TWI298723B - Farnesyl transferase inhibiting 1,2-annelated quinoline enantiomer - Google Patents

Description

A7 1298723 ^— _B7____ 五、發明說明（1 ) (請先閱讀背面之注意事項再填寫本頁) 本發明係有關新穎1，2-環節化喳啉對掌異構物、其 之製備、包含該新穎化合物之醫藥組合物以及使用此化 合物做為藥物和投與該化合物之治療方法。 經濟部智慧財產局員工消費合作社印製 致癌基因經常編碼有訊號轉導徑路之蛋白質成份， 其可刺激細胞的生長和有絲***。致癌基因表現在培養 細胞則導致細胞轉化作用，其特徵為能使細胞在軟複脂 内生長以及呈現非-轉化細胞缺乏接觸抑制之稠核細胞的 生長。某種致癌基因的突變和/或過度表現經常導致人類 的癌症。熟知之拉司致癌基因（ras)為一種特殊種類的致 癌基因，其可在哺乳類、烏類、昆虫類、軟体動物、植 物、真菌、酵母菌中被鑑定出。哺乳類之拉司致癌基因 由三種主要成員所構成（“同形物，，）：拉司、κ-拉司和 N_拉司致癌基因。此拉司致癌基因密碼有高度關聯之蛋 白質總稱為p21ras。一旦其觸及細胞膜，此突變或致癌型 之p2lras會傳遞一轉化訊號而造成惡性腫瘤細胞之成長失 控。在獲得此轉化潛力之前，此P21ras致癌蛋白之前驅物 位於綾基端四肽的半胱胺酸基必需先進行法尼基化的酵 素催化作用。因此，催化此作用之酶類的抑制劑，即法 尼基轉移酶，可避免p21ras接觸細胞膜而阻止拉司-轉化 腫瘤的異常生長。因此，法尼基蛋白質轉化酶抑制劑一 般在本技術領域中被視為是對抗拉司致癌基因所造成之 轉化作用的一種非常有效腫瘤抗癌劑。 由於此突變型拉司致癌基因經常發現於許多人類之 癌細胞中，尤其以50%以上之結腸和胰臟癌為最顯著 -3·A7 1298723 ^— _B7____ V. INSTRUCTIONS (1) (Please read the notes on the back and fill out this page.) The present invention relates to novel 1,2-linked porphyrin-p-isomers, preparation thereof, and inclusion thereof. A pharmaceutical composition of a novel compound and a method of using the same as a medicament and administering the compound. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives. Oncogenes often encode protein components that are signal transduction pathways that stimulate cell growth and mitosis. The oncogene is expressed in cultured cells resulting in cell transformation, which is characterized by the ability to grow cells in soft refolding and to present the growth of non-transformed cells that lack contact inhibition. Mutations and/or overexpression of certain oncogenes often lead to cancer in humans. The well-known rapper oncogene (ras) is a special kind of oncogene that can be identified in mammals, blacks, insects, mollusks, plants, fungi, and yeasts. The mammalian oncogene is composed of three major members ("homomorphs,"): ras, kappa-ras, and N-ras oncogenes. The protein with high correlation with the oncogene code is called p21ras. Once it touches the cell membrane, this mutant or oncogenic p2lras transmits a transformation signal that causes the growth of malignant cells to be out of control. Before the potential for this transformation, the P21ras oncoprotein precursor is located at the thiol-terminal tetrapeptide of cysteine. The base must first be subjected to enzyme catalysis of farnesylation. Therefore, an inhibitor of the enzyme that catalyzes this action, the farnesyl transferase, can prevent p21ras from contacting the cell membrane and preventing abnormal growth of the lins-transformed tumor. Farnesyl protein invertase inhibitors are generally considered in the art to be a very potent tumor anticancer agent against the transformation caused by the larvae oncogene. Since this mutant lysine oncogene is often found in many humans Among the cancer cells, especially 50% or more of colon and pancreatic cancer is the most significant -3

本紙張尺度剌㈣碎規格⑽x 2ir^iT 1298723 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明（2 ) (Kohl等人，科學，第260卷，1834〜1837，1993年），因 此遇為法尼基蛋白質轉移酶抑制劑可有效對抗此類型之 癌症。 在 W097/16443、WO97/21701、WO98/40383 和 W098/49157中指出2·喳唯衍生物具有抑制法尼基轉移酶 之活性。WOOO/12498、00/12499 和 〇〇/47574 中指出其它 之啥啡化合物亦具有抑制法尼基轉移酶之活性。 WO00/39082指出一類攜帶氮_或碳-鏈咪唑之新穎的12_ 環節喳啉和喳唑啡化合物顯示有抑制法尼基蛋白質轉移 酶之活性。此化合物於其後之專利說明書中被提及者為 (土）-5-(3-氣苯基)-α ♦氣苯基)+(1-甲基m味嗤j基) 四唑基[l，5-a]喳唑啉_7-甲胺，其可於對掌異構混合物的 形式中取得。目前，將此混合物分離後發現(_)對掌異構 物比對掌異構混合物有較佳的醫藥性質。 因此，本發明係有關㈠-5-(3-氣苯基曱基- 1Η-咪唑-5-基）四唑基[l55_a】喳唑啉甲胺和其醫藥上可 接受之酸加成鹽類。 在下文中即將上述之㈠對掌異構物視為根據本發明 之化合物。 本發明之化合物通常以非常純化的形式存在，即不 混雜(+)對掌異構物，例如低於5%重量/重量，以低於2% 重量/重量為佳，並且以低於1%重量/重量之後者對掌異 構物最佳。 在上文中所提及之醫藥上可接受之酸加成鹽類意指The paper size 剌 (4) broken specifications (10) x 2ir^iT 1298723 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives printed A7 V, invention description (2) (Kohl et al., Science, Vol. 260, 1834~1837, 1993), therefore In case of a farnesyl protein transferase inhibitor, it is effective against this type of cancer. It is indicated in W097/16443, WO97/21701, WO98/40383 and W098/49157 that the ruthenium derivative has an activity of inhibiting farnesyl transferase. Other morphine compounds are also shown to inhibit the activity of farnesyltransferases as taught in WOOO/12498, 00/12499 and 〇〇/47574. WO00/39082 teaches that a novel class of 12-linked porphyrins and oxazolines carrying nitrogen- or carbon-chain imidazoles exhibit activity in inhibiting farnesyl protein transferases. This compound is referred to in the subsequent patent specification as (earth)-5-(3-phenylphenyl)-α ♦ phenylene) + (1-methyl m misojyl) tetrazolyl [ L,5-a]oxazoline-7-methylamine, which can be obtained in the form of a mixture of palms and isomers. At present, separation of this mixture reveals that (_) has superior medicinal properties to the palmosome isomer mixture. Accordingly, the present invention relates to (i)-5-(3-phenylphenylindolyl-1 Η-imidazol-5-yl)tetrazolyl[l55_a]oxazolinemethylamine and pharmaceutically acceptable acid addition salts thereof . In the following, the above-mentioned (i) palmar isomer is regarded as a compound according to the present invention. The compounds of the invention are generally present in very purified form, i.e., unmixed (+) palmar isomers, such as less than 5% w/w, preferably less than 2% w/w, and less than 1% Weight/weight is best for palm isomers. The pharmaceutically acceptable acid addition salt referred to above means

本紙張尺度適用中國國家標準(CNS)A4規格（21〇 X (請先閱讀背面之注意事項再填寫本頁)This paper size applies to the Chinese National Standard (CNS) A4 specification (21〇 X (please read the notes on the back and fill out this page)

