節食用慾望之醫藥组 合物，其包含有效量之N-六氳吡啶-5·(4_氣苯基）卜 (2,4·二氣苯基）·4_甲基吡唑羧磕胺，或其醫藥上可 接受的鹽或其溶劑化物，和赘藥上可接受之賦形劑。 3. 一種經由CBi受醴拮抗作用而用於治療與_種物質有關之 障礙的醫藥组合物，其包含有效量之N-六氩吡啶_5 (4_ 氣笨基）·1·(2,4 -二氣苯基）_4_甲基峨嗤·3·羧睹胺，戋 其醫藥上可接受的鹽或其溶劑化物，和醫藥上可接受之 賦形劑。 & 4. 一種經由〇8丨受體拮抗作用而用於治療飲食行為障礙之醫 藥組合物，其包含有效量之Ν_六氫吡啶·5_(4·氣苯基）· 1-(2,4·二氣苯基）_4_甲基吡唑_3_羧醯胺，或其醫藥上 可接受的鹽或其溶劑化物，和醫藥上可接受之賦形劑^ 5. —種經由CBl受體拮抗作用而用於治療肥胖之醫藥組合 物，其包含有效量之N-六氫吡啶_5_(4•氣苯基） (2,4 -二氣苯基）·4·甲基吡唑_3 -羧醢胺，或其醫藥上可 接受的鹽或其溶劑化物，和醫藥上可接受之賦形劑。 6. 根據_請專利範圍第5項之醫藥組合物’其係用於治療與 非胰島素依賴性糖尿病有關之肥胖。 7. —種經由（：比受體拮抗作用而用於治療由於病人超重而引 本纸張又度逍用中«國家梯率（CNs) A4洗格（21〇χ297公羡） (請先《讀背面之注$項再填寫本筲) 訂 A— n^i —A— » A8 B8 CS D8 9 450808 六'申請專利範固 起之任何疾病的醫藥組合物，其包含有效量之N -六氟吼 硬-5-(4 -氣苯基二氣苯基）_4_甲基吡吨_3羧 随胺，或其醫藥上可接受的鹽或其溶劑化物，和醫藥上 可接受之賦形劑。 8. —種經由〇；81受體拮抗作用而用於治療饑蛾症之醫藥组合 物’其包含有效量之N -六氫吡啶-5-(4 -氣苯基）-1_ (2,4-二氣苯基）-4-甲基吡唑-3-羧醮胺，或其醫藥上可 接受的鹽或其溶劑化物，和醫藥上可接受之賦形劑。 一種經由〇8!受體拮抗作用而用於治療濫用藥物或對藥物 依賴之醫藥组合物，其包含有效量之N-六氩吹咬_5·(4· 氣苯基）-1-(2,4 -二氣笨基）·4 -甲基吹吐-3-幾斑按，或 其骜藥上可接受的鹽或其溶劑化物，和醫藥上可接受之 賦形劑》 <請先Η讀背面之注f項再填寫本賈) 訂 經濟部中央揉準局貝工消费合作杜印«. 本紙張尺度逋用肀國因家猱率（CNS > A4规格（210X297公釐） 申請日期 案 號 類 別 公告本 87101128 以上各棚由本局填症） 中文說明書修正頁(89年2月） A4 C4450808 發明 新型 名稱 $_J專利説明書 中 文 以中央類大麻酚受體拮抗劑製備藥劑之用途 英 文 USE OF CENTRAL CANNABINOID RECEPTOR ANTAGONISTS FOR THE PREPARATION OF DRUGS 姓 名 人 國 藉 1·潔恩馬洛尼 2.菲利普索布萊 均法國 裝 住 '居所 1. 法國淮哈克斯市洛提斯曼特拉柯林路8號 2. 法國聖馬休德_崔佛市瓦弗朗斯 訂 姓 名 (名稱） 法商沙諾費一辛芷拉保公司 線 法國 國 籍 三、申請人 住、居所 (事務所） 法國巴黎市第174大道 高登萊特 代表人 姓 名 Μ氏诔尺度適用中國國家標準（CMS ) A4洗格（210X297公釐） 經濟部t央樣準局貝工消t合作社印製 '钱發成觀號專利，請案 Jr 圍修正本(9〇年6月）er ^ 、申請專利範圍 •—種經由體拮抗作用而用於治療慾望障礙之醫藥组 合物，其包含有效量之N_六氫吡啶_5_(4·氣苯基卜^ (2,4-二氣苯基）-4-甲基吡唑羧醢胺，或其醫藥上可 接觉的鹽或其溶劑化物，和醫藥上可接受之賦形劑。 2’ 一種經由匚8!受鱧拮抗作用而用於調節食用慾望之醫藥组 合物，其包含有效量之N-六氳吡啶-5·(4_氣苯基）卜 (2,4·二氣苯基）·4_甲基吡唑羧磕胺，或其醫藥上可 接受的鹽或其溶劑化物，和赘藥上可接受之賦形劑。 3. 一種經由CBi受醴拮抗作用而用於治療與_種物質有關之 障礙的醫藥组合物，其包含有效量之N-六氩吡啶_5 (4_ 氣笨基）·1·(2,4 -二氣苯基）_4_甲基峨嗤·3·羧睹胺，戋 其醫藥上可接受的鹽或其溶劑化物，和醫藥上可接受之 賦形劑。 & 4. 一種經由〇8丨受體拮抗作用而用於治療飲食行為障礙之醫 藥組合物，其包含有效量之Ν_六氫吡啶·5_(4·氣苯基）· 1-(2,4·二氣苯基）_4_甲基吡唑_3_羧醯胺，或其醫藥上 可接受的鹽或其溶劑化物，和醫藥上可接受之賦形劑^ 5. —種經由CBl受體拮抗作用而用於治療肥胖之醫藥組合 物，其包含有效量之N-六氫吡啶_5_(4•氣苯基） (2,4 -二氣苯基）·4·甲基吡唑_3 -羧醢胺，或其醫藥上可 接受的鹽或其溶劑化物，和醫藥上可接受之賦形劑。 6. 根據_請專利範圍第5項之醫藥組合物’其係用於治療與 非胰島素依賴性糖尿病有關之肥胖。 7. —種經由（：比受體拮抗作用而用於治療由於病人超重而引 本纸張又度逍用中«國家梯率（CNs) A4洗格（21〇χ297公羡） (請先《讀背面之注$項再填寫本筲) 訂 A— n^i —A— »
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| FR9700870A FR2758723B1 (fr) | 1997-01-28 | 1997-01-28 | Utilisation des antagonistes des recepteurs aux cannabinoides centraux pour la preparation de medicaments |
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| IL79323A (en) | 1985-07-10 | 1990-03-19 | Sanofi Sa | Phenylethanolaminotetralines,their preparation and pharmaceutical compositions containing them |
| IE65511B1 (en) * | 1989-12-29 | 1995-11-01 | Sanofi Sa | New phenylethanolaminomethyltetralins |
| FR2692575B1 (fr) * | 1992-06-23 | 1995-06-30 | Sanofi Elf | Nouveaux derives du pyrazole, procede pour leur preparation et compositions pharmaceutiques les contenant. |
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| EP0627407A1 (fr) * | 1993-05-28 | 1994-12-07 | MIDY S.p.A. | Acide (7S)-7-[(2R)-2(3-chlorophényl)-2-hydroxyéthylamino]-5,6,7,8-tétrahydronaphtalèn-2-yloxy acétique, ses sels pharmaceutiquement acceptables, à action agoniste bêta-3 adrénergique et compositions pharmaceutiques le contenant |
| US5578638A (en) * | 1993-11-05 | 1996-11-26 | American Cyanamid Company | Treatment of glaucoma and ocular hypertension with β3 -adrenergic agonists |
| EP0795327A1 (en) * | 1996-03-13 | 1997-09-17 | Pfizer Inc. | Use of Amlodipine for the treatment and prophylaxis of congestive cardiac failure of non-ischaemic origin |
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