TW200530191A - Imidazoline derivatives having CB1-antagonistic activity - Google Patents
Imidazoline derivatives having CB1-antagonistic activity Download PDFInfo
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200530191 九、發明說明: L考务明戶斤屬才支名好冷員】 本發明涉及作為CBj#抗劑的1,2,4-三取代的咪唑啉衍生物,製備 這些化合物的方法以及適用於合成所述咪唑啉衍生物的新型中間體。 5 本發明還涉及本文公開的化合物在生產給出有益效果的藥物中的應 用。有益效果公開於本文中或者是本領域技術人員從本說明書和本領 ’ 域一般知識顯而易見的。本發明還涉及本發明的化合物在生產用於治 ' 療或預防疾病或病況的藥物中的應用。更具體地說,本發明涉及治療 B 本文公開的或者本領域技術人員從本說明書和本領域一般知識顯而易 1〇 見的疾病或病況的新用途。在本發明的實施方案中,本文公開的特定 化合物被用來生產這樣的藥物,即,適用於治療涉及大麻素 ((^nnabmoid)^:體的障礙,或者可通過控制這些受體來治療的障礙。 L· ]| 從WO 03/101954和WO 03/101969已知多取代的咪唑啉衍生物。 15本文描述的化合物是轉錄因子NF-KB的有效抑制劑,使它們適用於治 _ 療某些麵驗瘤。所《娜衍生觸具有料抗炎劑和抗生素的 有效活性,導致另U的指徵’其中,它們可能具有治療意義,包 括炎性和傳·疾病。沒有_上述專辦請中描述的化合物對大麻 ^ 素具有任何親合性,所以它靖涉及這些大麻素受體的障礙不可能有 20 治療價值。 本發明的目的是敎這樣的心姆衍生物,即,具有作為大麻素 -CB】受體調的有效活性,同時基本保持使—些心純衍生物適用 作治療劑的物理化學性質。 C發明内容3 5 200530191 現已意外地發現了,大麻,_CBi受體的有效的拮抗作用戋逆興八 作用存在於式(I)的新型4,5_二氫咪嗤衍生物及其互變異構㈣ 體異構體,前體藥物和鹽中200530191 IX. Description of the invention: L is a well-known member of the genus Liaowuming] The present invention relates to 1,2,4-trisubstituted imidazoline derivatives as CBj # antagonists, methods for preparing these compounds, and applications A novel intermediate for synthesizing the imidazoline derivative. 5 The present invention also relates to the use of a compound disclosed herein in the manufacture of a medicament giving a beneficial effect. The beneficial effects are disclosed herein or will be apparent to those skilled in the art from the present specification and general knowledge in the field. The invention also relates to the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention of a disease or condition. More specifically, the present invention relates to new uses for the treatment of diseases or conditions disclosed herein or apparent to those skilled in the art from this specification and general knowledge in the art. In an embodiment of the invention, the specific compounds disclosed herein are used to produce a medicament that is suitable for treating disorders involving cannabinoids ((^ nnabmoid) :), or which can be treated by controlling these receptors Obstacles. L ·] | Multi-substituted imidazoline derivatives are known from WO 03/101954 and WO 03/101969. 15 The compounds described herein are potent inhibitors of the transcription factor NF-KB, making them suitable for treating certain diseases Examination of the tumor. Therefore, "Nana-derived contact has effective anti-inflammatory agents and antibiotics, leading to another indication. Among them, they may have therapeutic significance, including inflammation and transmission. Diseases. The compound described has any affinity for cannabinoids, so it is unlikely that the disorders involving these cannabinoid receptors have a therapeutic value of 20. The object of the present invention is to have such a cardiac derivative, that is, to have as a cannabinoid -CB] receptor-modulated effective activity, while basically maintaining the physicochemical properties of some pure heart derivatives suitable for use as therapeutic agents. C SUMMARY 3 5 200530191 It has now been unexpectedly discovered that cannabis, _CBi accepts Effective antagonism of the body 体 Ni Xingba The effect exists in the novel 4,5_dihydroimidium derivatives of formula (I) and their tautomeric isomers, prodrugs and salts
XX
r2 5 其中: -R^R2獨立地表示本基,π塞吩基或。比咬基,這些基可被1,2戈^ 個可能相同或不同的取代基Υ取代,取代基γ選自下組基:支化或線形 Q-r烷基或C〗·3·烷氧基,苯基,羥基,氯,溴,氟,碘,三ι甲基, 三氟甲硫基,三氟甲氧基,羧基,三氟甲磺醯,氰基,甲氨醯, 10 醯和乙醯基’或者Ri和/或R2表示萘基, -X表示亞組⑴或(ii)之一,r2 5 wherein: -R ^ R2 independently represents a radical, π-phenenyl or. These groups may be substituted by 1, 2 or 3 substituents Υ which may be the same or different, and the substituent γ is selected from the group consisting of a branched or linear Qr alkyl group or a C3 · alkoxy group, Phenyl, hydroxyl, chlorine, bromine, fluorine, iodine, trimethyl, trifluoromethylthio, trifluoromethoxy, carboxyl, trifluoromethanesulfonium, cyano, methylaminosulfonium, 10 fluorene and acetamidine Group 'or Ri and / or R2 represents naphthyl, -X represents one of subgroups ⑴ or (ii),
VR3VR3
(ί)(ί)
IIVR7 其中: -R3表示氫原子或者支化或線形Ci3烧基, 15 -1^4表示支化或線形^^·8烷基或C3·8-環烧基-C】_r烷基,支化或線形 c卜&烧氧基’ &環烷基,C5_】G雙環烷基,(^三環烷基 ,這些基可包 含一個或多個選自組(〇,N,S)的雜原子,而且這些基可被一個羥基, 個甲基,一個乙基或1-3個氟原子取代,或者^表示苯基,苯氧基,苄 200530191 ^本乙基或本丙基,在它們的笨基環上任選被_取代基Y取代, 其中Υ具有上述含義,或者_ _,射, 表_基_基,或执表示基 嶋物、子—㈣彡成―㈣有㈣個環原子的 或不飽和的、單環或雙環的雜環基,該雜環基包含-個或兩個選 .:_N,物軒,而聯物嫩物43絲,苯基, 羥土或二氟甲基或氟原子取代,或者 崎v與它們連接的氮原子_起_形成—個具有4__環原子的 10 15 20 飽和或不飽和的、單環或雙環的雜環基,該雜環基包含-個或兩個選 自組(0爛_軒,而且_縣可被支化或線形^絲,苯基, 氨基,羥基或三氟甲基或氟原子取代, 如表示«,苯基,嗟吩基或啊基,這些基在它們的芳環上 可被1,2,域4個取嫌取代,其中γ具讀述含義,它們可相同或 不同,織7表示Cl_8支化或線形燒基,C3 8鏈烯基,C31。環院基,‘ 雙城基,(:㈣三舰基似8環烯基,或者&表示萘基,或执表示 氨基,或者_祝,.8二綠氨基,c18單絲氨基或者具抑個環 肩子的飽和或不飽和的、單環或雙環的雜環基,該雜環基包含阳個 氮原子’而且該雜環基可包含一個選自組(明的雜原子,並且該雜環 基可被支化或線形C1_3絲,笨基,織或三氟?基或氟原子取代, -¾表示氫原子或曱基, -R9表示氫原子或甲基,乙基或甲氧基。 式(I)的化合物中存在至少一個手性中心(在•琳部分的^位)。 本發明既涉及式_化合物的外消補,麵映體的混合物,又涉及 式_化合物的單個立體異構體。本發明還涉及式⑴的化合物的£異 7 200530191 構體,Z異構體和E/z混合物。 前體藥物是本身無活性的但被轉化為一種或多種活性代謝物的 治療劑。前體藥物是用來克服利用母體藥物分子時某些障礙的、藥物 分子的生物可逆的衍生物。這些障礙包括但不限於,溶解度,滲透性, 5 穩定性,系統前代謝(presystemic metabolism)和尋靶的限制(Medicinal Chemistry: Principles and Practice, 1994JSBN 0-85186-494-5?Ed.: F. D. King?p. 215; J. Stella, uProdrugs as therapeutics' ,Expert Opin. Ther. Patents4(3) » 277-280,2004; P. Ettmayer et al.? "Lessons learned from marketed and investigational prodrugs ” 10 J.Med.Chem.,47,2393-2404,2004)。前體藥物,即,當通過任何已知途 徑對人給藥時被代謝為式(I)化合物的化合物,屬於本發明。特別是這 涉及具有伯氨基或仲氨基或經基的化合物。這樣的化合物可與有機酸 反應而生成式⑴化合物,其中,存在給藥後容易除去的另外的基,例 如,但不限於,脒,烯胺,曼尼希域,羥基-亞甲基衍生物,〇_(酸基 15 亞甲基氨基甲酸酯)衍生物,氨基甲酸酯,酯,醯胺或烯胺酮。 