-4· 1298723 A7 B7 五、發明說明（3) 含醫藥上無毒性之酸加成鹽類形式，以其形成本發明之 化合物。可將該驗性形式之化合物以適當之酸處理使後 者之化合物轉化成醫藥上可接受之酸加成鹽類Q適當之 酸包括，例如氫氣酸或氫溴酸、硫酸、硝酸、磷酸和其 類似之氫鹵酸的無機酸；或例如醋酸、丙酸、羥乙酸、 乳酸、丙酮酸、草酸、丙二酸、琥珀酸（即丁二酸）、順丁 烯一酸、反丁烯二酸、塔日酸、檸檬酸、甲磺酸、乙磺 酸本㈣酸、對甲苯確酸、環酿胺酸(cyclamic acid)、柳 酸、對_胺基-柳酸、棕櫚酸和其類似酸類。 酸加成一詞亦包括本發明之化合物能形成的水合物 和溶劑附加形式。此類形式的例子如水合物、乙醇化物 和其類似物。 下文中任何時候使用，，本發明之化合物，，一詞意指包 括醫藥上可接受之酸加成鹽類。 經濟部智慧財產局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 根據本發明可藉上述WO00/39082中分離其母對掌 混合物來製備此㈠對掌異構物。其可用傳統的方法例如 適合之對掌酸的反應來製備，例如以（+)-6-胺基青黴烷 酸、右旋或左旋天門冬胺酸、（1S3R)或（1R3S)_樟腦二 酸、（1S)或（1幻_1〇_樟腦磺酸、碳苄氧基-左旋-脯胺酸、 膽酸、去氫膽酸、去氧膽酸、（2S，3R)二苯甲醯基酒石 酸、（2S，3S)或（2RJR)二乙醯基酒石酸、（2S，3S)或 (2R，3R)-酒石酸、（2S，3S)或（2R，3R)二甲苯醯酒石酸、 2,3 : 4,6·二-鄰·亞異丙基酮基-左旋_古羅酸、二 氫苯并哌喃·2_羧酸、（R)或(S)_4-(2-對氯苯)-2-經基_ •5· 本紙張尺度適用中國國豕標準（CNS)A4規格（21〇 X 297公爱） 1298723 A7 ____B7____ 五、發明說明（4 ) 5,5-二甲基-1，3,2-二噁磷酸-2-氧化物、右旋-葡萄庚酸、 右旋或左旋-麩胺酸、右旋—異抗壞血酸、（s)或(R)_2_羥丙 酸、乳糠醛酸、右旋或左旋_蘋果酸、左旋-2-((4_甲氧苯 基)磺醯)_胺戊二酸、左旋-2-((4-曱基苯基)磺醯）_胺戊二 酸、（S)-6-甲氧基-α_甲基_2-萘醋酸、（s)-2-(笨胺甲醯基 羥)-丙酸、（-)-3-苹羧酸、（R)或（s)-2-咄咯啶酮_5_羧酸或 9R)-四氫噻唑_4_黢酸。接著分離出其最後形式的鹽類， 例如以選擇或分凝其結晶的方法產生所要求的對掌異構 物。 另外一種從母混合物分離所欲之對掌異構物的方法 為利用對掌靜止相的液態色層分離法。假若其為立体有 擇反應，此純化對掌異構物形式亦可源自於適當起始材 料之對應純化對掌異構物形式。假若其為對掌有擇反 應，則此純化對掌異構物形式亦可源自於適當的外消旋 起始材料。藉其母對掌異構混合物和一對掌異構物的一 些對掌劑如酸類或氣化酸反應而得到非對掌立体異構混 合物，然後再以例如選擇或分凝其結晶或以液態色層分 離法將其分離而得到純化之非對掌立体異構物。此適; 之非對掌立体異構物可斷裂成所要求之對掌異構物。2 母對掌異構混合物可根據上述WOOO/39082的方法戋以 此處更特異性的方法製備。 < 本發明之化合物和其醫藥上可接受之酸加成鹽類在 醫藥性質上’和其母㈣異構混合物比較，有明顯的法 尼基蛋白質轉移酶(FPTase)抑制效果。因此，後者之混人 (請先閱讀背面之注意事項再填寫本頁) f:· --線· -6- 1298723 A7 B7 五、發明說明（ :的㈣法尼基蛋白質轉移酶抑翁㈣u納莫耳濃 而㈠對掌異構物的相對抑制活性則為〇 7納莫耳 濃度。 本發明藉投與本發明之化合物而提供一種抑制，包 f轉化細胞，之細胞異常生長的方法。細胞異常生長意 指細胞在正㈣節機制下獨立地生長(例如失去接觸抑制 的功能）。此異常生長包括：⑴呈現—活性拉司致癌基 因之腫瘤細胞（腫瘤）；⑵㈣蛋白被活化之腫瘤細胞造 成其它基因之致癌突變；⑶其它增生性疾狀良性和惡 性細胞發生異常拉司致癌基因活性。而且，有許多報告 %、為拉司致癌基因不僅直接影響生体内腫瘤細胞的生， 長，亦會間接影響腫瘤細胞的生長，即藉促使腫癟_引起 的血&形成(Rak. J·等人，癌症之研究，55，4575〜458〇， 1995年）。因此，醫藥上針對變異之拉司致癌基因在生体 内可抑制固態腫瘤的生長，其一部份歸因於抑制腫瘤_引 起的血管形成。 本發明亦藉投與有效量之本發明化合物，例如一需 要治療之哺乳類動物（更明確地說如人類），而提供一種抑 制腫瘤生長的方法。特別是，本發明亦藉投與有效量之 本發明化合物來抑制呈現一活性拉司致癌基因的腫瘤生 長。可被抑制之腫瘤的例子，例如肺癌（例如腺癌以及包 括非·小細胞肺癌）、胰臟癌（例如外分泌胰臟癌之胰臟 癌）、結腸癌（例如結腸腺癌和結腸腺瘤之結直腸癌）、類 淋巴系的造血腫瘤（例如急性淋巴球白血病、B_細胞淋巴 -------------R ___ (請先閱讀背面之注意事項再填寫本頁) · -線- 經濟部智慧財產局員工消費合作社印製 表紙張尺度適用中國國家標準(CNS)A4規格（21G χ 297公爱 經濟部智慧財產局員工消費合作社印製 1298723 ____B7 _ 五、發明說明（6 ) 廇、Burkitt’s淋巴瘤）、骨趙樣白血病（例如急性骨髓性白 血病（AML))、甲狀腺濾泡癌、脊髓發育不全症候群 (MDS)、源自於間葉的腫瘤（例如纖維肉瘤、橫紋肌肉 瘤）、黑色瘤、四体瘤（tetratocarcinomas)、神經母細胞 瘸、神經膠瘤、皮膚良性腫瘤（例如角質棘皮瘤）、***癌 (例如進化的***癌）、腎癌、卵巢癌以及表皮癌。 本發明亦知*供種抑制良性和惡性之增生性疾病的 方法，其中拉司致癌蛋白之異常活性為基因造成致癌基 因突變之原因。針對需要治療之主体投與本文所述有效 量之化合物可達到違抑制的效果。本發明之化合物可抑 制，例如，神經纖維瘤病之良性增生性疾病、或由於突 變或酪胺酸激酶致癌基因過度表現而活化拉司致癌基因 所造成之腫瘤。 根據本發明之化合物可應用於其它治療上之目的， 例如： a) 治療癌症時以玫射線照射之前、期間或之後投 與根據本發明之化合物做為腫瘤起敏作用之射 線療法，例如WO00/01411中所述； b) 治療關節病’例如風濕性關節炎、骨關節炎、 幼性關節炎、痛風、多發性關節炎、牛皮癬性 關節炎、風濕性脊椎炎和全身性紅斑性狼瘡， 例如WO00/01386中所述； c) 抑制平滑肌細胞的增生，包括血管增生性疾 病、動脈粥樣硬化和再狹窄，例如W098/55124 •8· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） (請先閲讀背面之注意事項再填寫本頁)-4· 1298723 A7 B7 V. INSTRUCTION DESCRIPTION (3) A pharmaceutically acceptable acid addition salt form is formed to form a compound of the present invention. The compound of the test form can be treated with a suitable acid to convert the latter compound into a pharmaceutically acceptable acid addition salt. Suitable acids include, for example, hydrogen or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. a mineral acid similar to a hydrohalic acid; or such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid (ie, succinic acid), maleic acid, fumaric acid , Taji acid, citric acid, methanesulfonic acid, ethanesulfonic acid, tetrakis acid, p-toluene acid, cyclamic acid, salicylic acid, p-amino-salic acid, palmitic acid and similar acids . The term acid addition also encompasses hydrate and solvent addition forms which the compounds of the invention can form. Examples of such forms are hydrates, ethanolates and the like. The term "a compound of the invention" as used hereinafter, is meant to include pharmaceutically acceptable acid addition salts. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives (please read the notes on the back and then fill out this page). According to the present invention, the parental mixture can be prepared by separating the mother-to-palm mixture in the above WO00/39082. It can be prepared by a conventional method such as a suitable reaction to palmitic acid, for example, (+)-6-aminopenicillanic acid, dextrorotatory or L-aspartate, (1S3R) or (1R3S)-camphoric acid , (1S) or (1 illusion 〇 樟 樟 樟 磺酸 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 碳 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟 樟Tartaric acid, (2S, 3S) or (2RJR) diethyl tartaric acid, (2S, 3S) or (2R, 3R)-tartaric acid, (2S, 3S) or (2R, 3R) xylene tartaric acid, 2, 3 : 4,6·di-ortho-isopropylidene-L-ro-guluric acid, dihydrobenzopyran-2-carboxylic acid, (R) or (S)_4-(2-p-chlorobenzene) -2-Based _ •5· This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public) 1298723 A7 ____B7____ V. Description of invention (4) 5,5-Dimethyl-1, 3,2-dioxa phosphate-2-oxide, dextro-glucoheptanoic acid, dextrorotatory or levo- glutamic acid, dextro-isoascorbic acid, (s) or (R)_2-hydroxypropionic acid, acetal aldehyde Acid, dextrorotatory or levorotatory-malic acid, L-?-2-((4-methoxyphenyl)sulfonyl)-amine glutaric acid, L-?-2-((4-mercaptophenyl)sulfonate _amine glutaric acid, (S)-6-methoxy-α-methyl 2 -naphthaleneacetic acid, (s)-2-(thlandamine methyl hydroxy)-propionic acid, (-)-3- Butyl carboxylic acid, (R) or (s)-2-oxaridone _5-carboxylic acid or 9R)-tetrahydrothiazole _4_decanoic acid. The salt of its final form is then isolated, for example by the method of selecting or condensing its crystals to produce the desired palmomer. Another method for separating the desired palmomers from the parent mixture is to utilize a liquid chromatography method for the stationary phase of the palm. If it is a stereospecific reaction, the purified palmomerate form can also be derived from the corresponding purified p-isomer form of the appropriate starting material. If it is a selective reaction to the palm, the purified palmomer form can also be derived from a suitable racemic starting material. A non-pivoting stereoisomeric mixture is obtained by reacting some of its parental mixture and a pair of palmomers, such as an acid or a gasified acid, and then, for example, selecting or segregating the crystal or in a liquid state The chromatographic separation method separates them to obtain a purified non-palphalinic isomer. This is suitable; the non-paired stereoisomers can be broken into the desired palmomers. 2 The mother-to-palm mixture can be prepared in a more specific manner according to the method of WOOO/39082 above. < The compound of the present invention and its pharmaceutically acceptable acid addition salt have a significant effect of inhibiting the growth of the farnesyl protein transferase (FPTase) in comparison with the parent (iv) isomer mixture thereof. Therefore, the latter is mixed (please read the note on the back and then fill out this page) f:· -- line · -6- 1298723 A7 B7 V. Description of invention (: (4) Farnesyl protein transferase inhibitor (four) u The relative inhibitory activity of morse and (i) against the palm isomer is 〇7 nanomolar. The present invention provides a method for inhibiting the abnormal growth of cells by transforming cells with the compound of the present invention. Abnormal growth means that the cells grow independently under the positive (four) node mechanism (for example, the function of losing contact inhibition). This abnormal growth includes: (1) presenting the tumor cells (tumor) of the active rass oncogene; (2) (d) the tumor cells activated by the protein Causes carcinogenic mutations of other genes; (3) abnormal proliferative and malignant cells produce abnormal oncogene activity. Moreover, many reports that the oncogenes directly affect not only the growth of tumor cells in vivo, but also It will indirectly affect the growth of tumor cells, that is, the formation of blood & caused by swelling (Rak. J. et al., Cancer Research, 55, 4575~458〇, 1995). The medicinally directed variant of the oncogene can inhibit the growth of solid tumors in vivo, in part due to inhibition of tumor-induced angiogenesis. The invention also employs an effective amount of a compound of the invention, such as a need Therapeutic mammals (more specifically, humans) provide a means of inhibiting tumor growth. In particular, the present invention also employs an effective amount of a compound of the invention to inhibit tumor growth that exhibits an active last oncogene. Examples of tumors that can be inhibited, such as lung cancer (eg, adenocarcinoma and including non-small cell lung cancer), pancreatic cancer (eg, pancreatic cancer of exocrine pancreatic cancer), colon cancer (eg, colon adenocarcinoma and colon adenoma) Hematopoietic tumors of the lymphoid lineage (such as acute lymphocytic leukemia, B_cell lymphoma -------------R ___ (please read the back of the note first and then fill out this page) · -Line - Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Table Paper Scale Applicable to China National Standard (CNS) A4 Specification (21G χ 297 Public Opinion Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives 1298723 ____B7 _ V. Description of invention (6) 廇, Burkitt's lymphoma), bone-like leukemia (eg acute myeloid leukemia (AML)), thyroid follicular carcinoma, spinal cord hypoplasia syndrome (MDS), originating from the mesenchyme Tumors (eg, fibrosarcoma, rhabdomyosarcoma), melanoma, tetratocarcinomas, neuroblasts, gliomas, benign skin tumors (eg, horny acanthoma), breast cancer (eg, estrogen breast cancer), Renal cancer, ovarian cancer, and epidermal cancer. The present invention also relates to a method for inhibiting benign and malignant proliferative diseases, wherein the abnormal activity of the lysine oncoprotein is the cause of a gene causing an oncogene mutation. Administration of an effective amount of a compound described herein to a subject in need of treatment achieves an inhibitory effect. The compounds of the present invention inhibit, for example, benign proliferative diseases of neurofibromatosis, or tumors caused by mutations or overexpression of tyrosine kinase oncogenes to activate lesbian oncogenes. The compounds according to the invention may be used for other therapeutic purposes, for example: a) radiation therapy for administration of a compound according to the invention as a tumor sensitization before, during or after irradiation with a rose, for example, WO00/ Said in 01411; b) treating joint diseases such as rheumatoid arthritis, osteoarthritis, jaundice, gout, polyarthritis, psoriatic arthritis, rheumatic spondylitis and systemic lupus erythematosus, for example WO00/01386; c) inhibition of smooth muscle cell proliferation, including vascular proliferative diseases, atherosclerosis and restenosis, such as W098/55124 • 8· This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the notes on the back and fill out this page)

1298723 A7 ___B7_ 五、發明說明（7 ) 中所述； (請先閱讀背面之注意事項再填寫本頁) d) 治療炎性狀況，例如溃瘍性結腸炎、局部性迴 腸炎、過敏性鼻炎、移植物和宿主疾病、結合 膜炎、氣喘、急性呼吸困難症候群（ARDS)、 Behcets氏疾病、移植的排斥、蓴麻療、過敏性 皮膚炎、簇狀禿髮、硬皮病、疹病、濕疹、皮 肌炎、痤瘡、糖尿病、全身性紅斑性狼瘡、 Kawasaki’s氏病、多發性硬化、氣腫、囊性纖 維變性和慢性支氣管炎； e) 治療子宮内膜組織異位、子宮纖維瘤、功能性 子宮出血和子宮内膜增殖； f) 治療眼之血管形成包括影響視網膜和脈絡膜血 管的血管萎縮； 經濟部智慧財產局員工消費合作社印製 g) 治療導因於異三聚体G蛋白質膜固定之病理 學，包括有關伴隨生物功能或障礙的疾病；嗅 覺、味覺、光覺、知覺、神經傳導、神經變 性、内分泌和外分泌腺功能、自体作用和旁分 泌的調節、血壓、胚胎形成、病毒感染、免疫 功能、糖尿病、肥胖病； h) 抑制病毒形体發育，例如藉抑制病毒蛋白質如 肝炎D病毒之大型占抗原的異戊烯化 (prenylation)或異戊稀化-後反應以及治療人類免 疫缺乏症病毒(HIV)之感染； i) 治療多囊性腎病； -9- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1298723 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（ j) 抑制包括硝酸之可誘導硝酸的誘導作用、或細 胞素_居間疾病、敗血病休克、抑制非原質性分 裂（apoptosis)以及抑制硝酸細胞毒性； k) 治療癔疾。 因此，本發明揭示做為藥物用途之本發明的化合物 以及用此化合物製造治療上述一種以上之疾病的藥物。 為了達到治療上述疾病之目的，本發明之化合物可 應用結合一種以上之其它抗-癌劑，例如選自如順式白金 (cisplatin)或碳白金(carb〇piatin)之白金配位化合物；如太 平洋紫杉醇(paclitaxel)或勉癌易（docetaxel)之taxane化合 物；如喜樹驗衍生物（irinotecan)或拓扑替康（topotecan)之 camptothecin(CPT)化合物；如長春花驗(vinblastine)、長 春新驗(vincristine)或異長春花驗(vinorelbine)之抗-腫瘤長 春花生物驗；如5-敗尿哺咬(5-fluorouracil)、二氟去氧胞 苷(gemcitabine)或截達瘤（capecitabine)之抗·腫瘤核苷衍生 物；如環麟酿胺、苯丁酸氣芥(chlorambucil)、亞硝基脲 氮芥(carmustine)或洛莫司汀(lomustine)之含氮介子或硝基 脲烧化劑；如道諾紅菌素（daunorubicin)、小紅每 (doxorubicin)或 idarubicin之抗-腫瘤蒽環衍生物 (anthracydine derivatives);如 trastzumab 之 HER2 抗体； 如依托泊（etoposide)或teniposide之抗-腫瘤龙臼毒素 (podophyllotoxin)衍生物；以及如***受体拮抗物或 選擇***受体調節劑之抗***劑，以抗*** (tamoxifen)為佳，或以 toremifene、droloxifene、 -10- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） {锖先閱讀背面之>±意事項再填寫本頁)1298723 A7 ___B7_ V. Description of invention (7); (Please read the notes on the back and fill out this page) d) Treat inflammatory conditions such as ulcerative colitis, colitis, allergic rhinitis, transplantation And host diseases, conjunctivitis, asthma, acute respiratory distress syndrome (ARDS), Behcets' disease, transplant rejection, ramie, allergic dermatitis, tufted baldness, scleroderma, rash, eczema , dermatomyositis, acne, diabetes, systemic lupus erythematosus, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis and chronic bronchitis; e) treatment of endometrial tissue ectopic, uterine fibroids, function Sexual uterine bleeding and endometrial proliferation; f) treatment of ocular angiogenesis including vascular atrophy affecting the retina and choroidal vessels; Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed g) Treatment caused by heterotrimeric G protein membrane fixation Pathology, including diseases associated with biological functions or disorders; olfactory, taste, light perception, perception, nerve conduction, neurodegeneration, endocrinology, and external division Regulation of gland function, autologous action and paracrine, blood pressure, embryo formation, viral infection, immune function, diabetes, obesity; h) inhibition of viral form development, for example, by inhibiting viral proteins such as hepatitis D virus Prenylation or isopentenylation-post-reaction and treatment of human immunodeficiency virus (HIV) infection; i) treatment of polycystic kidney disease; -9- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298723 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (j) Inhibition of nitric acid-induced inducible nitric acid, or cytokine_intermediate disease, septic shock, Inhibition of non-primative division (apoptosis) and inhibition of nitric acid cytotoxicity; k) treatment of dysentery. Accordingly, the present invention discloses a compound of the present invention for pharmaceutical use and a medicament for the manufacture of a medicament for treating at least one of the above diseases. For the purpose of treating the above diseases, the compound of the present invention may be applied in combination with one or more other anti-cancer agents, for example, a platinum coordination compound selected from, for example, cisplatin or carbopipin; such as paclitaxel (paclitaxel) or a taxane compound of docetaxel; a camptothecin (CPT) compound such as irinotecan or topotecan; such as vinblastine, vincristine (vincristine) Or anti-tumor periwinkle bioassay of vinorelbine; such as 5-fluorouracil, gemcitabine or capecitabine a tumor nucleoside derivative; a nitrogen-containing meson or a nitrourea burning agent such as cyclamin, chlorambucil, carmustine or lomustine; Anti-tumordine derivatives of daunorubicin, doxorubicin or idarubicin; HER2 antibodies such as trastzumab; anti-tumor dragons such as etoposide or teniposide a derivative of podophyllotoxin; and an anti-estrogen agent such as an estrogen receptor antagonist or an estrogen receptor modulator, preferably tamoxifen or toremifene, droloxifene, -10- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). {Read the back of the article first>