本發明尤其涉及式(I )的化合物IIVR7 where: -R3 represents a hydrogen atom or a branched or linear Ci3 alkyl group, 15 -1 ^ 4 represents a branched or linear ^^ 8 alkyl group or C3 · 8-cycloalkyl group-C] _r alkyl group, branched Or linear c & alkoxy '& cycloalkyl, C5_] G bicycloalkyl, (^ tricycloalkyl, these groups may contain one or more hetero groups selected from the group (0, N, S) Atoms, and these groups may be substituted by a hydroxyl group, a methyl group, an ethyl group, or 1-3 fluorine atoms, or ^ represents a phenyl group, a phenoxy group, or a benzyl group 200530191 ^ this ethyl group or this propyl group, The benzylic ring is optionally substituted by _ substituent Y, where Υ has the above meaning, or _ _, y, _ _ _ _, or 执 represents a radical, a sub-㈣ 彡-㈣ has ㈣ ring atoms Or unsaturated, monocyclic or bicyclic heterocyclic group, the heterocyclic group contains-one or two options .: _N, Wuxuan, and the complex tender 43 silk, phenyl, hydroxyl earth or difluoromethyl Group or fluorine atom substitution, or the nitrogen atom to which they are attached _ form _ a 10 15 20 saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4__ ring atoms, the heterocyclic group containing -One or two Self-organized (0 _ 轩, and _ can be substituted by branched or linear ^ silk, phenyl, amino, hydroxyl or trifluoromethyl or fluorine atom, such as «, phenyl, methylphenyl or ahyl, These groups can be substituted by 1, 2, and 4 domains on their aromatic rings. Among them, γ has the meaning of reading. They can be the same or different. Weave 7 represents Cl_8 branched or linear alkyl group, and C3 8 alkenyl group. , C31. Cyclopentyl, 'Shuangchengji, (: ㈣Sankenyl is like 8-cycloalkenyl, or & represents naphthyl, or exemplified represents amino, or _ Zhu, .8 digreen amino, c18 monofilament amino Or a saturated or unsaturated, monocyclic or bicyclic heterocyclic group with a ring shoulder, the heterocyclic group containing a positive nitrogen atom 'and the heterocyclic group may contain a heteroatom selected from the group ( And the heterocyclic group may be substituted by branched or linear C1_3 silk, benzyl, woven or trifluoro? Group or fluorine atom, -¾ represents a hydrogen atom or a fluorenyl group, -R9 represents a hydrogen atom or a methyl group, an ethyl group or a methyl group There is at least one chiral center in the compound of formula (I) (the ^ position at the Lynn part). The present invention relates to the external complementation of compounds of formula The compound also relates to a single stereoisomer of the compound of formula _. The present invention also relates to the isomer of the compound of formula VII 200530191, the Z isomer, and the E / z mixture. Prodrugs are themselves inactive but are not Therapeutic agents that are converted into one or more active metabolites. Prodrugs are bioreversible derivatives of drug molecules that overcome certain obstacles in the use of the parent drug molecule. These obstacles include, but are not limited to, solubility, permeability, 5 Stability, presystemic metabolism and restriction of targeting (Medicinal Chemistry: Principles and Practice, 1994JSBN 0-85186-494-5? Ed .: FD King? P. 215; J. Stella, uProdrugs as therapeutics ', Expert Opin. Ther. Patents 4 (3) »277-280,2004; P. Ettmayer et al.? &Quot; Lessons learned from marketed and investigational prodrugs'' 10 J. Med. Chem., 47, 2393-2404, 2004 ). Prodrugs, i.e. compounds that are metabolized to a compound of formula (I) when administered to a human by any known route, belong to the present invention. In particular, this relates to compounds having primary or secondary amino groups or vias. Such a compound can react with an organic acid to form a compound of formula (I), in which there are additional groups that can be easily removed after administration, such as, but not limited to, amidine, enamine, Mannich domain, hydroxy-methylene derivative 0- (acid 15 methylene carbamate) derivatives, carbamates, esters, amidines or enaminones. The invention relates in particular to compounds of formula (I)
r2 (|) 其中: •R〗和獨立地表示苯基,該苯基可被1,2或3個可能相同或不同 20的取代基Y取代,取代基Y選自下組基:支化或線形烷基或C!-3-烷 氧基’笨基,羥基,氯,溴,氟,碘,三氟甲基,三氟曱硫基,三氟 200530191 曱氧基,羧基,三氟曱磺醯,氰基,甲氨醯,氨磺醯和乙醯基,或者 R】和/或R〗表示萘基,售吩基或吼咬基,r2 (|) where: R and independently represent a phenyl group, which may be substituted by 1, 2 or 3 substituents Y which may be the same or different from 20, and the substituent Y is selected from the group consisting of: branched or Linear alkyl or C! -3-alkoxy 'benzyl, hydroxyl, chlorine, bromine, fluorine, iodine, trifluoromethyl, trifluorosulfanylthio, trifluoro200530191 fluorenyloxy, carboxyl, trifluorosulfanyl Fluorene, cyano, methylaminosulfonium, sulfamidine, and ethynyl, or R] and / or R] represents a naphthyl group, a phenoxy group, or a sulfonyl group,
-X表示亞組(i)或⑻之一 X /R3 (i)-X represents one of subgroups (i) or ⑻ X / R3 (i)
5 其中: -R3表示氫原子, -¾表不支化或線形Cm烧基,支化或線形C"烧氧基或Cw環燒 基,這些基可被-個經基,W個甲基,一個乙基或μ3個氣原子取代, 或者R4表不苯基,笨氧基,吼咬基或嗟吩基,或者仏表示細队, 10 其中, r5和心與它們連接的氮原子一起-形成一個具有4-1〇個環原子的 飽和或不飽和的、單環或雙環的雜環基,該雜環基包含—個或兩個選 自組(0,N,S)的雜原子,或者 15 3和它們連接的氮原子一起形成一個具朴職環原子的 飽和或不飽和的、單環或雙環_環基,_環基包含_個或兩個選 自組(〇,N,S)的雜原子,而且該雜環基可被甲基,經基或三氟 原子取代, / ,而表示苯基’該苯基在它的芳環上糊,2,3或4個取代基丫取 二含義’它們可相同或不同’或者〜表示Ci-8支化或 —'Μ 基或k。雙魏基,或者R7絲萘基,或者化表 不減’或者R7表祝,·8:峨基,^歲基氨基或具有4⑼個環 20 200530191 原子的飽和或不飽和的、單 ...^ 又㈣騎基,_縣包含〗或2個 虱原子,而且該雜環基可包含 固 # m 込目組(〇,S)的雜原子,並且該雜严 基可被支化或線形c成基或經基取代, 雜衣 -¾表示氫原子, 5 10 15 -¾表示氫原子, 及其互變異構體、立體異構體、前«物和鹽。 '有賴⑶点抗雜,本發_化合物_於絲精神病學 _’例如精神病,焦慮勢注意缺陷,一^ 食愁障礙’轉症,_是解肥胖症和藥物引起的肥胖症,癖嗜, 衝動控制障礙’肉慾,藥物依賴性和神經障礙例如神經變性障礙,癡 呆’張力障礙’肌肉強直’震顫’癲癇’多發性硬化,外傷性腦損傷, 中風’帕金森病,早老性癡呆,_,亨廷頓舞蹈病,圖雷特综合微, 腦缺血’大腦卒中,顱腦創傷,中風,脊髓損傷,神經紐障礙"蜜 斑硬化’病毒性職’脫_相_障礙,以及胁治療疼痛障礙, 包括神經雜疼猶礙,還有涉及A麻素神經傳遞的其他疾病,包括 下列疾病的治療:敗血症性休克,青光眼,癌症,糖尿病,唱吐,嚼 心’哮喘,呼吸疾病,胃腸障礙’胃潰瘍,腹濕,心血管障礙,動脈 粥樣硬化,肝硬變和性障礙。 本發明的化合物的大麻素受體調節活性使它們在與脂肪酶抑制 2〇劑結合使㈣制_於治療肥胖症、幼年肥胖症和藥剌起的肥胖 症。