1298723 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明（9 ) faslodex、和 raloxifene 代替；或如依曼適達 (exemestane) ' anastrozole ' letrazole ^ vorozole 之芳香 環轉化酶(aromatase)抑制劑。 以其醫藥性質之利用角度來看，此化合物可製成適 合投藥之各種醫藥形式。 製備本發明之醫藥組成物，將足夠量之化合物以附 加鹼或酸之鹽類形式做為其活性成份和醫藥上可接受之 載体充份混合，視投藥上的需要其載体可有各種不同的 形式。其醫藥組成物以適合單一投藥劑量為佳，其投藥 方式以口服、直腸投與、經由表皮、或腸道外的注射較 佳。例如，可應用任何醫藥上可用之介質製備口服形式 的組成物，例如，製備如懸浮液、糖漿、醜劑和溶液之 口服液体製備物時應用例如水、葡萄糖、油、酒精和其 類似物；製備如粉末、丸劑、膠囊和錠劑之製備物時應 用例如澱粉、糖、高嶺土、潤滑劑、黏合劑、蛻變劑和 其類似物。由於錠劑和膠囊為最佳的口服投藥方式，此 時則應用固態醫藥載体。應用於腸道外投藥之組成物 時，其通常應用大量的滅菌水做為載体，但亦包含其它 的成份，例如增加其溶解度之成份。注射用之水溶液， 例如其載体可能包含生理食鹽水、葡萄糠溶液或生理食 鹽水和葡萄糖之混合溶液。注射用之懸浮液可能亦以適 當之液態載体、懸浮劑和其類似物製備。經由表皮投藥 之組成物，其載体可應用滲透加強劑和/或適合之濕潤 劑，其可加入小量之天然添加劑，此添加劑不能對皮膚 -11- (請先閱讀背面之注意事項再填寫本頁) 丨裝 訂： 線· 本紙張尺度適时@國家標準(CNS)A4規格（21〇 297公釐） A7 1298723 B7 _______ 玉、發明說明（1G) 造成有害的毒性。該添加劑之作用為增加使用於皮膚之 容易性和/或可能有助於組成物之製備。此組成物可用各 種不同的方式投與，例如經由皮膚徑路、局部塗敷、或 做為軟膏使用。 將上述醫藥組成物製成方便投與和統一劑量之單位 劑量形式可獲得很大的益處。使用於說明書和專利申請 中之單位劑量形式意指在物理上適合單獨投與之獨立單 位劑量，每一單位内含能產生預期治療效果之預定劑量 的活性成份並配合所需要之醫藥上載体。此單位劑量形 式的例子為錠劑（包括刻劃或包覆錠劑）、膠囊、丸劑、粉 末包、薄片、可注射溶液或懸浮液、茶匙、食匙和其類 似方法，以及其之分隔複劑。 在本技術領域的範圍内可很容易地從上述之測試結 果決定其有效劑量。一般要求之有效劑量約從0·01毫克/ 公斤至100毫克/公斤体重，特別以0·05毫克/公斤至10 毫克/公斤体重較佳。一般成年人每日投與劑量以10至 600毫克，以50至500毫克為佳，並且特別以100至 400毫克之活性成份較佳，以200或300毫克之劑量最 佳。可將此所需劑量在適當間隔時間内每日分成2、3、4 次或以上之次劑量分開投與。該次劑量可製備成單位劑 量形式，例如，每一單位劑量形式内含10至500毫克之 活性成份，並且以含50毫克至300毫克之活性成份較 佳；單位劑量以含50毫克、1〇〇毫克、2〇〇毫克或3〇〇 毫克之活性成份較佳。1298723 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 5, Invention Description (9) faslodex, and raloxifene instead; or such as aromastase ' anastrozole ' letrazole ^ vorozole aromatic ring invertase (aromatase) inhibition Agent. From the point of view of its pharmaceutical use, the compound can be formulated into various pharmaceutical forms suitable for administration. The pharmaceutical composition of the present invention is prepared by mixing a sufficient amount of the compound as an active ingredient in an additional base or an acid salt with a pharmaceutically acceptable carrier, and the carrier may have various kinds depending on the administration requirements. form. Preferably, the pharmaceutical composition is suitable for a single administration, and the administration method is preferably oral, rectal administration, transdermal or parenteral injection. For example, any pharmaceutically acceptable medium can be used to prepare a composition in an oral form, for example, when preparing an oral liquid preparation such as a suspension, syrup, ugly agent, and solution, such as water, glucose, oil, alcohol, and the like; For example, starch, sugar, kaolin, lubricants, binders, mutating agents and the like are used in the preparation of preparations such as powders, pills, capsules and lozenges. Since tablets and capsules are the best oral administration, solid pharmaceutical carriers are used at this time. When applied to compositions for parenteral administration, it is usually applied as a carrier with a large amount of sterilized water, but also contains other ingredients such as ingredients which increase the solubility thereof. The aqueous solution for injection, for example, the carrier thereof may contain a physiological saline solution, a grapevine solution or a mixed solution of physiological saline and glucose. Suspensions for injection may also be prepared with suitable liquid carriers, suspensions and the like. The composition to be administered via the epidermis may be applied with a osmotic enhancer and/or a suitable humectant, which may be added with a small amount of a natural additive, which may not be applied to the skin -11- (please read the following notes on the back) Page) 丨 Binding: Line · The paper size is timely @国标准(CNS)A4 Specification (21〇297 mm) A7 1298723 B7 _______ Jade, invention description (1G) Harmful toxicity. The additive acts to increase ease of use to the skin and/or may contribute to the preparation of the composition. This composition can be administered in a variety of different ways, such as via a skin route, topical application, or as an ointment. It is of great benefit to formulate the above pharmaceutical compositions in unit dosage forms for convenient administration and uniform dosage. Unit dosage forms for use in the specification and patent applications are meant to be physically separate for individual dosages, each of which contains a predetermined amount of the active ingredient which produces the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such unit dosage forms are lozenges (including scoring or coating lozenges), capsules, pills, powder packs, flakes, injectable solutions or suspensions, teaspoon, spoons and the like, and the partitioning thereof Agent. The effective dose can be easily determined from the above test results within the scope of the art. The effective dosage generally required is from about 0. 01 mg/kg to 100 mg/kg body weight, especially from 0. 05 mg/kg to 10 mg/kg body weight. A typical adult daily dose is 10 to 600 mg, preferably 50 to 500 mg, and particularly preferably 100 to 400 mg of the active ingredient, preferably 200 or 300 mg. The desired dose can be administered separately in divided doses of 2, 3, 4 or more daily at appropriate intervals. The dosage may be prepared in unit dosage form, for example, containing 10 to 500 mg of the active ingredient per unit dosage form, and preferably containing 50 mg to 300 mg of the active ingredient; unit dose containing 50 mg, 1 〇 The active ingredient of 〇 mg, 2 mg or 3 mg is preferred.

本紙張尺度適用中國國家標準(CNS)A4規格（210 X ----；----------裝—— (請先閱讀背面之注意事項再填寫本頁) 訂·· -線- 經濟部智慧財產局員工消費合作社印製 -12- [298723 A7 B7 五、發明說明（ 提供下列實例做為說明： 試驗部份 爾後，’THF’，代表四氫呋喃（tetrahydrofuran)，’’DIPE，， 代表二異丙鱗（diisopropylether)，以及’’EtOAc”代表醋酸 乙酯。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -13- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐）This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X ----;----------Installation - (please read the notes on the back and fill out this page). Line - Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed -12- [298723 A7 B7 V. Invention Description (The following examples are provided for explanation: After the test part, 'THF' stands for tetrahydrofuran, ''DIPE, Represents diisopropylether, and ''EtOAc' stands for ethyl acetate. (Please read the note on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative Printed - 13 - This paper size applies China National Standard (CNS) A4 specification (210 X 297 mm)

1298723 五、發明說明（12)J[_K A7 B71298723 V. Description of invention (12) J[_K A7 B7

中間物(2) 如wcrnArn57中所述在P〇C13(1〇〇毫升）中製備6_ (4-氣苯甲醯基）-4-(3-氣苯基）·2(1Η)·喳唑咐酮（中間物 1)(0.0506莫耳濃度)並攪拌和回流1小時。將溶劑揮發乾 燥。其殘留物於CHbCh中谇取數次。將溶劑揮發乾燥。 再將殘留物以CH^Cl2淬取。將此混合物倒入冰。 分離其其有機層、乾燥(MgS〇4)、過濾，並將溶劑揮發乾 燥。將此殘留物(24.2公克)從CKbCN中結晶。將沉澱物 (請先閱讀背面之注意事項再填寫本頁) 過濾乾燥，而產生19.8公克溶點為1521之中間物 (2)(94%) 〇Intermediate (2) Preparation of 6-(4-carbobenzylidene)-4-(3-cetophenyl)-2(1Η)·carbazole in P〇C13 (1 mL) as described in wcrnArn57 Anthrone (Intermediate 1) (0.0506 molar concentration) was stirred and refluxed for 1 hour. The solvent is evaporated to dryness. The residue was taken several times in CHbCh. The solvent was evaporated to dryness. The residue was then taken up in CH^Cl2. Pour this mixture into ice. The organic layer was separated, dried (MgSO.sub.4), filtered, and evaporated to dryness. This residue (24.2 g) was crystallized from CKbCN. Precipitate (please read the note on the back and fill out this page) Filter and dry to produce an intermediate of 19.8 grams of melting point to 1521 (2) (94%) 〇