可用於這種結合製劑的化合物的具體實例是(但不限於)合成脂肪 酶抑制劑奥利司他(orlistat),從微生物分離的脂肪酶抑制劑,例如裏卜 斯他丁(lipstatin)[得自#三麵/紐阶 免疫®1 B(ebelact〇ne B)[得自哿爷在鏈黴磨伽寧㈣⑽ 10 200530191 ,這些化合物的合成衍生物,以及已知具有脂肪酶抑制 活性的植物提取物,例如良薑(Alpinia officinarum)的提取物或者從這 樣的提取物分離的化合物,例如3-甲基醚高良薑精(得自良薑)。 合成的一般方面 5 圖解1中概述了其中X表示亞組(i)的式(I)化合物的合成。通式(Π) 的中間體可根據已知方法獲得,參見例如:I. K. Khanna et al.5J. Med.5 Among them: -R3 represents a hydrogen atom, -¾ represents a branched or linear Cm alkyl group, a branched or linear C " oxyl group or a Cw cycloalkyl group, and these groups can be substituted by a methyl group, W methyl groups, and Ethyl or μ3 gas atoms are substituted, or R4 represents phenyl, benzyloxy, cyno or phenphenyl, or 仏 represents a line, 10 where R5 and the heart are together with the nitrogen atom to which they are attached-forming one A saturated or unsaturated, monocyclic or bicyclic heterocyclic group having 4 to 10 ring atoms, the heterocyclic group containing one or two heteroatoms selected from the group (0, N, S), or 15 3 and the nitrogen atom to which they are attached form a saturated or unsaturated, monocyclic or bicyclic cyclic group with a simple ring atom, the cyclic group contains _ or two selected from the group (0, N, S) A heteroatom, and the heterocyclic group may be substituted by a methyl group, a group or a trifluoro atom, /, and represents a phenyl group. The phenyl group is pasted on its aromatic ring. Two, three or four substituents are selected. Meaning 'they may be the same or different' or ~ means Ci-8 branched or-'M group or k. Bisweilyl, or R7 silk naphthyl, or the chemical formula is not diminished, or R7 means, · 8: eryl, ^ aryl amino or a saturated or unsaturated, single, ... ^ Also cyclyl, _x contains two or two lice atoms, and the heterocyclyl may contain a solid atom of the solid group (0, S), and the heteroacyl group may be branched or linear c Formed or substituted by a group, heterodrug -¾ represents a hydrogen atom, 5 10 15 -¾ represents a hydrogen atom, and tautomers, stereoisomers, precursors and salts thereof. 'Relying on anti-miscellaneous, this issue _ compound _ Yu silk psychiatry _' such as psychosis, anxiety, attention deficit, ^ anxiety disorder 'transition, _ is an anti-obesity and drug-induced obesity, addiction, Impulse control disorders' carnal, drug-dependent and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle rigidity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, _, Huntington's disease, Tourette Syndrome, Cerebral ischemia, 'Cerebrostroke, Craniocerebral trauma, Stroke, Spinal cord injury, Neurokinetic disorders' " Variation of plaques, Viral function, Disorders and disorders, and treatment of pain disorders , Including neuropathic pain, and other diseases involving neurotransmission of Amaxin, including the treatment of the following diseases: septic shock, glaucoma, cancer, diabetes, vomiting, chewing heart 'asthma, respiratory disease, gastrointestinal disorders' Gastric ulcers, abdominal wetness, cardiovascular disorders, atherosclerosis, cirrhosis and sexual disorders. The compounds of the present invention have a cannabinoid receptor-modulating activity so that they can be combined with lipase inhibitory agents to suppress the treatment of obesity, juvenile obesity, and drug-induced obesity. Specific examples of compounds that can be used in such combination preparations are, but are not limited to, synthetic lipase inhibitors orlistat, lipase inhibitors isolated from microorganisms, such as lipstatin [available From # 三 面 / 新 级 immunity® 1 B (ebelact〇ne B) [obtained from Ye Ye in Streptomyces moganin 10 200530191, synthetic derivatives of these compounds, and plant extracts known to have lipase inhibitory activity A substance such as an extract of Alpinia officinarum or a compound isolated from such an extract, such as 3-methyl ether galangal extract (obtained from Alpinia officinalis). General aspects of synthesis 5 The synthesis of compounds of formula (I) where X represents subgroup (i) is outlined in Scheme 1. Intermediates of general formula (Π) can be obtained according to known methods, see for example: I. K. Khanna et al. 5J. Med.
Chem· 2000,43,3168-3185; Ι· K. Khanna et al”J. Med· Chem. 1997,40,1634·1647; WO 03/027076或WO 03/040107。通式(IV)的中間體 可根據已知方法獲得’參見例如:Ι· K. Khanna et al.,J. Med. Chem. 10 2000,43,3168-3185。 可將通式(Π)的甲脒化合物與2·氯丙烯腈反應而給出通式(IV) 的4,5-二氫-1H-味唑衍生物。該反應優選在域例如n,N_:異丙基乙胺存 在下進行。可用醇R1(r〇H酯化獲得的通式(iv)的衍生物而給出通式(v) 的4,5-二氫-1H-咪唑衍生物,其中,Rl〇表示支化或線烷基或苄 15基。該反應優選在酸性條件下進行。可將通式(v)的化合物與胺 R3R4NH優選在三甲基鋁(ΜαΑ1)存在下反應,給出式(j )的化合物,其 中,X表示亞組⑴,而且^和^具有前文第2頁上給出的含義。關於三 曱基鋁A1(CHS)3促進的酯的醯胺化反應的更多資訊可見於:J ;[丄evin,E.Chem. 2000, 43, 3168-3185; I. K. Khanna et al "J. Med. Chem. 1997, 40, 1634 · 1647; WO 03/027076 or WO 03/040107. Intermediates of general formula (IV) Available according to known methods' See, for example: I. K. Khanna et al., J. Med. Chem. 10 2000, 43, 3168-3185. Formamidine compounds of general formula (Π) can be combined with 2.chloropropene The nitrile reaction gives a 4,5-dihydro-1H-imidazole derivative of the general formula (IV). The reaction is preferably carried out in the presence of a domain such as n, N_: isopropylethylamine. The alcohol R1 (r. The derivative of the general formula (iv) obtained by H esterification gives a 4,5-dihydro-1H-imidazole derivative of the general formula (v), wherein R10 represents a branched or linear alkyl group or a benzyl 15 group The reaction is preferably performed under acidic conditions. The compound of general formula (v) can be reacted with the amine R3R4NH, preferably in the presence of trimethylaluminum (MαA1), to give a compound of formula (j), where X represents a subgroup ⑴, and ^ and ^ have the meanings given above on page 2. More information on the hydrazone amination reaction of esters promoted by trisaluminum aluminum A1 (CHS) 3 can be found in: J; [丄 evin, E.