中間物(3) 經濟部智慧財產局員工消費合作社印製 將溶於己烷（1·6莫耳濃度)(90毫升）之正丁基鋰溶液 於-7(TC之氮流下滴狀加入溶於THF(12〇毫升）之^甲基 咪唑(0.144莫耳濃度)混合物。此混合物於-川它之下攪拌 15分鐘◊於·70°(：之下以滴狀加入氣三乙基矽烷(〇148莫 耳濃度），並於此溫度下將此混合物攪拌15分鐘。以滴狀 加入溶於己烷（1·6莫耳濃度）(80毫升）之正丁基鋰溶液。 -14- 本紙張尺度適用中國國家標準(CNS)A4 ^i^(2i〇 x 297 1298723 Α7 Β7 五、發明說明（13) 將此混合物於-70°C之下攪拌15分鐘。以滴狀加入溶於 THF(300毫升)之中間物(2)(0.0822莫耳濃度）的混合物。 將此混合物於_7〇t：之下攪拌1小時、水解，以EtOAc淬 取並加以傾析。將其有機層乾燥(MgS04)、過濾並使其溶 劑揮發。以柱色譜分析法用矽膠將此殘留物純化。收集 其純化的部份，並將其溶劑揮發，而產生24·9公克(61%) 之中間物（3)。Intermediate (3) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printing a solution of n-butyllithium dissolved in hexane (1.6 mol) (90 ml) in -7 (TC nitrogen flow) a mixture of methimidazole (0.144 molar concentration) in THF (12 mL). This mixture was stirred under a solution for 15 minutes at -70 ° (:: trimethyl decane was added dropwise in the form of a drop. 〇148 molar concentration), and the mixture was stirred at this temperature for 15 minutes. A solution of n-butyllithium dissolved in hexane (1.6 mol) (80 ml) was added dropwise. The paper scale is applicable to the Chinese National Standard (CNS) A4 ^i^(2i〇x 297 1298723 Α7 Β7 5. Inventive Note (13) The mixture is stirred at -70 ° C for 15 minutes and added to the THF in drops. 300 ml) of a mixture of intermediate (2) (0.0822 molar). The mixture was stirred under _7 〇t: 1 hour, hydrolyzed, extracted with EtOAc and decanted. MgS04), filter and volatilize the solvent. Purify the residue with tannin by column chromatography. Collect the purified fraction and evaporate the solvent. And produces 24.9 grams (61%) of the intermediate (3).

(請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 C)將中間物(3)(〇.〇〇61莫耳濃度)和溶於NN-二甲 基乙醯胺(DMA)(20毫升)之疊氮化納(0.0079莫耳濃度)的 混合物於50°C之下攪拌18小時。待冷卻至室溫後將其倒 入冰水中。將其沉殿物過據、用水充份清洗後再以 CH2C12淬取。將其有機溶液乾燥、過濾並使其溶劑揮 發。將此殘留物從CH3CN DIPE中結晶。將沉澱物過濾 乾燥，而產生2.3公克（75%)溶點為232〜233。(：之(± )-5-(3-氣苯基)-α -(4-氣苯基)-α -(1-甲基-in-咪唑-5-基）四唑 基[l，5_a]啥唾琳-7-甲醇。 d)中間物(4)(0.0573毫莫耳濃度)和磺醯脲(300公克) 之混合物於16(TC之下攪拌5小時然後使其冷卻。加入冰 •15· 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1298723 A7 B7 五、發明說明（14) --------------^--- (睛先閱讀背面之注意事項再填寫本頁) 水、然後加入二氣甲烷，並將此混合物置於寅式鹽(celite) 上過濾。分離其有機層、乾燥(Mgs04)、過濾，並使溶劑 揮有直至乾燥為止。以柱色譜分析法用矽膠將此殘留物 純化。收集其純化的部份，並將其溶劑揮發，而產生7 5 公克(26%)之(± )-5-(3-氣笨基)_α ·(4-氣苯基彳卜甲基_ 1Η_咪唑-5-基）四唑基[i，5_a]喳唑啉冬甲胺（中間物5)。 e)將中間物(5)分開成為其對掌異構物，並以柱色譜 分析法在Chirlpak AD"®(溶析液：正己烷/Et〇H 50/50 ; 15〜35微米）上將其純化。收集其純化的第一（A)部份，並 將其溶劑揮發，而產生3.3公克的殘留物，並將其從 CHsCN/DIPE中結晶。將其沉澱物過濾乾燥，而產生255 公克之㈠-5-(3_氣笨基)-α 氣笨基>以甲基心仏咪 嗤基）四唑基[l，5_a]喳唑啉冬甲胺(化合物=- 7·16° (c=5 毫克/毫升 MeOH);溶點=178〜180。(： ； 1H- 線· NMR(DMSO，400MHz) 5 之 ppm ·· 8 73(d，J=8 6Hz lH)， 8.38(dd，J=8,6Hz，J=l,5Hz，lH) ； 7·74 〜7.67(m，3H)； 7.64(s,lH) ； 7.62^7.56(m?2H) ； 7.40(d,J=8.6Hz92H)； 7.21(d，J=8.6Hz，2H) ; 5.93(s，lH)，3.43(s，3H) ; 3.40(s， 經濟部智慧財產局員工消費合作社印製 寬，2H) ; MS(電喷，模式位置: 501 〜505(M+H)+ ; 473〜477, 391 〜395, 83 ；(Please read the notes on the back and fill out this page.) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives C) Intermediate (3) (〇.〇〇61 molar concentration) and dissolved in NN-dimethyl B A mixture of guanamine (DMA) (20 mL) of sodium azide (0.0079 molar) was stirred at 50 °C for 18 hours. After cooling to room temperature, pour it into ice water. The sulphate was washed and washed with water and then extracted with CH2C12. The organic solution was dried, filtered and the solvent was evaporated. This residue was crystallized from CH3CN DIPE. The precipitate was filtered and dried to give a 2.3 g (75%) melting point of 232 to 233. (:(±)-5-(3-Phenylphenyl)-α-(4-phenylphenyl)-α-(1-methyl-in-imidazol-5-yl)tetrazolyl [l,5_a啥 琳 琳 -7-7- methanol. d) Mixture of intermediate (4) (0.0573 millimolar concentration) and sulfonylurea (300 grams) was stirred at 16 (TC for 5 hours and then allowed to cool. Add ice • 15· The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1298723 A7 B7 V. Invention Description (14) --------------^--- ( Read the back of the book and fill in the page. Water, then add di-methane, and filter the mixture on celite. Separate the organic layer, dry (Mgs04), filter, and solvent. The residue was purified by column chromatography using a silica gel, and the purified fraction was collected, and the solvent was evaporated to give 7 5 g (26%) of (±)-5-(3) - a gas base) _α · (4-gas phenyl oxime methyl _ 1 Η _ imidazole-5-yl) tetrazolyl [i, 5_a] oxazoline amylamine (intermediate 5). e) intermediates ( 5) Separate into the palm of the isomer and use column chromatography in Chirlpak AD" (Solution: N-hexane/Et H 50/50; 15~35 micron) which was purified on. The purified first (A) fraction was collected and its solvent was volatilized to yield 3.3 g of residue which was crystallized from CHsCN/DIPE. The precipitate was filtered and dried to give 255 g of (i)-5-(3_qiqiji)-α gas base>methylmethyl oxime)tetrazolyl[l,5-a]oxazoline Methylamine (Compound=- 7.16° (c=5 mg/ml MeOH); melting point = 178~180. (: ; 1H-line · NMR (DMSO, 400MHz) 5 ppm ·· 8 73(d , J=8 6Hz lH), 8.38 (dd, J=8, 6Hz, J=l, 5Hz, lH); 7·74 ～7.67(m,3H); 7.64(s,lH) ; 7.62^7.56(m ? 2H) ; 7.40 (d, J = 8.6 Hz 92H); 7.21 (d, J = 8.6 Hz, 2H); 5.93 (s, lH), 3.43 (s, 3H); 3.40 (s, Ministry of Economic Affairs Intellectual Property Office staff Consumer cooperatives printed wide, 2H); MS (electrospray, mode position: 501 ~ 505 (M + H) +; 473 ~ 477, 391 ~ 395, 83;

Anal.(C25H18C12N8)C calcd· 59·89 found 59.71，H calcd· 3.62 found 3.52, N calcd. 22·35 found 22.17。此化合物以 HPLC(Chiralpak ADio微米溶析液：正己烧/乙醇50/50) 測定時含少於0.5%重量/重量之(+)對掌異構物。 •16- 本紙張尺度適用中國國家標準（CNS)A4規格（210 X 297公釐） 1298723 經濟部智慧財產局員工消費合作社印製 -I------裝 i — (請先閱讀背面之注意事項再填寫本頁) 線· Α7 Β7 五、發明說明（15) 收集第二(B)部份’在揮發後產生33公克之殘留 物，並將其從CHsCN/DIPE中結晶。將其沉澱物過濾乾 燥而產生2.6公克之(+)-5-(3-氣苯基)_α-(4-氣苯基-(1_曱基-1Η-咪唑-5-基）四唑基喳唑啉_7-甲胺（化合 物2)[a]D20 = +5·9° (c=：5毫克/毫升MeOH)。此化合物以 HPLC(Chiralpak ΑΟ®1〇微米溶析液：正己烧/乙醇50/50) 測定時含少於4%重量/重量之㈠對掌異構物。 C.醫藥上實例 宽金匕ς·ι: 生体外須；[发法尼基蛋白皙棘鉻醢之抑制作爾” WO98/40383第33〜34頁中描述於生体外測定法尼 基蛋白質轉移酶之抑制作用。 實例C.2 : ”拉司-棘也細胞表現型回復澍定” WO98/40383第34〜36頁中描述拉司-轉化細胞表現 型回復測定。 貧姓Jg·3 : ”法尼基蛋―白質轉移酶對次級腫瘤槿式夕抑申丨 作用” WO98/40383第37頁中描述法尼基蛋白質轉移酶對 次級腫瘤模式之抑制作用。 D·組—成物的實例：薄膜-句·釋錄劑 錠劑核心之Μ備 100公克本發明之化合物、570公克乳糖和2〇〇公克 澱粉之混合物將其充份混合後再以5公克之硫酸十二醋 -17- 本紙張尺度適用中國國家標準（CNS)A4規格（21〇 X 297公楚） '~' --—--- 1298723 〜___B7____ 五、發明說明（le) 納'合液和10公克聚乙烯-咄咯啶酮於約200毫升之水中使 、邊網化。將此濕潤化之混合物過滤、乾燥之後再過 濾。然後加入100公克微晶纖維雙糖和15公克的氫化植 物/由。全部混合均勻之後將其壓製成錠劑，總共10,000 顆鍵劑，每顆錠劑内含10毫克分子式（1)之化合物。 直—覆 將5公克乙基纖維雙糖溶於150毫升二氣甲炫之溶 液加入10公克甲基纖維雙糖溶於75毫升變性乙醇之溶 液。然後’再加入75毫升二氣甲烷和2.5毫升1，2,3-丙 三醇。將10公克聚乙烯甘油溶化，並使其溶於75毫升 之二氯曱烧。將前者溶液加入後者溶液，然後再加入2.5 公克硬脂酸鎂、5公克聚乙烯-吡咯啶酮和3〇毫升之濃縮 顏色懸浮液，並將其全部均質化。以包覆裝置將此混合 物包覆此錠劑之核心° (請先閲讀背面之注意事項再填寫本頁)Anal.(C25H18C12N8)C calcd· 59·89 found 59.71,H calcd· 3.62 found 3.52, N calcd. 22·35 found 22.17. This compound contained less than 0.5% w/w of (+) palmar isomers as determined by HPLC (Chiralpak ADio micronution: n-hexanol/ethanol 50/50). • 16- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298723 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -I------ loading i - (Please read the back Precautions Fill in this page again) Line · Α7 Β7 V. OBJECT DESCRIPTION (15) Collect the second (B) part to produce 33 grams of residue after volatilization and crystallize it from CHsCN/DIPE. The precipitate was filtered and dried to give 2.6 g of (+)-5-(3-phenylphenyl)-α-(4-phenylphenyl-(1-fluorenyl-1Η-imidazol-5-yl)tetrazolyl. Oxazoline 7-methylamine (Compound 2) [a] D20 = +5·9° (c=: 5 mg/ml MeOH). This compound was purified by HPLC (Chiralpak®® 1 〇 micron lysate: hexane / ethanol 50 / 50) The determination contains less than 4% by weight / weight of (a) palmar isomers. C. Pharmacological examples of wide gold 匕ς · ι: raw body; [faminyl protein 皙 醢 醢 醢Inhibition of farnesyl protein transferase in vitro was described in WO 98/40383, pages 33 to 34. Example C.2: "Lass-thorn also cell phenotype response confirmation" WO98/40383 The morphological recovery assay of ras-transformed cells is described on pages 34 to 36. Poor surname Jg·3: "Fanoji egg-white matter transferase effect on secondary tumors" WO98/40383 page 37 The inhibitory effect of farnesyl protein transferase on secondary tumor patterns is described. Example of D·group-formation: preparation of film-sentence-release-release tablet core 100 g of the compound of the invention, 570 g of lactose and 2〇〇公克淀The mixture is fully mixed and then 5 g of sulfuric acid 12-vinegar -17- This paper scale is applicable to China National Standard (CNS) A4 specification (21〇X 297 public Chu) '~' ------ 1298723 ~___B7____ V. INSTRUCTIONS (LE) Na's liquid and 10 g of polyethylene-pyridone are netted in about 200 ml of water. The humidified mixture is filtered, dried and then filtered. 100 g of microcrystalline fiber disaccharide and 15 g of hydrogenated plant/yield. After mixing well, press it into a tablet, a total of 10,000 bonds, each containing 10 mg of the compound of formula (1). Dissolve 5 grams of ethylcellulose disaccharide in 150 ml of dioxomethyst solution and add 10 g of methylcellulose disaccharide to 75 ml of denatured ethanol. Then add '75 ml of di-methane and 2.5 ml of 1, 2,3-propanetriol. Dissolve 10 g of polyvinyl glycerol and dissolve it in 75 ml of dichlorohydrazine. Add the former solution to the latter solution, then add 2.5 g of magnesium stearate, 5 g of polyethylene. a concentrated color suspension of pyrrolidone and 3 liters of water, and It is homogenized in its entirety. The mixture is coated with the mixture at the core of the tablet. (Please read the notes on the back and fill out this page)

經濟部智慧財產局員工消費合作社印製 本紙張尺度適射關冢標準(CNS)A4規格（210 X 297公釐）Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives. This paper is suitable for the standard (CNS) A4 specification (210 X 297 mm).

Claims (1)