Turos,S.M· Weinreb,5>—C漏m亂(1982),72,989-993。 20 備遥地,可將通式(V)的化合物水解成相應的通式(VI)的羧酸衍 生物’其中’:^表利或鹼土金屬,特別是Li、Na^。也可將通式㈤ 的化口物與氣化試翻如亞硫醯氯反應而給出相應祕氯。可將通式 (VI)的化合物與胺RshNH反應而給出式(1)的化合物,其中,χ表示亞 組⑴,而且Rs和比具有前文第2頁上給出的含義,即,通過活化和偶聯 200530191 方法,例如活性酯的形成,或者在所謂的偶聯劑例如DCC、HBTU、 BOP(苯並三唑-1-基氧基三(二甲氨基)六氟磷酸鱗)等存在下。關於胺與 羧酸的活化和偶聯方法的更多資訊可見於·· a)M.Bodanszky and A.Bodanszky : The Practice of Peptide 5 办扣,Springer-Verlag,New York,1994; ISBN: 0-387-57505-7 ; b)K.AkdL]i et aL,Tetrahedron Lett.(\99A) » 35,3315-3318); c)F.Albericioeia/.,7>ira/ze(iiFW2Z^".(1997),38,4853·4856)。Turos, S.M. Weinreb, 5 > —C Leakage and Chaos (1982), 72,989-993. 20 In a remote place, a compound of the general formula (V) can be hydrolyzed to the corresponding carboxylic acid derivative of the general formula (VI) 'wherein': ^ Table Lee or alkaline earth metals, especially Li, Na ^. It is also possible to react a chemical substance of the general formula ㈤ with a gasification test such as thionyl chloride to give the corresponding secret chlorine. A compound of formula (VI) can be reacted with an amine RshNH to give a compound of formula (1), where χ represents the subgroup ⑴, and Rs and ratio have the meanings given on page 2 above, that is, by activation And coupling 200530191 methods, such as the formation of active esters, or in the presence of so-called coupling agents such as DCC, HBTU, BOP (benzotriazol-1-yloxytris (dimethylamino) hexafluorophosphate scale) and the like . More information on the activation and coupling methods of amines and carboxylic acids can be found in a) M. Bodanszky and A. Bodanszky: The Practice of Peptide 5, Springer-Verlag, New York, 1994; ISBN: 0- 387-57505-7; b) K. AkdL] i et aL, Tetrahedron Lett. (\ 99A) »35,3315-3318); c) F.Albericioeia /., 7 > ira / ze (iiFW2Z ^ ". (1997), 38,4853-4856).
(CH3)aAI / R3R4NH(CH3) aAI / R3R4NH
(V)(V)
其中X表示亞組(i)Where X represents the subgroup (i)
圖解1 10 圖解2概述了其中X表示亞組⑻的式(I)化合物的合成。 通式R7S〇2NH2的中間體是可商購的或者可通過標準合成方 法,例如從相應的化合物R7S〇2Cl製備(參見例如McMmius et al.,J. Med. Chem· 1965,8/766)。可將通式(IV)的化合物與通式邮〇2皿2的化合物 在路易士酸例如AlMes存在下在惰性有機溶劑例如苯中反應而給出通 15式(1)的化合物,其中,X表示亞組⑴),而且1^,112和117具有前文第1〜 3頁上給出的含義,而且其中R8和A表示氫原子。可將通式(v)的化合 物與通式RySC^NH2的化合物反應而給出通式(V[[)的化合物。該反應優 12 200530191 選在強的非親驗猶在下進行。可㈣細)的化合物與氣化劑在 氣醒亞胺化反應中反應,隨後驗哪顺處理而給出式⑴的化合 物,其中,X表示亞組(U)。Scheme 1 10 Scheme 2 outlines the synthesis of compounds of formula (I) where X represents the subgroup VII. Intermediates of the general formula R7SO2NH2 are commercially available or can be prepared by standard synthetic methods, for example from the corresponding compound R7SO2Cl (see, for example, McMmius et al., J. Med. Chem. 1965, 8/766). A compound of the general formula (IV) can be reacted with a compound of the general formula 0022 in the presence of a Lewis acid such as AlMes in an inert organic solvent such as benzene to give a compound of formula (1), where X Represents a subgroup ⑴), and 1 ^, 112, and 117 have the meanings given on pages 1 to 3 above, and wherein R8 and A represent a hydrogen atom. A compound of the general formula (v) can be reacted with a compound of the general formula RySC ^ NH2 to give a compound of the general formula (V [[). The reaction was excellent. 12 200530191 Election was performed under strong non-parent test. Compounds that can be refined) are reacted with a gasification agent in an awake imidization reaction, and then tested by cis-treatment to give compounds of the formula (I), where X represents a subgroup (U).
(I) 其中X表示亞組(ii) 其中1¾和R9表示}1(I) where X represents a subgroup (ii) where 1¾ and R9 represent} 1
υ氣酰亞胺化。 2) R8RbNHυ gas imidization. 2) R8RbNH
(I) 其中X表示亞組 圖解2 疋成方法的選擇取決於這樣的因素,例如官能團與應用的 。式月J的相谷性’應用保護基、催化劑、活化和偶聯劑的可能性,以及 製備的最終化合物中存在的最終結構特徵。 根據這些方法,可製備下列化合物。它們旨在進-步更詳細闡述 10本發明’所以不應被視為以任何方式限制本發明的範圍。 藥物製劑 可通過常規方法利用輔助物質例如液態或固態載體物質將本發 明的化合物製成適合給藥的形式。可經腸、經口、腸胃外(肌内或靜脈 内)、經直腸絲部給予本發明的藥學組成物。可呈溶液、粉末、片、 15膠囊(包括微膠囊)、軟膏(乳膏或凝膠)或检劑的形式將它們給藥。用於 這類製劑的合適的賦形劑是藥物上的常規液態或固態填充劑和增量 劑、溶劑、乳化劑、潤滑劑、調味劑、著色劑和/或緩衝物質。可提到 的常用輔助物質有碳酸鎮、二氧化鈦、乳糖、甘露糖醇和其他糖,滑 13 200530191 石、乳蛋白、_、麟、纖維素及其衍生物,動物油和植物油,例 如魚肝油、葵花油、花生油或芝麻油,聚乙二醇和溶劑,例如無菌水 和一元醇或多元醇,例如甘油。 本發明的化合物通常作為藥學組成物給藥,它們是本發明重要的 5和新的實施方案,這是由於所述化合物、更具體地說本文公開的特定 化合物的存在。可應用的藥學組成物類型包括但不限於:片劑、咀嚼 • 片、膠囊、溶液、腸胃外溶液、栓劑、懸浮液和本文公開的或者本領 . 域技術人員從本說明書和本領域一般知識顯而易見的其他類型。在本 .發明的實施方案中,提供了包括一個或多個容器的藥物包或試劑盒, 10所述容為中裝填了本發明藥學組成物的組分中的一個或多個。與這樣 的容态相關的可以是各種書面材料,例如使用說明,或是呈管理藥品 生產、使用或銷售的政府機構規定的形式的注意事項,這些注意事項 反映了政府機構關於人或獸醫給藥的生產、使用或銷售的許可。 藥理方法 15 對大麻素-CB!受體的體外親合性 _ 可利用中國倉鼠卵巢(CHO)細胞的膜製品測定本發明的化合物 對大麻素CB〗受體的親合性,在所述細胞中穩定地轉染了人大麻素CBi 受體連同作為放射性配體的[3H]CP_55,94〇。將新鮮製備的細胞膜製品 與[3H]配體一起在添加或沒有添加本發明的化合物的情況下保溫後, 20通過在玻璃纖維濾器上過濾而分離結合的和游離的配體。通過液體閃 爍計數測定了濾器上的放射性。 體外大麻素-CB!受體拮抗作用 可應用克隆在中國倉鼠卵巢(CH〇)細胞中的人CB】受體估測體外 CB]受體拮抗作用。使CH〇細胞在添加了 1〇%熱滅活的胎牛血清的 14 200530191(I) where X represents a subgroup. Scheme 2 The choice of the formation method depends on such factors as the functional group and the application. Phase Valley of Formula J 'The possibility of applying protecting groups, catalysts, activation and coupling agents, and the final structural features present in the final compounds prepared. According to these methods, the following compounds can be prepared. They are intended to further elaborate the invention ' so they should not be seen as limiting the scope of the invention in any way. Pharmaceutical formulations The compounds of the present invention can be made into a form suitable for administration using auxiliary substances such as liquid or solid carrier substances by conventional methods. The pharmaceutical composition of the present invention can be administered enterally, orally, parenterally (intramuscularly or intravenously), or transrectally. They can be administered in the form of solutions, powders, tablets, 15 capsules (including microcapsules), ointments (creams or gels) or test agents. Suitable excipients for such formulations are conventional liquid or solid fillers and extenders, solvents, emulsifiers, lubricants, flavoring agents, coloring agents and / or buffering substances for pharmaceutical use. Common auxiliary substances that can be mentioned are carbonates, titanium dioxide, lactose, mannitol and other sugars, slip 13 200530191 stone, milk protein, cellulose, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, Peanut or sesame oil, polyethylene glycol and solvents such as sterile water and mono- or polyhydric alcohols such as glycerol. The compounds of the present invention are generally administered as pharmaceutical compositions, which are important 5 and new embodiments of the present invention due to the presence of said compounds, and more particularly the specific compounds disclosed herein. The types of pharmaceutical compositions that can be applied include, but are not limited to: tablets, chewable tablets, capsules, solutions, parenteral solutions, suppositories, suspensions, and those disclosed herein or in the art. It will be apparent to those skilled in the art from this description and general knowledge in the art Other types. In an embodiment of the present invention, a pharmaceutical pack or kit comprising one or more containers is provided, said container being filled with one or more of the components of the pharmaceutical composition of the present invention. Associated with such a state may be various written materials, such as instructions for use, or precautions in the form prescribed by government agencies that regulate the production, use, or sale of pharmaceuticals, and these precautions reflect government agencies regarding human or veterinary administration License to produce, use or sell. Pharmacological method 15 In vitro affinity for cannabinoid-CB! Receptor _ The affinity of the compound of the present invention for the cannabinoid CB receptor can be determined using a membrane product of Chinese hamster ovary (CHO) cells, in said cells The human cannabinoid CBi receptor was stably transfected with [3H] CP_55,94. After the freshly prepared cell membrane preparation was incubated with [3H] ligand with or without the compound of the present invention, 20 the bound and free ligands were separated by filtration on a glass fiber filter. Radioactivity on the filter was determined by a liquid flicker count. Cannabinoid-CB! Receptor antagonism in vitro Human CB] receptors cloned in Chinese hamster ovary (CH0) cells can be used to estimate CB] receptor antagonism in vitro. CH 0 cells were incubated with 10% heat-inactivated fetal calf serum 14 200530191
Dulbecco’ s Modified Eagle’ s medium(DMEM)培養基中生長。將培養 基抽出和用不含胎牛血清但包含[3H]-花生四烯酸的DMEM置換,在細 胞培養溫室(5%CCV95%空氣;37°C ;水飽和的氣氛)中培養一夜。在 此期間,將[3H]-花生四烯酸摻入膜磷脂中。在試驗日,將培養基抽出, 5 用〇_5 ml含有0.2%牛血清白蛋白(BSA)的DMEM將細胞洗滌三次。用 WIN 55,212-2刺激CBA體導致PLA2的活化,隨後將[3H]_花生四稀酸 釋放入培養基。該WIN 55,212-2-誘導的釋放被CB〗受體拮抗劑依賴於 濃度地拮抗。It was grown in Dulbecco's Modified Eagle's medium (DMEM) medium. The culture medium was drawn out and replaced with DMEM without fetal bovine serum but containing [3H] -arachidonic acid, and cultured overnight in a cell culture greenhouse (5% CCV 95% air; 37 ° C; water-saturated atmosphere). During this time, [3H] -arachidonic acid was incorporated into the membrane phospholipid. On the test day, the medium was withdrawn and the cells were washed three times with 0-5 ml of DMEM containing 0.2% bovine serum albumin (BSA). Stimulation of the CBA body with WIN 55,212-2 resulted in the activation of PLA2 followed by the release of [3H] _arachidonic acid into the culture medium. This WIN 55,212-2-induced release is antagonized by the CB receptor antagonist in a concentration-dependent manner.
體内大麻素-CB!受體拮抗作用 10 體内CB!拮抗作用可利用在大鼠中CP-55,940-誘導的低血壓試驗 來估測。用戊巴比妥(80 mg/kg篪廯巧)麻醉雄性血壓正常的大鼠 (225-300 g ; Harlan,Horst,The Netherlands)。通過Spectramed DTX-plus 壓力感測器(Spectramed B.V·,Bilthoven,The Netherlands),經由插入左 頸動脈的插管測定了血壓。通過Nihon Kohden Carrier Amplifier (Type 15 AP-621G; Mhon Kohden B.V·,Amsterdam,The Netherlands)放大後,利 用Po-Ne-Mah資訊-獲取程式(P〇-Ne-Mah Inc·,Storrs,USA)在個人電腦 (Compaq Deskpro 386s)上記錄了血壓信號。從脈動壓力信號推導了心 率。所有化合物都在引起麻醉前30分鐘以1%曱基纖維素中的微懸浮液 的形式經口給予,它比給予CB〗受體興奮劑CP-55,940早60分鐘。注射 20 量是l〇ml/kg。血液動力學穩定化以後,給予CB丨受體興奮劑CP-55,940 (0.1 mg/kg#廉冷)而產生低血壓效果。(Wagner,J. A· ; Jarai,Z. ; Batkai, S. ; Kunos, G.Hemodynamic effects of cannabinoidsxoronary and cerebral vasodilation mediated by cannabinoid CB] receptors. Eur.J.Pharmacol 2001 203-10)。 15 200530191 藥物上可接文的鹽可利用本領域熟知的標準方法獲得,例如通過 將本發明的化合物與合適,例如無鑛,如_,或者與有機酸 混合。 劑量 5 如上述測定了本發明的化合物對大麻素受體的親合性。從關於一 個給疋的式(1)化合物測定的結合親合性,人們可估測理論最低有效劑 買。在等於兩倍測定的κΓ值的化合物濃度下,100%大麻素受體很可 能將被化合物佔用。假定理想的生物利用率,將該濃度轉化為化合 物/kg患者產生理論最低有效劑量。藥代動力學的、藥效學的和其他考 10慮因素可將實際給予的劑量改變為更高或更低的值。給予的適當劑量 是0.001-1000 mg/kg,優選是0.1-100 mg/kg患者體重。Cannabinoid-CB! Receptor Antagonism in vivo 10 CB! Antagonism in vivo can be estimated using a CP-55,940-induced hypotension test in rats. Normally blood pressure male rats (225-300 g; Harlan, Horst, The Netherlands) were anesthetized with pentobarbital (80 mg / kg). Blood pressure was measured by a Spectramed DTX-plus pressure sensor (Spectramed B.V., Bilthoven, The Netherlands) via a cannula inserted into the left carotid artery. After zooming in by Nihon Kohden Carrier Amplifier (Type 15 AP-621G; Mhon Kohden BV ·, Amsterdam, The Netherlands), use the Po-Ne-Mah information-acquisition program (P〇-Ne-Mah Inc ·, Storrs, USA) in Blood pressure signals were recorded on a personal computer (Compaq Deskpro 386s). Heart rate is derived from the pulsating pressure signal. All compounds were administered orally 30 minutes before inducing anesthesia in the form of a microsuspension in 1% amidine cellulose, which was 60 minutes earlier than the administration of CB receptor stimulant CP-55,940. The injection volume was 10 ml / kg. After hemodynamic stabilization, the CB 丨 receptor stimulant CP-55,940 (0.1 mg / kg # inexpensive cold) was administered to produce a hypotensive effect. (Wagner, J. A .; Jarai, Z .; Batkai, S .; Kunos, G. Hemodynamic effects of cannabinoids xoronary and cerebral vasodilation mediated by cannabinoid CB] receptors. Eur. J. Pharmacol 2001 203-10). 15 200530191 Pharmaceutically acceptable salts can be obtained using standard methods well known in the art, for example, by mixing a compound of the invention with a suitable, such as non-mineral, such as, or with an organic acid. Dose 5 The affinity of the compound of the invention for the cannabinoid receptor was determined as described above. From the binding affinity determined for a given compound of formula (1), one can estimate the theoretically least effective agent to buy. At a compound concentration equal to twice the measured κΓ value, a 100% cannabinoid receptor is likely to be occupied by the compound. Assuming ideal bioavailability, converting this concentration to a compound / kg patient results in a theoretically lowest effective dose. Pharmacokinetic, pharmacodynamic, and other considerations can change the actual dose administered to higher or lower values. A suitable dose is 0.001 to 1000 mg / kg, preferably 0.1 to 100 mg / kg of the patient's body weight.
【賞 U 實施例1 :特定的化合物的合成 化合物1-2 15 些分:將叫4·氣苯基)_2,4_二氣苯曱脒(1〇.〇克,0.033 mol),2- 氣丙烯腈(5.7克,0.065 mol)和N,N-二異丙基乙胺(DIPEA)(12.5 ml,0.069 mol)在四氫呋喃(150 ml)中的磁力攪拌混合物在回流溫度下加熱4〇小 時(N2氣氛)。冷卻到室溫後將混合物真空濃縮。將殘餘物溶於二氣曱 烷和水(200 ml/200 ml)的混合物中。收集二氣曱烷層,在MgS04上乾 20 燥,過濾後真空濃縮。將殘餘物從乙醇/水中重結晶而給出1-(4-氣苯 基)-2-(2,4-二氣苯基)-4,5·二氫-1H-味唑冰曱腈(11.23克,97%產率)。 WNMRGOO MHz,CDC13) : δ 4.28(dd,J = 10和8 Hz,1H),4.36(t,J = 1〇 Ηζ,1Η),5.07(dd,J = 10和8 Ηζ,ΙΗ),6.68(br d,J = 8 Hz,2H),7.16(br d,卜 8Hz,2H),7.32-7.36(m,2H),7.45(d,J = 8Hz,lH)。 16 200530191 越这·將乙酿氣(n·76 ml,〇·25 mol)緩慢地加到乙醇(1 D中而給 出溶液A。將1-(4'氣笨基>2_(2,4_二氣苯基米吐冰甲猜 (17·52克’ 0.05 md)-次性加到溶液a中。冷卻到室溫後將混合物又擾 拌4〇小時,真空濃縮。將殘餘物溶於二氣甲烷,用含水(5%)NaHC03 5洗務(3x)。刀離一氣曱烧層,在MgS〇4上乾燥,過遽後真空濃縮而給 出1-(4·氯苯基)-2-(2,4_二氣苯基緩酸乙西旨(18 〇 克,90%產率),為棕色油,它在靜置時緩慢地固化。1h_nmr(4〇〇 MHz,CDC13) : δ 1.34(U = 7 Hz,3H),4.15(dcU = 10和8 Ηζ,ΙΗ), 4·22·4·41(ιή,3Η) ’ 4.91(dd,J = 10和8 Ηζ,ΙΗ),祕扣 d,J = 8 Hz,2H), 10 7.11(brd,J = 8Hz,2H),7.30(d(U = 8和2Hz,lH),7.33(d,J = 2Hz,lH), 7.46(dd,J = 8 Hz,lH)。 —^ •向外型氨基雙環[2·2·1]庚烷(0.67 ml,0.009 mol)在無水 二氣曱烷(10 ml)中的磁力攪拌溶液中添加三曱基鋁(5 4 ml的2N己烷溶 液,0.0108 mol) ’在室溫下將所得溶液擾拌2〇分鐘。緩慢地添加丨普 15氣苯基)·2-(2,4-二氣苯基)-4,5-二氫]私咪唾-4-魏酸乙醋(2.385 g,0.006 mol)在無水二氯曱烷(1〇 mi)中的溶液,使形成的混合物在4〇〇c下反應 40小時(N2氣氛)。冷卻到室溫後,用含水(5%) NaHC〇3猝滅混合物並 用一氣曱烧萃取。分離二氯甲烷層,在MgS〇4上乾燥,過濾後真空濃 縮而給出粗的黃色漿料(2.58克),用急驟色譜法(矽膠,乙酸乙酯/石油 20醚=8/2(v/v))將它進一步純化而給出更迅速移動的丨并氯苯基)_2·(2,4_ 二氣苯基)-Ν-(外型-2-雙環[2·2·1]庚基)-4,5_二氫_1凡味唑·4·曱醯胺(非 對映體Α)(0.70克,25%產率)和更緩慢移動的丨并氣笨基)冬(2,4-二氣 苯基)-Ν-(外型-2-雙環[2.2.1]庚基>4,5-二氫-1Η-味唑*4-甲醯胺(非對映 體Β)(0·69克,25%產率)。 17 200530191 非對映體A : W-NMRGOO MHz,CDC13) : δ l.l(M.58(m,7H), 1.76-1.84 (m,lH),2·26-2·30(ιή52Η),3.74-3.82(m,lH),4.27(d,J 〜10 Hz,2H),4.78(tJ 〜l〇 Hz,1H),6.65(br dj = 8 Hz,2H),6.70-6.78(m,lH), 7.12(br d,J = 8 Hz,2H),7.29(br s,2H),7.40(br s,lH)。 非對映體B : h-NMRGOO MHz,CDC13) : δ U0-1.56(m,7H), 1.78-1.85 (m,lH) ’ 2.17-2.20(m,lH) ’ 2.26-2.30(m,lH),3.76-3.82 (m,lH), 4.25- 4.30(m,2H) ’ 4.78(dd,J = 10和8 Hz,lH),6.66(br d,J = 8 Hz,2H), 6.80(br d,J 〜7 Hz,lH),7.11(br d,J = 8 Hz,2H),7.30(br s,2H),7.41(br s,lH)。[U U Example 1: Synthesis of Specific Compounds Compounds 1-2 15 Some points: will be called 4-gas phenyl) _2,4-digas phenylhydrazone (10.0 g, 0.033 mol), 2- The magnetically stirred mixture of gas acrylonitrile (5.7 g, 0.065 mol) and N, N-diisopropylethylamine (DIPEA) (12.5 ml, 0.069 mol) in tetrahydrofuran (150 ml) was heated at reflux temperature for 40 hours. (N2 atmosphere). After cooling to room temperature, the mixture was concentrated in vacuo. The residue was dissolved in a mixture of dioxane and water (200 ml / 200 ml). The dioxane layer was collected, dried over MgS04, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol / water to give 1- (4-fluorophenyl) -2- (2,4-difluorophenyl) -4,5 · dihydro-1H-amidazole melamine nitrile ( 11.23 g, 97% yield). WNMRGOO MHz, CDC13): δ 4.28 (dd, J = 10 and 8 Hz, 1H), 4.36 (t, J = 1〇Ηζ, 1Η), 5.07 (dd, J = 10 and 8 Ηζ, 1Η), 6.68 ( br d, J = 8 Hz, 2H), 7.16 (br d, Bu 8Hz, 2H), 7.32-7.36 (m, 2H), 7.45 (d, J = 8Hz, 1H). 16 200530191 Kyoto · Slowly add ethyl alcohol gas (n · 76 ml, 0.25 mol) to ethanol (1 D to give solution A. Add 1- (4'air-benzyl group> 2_ (2, 4-Diphenylphenylmethyl methotine (17.52 g '0.05 md)-added once to solution a. After cooling to room temperature, the mixture was stirred for another 40 hours and concentrated in vacuo. The residue was dissolved in Wash (3x) with dichloromethane in water (5%) NaHC03 5. Cut off the sintered layer, dry over MgS04, and concentrate under vacuum to give 1- (4-chlorophenyl). -2- (2,4-Difluorophenyl tartaric acid ethyl ester (180 g, 90% yield)) is a brown oil, which solidifies slowly upon standing. 1h_nmr (400 MHz, CDC13) : δ 1.34 (U = 7 Hz, 3H), 4.15 (dcU = 10 and 8 Ηζ, ΙΗ), 4.22 · 4 · 41 (ιή, 3Η) '4.91 (dd, J = 10 and 8 Ηζ, ΙΗ) , Secret button d, J = 8 Hz, 2H), 10 7.11 (brd, J = 8Hz, 2H), 7.30 (d (U = 8 and 2Hz, lH), 7.33 (d, J = 2Hz, lH), 7.46 (dd, J = 8 Hz, lH). — ^ • Magnetic stirring solution of outward aminobicyclo [2 · 2 · 1] heptane (0.67 ml, 0.009 mol) in anhydrous dioxane (10 ml) Add trimethyl aluminum (54 ml of 2N hexane Solution, 0.0108 mol) 'Stir the resulting solution for 20 minutes at room temperature. Slowly add 15-phenyl) -2- (2,4-diphenylphenyl) -4,5-dihydro] A solution of Ethyl sialo-4-weilate (2.385 g, 0.006 mol) in anhydrous dichloromethane (10 mi), the resulting mixture was reacted at 400 c for 40 hours (N 2 atmosphere). After cooling to room temperature, the mixture was quenched with aqueous (5%) NaHC03 and extracted with a gas burner. The dichloromethane layer was separated, dried over MgS04, filtered and concentrated in vacuo to give a crude yellow slurry ( 2.58 g), which was further purified by flash chromatography (silica gel, ethyl acetate / petroleum 20 ether = 8/2 (v / v)) to give a more rapidly moving chlorochlorophenyl) _2 · (2, 4-diphenylphenyl) -N- (exo-2-bicyclo [2 · 2 · 1] heptyl) -4,5_dihydro_1fanweizol · 4 · amine (diastereomer A ) (0.70 g, 25% yield) and slower moving Benzenebenzyl) winter (2,4-dioxophenyl) -N- (exo-2-bicyclo [2.2.1] heptyl> ; 4,5-dihydro-1fluorene-amidazole * 4-formamidine (diastereomer B) (0.69 g, 25% yield). 17 200530191 Diastereomer A: W-NMRGOO MHz, CDC13): δ ll (M.58 (m, 7H), 1.76- 1.84 (m, lH), 2.26-2.30 (ιή 52Η), 3.74-3.82 (m, lH), 4.27 (d, J ~ 10 Hz, 2H), 4.78 (tJ ~ 10Hz, 1H), 6.65 (br dj = 8 Hz, 2H), 6.70-6.78 (m, lH), 7.12 (br d, J = 8 Hz, 2H), 7.29 (br s, 2H), 7.40 (br s, lH). Diastereomer B: h-NMRGOO MHz, CDC13): δ U0-1.56 (m, 7H), 1.78-1.85 (m, lH) '2.17-2.20 (m, lH)' 2.26-2.30 (m, lH) , 3.76-3.82 (m, lH), 4.25- 4.30 (m, 2H) '4.78 (dd, J = 10 and 8 Hz, lH), 6.66 (br d, J = 8 Hz, 2H), 6.80 (br d , J ~ 7 Hz, lH), 7.11 (br d, J = 8 Hz, 2H), 7.30 (br s, 2H), 7.41 (br s, lH).
化合物3和4 分:在室溫下將K4-氣苯基)-2-(2,4-二氣苯基)-4,5-二氫-1H-咪唑-4-羧酸乙酯(3.97 g,0.01 mol)在甲醇/水中的混合物與Li〇H(13 克,0.054 mol)反應16小時。將形成的混合物真空濃縮而給出粗的丨普 I5 氣本基)-2·(2,4-二氯苯基)_4,5_二氫-1HH4-魏酸經(4·7克)。 碰分••在室溫下將粗的Κ4-氯苯基)-2·(2,4-二氯苯基)-4,5-二氫 -1Η-^。坐-4-魏酸經(1.0克’〜0.0027 mol)、苯並三ϋ坐小基氧基三(二甲氨 基)六磷酸嗉(ΒΟΡ)(1·2克,0.0027 mol)、1-氨基呱咬(〇 3克,〇 〇〇3 mol) 和三乙胺(1 ml)在DMF(30 ml)中的混合物攪拌16小時。真空濃縮後, 18 200530191 添加水,用二氯甲烷萃取(2χ)形成的混合物。收集二氯甲烷層,在 MgS〇4上乾燥,過濾後真空濃縮而給出殘餘物,通過急驟色譜法(矽 膠’二氯甲烷/甲醇=95/5(v/v))將它進一步純化而給出i_(4-氣苯 基)-2·(2,4-二氯苯基)-N-(狐啶· 基)-4,5-二氫-1H-咪唑-4-甲醯胺(3 80 5 mg,31 %產率)。炫點:113-116°C。h-NMRQOO MHz,CDC13) : δ 1.33-1.48(m,2H),1.60-1.80(m,4H),2.68-2.82 (m,4H),4.28-4.35(m,2H), 4.84(dd,J = 11 和9 Hz,lH),6.65(br d,J = 8 Hz,2H),7.11(br d,J = 8 Hz,2H),7.23-7.33(m,2H),7.41(d,J = 2Hz,lH),7.57(brs,lH)。Compounds 3 and 4: K4-Gaphenyl) -2- (2,4-difluorophenyl) -4,5-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (3.97 g, 0.01 mol) in a methanol / water mixture was reacted with LiOH (13 g, 0.054 mol) for 16 hours. The resulting mixture was concentrated in vacuo to give the crude acetone (I5abenzyl) -2 · (2,4-dichlorophenyl) -4,5_dihydro-1HH4-weiric acid (4 · 7 g). Breaking the points •• Crude K4-chlorophenyl) -2 · (2,4-dichlorophenyl) -4,5-dihydro-1Η- ^ at room temperature. Zy-4-weiric acid (1.0 g '~ 0.0027 mol), benzotrifluorene bis (small group) oxytri (dimethylamino) fluorene hexaphosphate (BOP) (1.2 g, 0.0027 mol), 1-amino A mixture of bite (03 g, 2003 mol) and triethylamine (1 ml) in DMF (30 ml) was stirred for 16 hours. After concentration in vacuo, 18 200530191 water was added and the resulting mixture was extracted (2x) with dichloromethane. The dichloromethane layer was collected, dried over MgS04, filtered and concentrated in vacuo to give a residue, which was further purified by flash chromatography (silica gel 'dichloromethane / methanol = 95/5 (v / v)) Gives i_ (4-aminophenyl) -2 · (2,4-dichlorophenyl) -N- (foxidinyl) -4,5-dihydro-1H-imidazole-4-carboxamide ( 3 80 5 mg, 31% yield). Hyun point: 113-116 ° C. h-NMRQOO MHz, CDC13): δ 1.33-1.48 (m, 2H), 1.60-1.80 (m, 4H), 2.68-2.82 (m, 4H), 4.28-4.35 (m, 2H), 4.84 (dd, J = 11 and 9 Hz, lH), 6.65 (br d, J = 8 Hz, 2H), 7.11 (br d, J = 8 Hz, 2H), 7.23-7.33 (m, 2H), 7.41 (d, J = 2Hz, 1H), 7.57 (brs, 1H).
10 按類似方法製備了化合物4 : 化合物4 · 1-(4-氣苯基)_2-(2,4-二氯苯基)-N-環己基-4,5-二氮-1H-咪唑-4-曱醯胺。熔點:127-129°C。iH-NMRGOO MHz,CDC13) : δ 1·04·2·03 (m,10H),3.73-3.92(m,lH),4.23-4.33(m,2H),4.81(t,J 〜10 Ηζ,1Η),6.66(br d,J = 8 Hz,2H),6.79(br d,J 〜7 Ηζ,1Η),7.12(br d,J = 8 15 Hz,2H),7.25-7.32(m,2H),7.41(brs,lH)。 19 20053019110 Compound 4 was prepared in a similar manner: Compound 4 1- (4-Gaphenyl) _2- (2,4-dichlorophenyl) -N-cyclohexyl-4,5-diaza-1H-imidazole- 4-Amine. Melting point: 127-129 ° C. iH-NMRGOO MHz, CDC13): δ 1.04 · 2 · 03 (m, 10H), 3.73-3.92 (m, 1H), 4.23-4.33 (m, 2H), 4.81 (t, J ~ 10 Ηζ, 1Η ), 6.66 (br d, J = 8 Hz, 2H), 6.79 (br d, J ~ 7 Ηζ, 1Η), 7.12 (br d, J = 8 15 Hz, 2H), 7.25-7.32 (m, 2H) , 7.41 (brs, lH). 19 200530191
化合物5-8Compound 5-8
:往4-氣苯磺醯胺(0.45克,0.00236 mol)在苯(5 ml)中的懸 浮液中滴加三甲基铭(1.2 ml的2N甲苯溶液,0.0024 mol)而給出清亮的 溶液’在室溫下將它攪拌1小時。添加1-(4-氯苯基)-2-(2,4-二氣苯基)-4,5-二氫-1拓咪°坐-4-甲腈(0.55克,0.00157mol),在90°C下將形成的混合物加 熱16小時。冷卻到室溫後,緩慢地添加甲醇/水(8/2(v/v))的混合物,通 過過濾除去固體物並用氯仿(50 ml)洗滌。真空濃縮濾液。將殘餘物與 正戊燒一起研製,從甲醇中重結晶兩次而給出1-(4-氯苯基)-2-(2,4-二氣 苯基)·Ν-[(4-氣苯基)磺醯]_4,5_二氫-1H-咪峻-4-甲脉(0.435克,51%產率)。 溶點:165-166°C。^-NMRQOO MHz,CDC13) : δ 4·11-4·35(γπ,2Η), 4.94(dd,J =12 和 10 Ηζ,1Η),6.63(bi* d,J = 8 Ηζ,2Η),7.12(br d,J = 8 Hz,2H),7.22-7.52(m,6H),7.90(brd,J = 8 Hz,2H),8.10-8.20 (m,lH)。 20 200530191: Trimethylammonium (1.2 ml of 2N toluene solution, 0.0024 mol) was added dropwise to a suspension of 4-gas besysulfame (0.45 g, 0.00236 mol) in benzene (5 ml) to give a clear solution. 'Stir it at room temperature for 1 hour. Add 1- (4-chlorophenyl) -2- (2,4-difluorophenyl) -4,5-dihydro-1 tomidazol-4-carbonitrile (0.55 g, 0.00157 mol) at The resulting mixture was heated at 90 ° C for 16 hours. After cooling to room temperature, a methanol / water (8/2 (v / v)) mixture was slowly added, and the solid matter was removed by filtration and washed with chloroform (50 ml). The filtrate was concentrated in vacuo. The residue was triturated with n-pentane and recrystallized twice from methanol to give 1- (4-chlorophenyl) -2- (2,4-difluorophenyl) · N-[(4-gas Phenyl) sulfofluorene] -4,5_dihydro-1H-midol-4-methyl vein (0.435 g, 51% yield). Melting point: 165-166 ° C. ^ -NMRQOO MHz, CDC13): δ 4 · 11-4 · 35 (γπ, 2Η), 4.94 (dd, J = 12 and 10 Ηζ, 1Η), 6.63 (bi * d, J = 8 Ηζ, 2Η), 7.12 (br d, J = 8 Hz, 2H), 7.22-7.52 (m, 6H), 7.90 (brd, J = 8 Hz, 2H), 8.10-8.20 (m, lH). 20 200530191
按類似方法製備了下文給出的式(I)的化合物:A compound of formula (I) given below was prepared in a similar manner:
化合物6 : 1-(4-氯苯基)-2-(2,4-二氯苯基)-N-[(4-氟苯基)-磺醯]-4,5-二氫-1H-咪唑-4-曱脒。熔點:172-175°C。iH-NMRQOOMHzfDCb): δ4·12-4.35(Γα,2Η),4.93(dd,J=12和 10Hz,lH),6.63(brd,J = 8Hz,2H), 7.08-7_43(m,8H),7.90-8.02(m,2H),8.10-8.20 (m,lH)。Compound 6: 1- (4-chlorophenyl) -2- (2,4-dichlorophenyl) -N-[(4-fluorophenyl) -sulfofluorene] -4,5-dihydro-1H- Imidazole-4- 曱 脒. Melting point: 172-175 ° C. iH-NMRQOOMHzfDCb): δ4 · 12-4.35 (Γα, 2Η), 4.93 (dd, J = 12 and 10Hz, 1H), 6.63 (brd, J = 8Hz, 2H), 7.08-7_43 (m, 8H), 7.90 -8.02 (m, 2H), 8.10-8.20 (m, 1H).
化合物7 : 2-(4-氣苯基)-N-(二甲氨基磺醯)-1-苯基-4,5-二氫-1H-咪 唑-4-甲脒。熔點:136-139°C。W-NMRQOO MHz,CDC13) : δ 2.79(s,6H), 4.20-4.40(m,2H),4.97(t,J 〜10 Ηζ,ΙΗ),6.83(br d,J = 8 Hz,2H), 7.05-7.50(m,8H),7.80-7.90(m,lH)。 21 10 200530191Compound 7: 2- (4-Gaphenyl) -N- (dimethylaminosulfonium) -1-phenyl-4,5-dihydro-1H-imidazole-4-carboxamidine. Melting point: 136-139 ° C. W-NMRQOO MHz, CDC13): δ 2.79 (s, 6H), 4.20-4.40 (m, 2H), 4.97 (t, J ~ 10 Ηζ, ΙΗ), 6.83 (br d, J = 8 Hz, 2H), 7.05-7.50 (m, 8H), 7.80-7.90 (m, 1H). 21 10 200530191
=〇= 〇
ClCl
nh2nh2
5實施例2:動物研究中應用的製劑5 Example 2: Formulations used in animal studies
化合物1的製劑: 經口㈣給予:向玻璃管内所需量(05〜15呵)的前文作為“化 合物Γ '給出的化合物中添加—些玻璃珠,通過渦旋將所述物質研磨2 分鐘。添加i ml的⑼甲基纖維素水溶液後,通·旋使化合物懸浮10 10分鐘。為了使濃度達到和高於丨mg姻,利用超聲浴使餘下的顆粒在懸 浮液令進一步懸浮。 實施例3 :藥理試驗結果 下表中顯示了根據前文給出的方案獲得的體外大麻素受體親合 性和功能資料。 22 200530191 表1:藥理數據 人大麻素-CB1受體 禮方親合性 禮分拮抗作用 化合物編號 pKi值 pA2-值(花生四婦酸釋放) 化合物1 7.7 - 化合物2 7.0 - 化合物4 7.0 7.7 化合物8 6.8 - L圖式簡單說明】 (無) 5 【主要元件符號說明】 (無)Formulation of Compound 1: Oral administration: Add some glass beads to the required compound ("Compound Γ ') given above in a glass tube (05 ~ 15 he), and grind the substance by vortexing for 2 minutes After adding 1 ml of methyl methylcellulose aqueous solution, the compound was suspended for 10 to 10 minutes. In order to achieve a concentration higher than and equal to mg mg, the remaining particles were further suspended in the suspension by using an ultrasonic bath. Example 3: Pharmacological test results The table below shows the in vitro cannabinoid receptor affinity and functional data obtained according to the protocol given above. 22 200530191 Table 1: Pharmacological data of human cannabinoid-CB1 receptor Antagonistic effect Compound number pKi value pA2-value (arachidic acid release) Compound 1 7.7-Compound 2 7.0-Compound 4 7.0 7.7 Compound 8 6.8-L Scheme Simple Description] (None) 5 [Description of Main Component Symbols] ( no)
23twenty three
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