經 部 智 慧 財 產 局 員 X 消 合 作 社 印 製 1298723 六 A8 B8 C8 D8 專利申請案第90114912號/ ROC Patent Appln. No.90114912 修正之申請專利範圍中文本替換頁—附件( —^Amended Claims in Chinese ~ (民國96年11月丨q日送呈） (Submitted on November 2007) 10 15 25 申,專利範揚 I公告本 ————J 丨购，恥产1 ▲種㈠_5_(3·氯苯基氯苯基)-士二 坐5基）四唑基喳唑咁_7_曱胺化合物以及其醫藥 上可接受之酸加成鹽類。 種（）5-(3-氣笨基)_α _(4_氯笨基)_q 基_他咪 唑-5-基）四唑基喳唑咁_7_甲胺化合物。 一種用於抑制腫瘤成長之醫藥組成物，其係含有醫药 ^可接又之載体，以及治療有效量之如申請專利範圍 第1項之化合物做為活性成份。 4·如申請專利範圍第3項之醫藥組成物，其中活性成份 係為如申請專利範圍第2項之化合物。 5·如申請專利範圍第3或4項之醫藥組成物，其係為劑 量單位之形式。 6.如申睛專利範圍第5項之醫藥組成物，其每一單位劍 量形式内含50至3〇〇毫克之活性成份。 7·如申請專利範圍第5或6項之醫藥組成物，其係為錠 劑的形式。 ’ 2· 3. 8·如申請專利範圍第i或2項之化合物，其係供使用於 藥物中。 9·如申請專利範圍第丨或2項之化合物，其仙於製造 抑制腫瘤生長之藥物。 1〇.如申請專利範圍第1或2項之化合物，其係用於治療 關節病。 11·如申請專利範圍第1〇項之化合物，其中關節病為風濕 性關節炎、骨關節炎、幼性關節炎、痛風、多發性關 -19 - 本紙張尺度適财_家標準(CNS)A4規格（21G x 297公#) 90240B-接 1 1298723 A8 B8 C8 D8_ 六、申請專利範圍 節炎、牛皮癬性關節炎、風濕性脊椎炎或全身性紅斑 性狼瘡。 12.如申請專利範圍第1或2項之化合物，其係用於治療 炎性狀況。 5 13.如申請專利範圍第12項之化合物，其中炎性狀況為潰 瘍性結腸炎、孔羅（Crohn’s)疾病、過敏性鼻炎、移 植物和宿主疾病、結合膜炎、氣喘、急性呼吸困難症 候群（ARDS)、Behcets氏疾病、移植的排斥、蓴麻 療、過敏性皮膚炎、簇狀禿髮、硬皮病、療病、濕 10 療、皮肌炎、痤瘡、糖尿病、全身性紅斑性狼瘡、 Kawasaki’s氏病、多發性硬化、氣腫、囊性纖維變性 或慢性支氣管炎。 14. 一種如申請專利範圍第1或2項之化合物於製備治療 關節病之藥物的用途。 15 15.如申請專利範圍第14項之用途，其中關節病為風濕性 關節炎、骨關節炎、幼性關節炎、痛風、多發性關節 炎、牛皮癬性關節炎、風濕性脊椎炎或全身性紅斑性 狼瘡。 經濟部智慧財產局員工消費合作社印製 16. —種如申請專利範圍第1或2項之化合物於製備治療 20 炎性狀況之藥物的用途。 17. 如申請專利範圍第16項之用途，其中炎性狀況為潰瘍 性結腸炎、孔羅（Crohn’s)疾病、過敏性鼻炎、移植 物和宿主疾病、結合膜炎、氣喘、急性呼吸困難症候 群(ARDS)、Behcets氏疾病、移植的排斥、蓴麻療、 -20 - 本紙張尺度適用中國國家標準(CNS)A4規格（210 X 297公釐） 1298723 C8 _D8_ 六、申請專利範圍 過敏性皮膚炎、簇狀禿髮、硬皮病、療病、濕療、皮 肌炎、痤瘡、糖尿病、全身性紅斑性狼瘡、Kawasaki’s 氏病、多發性硬化、氣腫、囊性纖維變性或慢性支氣 管炎。 5 18.—種用於治療關節病之醫藥組成物，其包含如申請專 利範圍第1或2項之化合物。 19. 如申請專利範圍第18項之醫藥組成物，其中關節病為 風濕性關節炎、骨關節炎、幼性關節炎、痛風、多發 性關節炎、牛皮癖性關節炎、風濕性脊椎炎或全身性 10 紅斑性狼瘡。 20. —種用於治療炎性狀況之醫藥組成物，其包含如申請 專利範圍第1或2項之化合物。 21. 如申請專利範圍第20項之醫藥組成物，其中炎性狀況 為潰瘍性結腸炎、孔羅（Crohn’s)疾病、過敏性鼻 15 炎、移植物和宿主疾病、結合膜炎、氣喘、急性呼吸 經濟部智慧財產局員工消費合作社印製 困難症候群(ARDS)、Behcets氏疾病、移植的排斥、 蓴麻療、過敏性皮膚炎、镇狀禿髮、硬皮病、療病、 濕療、皮肌炎、痤瘡、糖尿病、全身性紅斑性狼瘡、 Kawasaki’s氏病、多發性硬化、氣腫、囊性纖維變性 20 或慢性支氣管炎。 -21 - 本紙張尺度適用中國國家標準(CNS)A4規格（210x297公釐）Ministry of Economic Affairs, Intellectual Property Office, X Consumers Cooperative, Printing 1298723 Six A8 B8 C8 D8 Patent Application No. 90114912 / ROC Patent Appln. No.90114912 Revised Patent Application Medium Text Replacement Page - Attachment ( —^Amended Claims in Chinese ~ ( Submitted on November 2007 in the Republic of China) (Submitted on November 2007) 10 15 25 Shen, Patent Fan Yang I Announcement ————J 丨购, shame 1 ▲ species (1) _5_(3·chlorophenylchlorophenyl ) - Shi 2 sit 5 base) tetrazolylcarbazole 咁 7_ guanamine compound and its pharmaceutically acceptable acid addition salt. (5-(3-indolyl)_α_(4_chlorophenyl)_q-yl-t-amidazole-5-yl)tetrazolyloxazolidine-7-methylamine compound. A pharmaceutical composition for inhibiting tumor growth, which comprises a pharmaceutical carrier, and a therapeutically effective amount of a compound as claimed in claim 1 as an active ingredient. 4. The pharmaceutical composition according to item 3 of the patent application, wherein the active ingredient is a compound as in the second item of the patent application. 5. A pharmaceutical composition as claimed in claim 3 or 4, which is in the form of a dosage unit. 6. A pharmaceutical composition according to item 5 of the scope of the patent application, which contains 50 to 3 mg of active ingredient per unit of the sword form. 7. A pharmaceutical composition as claimed in claim 5 or 6, which is in the form of a tablet. ' 2 · 3. 8 · For the application of the compound of item i or 2 of the patent scope, it is for use in medicine. 9. If the compound of claim No. 2 or 2 is applied, it is used to manufacture a drug that inhibits tumor growth. 1. A compound according to claim 1 or 2 for use in the treatment of arthropathy. 11. The compound of the first paragraph of the patent application, wherein the joint disease is rheumatoid arthritis, osteoarthritis, juvenile arthritis, gout, multiple seizures - this paper scale is suitable for the family - (CNS) A4 size (21G x 297 public #) 90240B-connected 1 1298723 A8 B8 C8 D8_ VI. Patent application range of inflammation, psoriatic arthritis, rheumatic spondylitis or systemic lupus erythematosus. 12. A compound according to claim 1 or 2 for use in the treatment of an inflammatory condition. 5 13. The compound of claim 12, wherein the inflammatory condition is ulcerative colitis, Crohn's disease, allergic rhinitis, graft and host disease, conjunctivitis, asthma, acute dyspnea syndrome (ARDS), Behcets' disease, transplant rejection, ramie therapy, allergic dermatitis, clustered baldness, scleroderma, treatment, wet 10, dermatomyositis, acne, diabetes, systemic lupus erythematosus , Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis or chronic bronchitis. 14. Use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment of arthropathy. 15 15. The use of the scope of claim 14 wherein the joint disease is rheumatoid arthritis, osteoarthritis, jaundice, gout, polyarthritis, psoriatic arthritis, rheumatic spondylitis or systemic Lupus erythematosus. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 16. The use of a compound as claimed in claim 1 or 2 for the preparation of a medicament for the treatment of 20 inflammatory conditions. 17. For the use of claim 16 of the patent application, wherein the inflammatory condition is ulcerative colitis, Crohn's disease, allergic rhinitis, graft and host disease, conjunctivitis, asthma, acute dyspnea syndrome ( ARDS), Behcets' disease, transplant rejection, ramie therapy, -20 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1298723 C8 _D8_ VI. Patented area of allergic dermatitis, Clustered baldness, scleroderma, treatment, moist therapy, dermatomyositis, acne, diabetes, systemic lupus erythematosus, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis or chronic bronchitis. A pharmaceutical composition for treating arthropathy, which comprises a compound as claimed in claim 1 or 2. 19. The pharmaceutical composition of claim 18, wherein the joint disease is rheumatoid arthritis, osteoarthritis, jaundice, gout, polyarthritis, psoriatic arthritis, rheumatic spondylitis or whole body Sexual 10 lupus erythematosus. 20. A pharmaceutical composition for treating an inflammatory condition, comprising a compound as claimed in claim 1 or 2. 21. The pharmaceutical composition of claim 20, wherein the inflammatory condition is ulcerative colitis, Crohn's disease, allergic rhinitis, graft and host disease, conjunctivitis, asthma, acute Department of Respiratory Economics Intellectual Property Bureau Staff Consumer Cooperative Printed Difficult Syndrome (ARDS), Behcets' disease, transplant rejection, ramie therapy, allergic dermatitis, alopecia areata, scleroderma, treatment, moist therapy, skin Myositis, acne, diabetes, systemic lupus erythematosus, Kawasaki's disease, multiple sclerosis, emphysema, cystic fibrosis 20 or chronic bronchitis. -21 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm)