TW202241846A - Salts, solvates and crystals of compounds with ep antagonistic activity - Google Patents

Salts, solvates and crystals of compounds with ep antagonistic activity Download PDF

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TW202241846A
TW202241846A TW110148402A TW110148402A TW202241846A TW 202241846 A TW202241846 A TW 202241846A TW 110148402 A TW110148402 A TW 110148402A TW 110148402 A TW110148402 A TW 110148402A TW 202241846 A TW202241846 A TW 202241846A
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大谷修平
藤戸貴之
西馬直希
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日商小野藥品工業股份有限公司
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Abstract

An object of the present disclosure is to provide a compound having antagonistic activity against the EP 2receptor and a suitable form for a drug substance thereof in the prevention and/or treatment of a disease caused by activation of the EP 2receptor. As a solution, provided is a compound I having an antagonistic activity against the EP 2receptor. Further, the crystals of compound I disclosed in the present specification, salts of compound I, solvates and crystals thereof are provided as drug substances.

Description

具有EP2拮抗活性之化合物的鹽、溶劑合物及結晶Salts, solvates and crystals of compounds having EP2 antagonistic activity

本揭示係關於(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸(以下，亦有簡稱為化合物I之情形)之結晶、化合物I的鹽、溶劑合物及此等之結晶等。This disclosure relates to (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Crystals of cyclopropane-1-carboxylic acid (hereinafter also referred to simply as compound I), salts and solvates of compound I, crystals thereof, and the like.

***素E 2(PGE 2)已知為花生四烯酸級聯反應(Arachidonic Acid CascadE)中的代謝產物，且已知具有細胞保護作用、子宮收縮作用、疼痛閾值的降低作用、消化道的蠕動運動促進作用、覺醒作用、胃酸分泌抑制作用、血壓降低作用、利尿作用等。 Prostaglandin E 2 (PGE 2 ) is known as a metabolite in the Arachidonic Acid CascadE, and is known to have cytoprotective effects, uterine contraction effects, pain threshold lowering effects, peristalsis of the digestive tract Exercise promoting effect, awakening effect, gastric acid secretion inhibitory effect, blood pressure lowering effect, diuretic effect, etc.

PGE 2受體中分別存在有作用不同的次類型，稱為EP 1受體、EP 2受體、EP 3受體、EP 4受體(非專利文獻1)。 There are different subtypes of PGE 2 receptors, which are called EP 1 receptors, EP 2 receptors, EP 3 receptors, and EP 4 receptors (Non-Patent Document 1).

該等次類型之中，已知由於EP 2受體有關cAMP的訊號，故與氣管或迴腸的輪狀肌的鬆弛或各種血管的擴張相關聯。又，已知PI3K、Akt、或GSK-3β的表現或與IL-1β、IL-6、IL-12、IL-23、IL-27有關聯。此外，咸認EP 2受體與來自巨噬細胞的MCP-1產生抑制，來自淋巴球的TNF-α、IL-2、及IFN-γ產生抑制，以及因IL-10產生增強導致的抗炎症、血管擴張、血管新生、彈性纖維的形成抑制，MMP-9表現調節相關聯。除此之外，EP 2受體亦與源自骨髓(Myeloid)的免疫抑制細胞(Myeoid Derived Suppressor Cells)、透過調節性T細胞及自然殺手細胞對癌症免疫調節相關聯。 Among these subtypes, it is known that the EP 2 receptor-related cAMP signal is associated with relaxation of the rotiform muscle of the trachea or ileum or dilation of various blood vessels. Also, expression of PI3K, Akt, or GSK-3β is known to be associated with IL-1β, IL-6, IL-12, IL-23, and IL-27. In addition, it is believed that EP2 receptor and MCP-1 production from macrophages are suppressed, TNF-α, IL-2, and IFN-γ production from lymphocytes are suppressed, and anti-inflammation due to enhanced IL-10 production is believed , vasodilation, angiogenesis, inhibition of elastic fiber formation, and regulation of MMP-9 expression. In addition, EP 2 receptors are also associated with myeloid-derived immunosuppressive cells (Myeoid Derived Suppressor Cells), through regulatory T cells and natural killer cells to cancer immune regulation.

由此來看，已知EP 2受體與抗炎症作用、神經保護作用、抗腫瘤效果有關聯，且咸認與EP 2受體強力結合且具有拮抗作用的化合物可用於起因於EP 2受體的活化之疾病，例如子宮內膜症、子宮肌瘤、月經過多、肌腺症、月經困難症、慢性骨盆痛症候群、癌症、炎症性疼痛、神經因性疼痛、頭痛、偏頭痛、術後疼痛、間質性膀胱炎、平滑肌瘤、過敏性大腸症候群、阿茲海默氏症、帕金森氏症、肌萎縮性側索硬化症(Amyotrophic Lateral Sclerosis)、多發性硬化症、風濕病、骨關節炎、痛風、過敏性疾病、高血壓、腦機能障礙、缺血、腦溢血、腎疾病、移植排斥反應、粥狀動脈硬化症、缺血性心臟病、尋常性痤瘡、氣喘、***炎、腎絲球性腎炎、類肉瘤病(sarcoidosis)、血管炎、及自體免疫疾病等的預防及/或治療(非專利文獻2至4)。 From this point of view, it is known that EP2 receptors are associated with anti-inflammatory effects, neuroprotective effects, and antitumor effects, and it is believed that compounds that strongly bind to EP2 receptors and have antagonistic effects can be used to treat diseases caused by EP2 receptors . Activation of diseases such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative Pain, Interstitial Cystitis, Leiomyoma, Irritable Bowel Syndrome, Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Rheumatism, Osteoarthritis, gout, allergic diseases, hypertension, brain dysfunction, ischemia, cerebral hemorrhage, kidney disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, Prevention and/or treatment of glomerulonephritis, sarcoidosis, vasculitis, and autoimmune diseases (Non-Patent Documents 2 to 4).

另一方面，專利文獻1所記載的下述通式(A)所示之化合物係記載使用於與SRS-A關聯的疾病，例如過敏性疾病、缺血性心臟病、或炎症等的治療。On the other hand, the compound represented by the following general formula (A) described in Patent Document 1 is described for use in the treatment of diseases associated with SRS-A, such as allergic diseases, ischemic heart disease, or inflammation.

通式(A)為

Figure 02_image001
(式中，A A表示氫原子、苯基、或苯氧基； n A表示3至10的整數； R 1A表示氫原子或低級烷氧基； X 1A表示-CO-Y 2A-(Y 2A為-NH-等)等；
Figure 02_image003
表示
Figure 02_image005
等， R 2A表示氫原子、鹵素、低級鹵烷基等， X 2A表示-Y 3A-Y 4A-，Y 3A表示單鍵等，Y 4A表示由1至6個碳原子所構成之伸烷基等； D A表示羧基、低級烷氧基羰基等(摘錄一部分之基的定義))。 General formula (A) is
Figure 02_image001
(In the formula, A A represents a hydrogen atom, phenyl, or phenoxy; n A represents an integer from 3 to 10; R 1A represents a hydrogen atom or a lower alkoxy group; X 1A represents -CO-Y 2A -(Y 2A for -NH- etc.), etc.;
Figure 02_image003
express
Figure 02_image005
etc., R 2A represents a hydrogen atom, halogen, lower haloalkyl, etc., X 2A represents -Y 3A -Y 4A -, Y 3A represents a single bond, etc., Y 4A represents an alkylene group composed of 1 to 6 carbon atoms etc.; D A represents a carboxyl group, a lower alkoxycarbonyl group, etc. (a part of the definition of the base is extracted)).

又，EP 2拮抗藥已知有例如專利文獻2中的下述通式(B)所示之化合物或、專利文獻3中的下述通式(C)所示之化合物等。 Also, known EP 2 antagonists include, for example, compounds represented by the following general formula (B) in Patent Document 2, or compounds represented by the following general formula (C) in Patent Document 3, and the like.

通式(B)為

Figure 02_image007
(式中，A B表示NR 5B等； U B表示CX 5B或N； W B表示CX 6B或N； n B表示1、2、3、或4； R 1B表示碳環、芳基、雜環等； X 1B、X 2B、X 3B、X 4B分別可為相同或不同，且表示氫原子、烷基、鹵素等； R 5B表示氫原子或烷基等； X 5B、X 6B分別可為相同或不同，且表示氫原子或烷基等(摘錄一部分之基的定義))。 General formula (B) is
Figure 02_image007
(In the formula, A B represents NR 5B etc.; U B represents CX 5B or N; W B represents CX 6B or N; n B represents 1, 2, 3, or 4; R 1B represents carbocyclic, aryl, heterocyclic etc.; X 1B , X 2B , X 3B , and X 4B can be the same or different, and represent a hydrogen atom, an alkyl group, a halogen, etc.; R 5B represents a hydrogen atom or an alkyl group, etc.; X 5B , X 6B can be the same respectively or different, and represent a hydrogen atom or an alkyl group, etc. (excerpt from the definition of a part of the group)).

通式(C)為

Figure 02_image009
(式中，A c表示可經取代之C5至12的雜芳基； R ’c表示‐S(O) p-C1至C6烷基等，p為0至2； R 1c表示氫原子或C1至C6烷基等； R 2c、R 3c、R 4c分別表示氫原子或鹵素等； X c表示-C=C-等； Y c表示-(CH 2) n-，n為2或3(摘錄一部分之基的定義))。 The general formula (C) is
Figure 02_image009
(In the formula, A c represents a C5 to 12 heteroaryl group that can be substituted; R'c represents -S(O) p -C1 to C6 alkyl, etc., p is 0 to 2; R 1c represents a hydrogen atom or C1 to C6 alkyl, etc.; R 2c , R 3c , R 4c represent hydrogen atoms or halogens, etc.; X c represents -C=C-, etc.; Y c represents -(CH 2 ) n -, n is 2 or 3 (excerpt part of the base definition)).

此外，專利文獻4中，記載了(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸係具有EP 2拮抗活性的化合物。 In addition, Patent Document 4 describes (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(tri Fluoromethyl)phenyl}cyclopropane-1-carboxylic acids are compounds with EP 2 antagonistic activity.

然而，任何先前技術文獻均未記載本說明書中揭示之化合物I之鹽、溶劑合物及此等之結晶。 [先前技術文獻] [專利文獻] However, the salts, solvates and crystals of Compound I disclosed in this specification are not described in any prior technical documents. [Prior Art Literature] [Patent Document]

[專利文獻1] 國際公開第1986/005779號冊子 [專利文獻2] 國際公開第2012/177618號冊子 [專利文獻3] 國際公開第2008/152097號冊子 [專利文獻4] 國際申請第2020/262603號冊子 [非專利文獻] [Patent Document 1] International Publication No. 1986/005779 Pamphlet [Patent Document 2] International Publication No. 2012/177618 Pamphlet [Patent Document 3] International Publication No. 2008/152097 [Patent Document 4] International Application No. 2020/262603 Booklet [Non-patent literature]

[非專利文獻1] Journal of Lipid Mediators and Cell Signalling、第12卷、379-391頁、1995年 [非專利文獻2] Journal of the Medicinal Chemistry、第57卷、4454-4465頁、2014年 [非專利文獻3] Trends in Pharmacological Science、第34卷、413-423頁、2013年 [非專利文獻4] International Journal of molecular medicine、第42卷 1203-1214頁、2018年 [Non-Patent Document 1] Journal of Lipid Mediators and Cell Signaling, Vol. 12, pp. 379-391, 1995 [Non-Patent Document 2] Journal of the Medicinal Chemistry, Vol. 57, Pages 4454-4465, 2014 [Non-Patent Document 3] Trends in Pharmacological Science, Vol. 34, Pages 413-423, 2013 [Non-Patent Document 4] International Journal of molecular medicine, Vol. 42, pp. 1203-1214, 2018

(發明欲解決之課題)(Problem to be solved by the invention)

本揭示之課題提供一種對於EP 2受體具有強力的拮抗活性，且有用作為起因於EP 2受體之活性化之疾病的預防及/或治療藥的化合物及適用於其醫藥品原藥的型態。 (解決課題之手段) The object of the present disclosure is to provide a compound having potent antagonistic activity against EP2 receptors and useful as a prophylactic and/or therapeutic drug for diseases caused by activation of EP2 receptors , and a form suitable for the active drug thereof state. (means to solve the problem)

本發明人等為了解決前述課題而深入研究，結果發現：化合物I對於EP 2受體具有強力的拮抗活性，且有用作為起因於EP 2受體之活性化之疾病的預防及/或治療藥，以及適用在化合物I之醫藥品原藥的型態(例如化合物I之結晶，以及化合物I之鹽、溶劑合物及此等之結晶)。 The inventors of the present invention conducted intensive studies to solve the aforementioned problems, and as a result, found that compound I has a strong antagonistic activity against EP2 receptors and is useful as a preventive and/or therapeutic agent for diseases caused by activation of EP2 receptors , As well as the form of the original pharmaceutical drug suitable for Compound I (such as the crystals of Compound I, and the salts, solvates and crystals of Compound I).

本揭示提供例如下述之實施態樣。The present disclosure provides, for example, the following implementation aspects.

[1]一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸的溶劑合物；[1] A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro A solvate of methyl)phenyl}cyclopropane-1-carboxylic acid;

[2]一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸的鹽、或其溶劑合物；[2] A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro A salt of methyl)phenyl}cyclopropane-1-carboxylic acid, or a solvate thereof;

[3]如前述[1]或[2]記載之化合物，其係結晶型態；[3] The compound described in [1] or [2] above, which is in a crystalline form;

[3’]一種如前述[1]或[2]記載之化合物的結晶，以及[3'] A crystal of the compound described in the aforementioned [1] or [2], and

[4]一種屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸；[4] A (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(tri Fluoromethyl)phenyl}cyclopropane-1-carboxylic acid;

[4’]一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶等。 (發明之效果) [4'] A kind of (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) Crystals of phenyl}cyclopropane-1-carboxylic acid, etc. (Effect of Invention)

由於化合物I對於EP 2受體具有強力的拮抗活性，故有用作為起因於EP 2受體之活性化之疾病的預防及/或治療藥。此外，本說明書中所揭示之化合物I之結晶、化合物I的鹽、溶劑合物及此等之結晶(以下，亦有簡稱為本發明之型態之情形)由於化學穩定性優異，因此有用作為醫藥品原藥。 Compound I is useful as a prophylactic and/or therapeutic agent for diseases caused by activation of EP2 receptor because of its strong antagonistic activity against EP2 receptor . In addition, the crystals of Compound I disclosed in this specification, the salts of Compound I, solvates, and these crystals (hereinafter, sometimes referred to simply as the form of the present invention) are excellent in chemical stability, so they are useful as Pharmaceutical raw materials.

本揭示中，(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸(化合物I)係意指以下之結構式所示之化合物。

Figure 02_image011
(式中，符號
Figure 02_image013
表示與紙面的另一側(亦即α-配置)鍵結) In this disclosure, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene The group}cyclopropane-1-carboxylic acid (compound I) refers to the compound represented by the following structural formula.
Figure 02_image011
(where, the symbol
Figure 02_image013
Indicates bonding to the other side of the paper (i.e. α-configuration))

本揭示中，作為本發明之型態，較佳係： (1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之水合物、 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之水合物、 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸、 鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]、 屬於結晶型態之鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]、 鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物、 屬於結晶型態之鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物、 (1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽、 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽、 鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]、 屬於結晶型態之鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]、 鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物、或 屬於結晶型態之鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物。 In this disclosure, as the form of the present invention, it is preferable to: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane -1-Carboxylic acid hydrate, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid hydrate, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid, Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }cyclopropane-1-carboxylate], Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate], Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }cyclopropane-1-carboxylate] hydrate, Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate] hydrate, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane -1-carboxylic acid dicyclohexylamine salt, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid dicyclohexylamine salt, Calcium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }cyclopropane-1-carboxylate], Calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate], Calcium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }cyclopropane-1-carboxylate] hydrate, or Calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate] hydrate.

本揭示中，作為本發明之型態，更佳係： 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之水合物、 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸、 屬於結晶型態之鎂雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物、 屬於結晶型態之(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸二環己胺鹽、 屬於結晶型態之鈣雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]之水合物。 In this disclosure, as the form of the present invention, it is more preferable to: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid hydrate, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid, Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate] hydrate, (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) in crystalline form Phenyl}cyclopropane-1-carboxylic acid dicyclohexylamine salt, Calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro Methyl)phenyl}cyclopropane-1-carboxylate] hydrate.

本揭示中，作為本發明之型態，再較佳係： (1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(C晶)、 (1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(D晶)、 鎂雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物之結晶(A晶)、或 (1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸二環己胺鹽之結晶(E晶)。 In this disclosure, as the form of the present invention, it is more preferable to: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane -1-Carboxylic acid monohydrate crystal (C crystal), (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane -1-Carboxylic acid crystal (D crystal), Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Cyclopropane-1-carboxylate] decahydrate crystal (A crystal), or (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane - Crystal of 1-carboxylic acid dicyclohexylamine salt (E crystal).

本揭示中，作為本發明之型態，特佳係：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(A晶)。In this disclosure, as the form of the present invention, the most preferred is: (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide Crystals of ]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid monohydrate (crystal A).

本揭示中，作為本發明之型態，亦以(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物為較佳。In this disclosure, (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]- 4-(Trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid monohydrate is preferred.

本揭示中，作為本發明之型態，較佳係化學穩定性優異者。更佳係以化學穩定性試驗中記載之方法所測量的條件1中之殘存率(%)為95%以上、再較佳係以化學穩定性試驗中記載之方法所測量的條件1中之殘存率(%)為99%以上。In the present disclosure, as an aspect of the present invention, those having excellent chemical stability are preferable. More preferably, the residual rate (%) in condition 1 measured by the method recorded in the chemical stability test is 95% or more, and more preferably the residual rate (%) in condition 1 measured by the method recorded in the chemical stability test The rate (%) is 99% or more.

本揭示中，結晶形之差異係藉由粉末X射線繞射譜、微差掃描熱量測量(DSC)、結晶學的數據及/或位置參數(部分原子座標)而區別。In the present disclosure, differences in crystal forms are distinguished by powder X-ray diffraction spectroscopy, differential scanning calorimetry (DSC), crystallographic data and/or positional parameters (partial atomic coordinates).

鎂雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物之結晶(A晶)係具以下(a)及(b)之至少一個物理化學數據的特徵。較佳係具(a)及(b)之兩者的物理化學數據的特徵。Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl The crystal of }cyclopropane-1-carboxylate] decahydrate (crystal A) is characterized by at least one of the following physicochemical data of (a) and (b). Preferably it is characterized by the physicochemical data of both (a) and (b).

(a)(i)圖1所示之粉末X射線繞射譜、(ii)與顯示圖1所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個、7個或者8個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同之粉末X射線繞射譜、(iii)在表1所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表1所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜，或者(v)在約6.8、約10.2、約13.6、約17.0、約18.6、約20.1、約23.9、及約26.3度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜。(a) (i) the powder X-ray diffraction spectrum shown in Figure 1, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 1 (for example, the highest 1, 2 in order of intensity , 3, 4, 5, 6, 7 or 8 peaks) or all peaks whose diffraction angles (2θ) belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) in the table Powder X-ray diffraction spectrum with a peak at the diffraction angle (2θ) shown in 1 or substantially the same diffraction angle (2θ), (iv) from the diffraction angle (2θ) shown in Table 1 or substantially the same Select more than one diffraction angle (2θ) on the same diffraction angle (2θ) to have more than one (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8 A powder X-ray diffraction spectrum of the peak of ), or (v) select one or more diffraction angles at about 6.8, about 10.2, about 13.6, about 17.0, about 18.6, about 20.1, about 23.9, and about 26.3 degrees (2θ) A powder X-ray diffraction spectrum having one or more (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8) peaks.

(b)圖2所示之DSC圖表、或DSC中之約25℃至約85℃之範圍內的吸熱峰(例如，寬吸熱峰)。(b) The DSC graph shown in FIG. 2 , or an endothermic peak (for example, a broad endothermic peak) in the range of about 25°C to about 85°C in DSC.

鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]m水合物(m表示4至8)之結晶(L晶)係具以下(c)之物理化學數據的特徵。Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl The crystals (L crystals) of }cyclopropane-1-carboxylate]m hydrate (m represents 4 to 8) are characterized by the following physicochemical data in (c).

(c)(i)圖4所示之粉末X射線繞射譜、(ii)與顯示圖4所示之粉末X射線繞射譜之主要的峰(以強度順序最高1個、2個、3個、4個、5個、6個或者7個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表2所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表2所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜，或者(v)在由約6.8、約10.2、約13.7、約16.1、約21.7、約24.3、及約25.5度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜。(c) (i) the powder X-ray diffraction spectrum shown in Figure 4, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 4 (highest 1, 2, 3 in order of intensity , 4, 5, 6 or 7 peaks) or the diffraction angles (2θ) of all peaks belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) the diffraction angles (2θ) shown in Table 2 A powder X-ray diffraction spectrum having a peak at a radiation angle (2θ) or a diffraction angle (2θ) substantially the same as it, (iv) from a diffraction angle (2θ) shown in Table 2 or a diffraction angle (2θ) substantially the same as it Angle (2θ) Select more than one diffraction angle (2θ) with more than one (for example, at least 1, 2, 3, 4, 5, 6 or 7) peaks of X-ray powder Diffraction spectrum, or (v) has more than one diffraction angle (2θ) selected from about 6.8, about 10.2, about 13.7, about 16.1, about 21.7, about 24.3, and about 25.5 degrees (for example, Powder X-ray diffraction spectrum of at least 1, 2, 3, 4, 5, 6 or 7) peaks.

鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　n水合物(n表示4至8)之結晶(H晶)係具以下(d)之物理化學數據的特徵。Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Cyclopropane-1-carboxylate] The crystal (H crystal) of n-hydrate (n represents 4 to 8) is characterized by the following physicochemical data in (d).

(d)(i)圖5所示之粉末X射線繞射譜、(ii)與顯示圖5所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個或者7個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表3所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表3所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜，或者(v)在由約6.9、約10.4、約13.9、約16.5、約18.4、約19.1、及約25.6度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜。(d) (i) the powder X-ray diffraction spectrum shown in Figure 5, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 5 (for example, the highest in order of intensity 1, 2 , 3, 4, 5, 6 or 7 peaks) or the diffraction angles (2θ) of all peaks belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) shown in Table 3 The diffraction angle (2θ) or its substantially identical diffraction angle (2θ) has a powder X-ray diffraction spectrum with a peak, (iv) from the diffraction angle (2θ) shown in Table 3 or its substantially identical The diffraction angle (2θ) selects more than one diffraction angle (2θ) with more than one (for example, at least 1, 2, 3, 4, 5, 6 or 7) peaks X-ray diffraction spectrum, or (v) has one or more diffraction angles (2θ) selected from about 6.9, about 10.4, about 13.9, about 16.5, about 18.4, about 19.1, and about 25.6 degrees ( For example, a powder X-ray diffraction spectrum of at least 1, 2, 3, 4, 5, 6 or 7) peaks.

鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]p水合物(p表示超過0且8以下)之結晶(M晶)係具以下(e)之物理化學數據的特徵。Magnesium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl The crystal (M crystal) of }cyclopropane-1-carboxylate]p hydrate (p represents more than 0 and less than 8) is characterized by the following physicochemical data of (e).

(e)(i)圖6所示之粉末X射線繞射譜、(ii)與顯示圖6所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個或者7個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)具有表4所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)的粉末X射線繞射譜、(iv)在從表4所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜，或者(v)在由約7.2、約10.8、約14.4、約16.3、約21.6、約22.8、及約23.7度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜。(e) (i) the powder X-ray diffraction spectrum shown in Figure 6, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 6 (for example, the highest in order of intensity 1, 2 , 3, 4, 5, 6 or 7 peaks) or the diffraction angles (2θ) of all peaks belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) have the powder X-ray diffraction spectrum shown in Table 4 The powder X-ray diffraction spectrum of the diffraction angle (2θ) or its substantially the same diffraction angle (2θ), (iv) at the diffraction angle (2θ) shown in Table 4 or its substantially the same diffraction angle The angle of incidence (2θ) selects more than one diffraction angle (2θ) with more than one (for example, at least 1, 2, 3, 4, 5, 6 or 7) peaks X A ray diffraction spectrum, or (v) has one or more diffraction angles (2θ) selected from about 7.2, about 10.8, about 14.4, about 16.3, about 21.6, about 22.8, and about 23.7 degrees (such as , at least 1, 2, 3, 4, 5, 6 or 7) peak powder X-ray diffraction spectrum.

(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　一水合物之結晶(C晶)係具以下(f)及(g)之至少一個之物理化學數據的特徵。較佳係具(f)及(g)之兩者的物理化學數據的特徵。(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane - The crystal of 1-carboxylic acid monohydrate (crystal C) is characterized by at least one of the following physicochemical data of (f) and (g). Preferably it is characterized by the physicochemical data of both (f) and (g).

(f)(i)圖7所示之粉末X射線繞射譜、(ii)與顯示圖7所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個、7個或者8個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表5所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表5所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜，或者(v)在由約7.0、約10.7、約14.0、約16.3、約21.5、約24.9、約25.9、及約27.8度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜。(f) (i) the powder X-ray diffraction spectrum shown in Figure 7, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 7 (for example, the highest in order of intensity 1, 2 , 3, 4, 5, 6, 7 or 8 peaks) or all peaks whose diffraction angles (2θ) belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) in the table Powder X-ray diffraction spectrum with a peak at the diffraction angle (2θ) shown in Table 5 or substantially the same diffraction angle (2θ), (iv) from the diffraction angle (2θ) shown in Table 5 or substantially the same Select more than one diffraction angle (2θ) on the same diffraction angle (2θ) to have more than one (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8 A powder X-ray diffraction spectrum of the peak of (v), or (v) diffraction at more than one selected from about 7.0, about 10.7, about 14.0, about 16.3, about 21.5, about 24.9, about 25.9, and about 27.8 degrees Angle (2θ) Powder X-ray Diffraction Spectrum having 1 or more (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8) peaks.

(g)圖8所示之DSC圖、或DSC中之(i)起始溫度為約30℃或峰溫度為約50℃的吸熱峰及/或(ii)起始溫度為約70℃或峰溫度為約77℃的吸熱峰。(g) the DSC diagram shown in Figure 8, or (i) an endothermic peak with an onset temperature of about 30° C. or a peak temperature of about 50° C. and/or (ii) an onset temperature of about 70° C. or a peak in the DSC The temperature is an endothermic peak at about 77°C.

(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(B晶)係具以下(h)之物理化學數據的特徵。(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane - The crystal of 1-carboxylic acid (crystal B) is characterized by the following physicochemical data in (h).

(h)(i)圖10所示之粉末X射線繞射譜、(ii)與顯示圖10所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個、7個或者8個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表6所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表6所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜，或者(v)在約7.6、約8.7、約11.4、約15.3、約17.6、約19.3、約22.6、及約26.5度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜。(h) (i) the powder X-ray diffraction spectrum shown in Figure 10, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 10 (for example, the highest in order of intensity 1, 2 , 3, 4, 5, 6, 7 or 8 peaks) or all peaks whose diffraction angles (2θ) belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) in the table Powder X-ray diffraction spectrum with a peak at the diffraction angle (2θ) shown in Table 6 or substantially the same diffraction angle (2θ), (iv) from the diffraction angle (2θ) shown in Table 6 or substantially the same Select more than one diffraction angle (2θ) on the same diffraction angle (2θ) to have more than one (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8 A powder X-ray diffraction spectrum of the peak of ), or (v) select one or more diffraction angles at about 7.6, about 8.7, about 11.4, about 15.3, about 17.6, about 19.3, about 22.6, and about 26.5 degrees (2θ) A powder X-ray diffraction spectrum having one or more (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8) peaks.

(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(D晶)係具以下(j)及(k)之至少一個之物理化學數據的特徵。較佳係具(j)及(k)之兩者的物理化學數據的特徵。(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane - The crystal of 1-carboxylic acid (D crystal) is characterized by at least one of the following physicochemical data of (j) and (k). Preferably it is characterized by the physicochemical data of both (j) and (k).

(j)(i)圖11所示之粉末X射線繞射譜、(ii)與顯示圖11所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個、7個或者8個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表7所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表7所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜，或者(v)在約7.7、約10.3、約13.4、約15.5、約16.9、約19.7、約21.3、及約22.9度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜。(j) (i) the powder X-ray diffraction spectrum shown in Figure 11, (ii) and the main peaks showing the powder X-ray diffraction spectrum shown in Figure 11 (for example, the highest in order of intensity 1, 2 , 3, 4, 5, 6, 7 or 8 peaks) or all peaks whose diffraction angles (2θ) belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) in the table A powder X-ray diffraction spectrum having a peak at the diffraction angle (2θ) shown in Table 7 or substantially the same diffraction angle (2θ), (iv) from the diffraction angle (2θ) shown in Table 7 or substantially the same Select more than one diffraction angle (2θ) on the same diffraction angle (2θ) to have more than one (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8 The powder X-ray diffraction spectrum of the peak of a), or (v) select one or more diffraction angles at about 7.7, about 10.3, about 13.4, about 15.5, about 16.9, about 19.7, about 21.3, and about 22.9 degrees (2θ) A powder X-ray diffraction spectrum having one or more (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8) peaks.

(k)圖12所示之DSC圖、或DSC中之起始溫度為約69℃或峰溫度為約76℃的吸熱峰。(k) The DSC chart shown in Fig. 12, or an endothermic peak with an onset temperature of about 69°C or a peak temperature of about 76°C in DSC.

(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽之結晶(E晶)係具以下(l)及(m)之至少一個之物理化學數據的特徵。較佳係具(l)及(m)之兩者的物理化學數據的特徵。(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane - The crystal of 1-carboxylic acid dicyclohexylamine salt (crystal E) is characterized by at least one of the following physical and chemical data of (l) and (m). Preferably it is characterized by the physicochemical data of both (l) and (m).

(l)(i)圖13所示之粉末X射線繞射譜、(ii)顯示圖13所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個或者7個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表8所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表8所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜，或者(v)在由約5.9、約7.9、約11.4、約18.8、約21.2、約22.7、及約25.3度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個或者7個)之峰的粉末X射線繞射譜。(l) (i) the powder X-ray diffraction spectrum shown in Figure 13, (ii) showing the main peaks of the powder X-ray diffraction spectrum shown in Figure 13 (e.g., highest in order of intensity 1, 2, 3, 4, 5, 6 or 7 peaks) or the diffraction angles (2θ) of all peaks belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) as shown in Table 8 A powder X-ray diffraction spectrum having a peak at a diffraction angle (2θ) or a diffraction angle (2θ) substantially the same as that, (iv) from a diffraction angle (2θ) shown in Table 8 or a diffraction angle (2θ) substantially the same as The angle of incidence (2θ) selects more than one diffraction angle (2θ) with more than one (for example, at least 1, 2, 3, 4, 5, 6 or 7) peaks X A ray diffraction spectrum, or (v) has one or more diffraction angles (2θ) selected from about 5.9, about 7.9, about 11.4, about 18.8, about 21.2, about 22.7, and about 25.3 degrees (such as , at least 1, 2, 3, 4, 5, 6 or 7) peak powder X-ray diffraction spectrum.

(m)圖14所示之DSC圖、或DSC中之起始溫度為約153℃或峰溫度為約155℃的吸熱峰。(m) The DSC chart shown in FIG. 14 , or an endothermic peak with an onset temperature of about 153°C or a peak temperature of about 155°C in DSC.

鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　q水合物(q表示4至8)之結晶(F晶)係具以下(n)、及(o)之至少一個之物理化學數據的特徵。較佳係具(n)及(o)之兩者的物理化學數據的特徵。Calcium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Cyclopropane-1-carboxylate] The crystal (F crystal) of q hydrate (q represents 4 to 8) is characterized by at least one of the following (n) and (o) physicochemical data. Preferably it is characterized by the physicochemical data of both (n) and (o).

(n)(i)圖16所示之粉末X射線繞射譜、(ii)顯示圖16所示之粉末X射線繞射譜之主要的峰(例如，以強度順序最高1個、2個、3個、4個、5個、6個、7個或者8個之峰)或全部的峰之繞射角(2θ)屬於相同或實質上相同的粉末X射線繞射譜、(iii)在表9所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)具有峰的粉末X射線繞射譜、(iv)從表9所示之繞射角(2θ)或與其實質上相同的繞射角(2θ)選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜，或者(v)由約7.1、約10.4、約12.3、約14.2、約16.8、約18.6、約23.3、及約25.7度選擇1個以上之繞射角(2θ)具有1個以上(例如，至少1個、2個、3個、4個、5個、6個、7個或者8個)之峰的粉末X射線繞射譜。(n) (i) the powder X-ray diffraction spectrum shown in Figure 16, (ii) showing the main peaks of the powder X-ray diffraction spectrum shown in Figure 16 (e.g., highest in order of intensity 1, 2, 3, 4, 5, 6, 7 or 8 peaks) or the diffraction angles (2θ) of all peaks belong to the same or substantially the same powder X-ray diffraction spectrum, (iii) in Table 9 A powder X-ray diffraction spectrum having a peak at the indicated diffraction angle (2θ) or substantially the same diffraction angle (2θ), (iv) from the diffraction angle (2θ) shown in Table 9 or substantially the same The same diffraction angle (2θ) selects more than one diffraction angle (2θ) with more than one (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8 ), or (v) one or more diffraction angles selected from about 7.1, about 10.4, about 12.3, about 14.2, about 16.8, about 18.6, about 23.3, and about 25.7 degrees ( 2θ) A powder X-ray diffraction spectrum having one or more (for example, at least 1, 2, 3, 4, 5, 6, 7 or 8) peaks.

(o)圖17所示之DSC圖、或DSC中之(i)起始溫度為約46℃或峰溫度為約62℃的吸熱峰及/或(ii)起始溫度為約74℃或峰溫度為約91℃的吸熱峰。(o) the DSC graph shown in Figure 17, or (i) an endothermic peak with an onset temperature of about 46°C or a peak temperature of about 62°C in the DSC and/or (ii) an onset temperature of about 74°C or a peak The temperature is an endothermic peak at about 91 °C.

上述粉末X射線繞射譜較佳係由實施例中記載之條件1至3之任一者所測量者。上述DSC較佳係由實施例中記載之條件1至5之任一者所測量者。The above-mentioned powder X-ray diffraction spectrum is preferably measured by any one of conditions 1 to 3 described in the embodiments. The above-mentioned DSC is preferably measured by any one of conditions 1 to 5 described in the examples.

本揭示中，化合物I、其鹽、其溶劑合物之各結晶雖依據本說明書所記載的物理化學數據而特定者，惟由於各光譜數據，其性質上多少會有變化者，故不應嚴格解釋。In this disclosure, each crystal of compound I, its salt, and its solvate is specified based on the physical and chemical data recorded in this specification, but since the properties of each spectral data may vary somewhat, it should not be strictly Explanation.

例如，粉末X射線繞射譜數據，因其性質上認定結晶之同一性，故繞射角(2θ)與整體的模式乃為重要，而相對強度則藉由結晶成長之方向、粒子之大小、測量條件而多少會有變化。For example, powder X-ray diffraction spectrum data, because of the identity of crystals in nature, the diffraction angle (2θ) and the overall mode are important, and the relative intensity is determined by the direction of crystal growth, particle size, May vary somewhat depending on measurement conditions.

此外，DSC數據中，亦因認定結晶之同一性，故整體的模式乃為重要，而藉由測量條件亦多少會有變化。In addition, in the DSC data, the overall pattern is important because the identity of the crystal is recognized, and the measurement conditions may vary somewhat.

據此，本發明之型態中之各結晶中，與粉末X射線繞射譜或DSC模式各別整體類似者係包含於該結晶者。Accordingly, among the crystals in the form of the present invention, those which are respectively overall similar to the powder X-ray diffraction spectrum or the DSC pattern are included in the crystals.

本說明書中、粉末X線繞射模式中之繞射角(2θ(度))及DSC分析中之吸熱峰的起始溫度(℃)及峰溫度(℃)之記載意指，包含該數據測量法中之通常可接受的誤差範圍，這意味著其大約係繞射角及吸熱峰之起始溫度及峰溫度。例如，粉末X線繞射中之繞射角(2θ(度))之「約」，作為某一態樣係±0.2度，作為又一其他態樣係±0.1度。DSC分析中之吸熱峰的起始溫度(℃)或峰溫度(℃)之「約」，作為某一態樣係±2℃，作為又一其他態樣係±1℃。In this specification, the description of the diffraction angle (2θ (degree)) in the powder X-ray diffraction mode and the onset temperature (°C) and peak temperature (°C) of the endothermic peak in the DSC analysis means that the data measured The generally acceptable error range in the method, which means that it is about the diffraction angle and the onset temperature and peak temperature of the endothermic peak. For example, the "approximately" of the diffraction angle (2θ (degrees)) in powder X-ray diffraction is ±0.2 degrees in a certain aspect, and ±0.1 degrees in another aspect. The "approximately" of the onset temperature (°C) or peak temperature (°C) of the endothermic peak in DSC analysis is ±2°C for a certain aspect, and ±1°C for another aspect.

本揭示之一實施型態中，化合物I、其鹽、其溶劑合物之各結晶實質上為純者。言及「實質上為純者」係意指，特定之結晶形(特定之型態之結晶)佔有存在之化合物I之中之至少50%。此外，另一實施型態中，特定之結晶形(特定之型態之結晶)佔有存在之化合物I之中之至少75%、至少85%、至少90%、至少95%或約94%至98%。In one embodiment of the present disclosure, each crystal of Compound I, its salt, and its solvate is substantially pure. The reference to "substantially pure" means that the specified crystalline form (crystals of a specified pattern) accounts for at least 50% of the compound I present. In addition, in another embodiment, a specific crystal form (crystal of a specific form) occupies at least 75%, at least 85%, at least 90%, at least 95%, or about 94% to 98% of the compound I present. %.

本揭示之一實施型態中，化合物I之結晶(例如，B晶、D晶)係化合物I之自由體之結晶。In one embodiment of the present disclosure, the crystals of compound I (eg, crystal B, crystal D) are free crystals of compound I.

本揭示中，自由體之結晶係意指由單一成分所構成之結晶。In the present disclosure, free-body crystals refer to crystals composed of a single component.

本揭示中，作為化合物I之溶劑合物，只要係使用藥學上可接受的溶劑之溶劑合物則無特別限定。作為溶劑，係列舉例如，水、甲醇、乙醇、異丙醇等醇，乙酸等羧酸，乙酸乙酯等酯，乙醇胺等烷醇胺，二甲亞碸等亞碸等。較佳的溶劑係包含水。作為化合物I之水合物，係列舉0.5水合物至10水合物。本揭示之一實施型態中，水合物係0.5水合物、1水合物、1.5水合物、2水合物、2.5水合物、或3水合物。本揭示之一實施型態中，水合物係0.5水合物至1水合物，特定之實施型態中，係0.5、0.6、0.7、0.8、0.9、或1水合物。本揭示之其他實施型態中，水合物係p水合物(p表示超過0且8以下)。本揭示之另一其他實施型態中，水合物係m水合物或n水合物(m及n各別表示4至8)。水合莫耳數可藉由熱重量分析而測量。該熱重量分析較佳係由實施例中記載之條件1至5之任一者所測量者。In the present disclosure, the solvate of Compound I is not particularly limited as long as it is a solvate using a pharmaceutically acceptable solvent. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropanol, carboxylic acids such as acetic acid, esters such as ethyl acetate, alkanolamines such as ethanolamine, and oxenes such as dimethylsulfoxide. Preferred solvents include water. As the hydrate of Compound I, the series include 0.5 hydrate to 10 hydrate. In one embodiment of the present disclosure, the hydrate is 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, 2.5 hydrate, or 3 hydrate. In one embodiment of the present disclosure, the hydrate is 0.5 hydrate to monohydrate, and in a specific embodiment, it is 0.5, 0.6, 0.7, 0.8, 0.9, or monohydrate. In other embodiments of the present disclosure, the hydrate is a p-hydrate (p represents more than 0 and less than 8). In another embodiment of the present disclosure, the hydrate is an m-hydrate or an n-hydrate (m and n respectively represent 4 to 8). Moles of hydration can be measured by thermogravimetric analysis. The thermogravimetric analysis is preferably measured by any one of conditions 1 to 5 described in the examples.

本揭示中，作為水合物，在通常保存-使用醫藥品之環境下(溫度、相對濕度等)，只要係可穩定且保持相當量之水的結晶則無特別限定。例如，於此，1水合物意指，在通常保存-使用醫藥品之環境下(溫度、相對濕度等)，穩定且保持1當量之水的結晶。In the present disclosure, the hydrate is not particularly limited as long as it is a crystal that can stably hold a considerable amount of water under the environment (temperature, relative humidity, etc.) in which pharmaceuticals are usually stored and used. For example, as used herein, monohydrate means a crystal that is stable and maintains 1 equivalent of water under the environment (temperature, relative humidity, etc.) in which pharmaceuticals are usually stored and used.

本揭示中，作為鹽，只要係藥學上可接受的鹽則無特別限定。作為鹽，係列舉例如，鹼土金屬鹽等無機鹽、胺鹽等有機鹽。作為鹼土金屬鹽，係列舉例如，鈣鹽及鎂鹽等。作為胺鹽，係列舉例如，三乙胺鹽、甲胺鹽、二甲基胺鹽、環戊胺鹽、二環己胺鹽、芐胺鹽、苯乙胺鹽、哌啶鹽、單乙醇胺鹽、二乙醇胺鹽、參(羥基甲基)胺基甲烷鹽、離胺酸鹽、精胺酸鹽、及N-甲基-D-還原葡糖胺鹽等。例如，在化合物I與2價陽離子形成鹽之情況，2分子之化合物I與1分子之陽離子形成鹽。作為2價之陽離子，係列舉例如，鎂離子、鈣離子等。例如，在2分子之化合物I與1分子之鎂離子形成鹽之情況，可標記為「鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]」、亦可標記為「(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　半鎂鹽」。In the present disclosure, the salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Examples of the salt include inorganic salts such as alkaline earth metal salts and organic salts such as amine salts. Examples of the alkaline earth metal salts include calcium salts, magnesium salts, and the like. As amine salts, the series include, for example, triethylamine salts, methylamine salts, dimethylamine salts, cyclopentylamine salts, dicyclohexylamine salts, benzylamine salts, phenethylamine salts, piperidine salts, monoethanolamine salts , diethanolamine salt, ginseng (hydroxymethyl) aminomethane salt, lysine salt, arginine salt, and N-methyl-D-reduced glucosamine salt, etc. For example, when Compound I forms a salt with a divalent cation, two molecules of Compound I form a salt with one molecule of the cation. Examples of divalent cations include magnesium ions, calcium ions, and the like. For example, in the case where 2 molecules of compound I and 1 molecule of magnesium ion form a salt, it can be labeled as "magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2 -phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate]", can also be marked as "(1R,2S)-2-{3 -[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid hemimagnesium salt".

本揭示中，本揭示化合物(化合物I及本發明之型態)可依據實施例及與此類似之方法而製造。又，進行再結晶之際，可使用或不使用種晶。In this disclosure, the disclosed compound (compound I and the form of the present invention) can be produced according to the examples and methods similar thereto. In addition, when performing recrystallization, a seed crystal may or may not be used.

例如，化合物I之鎂鹽之水合物之結晶(例如，A晶、L晶、H晶、M晶)，可藉由包含將非晶質之化合物I經溶解於甲醇及氫氧化鉀水溶液之溶液與氯化鎂六水合物之水溶液混合的步驟的方法而製造。前述混合，例如，於室溫實施1至24小時、較佳係實施2至18小時、更佳係實施3至12小時。前述方法亦可更包含在氮氣流下加熱藉由前述混合之晶析物的步驟。前述加熱溫度可為例如，約40至70℃。For example, the crystals of the hydrate of the magnesium salt of compound I (for example, crystal A, crystal L, crystal H, crystal M) can be prepared by dissolving amorphous compound I in methanol and aqueous potassium hydroxide solution Manufactured by the step of mixing with an aqueous solution of magnesium chloride hexahydrate. The aforementioned mixing is, for example, carried out at room temperature for 1 to 24 hours, preferably for 2 to 18 hours, more preferably for 3 to 12 hours. The aforementioned method may further include a step of heating the crystallized product obtained by the aforementioned mixing under nitrogen flow. The aforementioned heating temperature may be, for example, about 40 to 70°C.

例如，化合物I之水合物之結晶(例如，C晶)，可藉由包含將非晶質之化合物I經溶解於乙酸及水之溶液，在攪拌下重複從20℃加熱至60℃為止、再從60℃冷卻至20℃為止所成之循環的方法而製造。前述循環，例如，可實施1次以上、較佳係實施2次至20次、更佳係實施5次至15次。For example, the crystal of the hydrate of compound I (for example, crystal C) can be prepared by dissolving amorphous compound I in acetic acid and water, heating repeatedly from 20°C to 60°C under stirring, and then Manufactured by a cycle of cooling from 60°C to 20°C. The aforementioned cycle can be performed, for example, once or more, preferably 2 to 20 times, and more preferably 5 to 15 times.

例如，化合物I之結晶(例如，B晶、D晶)，可藉由包含將化合物I之水合物之結晶在室溫、濕度0%之氛圍放置的步驟，或者，在氮氣流下進行加熱的步驟的方法而製造。前者之步驟中，在該氛圍放置例如，5分鐘至60分鐘、較佳係10分鐘至30分鐘。後者之步驟中，加熱溫度可為例如，約40至50℃。For example, the crystals of Compound I (e.g., crystal B, crystal D) can be prepared by a step comprising placing the crystal of the hydrate of Compound I at room temperature in an atmosphere with a humidity of 0%, or by heating under a nitrogen stream. method of manufacture. In the former step, the atmosphere is left for, for example, 5 minutes to 60 minutes, preferably 10 minutes to 30 minutes. In the latter step, the heating temperature may be, for example, about 40 to 50°C.

例如，化合物I之二環己胺鹽之結晶(例如，E晶)，可藉由包含將非晶質之化合物I經溶解於甲基三級丁基醚之溶液與二環己胺混合的步驟的方法而製造。前述混合，例如，在室溫實施6至84小時、較佳係實施12至78小時、更佳係實施24至72小時。For example, the crystallization of the dicyclohexylamine salt of compound I (for example, crystal E) can be obtained by a step comprising mixing the amorphous compound I in a solution dissolved in methyl tertiary butyl ether and dicyclohexylamine method of manufacture. The aforementioned mixing is, for example, carried out at room temperature for 6 to 84 hours, preferably for 12 to 78 hours, more preferably for 24 to 72 hours.

例如，化合物I之鈣鹽之水合物之結晶(例如，F晶)，可藉由包含將非晶質之化合物I與氫氧化鈣、異丙醇、及水混合的步驟的方法而製造。前述混合，其混合順序等並無特別限定，例如，在室溫實施6至84小時、較佳係實施12至78小時、更佳係實施24至72小時。前述方法，亦可更包含乾燥藉由前述混合的晶析物之步驟，亦可更包含將前述乾燥物與水混合之步驟。For example, a hydrate crystal of the calcium salt of Compound I (eg, crystal F) can be produced by a method comprising the step of mixing amorphous Compound I with calcium hydroxide, isopropanol, and water. There is no particular limitation on the above-mentioned mixing, the mixing order, etc. For example, it is carried out at room temperature for 6 to 84 hours, preferably for 12 to 78 hours, and more preferably for 24 to 72 hours. The aforementioned method may further include a step of drying the crystallized product obtained by the aforementioned mixing, and may further include a step of mixing the aforementioned dried product with water.

本揭示中，作為鹽而記載者亦可為共結晶。 [毒性] In this disclosure, what is described as a salt may be a co-crystal. [toxicity]

由於本揭示化合物的毒性低，故可安全地作為醫藥品使用。 [對醫藥品之適用] Due to the low toxicity of the disclosed compounds, they can be safely used as medicines. [Applicability to pharmaceuticals]

本揭示之課題係發現創製對於EP 2受體具有強力的拮抗活性的化合物，且屬於有用於作為起因於EP 2受體的活性化之疾病的預防及/或治療藥的化合物，以及適用於其醫藥品原藥的型態。 The subject of the present disclosure is to discover and create a compound having strong antagonistic activity against EP2 receptors , which is a compound useful as a prophylactic and/or therapeutic drug for diseases caused by activation of EP2 receptors , and applicable to the same Types of active pharmaceutical ingredients.

本揭示化合物由於對於EP 2受體顯示強力的拮抗活性，故可有用於作為起因於EP 2受體的活化之疾病，例如子宮內膜症、子宮肌瘤、月經過多、腺肌症、月經困難症、慢性骨盆痛症候群、癌、炎症性疼痛、神經因性疼痛、頭痛、術後疼痛、間質性膀胱炎、平滑肌瘤、過敏性大腸症候群、阿茲海默氏症、帕金森氏症、肌萎縮性側索硬化症、多發性硬化症、風濕病、骨關節炎、痛風、過敏性疾病、高血壓、腦機能障礙、缺血、腦溢血、腎疾病、移植排斥反應、粥狀動脈硬化症、缺血性心疾病、尋常性痤瘡、氣喘、***炎、腎絲球性腎炎、類肉瘤病、血管炎、自體免疫疾病等之預防及/或治療劑。 Since the disclosed compounds exhibit potent antagonistic activity against EP2 receptors , they can be useful as diseases caused by the activation of EP2 receptors , such as endometriosis, uterine fibroids, menorrhagia, adenomyosis, menstruation Difficulty, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, hypertension, brain dysfunction, ischemia, cerebral hemorrhage, kidney disease, transplant rejection, atherosclerosis Preventive and/or therapeutic agents for sclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, autoimmune diseases, etc.

更具體而言，癌例如可列舉乳癌、卵巢癌、大腸癌(例如結腸癌等)、肺癌(例如非小細胞肺癌等)、***癌、頭頸部癌(例如口腔扁平上皮癌、頭頸部扁平上皮癌、咽頭癌、喉頭癌、舌癌、甲狀腺癌、聽神經鞘瘤等)、淋巴瘤(例如B細胞淋巴瘤、T細胞淋巴瘤等)、葡萄膜黑色素瘤、胸腺瘤、間皮瘤、食道癌、胃癌、十二指腸癌、肝細胞癌、膽管癌、膽囊癌、胰臟癌、腎細胞癌、腎盂/尿道癌、膀胱癌、陰莖癌、睪丸癌、子宮癌、***癌、外陰癌、皮膚癌(例如惡性黑色素瘤等)、惡性骨腫瘤、軟組織肉瘤、軟骨肉瘤、白血病(例如急性骨髓性白血病、急性淋巴性白血病、慢性骨髓性白血病、慢性淋巴性白血病等)、骨髓發育不良症候群、神經膠質母細胞瘤或多發性骨髓瘤等。自體免疫疾病例如可列舉肌萎縮性側索硬化症(ALS)、多發性硬化症、修格蘭氏症候群(Sjogren's syndrome)、全身性紅斑性狼瘡、AIDS等。過敏性疾病例如可列舉過敏性結膜炎、過敏性鼻炎、接觸性皮膚炎、乾癬等。頭痛例如可列舉偏頭痛、緊張型頭痛或該等的混合型頭痛、或叢發性頭痛等。More specifically, cancers include, for example, breast cancer, ovarian cancer, large intestine cancer (such as colon cancer, etc.), lung cancer (such as non-small cell lung cancer, etc.), prostate cancer, head and neck cancer (such as oral squamous cell carcinoma, head and neck squamous cell carcinoma, etc. cancer, pharynx cancer, larynx cancer, tongue cancer, thyroid cancer, acoustic nerve sheath tumor, etc.), lymphoma (such as B-cell lymphoma, T-cell lymphoma, etc.), uveal melanoma, thymoma, mesothelioma, esophageal cancer , gastric cancer, duodenal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis/urethral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer ( Such as malignant melanoma, etc.), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia (such as acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, etc.), myelodysplastic syndrome, glial cell tumor or multiple myeloma, etc. Examples of autoimmune diseases include amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, and AIDS. Examples of allergic diseases include allergic conjunctivitis, allergic rhinitis, contact dermatitis, psoriasis and the like. Examples of the headache include migraine, tension-type headache, or a combination thereof, or cluster headache.

本揭示化合物係可以為了下述情形而與其他的藥物組合而作為併用藥投予。 1)其化合物之預防及/或治療效果的補充及/或增強、 2)其化合物之動態/吸收改善、投予量的減低、及/或 3)其化合物之副作用的減輕。 The compound of the present disclosure can be administered as a concomitant drug in combination with other drugs for the following situations. 1) Supplementation and/or enhancement of the preventive and/or therapeutic effects of its compounds, 2) Dynamic/absorption improvement of its compound, reduction in dosage, and/or 3) Alleviation of side effects of the compound.

本揭示化合物與其他藥物的併用藥係可為1種製劑中調配有兩種成分之調配劑的形態，亦可為形成各個製劑而投予之形態。該形成各個製劑而投予之情況，包含同時投予及間隔時間差投予。此外、以間隔時間差投予，係可為先投予本揭示化合物，然後投予其他藥劑，亦可為先投予其他藥劑，然後投予本揭示化合物。各個投予方法可為相同或不同。The concomitant use of the compound of the present disclosure and other drugs may be in the form of a preparation in which two components are blended in one preparation, or may be in the form of administration as separate preparations. The case of administering each formulation includes simultaneous administration and administration with a difference in time interval. In addition, the administration with a difference in time interval may be to administer the compound of the present disclosure first, and then to administer other pharmaceuticals, or to administer other pharmaceuticals first, and then to administer the compound of the present disclosure. Each method of administration may be the same or different.

藉由上述併用藥，展現預防及/或治療效果的疾病並無特別限定，只要是本揭示化合物之預防及/或治療效果補充及/或增強之疾病即可。The diseases exhibiting preventive and/or therapeutic effects through the above-mentioned concomitant administration are not particularly limited, as long as the preventive and/or therapeutic effects of the disclosed compounds are supplemented and/or enhanced.

就本揭示化合物對於癌的預防及/或治療效果的補足及/或增強用的其他藥劑而言，例如可列舉烷基化劑、代謝拮抗劑、抗癌性抗生物質、植物性製劑、荷爾蒙劑、鉑化合物、免疫檢查點抑制劑、拓樸異構酶抑制劑、激酶抑制劑、抗CD20抗體、抗HER2抗體、抗EGFR抗體、抗VEGF抗體、蛋白質體抑制劑、HDAC抑制劑、及免疫調整藥等。Other agents for supplementing and/or enhancing the preventive and/or therapeutic effects of the disclosed compounds on cancer include, for example, alkylating agents, metabolic antagonists, anticancer antibiotics, herbal preparations, and hormone agents , platinum compounds, immune checkpoint inhibitors, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteosome inhibitors, HDAC inhibitors, and immune modulation medicine etc.

烷基化劑例如可列舉環磷醯胺、依弗醯胺、達卡巴仁(Dacarbazine)、替莫唑胺(Temozolomide)、鹽酸尼莫司汀(nimustine hydrochloride)、拉尼莫司汀( (Ranimustine)、苯達莫司汀(bendamustine)、噻替哌(Thiotepa)、及卡波醌(carboquone)等。Examples of the alkylating agent include cyclophosphamide, eflumide, dacarbazine, temozolomide, nimustine hydrochloride, ranimustine, benzene Bendamustine, Thiotepa, Carboquone, etc.

代謝拮抗劑例如可列舉氨甲蝶呤(Methotrexate)、培美曲塞(Pemetrexed)、5-氟尿嘧啶(fluorouracil)、替加弗(Tegafur)、替加弗-尿嘧啶(Tegafur-uracil)、替加弗-吉美斯特-奧特斯特鉀(tegafur-gimestat-otastat potassium)、去氧氟尿苷(Doxifluridine)、卡培他濱(Capecitabine)、阿糖胞苷(Cytarabine)、鹽酸吉西他濱(Gemcitabine hydrochloride)、氟達拉濱(Fludarabine)、奈拉濱(nelarabine)、卡莫氟(Carmofur)、及鹽酸甲基苄肼(Procarbazine Hydrochloride)等。Metabolic antagonists include, for example, methotrexate, pemetrexed, 5-fluorouracil, Tegafur, Tegafur-uracil, tegafur Tegafur-gimestat-otastat potassium, Doxifluridine, Capecitabine, Cytarabine, Gemcitabine hydrochloride ), Fludarabine, Nelarabine, Carmofur, and Procarbazine Hydrochloride, etc.

抗癌性抗生物質例如可列舉絲裂黴素C、鹽酸多柔比星 (Doxorubicin Hydrochloride)、鹽酸阿柔比星(Aclarubicin hydrochloride)、鹽酸畢拉魯比辛(Pirarubicin Hydrochloride)、泛艾黴素(Epirubicin)、色黴素A3 (Chromomycin A3)、博來黴素(bleomycin)、硫酸培洛黴素(Peplomycin sulfate)、及畢拉魯比辛(Pirarubicin)等。Anticancer antibiotics include, for example, mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, pan-erubicin ( Epirubicin), Chromomycin A3, Bleomycin, Peplomycin sulfate, and Pirarubicin, etc.

植物性製劑例如可列舉鹽酸愛萊諾迪肯(irinotecan)、依託泊苷(Etoposide)、硫酸長春新鹼(Vincristine Sulfate)、硫酸長春鹼(Vinblastine sulfate)、硫酸長春地辛(Vindesine Sulfate)、酒石酸必諾賓(Vinorelbine ditartrate)、多西紫杉醇水合物(Docetaxel Hydrate)、艾日布林甲磺酸鹽(Eribulin Mesilate)、及紫杉醇(Paclitaxel)等。Herbal preparations include, for example, irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, tartaric acid Vinorelbine ditartrate, Docetaxel Hydrate, Eribulin Mesilate, Paclitaxel, etc.

荷爾蒙劑例如可列舉雌莫司汀磷酸鈉(Estramustine phosphate sodium)、氟他胺(Flutamide)、比卡魯胺(Bicalutamide)、乙酸戈舍瑞林(Goserelin Acetate)、乙酸亮丙瑞林(Leuprorelin Acetate)、檸檬酸泰模西芬(Tamoxifen Citrate)、檸檬酸托瑞米芬(Toremifene citrate)、阿那曲唑(Anastrozole)、來曲唑(Letrozole)、依西美坦(Exemestane)、美雄烷(Mepitiostane)、乙酸甲羥黃體酮(Medroxyprogesterone Acetate)、環硫雄醇(Epitiostanol)、雌磷酚(Fosfestrol)、鹽酸法倔唑水合物(Fadrozole hydrochloride hydrate)、阿比特龍(Abiraterone)、氟維司群(Fulvestrant)、及氨魯米特(Aminoglutethimide)等。Hormone agents include, for example, estramustine phosphate sodium, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate ), Tamoxifen Citrate, Toremifene citrate, Anastrozole, Letrozole, Exemestane, Mepitiostane ), Medroxyprogesterone Acetate, Epitiostanol, Fosfestrol, Fadrozole hydrochloride hydrate, Abiraterone, Fulvestrant (Fulvestrant), and aminoglutethimide (Aminoglutethimide), etc.

鉑化合物例如可列舉卡鉑(Carboplatin)、順鉑(cisplatin)、奈達鉑(Nedaplatin)、及奧沙利鉑(oxaliplatin)等。Examples of platinum compounds include carboplatin, cisplatin, nedaplatin, and oxaliplatin.

作為免疫檢查點抑制劑，係例如，抗CTLA-4抗體(例如，易普利姆單抗(Ipilimumab) (YERVOY(註冊商標))、曲美單抗(Tremerimumab)、AGEN-1884、抗PD-1抗體(例如，納武利尤單抗(nivolumab)(註冊商標))、REGN-2810、派姆單抗(Pembrolizumab) (KEYTRUDA(註冊商標))、PDR-001BGB-A317、AMP-514 (MEDI0680)、BCD-100、IBI-308、JS-001、PF-60801591、TSR-042、抗PD-L1抗體(例如，阿特珠單抗(Atezolizumab) (RG7446、 MPDL3280A)、阿維魯單抗(Avelumab) (PF-06834635、MSB0010718C) 、杜瓦魯單抗(Durvalumab) (MEDI4736)、BMS-936559、CA0170、LY-3300054、抗PD-L2抗體(例如，rHIgM12B7)、PD-L1融合蛋白、PD-L2融合蛋白(例如，AMP-224)、抗Tim-3抗體(例如，MBG453)、抗LAG-3抗體(例如，BMS-986016、LAG525)、抗KIR抗體(例如，利魯單抗(Lirilumab))等。As immune checkpoint inhibitors, for example, anti-CTLA-4 antibodies (for example, Ipilimumab (Ipilimumab) (YERVOY (registered trademark)), tremelimumab (Tremerimumab), AGEN-1884, anti-PD- 1 Antibodies (eg, nivolumab (registered trademark)), REGN-2810, pembrolizumab (KEYTRUDA (registered trademark)), PDR-001BGB-A317, AMP-514 (MEDI0680) , BCD-100, IBI-308, JS-001, PF-60801591, TSR-042, anti-PD-L1 antibodies (eg, Atezolizumab (RG7446, MPDL3280A), Avelumab ) (PF-06834635, MSB0010718C), Durvalumab (MEDI4736), BMS-936559, CA0170, LY-3300054, anti-PD-L2 antibody (eg, rHIgM12B7), PD-L1 fusion protein, PD- L2 fusion protein (eg, AMP-224), anti-Tim-3 antibody (eg, MBG453), anti-LAG-3 antibody (eg, BMS-986016, LAG525), anti-KIR antibody (eg, Lirilumab )Wait.

拓樸異構酶抑制劑之例例如可列舉托普樂肯(topotecan)及索布佐生(sobuzoxane)等。Examples of topoisomerase inhibitors include topotecan, sobuzoxane, and the like.

激酶抑制劑例如可列舉屬於EGFR抑制劑之厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、阿法替尼(Afatinib)，屬於HER2抑制劑之拉帕替尼(Lapatinib)，屬於BCR-ABL抑制劑之伊馬替尼(imatinib)，屬於ALK抑制劑之克唑替尼(Crizotinib)，屬於多重激酶抑制劑之瑞格非尼(Regorafenib)、及達沙替尼(dasatinib)等。Kinase inhibitors include, for example, Erlotinib, Gefitinib, and Afatinib belonging to EGFR inhibitors, Lapatinib belonging to HER2 inhibitors, and BCR -Imatinib as an ABL inhibitor, Crizotinib as an ALK inhibitor, Regorafenib as a multi-kinase inhibitor, and dasatinib, etc.

抗CD20抗體例如可列舉利妥昔單抗(Rituximab)、替伊莫單抗(Ibritumomab)、替伊莫單抗替坦(Ibritumomab tiuxetan)、及奧美珠單抗(Ocrelizumab)等。Examples of anti-CD20 antibodies include Rituximab, Ibritumomab, Ibritumomab tiuxetan, and Ocrelizumab.

抗HER2抗體例如可列舉曲妥珠單抗(Trastuzumab)、曲妥珠單抗美坦辛(Trastuzumab-emtansine)、及帕妥珠單抗(Pertuzumab)等。Examples of anti-HER2 antibodies include Trastuzumab, Trastuzumab-emtansine, and Pertuzumab.

抗EGFR抗體例如可列舉西妥昔單抗(Cetuximab)及帕尼單抗(Panitumumab)等。Examples of anti-EGFR antibodies include Cetuximab and Panitumumab.

抗VEGF抗體例如可列舉貝伐單抗(Bevacizumab)等。Examples of anti-VEGF antibodies include Bevacizumab and the like.

蛋白質體抑制劑例如可列舉硼替佐米(Bortezomib)等。Examples of proteosome inhibitors include Bortezomib and the like.

HDAC抑制劑例如可列舉伏立諾他(Vorinostat)等。Examples of HDAC inhibitors include Vorinostat and the like.

免疫調整藥例如可列舉沙利竇邁(thalidomide)、來那度胺(Lenalidomide)及泊馬度胺(Pomalidomide)等。Examples of immunomodulators include thalidomide, lenalidomide, and pomalidomide.

其他藥劑可組合任意2種以上而投予。Other pharmaceuticals may be administered in combination of any two or more.

此外，對本揭示化合物之預防及/或治療效果補充及/或增強之其他藥劑中，根據上述機制，不只包含目前為止所發現者，尚包含今後發現者。In addition, other agents that supplement and/or enhance the preventive and/or therapeutic effects of the disclosed compounds include not only those discovered so far, but also those discovered in the future based on the above mechanism.

本揭示化合物通常係與藥學上可接受之載體作為適當的醫藥組成物一起製劑化後，以口服或非口服的形式全身性或局部性地投予。作為口服劑，係列舉例如，內服用液劑(例如，酏劑、糖漿、藥學上可接受的水劑、混懸劑、乳劑)、內服用固體劑(例如，錠劑(包含舌下錠、口腔內崩解錠)、丸劑、膠囊劑(包含硬膠囊、軟膠囊、明膠膠囊、微膠囊)、散劑、顆粒劑、***錠劑)等。作為非口服劑，係列舉例如，液劑(例如，注射劑(皮下注射劑、靜脈內注射劑、筋肉內注射劑、腹腔內注射劑、點滴劑等)、點眼劑(例如，水性點眼劑(水性點眼液、水性懸浮點眼液、黏性點眼液、可溶化點眼液等)、非水性點眼劑(非水性點眼液、非水性懸浮點眼液等))等)、外用劑(例如，軟膏(眼軟膏等))、點耳劑等。此等之製劑可為速崩性製劑、緩釋性製劑等之釋放調節製劑。此等之製劑，可藉由習知方法，例如，日本藥典中記載之方法等而製造。The disclosed compounds are usually formulated together with pharmaceutically acceptable carriers as appropriate pharmaceutical compositions, and administered orally or parenterally, systemically or locally. As oral preparations, for example, liquid preparations for internal administration (e.g., elixirs, syrups, pharmaceutically acceptable liquids, suspensions, emulsions), solid preparations for internal administration (e.g., lozenges (including sublingual tablets, Orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, microcapsules), powders, granules, buccal lozenges), etc. As parenteral preparations, the series include, for example, liquid preparations (for example, injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drips, etc.), eye drops (for example, water-based eye drops (water-based eye drops) liquid, aqueous suspension eye drops, viscous eye drops, soluble eye drops, etc.), non-aqueous eye drops (non-aqueous eye drops, non-aqueous suspension eye drops, etc.)), external agents (such as , ointment (eye ointment, etc.)), ear drops, etc. These preparations may be release-modified preparations such as fast-disintegrating preparations and sustained-release preparations. These preparations can be produced by known methods, for example, methods described in the Japanese Pharmacopoeia.

作為口服劑之內服用液劑，係藉由例如，將本揭示化合物溶解於通常使用之稀釋劑(例如，純化水、乙醇或此等之混液等)，使其懸浮或乳化而製造。更且，該液劑可含有濕潤劑、懸浮化劑、乳化劑、甜味劑、調味劑、芳香劑、保存劑、緩衝劑等。Liquids for oral administration are produced, for example, by dissolving the disclosed compound in a commonly used diluent (for example, purified water, ethanol, or a mixture thereof), and suspending or emulsifying it. Furthermore, the liquid preparation may contain a wetting agent, a suspending agent, an emulsifying agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative, a buffering agent, and the like.

作為口服劑之內服用固體劑，係例如，將本揭示化合物與賦形劑(例如，乳糖、甘露醇、葡萄糖、微結晶纖維素、澱粉等)、黏合劑(例如，羥基丙基纖維素、聚乙烯吡咯烷酮、偏矽酸鋁鎂等)、崩解劑(例如，乙醇酸纖維素酸鈣等)、潤滑劑(例如，硬脂酸鎂等)、穩定劑、溶解輔助劑(谷胺酸、天冬胺酸等)等混合，並依據常規方法而製劑化。此外，因應需要，可以包衣劑(例如，白糖、明膠、羥基丙基纖維素、羥基丙基甲基纖維素鄰苯二甲酸酯等)進行包覆，亦可以2以上之層進行被覆。As a solid dosage form for oral administration, for example, the compounds of the present disclosure are mixed with excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (for example, hydroxypropyl cellulose, polyvinylpyrrolidone, aluminum magnesium metasilicate, etc.), disintegrants (e.g., calcium glycolate cellulose, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, dissolution aids (glutamic acid, aspartic acid, etc.) etc. were mixed, and formulated according to a conventional method. In addition, if necessary, it may be coated with a coating agent (for example, sugar, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or may be coated in two or more layers.

作為非口服劑之外用劑，可藉由習知方法或通常使用的處方而製造。例如，軟膏劑係將本揭示化合物在基劑使其研磨、或溶融而製造。軟膏基劑係選自習知或通常使用者。選擇例如，高級脂肪酸或高級脂肪酸酯(例如，己二酸、肉荳蔻酸、棕櫚酸、硬脂酸、油酸、己二酸酯、肉荳蔻酸酯、棕櫚酸酯、硬脂酸酯、油酸酯等)、蠟類(例如，蜂蠟、鯨蠟、地蠟等)、界面活性劑(例如，聚氧乙烯烷基醚磷酸酯等)、高級醇(例如，鯨蠟醇、硬脂醇、鯨蠟硬脂醇等)、矽油(例如，二甲基聚矽氧烷等)、烴類類(例如，親水性凡士林、白凡士林、純化羊毛脂、液體石蠟等)、二醇類(例如，乙二醇、二甘醇、丙二醇、聚乙二醇、聚乙烯二醇等)、植物油(例如，蓖麻油、橄欖油、芝麻油、萜烯油等)、動物油(例如，貂油、蛋黃油、角鯊烷、角鯊烯等)、水、吸收促進劑、抗皮疹劑者單獨或2種以上混合使用。更且，亦可包含保濕劑、保存劑、穩定化劑、抗氧化劑、著香劑等。As external preparations for parenteral preparations, they can be produced by known methods or commonly used prescriptions. For example, an ointment is prepared by grinding or melting a compound of the present disclosure in a base. Ointment bases are selected from those known or commonly used. Select, for example, higher fatty acids or higher fatty acid esters (for example, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate, myristate, palmitate, stearate, oleic acid ester, etc.), waxes (for example, beeswax, spermaceti, ozokerite, etc.), surfactants (for example, polyoxyethylene alkyl ether phosphate, etc.), higher alcohols (for example, cetyl alcohol, stearyl alcohol , cetearyl alcohol, etc.), silicone oils (such as dimethylpolysiloxane, etc.), hydrocarbons (such as hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (such as , ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, polyethylene glycol, etc.), vegetable oils (eg, castor oil, olive oil, sesame oil, terpene oil, etc.), animal oils (eg, mink oil, egg oil , squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents are used alone or in combination of two or more. Furthermore, a humectant, a preservative, a stabilizer, an antioxidant, a flavoring agent, etc. may be included.

作為非口服劑之注射劑中，包含溶解或懸浮於溶液、懸浮液、乳濁液及使用時的溶劑，使用的固體注射劑。注射劑，例如將本揭示化合物溶解於溶劑，使其懸浮或乳化而使用。作為溶劑，係使用例如，注射用蒸餾水、生理食鹽水、植物油、丙二醇、聚乙二醇、乙醇等醇類等及此等之組合。更且，該注射劑亦可包含穩定劑、溶解輔助劑(例如，谷胺酸、天冬胺酸、聚山梨醇酯80(註冊商標)等)、懸浮化劑、乳化劑、無痛化劑、緩衝劑、保存劑等。此等在最終步驟中，藉由進行滅菌或無菌操作法而製造。此外，亦可製造無菌之固體劑，例如凍結乾燥品，在其使用前將其無菌化或溶解於無菌之注射用蒸餾水或其他溶劑而使用。Injections as parenteral preparations include solid injections that are dissolved or suspended in solutions, suspensions, emulsions, and solvents when used. Injections are used, for example, by dissolving the compound of the present disclosure in a solvent, suspending or emulsifying it. As the solvent, for example, distilled water for injection, physiological saline, vegetable oil, alcohols such as propylene glycol, polyethylene glycol, and ethanol, etc., and combinations thereof are used. Furthermore, the injection may also contain stabilizers, dissolution aids (for example, glutamic acid, aspartic acid, polysorbate 80 (registered trademark), etc.), suspending agents, emulsifiers, pain-relieving agents, buffers, etc. agents, preservatives, etc. These are manufactured by performing sterilization or aseptic manipulation in the final step. In addition, sterile solid preparations, such as freeze-dried products, can also be produced, which are sterilized or dissolved in sterile distilled water for injection or other solvents before use.

本揭示化合物之投予量係依據症狀、年齡、劑型等而可適宜選擇，惟只要係口服劑，則以較佳係1至100mg、更佳係5至30mg在1天1至數次(例如，1至3次)投予即可。或者，每一次以50μg至500mg之範圍在一天1至數次非口服投予、或一天以1小時至24小時之範圍靜脈內持續投予。The dosage of the disclosed compound can be appropriately selected according to the symptoms, age, dosage form, etc., but as long as it is an oral dosage, it is preferably 1 to 100 mg, more preferably 5 to 30 mg in one to several times a day (such as , 1 to 3 times) can be cast. Alternatively, it can be administered parenterally one to several times a day in the range of 50 μg to 500 mg each time, or continuously administered intravenously in the range of 1 hour to 24 hours a day.

當然，如前所述，投予量會因各種條件而變動，故有時以上述投予量的更少量則足夠，也有時需要超過範圍。Of course, as mentioned above, the dose varies depending on various conditions, and therefore, a smaller amount than the above dose may be sufficient, and may need to exceed the range.

本揭示提供例如下述之實施態樣。 [1]　一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之溶劑合物； [2]　如前述[1]記載之化合物，其中，溶劑合物為水合物； [3]　如前述[1]或[2]記載之化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物； [4]　如前述[1]至[3]中任一項記載之化合物，其係結晶型態； [4’]　一種前述[1]至[3]中任一項記載之化合物之結晶； [5]　一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物； [6]　如前述[5]記載之化合物，其係結晶型態； [6’]　一種前述[5]記載之化合物之結晶； [7]　一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸、或其溶劑合物，其係結晶型態； [7’]　一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸、或其溶劑合物之結晶； [8]　如前述[7]或[7’]記載之結晶，其中，溶劑合物係水合物； [9]　如前述[7]、[7’]或[8]記載之結晶，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物； [10]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]、[8]及[9]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.0、約10.7、約14.0、約16.3、約21.5、約24.9、約25.9、及約27.8度之繞射角(2θ)，具有至少2個以上的繞射峰； [11]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]及[8]至[10]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.0、約10.7、約14.0、約16.3、約21.5、約24.9、約25.9、及約27.8度之繞射角(2θ)，具有繞射峰； [12]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]及[8]至[11]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.0、約9.4、約9.7、約9.9、約10.6、約10.7、約12.5、約12.8、約13.4、約14.0、約14.2、約14.8、約15.2、約15.4、約16.3、約16.9、約17.4、約17.8、約18.4、約18.6、約18.7、約18.9、約19.2、約19.6、約20.1、約20.3、約20.5、約20.8、約21.0、約21.5、約22.3、約23.0、約23.4、約23.8、約24.6、約24.9、約25.2、約25.9、約26.4、約26.9、約27.1、約27.8、約28.3、約28.5、約29.0、約29.2、約29.4、約30.7、約31.3、約31.9、約32.3、約33.1、約33.5、及約34.4度之繞射角(2θ)，具有繞射峰； [13]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]及[8]至[12]中任一項記載之結晶，其特徵為圖7所示之粉末X射線繞射譜圖； [14]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]及[8]至[13]中任一項記載之結晶，其中，微差掃描熱量測量中，起始溫度為約30℃或吸熱峰溫度為約50℃； [15]　如前述[4]、[4’]、[6]、[6’]、[7]、[7’]及[8]至[14]中任一項記載之結晶，其特徵為圖8所示之微差掃描熱量測量圖； [16]　一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸，其係結晶型態； [16’]　一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶； [17]　如前述[7]、[7’]、[16]或[16’]記載之結晶，其中，粉末X射線繞射譜中，在約7.7、約10.3、約13.4、約15.5、約16.9、約19.7、約21.3、及約22.9度之繞射角(2θ)，具有至少2個以上的繞射峰； [18]　如前述[7]、[16]或[17]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.7、約10.3、約13.4、約15.5、約16.9、約19.7、約21.3、及約22.9度之繞射角(2θ)，具有繞射峰； [19]　如前述[7]、[7’]、[16]、[16’]、[17]及[18]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.0、約7.7、約10.3、約10.5、約12.2、約12.6、約13.4、約14.2、約15.5、約16.2、約16.7、約16.9、約17.3、約17.9、約18.2、約18.6、約19.4、約19.7、約20.6、約21.3、約21.7、約22.1、約22.4、約22.9、約23.4、約24.2、約24.6、約24.8、約25.1、約25.9、約27.9、約28.2、約30.2、及約31.3度之繞射角(2θ)，具有繞射峰； [20]　如前述[7]、[7’]、[16]、[16’]及[17]至[19]中任一項記載之結晶，其特徵為圖11所示之粉末X射線繞射譜圖； [21]　如前述[7]、[7’]、[16]、[16’]及[17]至[20]中任一項記載之結晶，其中，微差掃描熱量測量中，起始溫度為約69℃或吸熱峰溫度為約76℃； [22]　如前述[7]、[7’]、[16]、[16’]及[17]至[21]中任一項記載之結晶，其特徵為圖12所示之微差掃描熱量測量圖； [23]　如前述[7]、[7’]、[16]或[16’]記載之結晶，其中，粉末X射線繞射譜中，在約7.6、約8.7、約11.4、約15.3、約17.6、約19.3、約22.6、及約26.5度之繞射角(2θ)，具有至少2個以上的繞射峰； [24]　如前述[7]、[7’]、[16]、[16’]或[23]記載之結晶，其中，粉末X射線繞射譜中，在約7.6、約8.7、約11.4、約15.3、約17.6、約19.3、約22.6、及約26.5度之繞射角(2θ)，具有繞射峰； [25]　如前述[7]、[7’]、[16]、[16’]、[23]或[24]記載之結晶，其中，粉末X射線繞射譜中，在約7.6、約8.1、約8.7、約9.1、約9.7、約10.6、約11.0、約11.4、約12.1、約12.5、約12.9、約13.0、約13.7、約13.9、約14.6、約15.3、約15.9、約16.0、約16.3、約17.0、約17.3、約17.6、約18.1、約18.6、約19.3、約19.8、約20.1、約20.4、約20.7、約21.1、約21.4、約21.7、約22.2、約22.6、約23.0、約23.5、約23.8、約24.0、約24.3、約24.7、約25.1、約26.5、約26.8、約27.3、約27.7、約28.1、約28.6、約28.8、約29.1、約29.5、約30.2、約30.6、約31.0、約32.2、約33.0、約33.6、及約34.5度之繞射角(2θ)，具有繞射峰； [26]　如前述[7]、[7’]、[16]、[16’]及[23]至[25]中任一項記載之結晶，其特徵為圖10所示之粉末X射線繞射譜圖； [27]　一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸的鹽、或其溶劑合物； [28]　如前述[27]記載之化合物，其中，鹽係鎂鹽； [29]　如前述[27]或[28]記載之化合物，其係鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物； [30]　如前述[27]至[29]中任一項記載之化合物，其係結晶型態； [30’]　一種前述[27]至[29]中任一項記載之化合物之結晶、 [31]　如前述[30]或[30’]記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約10.2、約13.6、約17.0、約18.6、約20.1、約23.9、及約26.3度之繞射角(2θ)，具有至少2個以上的繞射峰； [32]　如前述[30]、[30’]或[31]記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約10.2、約13.6、約17.0、約18.6、約20.1、約23.9、及約26.3度之繞射角(2θ)，具有繞射峰； [33]　如前述[30]、[30’]、[31]及[32]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約8.3、約10.2、約12.1、約12.5、約12.7、約13.6、約14.0、約15.1、約15.6、約16.1、約16.6、約17.0、約17.5、約17.7、約18.1、約18.6、約19.2、約20.1、約21.3、約21.5、約21.8、約22.8、約23.0、約23.9、約24.7、約25.1、約25.6、約26.3、約28.1、約28.4、及約28.9度之繞射角(2θ)，具有繞射峰； [34]　如前述[30]、[30’]及[31]至[33]中任一項記載之結晶，其特徵為圖1所示之粉末X射線繞射譜圖； [35]　如前述[30]、[30’]及[31]至[34]中任一項記載之結晶，其中，微差掃描熱量測量中，在約25℃至約85℃之範圍內具有吸熱峰； [36]　如前述[30]、[30’]及[31]至[35]中任一項記載之結晶，其特徵為圖2所示之微差掃描熱量測量圖； [37]　如前述[27]或[28]記載之化合物，其係鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]m水合物(m表示4至8)； [38]　如前述[37]記載之化合物，其係結晶型態； [38’]　一種前述[37]記載之化合物之結晶； [39]　如前述[38]或[38’]記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約10.2、約13.7、約16.1、約21.7、約24.3、及約25.5度之繞射角(2θ)，具有至少2個以上的繞射峰； [40]　如前述[38]、[38’]或[39]記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約10.2、約13.7、約16.1、約21.7、約24.3、及約25.5度之繞射角(2θ)，具有繞射峰； [41]　如前述[38]、[38’]、[39]及[40]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約6.8、約8.3、約10.2、約12.1、約12.5、約12.8、約13.4、約13.7、約15.7、約16.1、約16.7、約17.2、約17.7、約18.3、約18.8、約19.2、約20.3、約21.4、約21.7、約22.0、約22.7、約23.3、約24.3、約25.5、約26.7、約28.7、及約29.4度之繞射角(2θ)，具有繞射峰； [42]　如前述[38]、[38’]及[39]至[41]中任一項記載之結晶，其特徵為圖4所示之粉末X射線繞射譜圖； [43]　如前述[27]或[28]記載之化合物，其係鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]n水合物(n表示4至8)； [44]　如前述[43]記載之化合物，其係結晶型態； [44’]　一種前述[43]記載之化合物之結晶； [45]　如前述[44]或[44’]記載之結晶，其中，粉末X射線繞射譜中，在約6.9、約10.4、約13.9、約16.5、約18.4、約19.1、及約25.6度之繞射角(2θ)，具有至少2個以上的繞射峰； [46]　如前述[44]、[44’]或[45]記載之結晶，其中，粉末X射線繞射譜中，在約6.9、約10.4、約13.9、約16.5、約18.4、約19.1、及約25.6度之繞射角(2θ)，具有繞射峰； [47]　如前述[44]、[44’]、[45]及[46]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約6.9、約10.2、約10.4、約12.5、約12.9、約13.9、約16.0、約16.5、約17.5、約17.7、約18.0、約18.4、約19.1、約20.5、約21.3、約22.7、約23.3、約24.3、約25.6、約26.7、約28.2、及約29.2度之繞射角(2θ)，具有繞射峰； [48]　如前述[44][44’]及[45]至[47]中任一項記載之結晶，其特徵為圖5所示之粉末X射線繞射譜圖； [49]　如前述[27]或[28]記載之化合物，其係鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]p水合物(p表示超過0且8以下)； [50]　如前述[49]記載之化合物，其係結晶型態； [50’]　一種前述[49]記載之化合物之結晶； [51]　如前述[50]或[50’]記載之結晶，其中，粉末X射線繞射譜中，在約7.2、約10.8、約14.4、約16.3、約21.6、約22.8、及約23.7度之繞射角(2θ)，具有至少2個以上的繞射峰； [52]　如前述[50]、[50’]或[51]記載之結晶，其中，粉末X射線繞射譜中，在約7.2、約10.8、約14.4、約16.3、約21.6、約22.8、及約23.7度之繞射角(2θ)，具有繞射峰； [53]　如前述[50]、[50’]、[51]及[52]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.2、約8.4、約10.0、約10.4、約10.8、約11.8、約12.3、約13.5、約13.8、約13.9、約14.4、約15.5、約16.0、約16.3、約16.6、約17.6、約18.8、約19.0、約20.8、約21.3、約21.6、約22.8、約23.7、約26.1、約27.3、及約28.9度之繞射角(2θ)，具有繞射峰； [54]　如前述[50]、[50’]及[51]至[53]中任一項記載之結晶，其特徵為圖6所示之粉末X射線繞射譜圖； [55]　如前述[27]記載之化合物，其中，鹽係二環己胺鹽； [56]　如前述[27]或[55]記載之化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽； [57]　如前述[56]記載之化合物，其係結晶型態； [57’]　一種前述[56]記載之化合物之結晶； [58]　如前述[57]或[57’]記載之結晶，其中，粉末X射線繞射譜中，在約5.9、約7.9、約11.4、約18.8、約21.2、約22.7、及約25.3度之繞射角(2θ)，具有至少2個以上的繞射峰； [59]　如前述[57]、[57’]或[58]記載之結晶，其中，粉末X射線繞射譜中，在約5.9、約7.9、約11.4、約18.8、約21.2、約22.7、及約25.3度之繞射角(2θ)，具有繞射峰； [60]　如前述[57]、[57’]、[58]及[59]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約5.9、約6.8、約7.9、約8.2、約11.4、約11.9、約13.7、約15.0、約15.9、約17.0、約17.3、約17.9、約18.3、約18.8、約19.6、約19.9、約20.4、約20.7、約21.2、約21.5、約21.9、約22.7、約23.9、約24.3、約24.7、約25.3、約26.8、及約28.9度之繞射角(2θ)，具有繞射峰； [61]　如前述[57]、[57’]及[58]至[60]中任一項記載之結晶，其特徵為圖13所示之粉末X射線繞射譜圖； [62]　如前述[57]、[57’]及[58]至[61]中任一項記載之結晶，其中，微差掃描熱量測量中，起始溫度為約153℃或吸熱峰溫度為約155℃； [63]　如前述[57]、[57’]及[58]至[62]中任一項記載之結晶，其特徵為圖14所示之微差掃描熱量測量圖； [64]　如前述[27]記載之化合物，其中，鹽係鈣鹽； [65]　如前述[27]或[64]記載之化合物，其係鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]q水合物(q表示4至8)； [66]　如前述[65]記載之化合物，其係結晶型態； [66’]　一種前述[65]記載之化合物之結晶； [67]　如前述[66]或[66’]記載之結晶，其中，粉末X射線繞射譜中，在約7.1、約10.4、約12.3、約14.2、約16.8、約18.6、約23.3、及約25.7度之繞射角(2θ)，具有至少2個以上的繞射峰； [68]　如前述[66]、[66’]或[67]記載之結晶，其中，粉末X射線繞射譜中，在約7.1、約10.4、約12.3、約14.2、約16.8、約18.6、約23.3、及約25.7度之繞射角(2θ)，具有繞射峰； [69]　如前述[66]、[66’]、[67]及[68]中任一項記載之結晶，其中，粉末X射線繞射譜中，在約7.1、約8.4、約10.4、約10.6、約11.8、約12.3、約13.1、約13.7、約13.9、約14.2、約15.3、約15.7、約15.8、約16.1、約16.8、約17.8、約18.1、約18.6、約19.1、約19.3、約19.8、約20.1、約20.8、約21.1、約21.3、約22.6、約22.9、約23.3、約23.5、約24.1、約24.6、約24.8、約25.0、約25.7、約26.3、約27.0、約27.7、約28.0、約28.6、約29.4、約29.7、約30.9、約31.2、約31.7、約32.2、約32.4、約33.1、約33.3、約33.5、約34.0、及約34.6度之繞射角(2θ)，具有繞射峰； [70]　如前述[66]、[66’]及[67]至[69]中任一項記載之結晶，其特徵為圖16所示之粉末X射線繞射譜圖； [71]　如前述[66]、[66’]及[67]至[70]中任一項記載之結晶，其中，微差掃描熱量測量中，起始溫度為約46℃或吸熱峰溫度為約62℃； [72]　如前述[66]、[66’]及[67]至[71]中任一項記載之結晶，其中，微差掃描熱量測量中，起始溫度為約74℃或吸熱峰溫度為約91℃； [73]　如前述[66]、[66’]及[67]至[72]中任一項記載之結晶，其特徵為圖17所示之微差掃描熱量測量圖； [74]　一種醫藥組成物，其係含有前述[1]至[73]、[4’]、[6’]、[7’]、[16’]、[30’]、[38’]、[44’]、[50’]、[57’]及[66’]中任一項記載之化合物或結晶與藥學上可接受之載體； [75]　如前述[74]記載之醫藥組成物，其係EP 2受體拮抗劑； [76]　如前述[74]或[75]記載之醫藥組成物，其係起因於EP 2受體之活性化之疾病的預防及/或治療劑； [77]　如前述[76]記載之醫藥組成物，其中，起因於EP 2受體之活性化之疾病為子宮內膜症、子宮肌瘤、月經過多、腺肌症、月經困難症、慢性骨盆痛症候群、癌症、炎症性疼痛、神經因性疼痛、頭痛、偏頭痛、術後疼痛、間質性膀胱炎、平滑肌瘤、過敏性大腸症候群、阿茲海默氏症、帕金森氏症、肌萎縮性側索硬化症、多發性硬化症、風濕病、骨關節炎、痛風、過敏性疾病、高血壓、腦機能障礙、缺血、腦溢血、腎疾病、移植排斥反應、粥狀動脈硬化症、缺血性心疾病、尋常性痤瘡、氣喘、***炎、腎絲球性腎炎、類肉瘤病、血管炎、或自體免疫疾病； [78]　如前述[76]記載之醫藥組成物，其中，起因於EP 2受體之活性化之疾病為癌症，癌症為乳癌、卵巢癌、大腸癌、肺癌、***癌、頭頸部癌、淋巴瘤、葡萄膜黑色素瘤、胸腺瘤、間皮瘤、食道癌、胃癌、十二指腸癌、肝細胞癌、膽管癌、膽囊癌、胰臟癌、腎細胞癌、腎盂/尿道癌、膀胱癌、陰莖癌、睪丸癌、子宮癌、***癌、外陰癌、皮膚癌(例如，惡性黑色素瘤等)、惡性骨腫瘤、軟組織肉瘤、軟骨肉瘤、白血病、骨髓發育不良症候群、神經膠質母細胞瘤或多發性骨髓瘤； [79]　如前述[74]至[78]中任一項記載之醫藥組成物，其係與由烷基化劑、代謝拮抗劑、抗癌性抗生物質、植物性製劑、荷爾蒙劑、鉑化合物、拓樸異構酶抑制劑、激酶抑制劑、抗CD20抗體、抗HER2抗體、抗EGFR抗體、抗VEGF抗體、蛋白質體抑制劑、HDAC抑制劑、及免疫調整藥選擇之至少1種以上組合投予； [80]　一種起因於EP 2受體之活性化之疾病的預防及/或治療方法，其係包含向需要起因於EP 2受體之活性化之疾病的預防及/或治療的患者投予有效量的前述[1]至[73]、[4’]、[6’]、[7’]、[16’]、[30’]、[38’]、[44’]、[50’]、[57’]及[66’]中任一項記載之化合物或結晶； [81]　如前述[1]至[73]、[4’]、[6’]、[7’]、[16’]、[30’]、[38’]、[44’]、[50’]、[57’]及[66’]中任一項記載之化合物或結晶，其係使用於起因於EP 2受體之活性化之疾病的預防及/或治療； [82]　一種前述[1]至[73]、[4’]、[6’]、[7’]、[16’]、[30’]、[38’]、[44’]、[50’]、[57’]及[66’]中任一項記載之化合物或結晶的用途，其係用於製造起因於EP 2受體之活性化之疾病的預防及/或治療劑； [83]　一種起因於EP 2受體之活性化之疾病的預防及/或治療劑，其係含有前述[1]至[73]、[4’]、[6’]、[7’]、[16’]、[30’]、[38’]、[44’]、[50’]、[57’]及[66’]中任一項記載之化合物或結晶。 [實施例] The present disclosure provides, for example, the following implementation aspects. [1] A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoro A solvate of methyl)phenyl}cyclopropane-1-carboxylic acid; [2] The compound described in [1] above, wherein the solvate is a hydrate; [3] The compound described in [1] or [2 above] ] is a compound described in (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform base) phenyl}cyclopropane-1-carboxylic acid monohydrate; [4] a compound as described in any one of the aforementioned [1] to [3], which is in a crystalline form; [4'] a aforementioned [1 ] to the crystal of the compound described in any one of [3]; [5] A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenyl Ethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid monohydrate; [6] The compound as described in [5] above, which is in crystalline form; [6'] A crystal of the compound described in [5] above; [7] A (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy) Benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid, or a solvate thereof, in crystalline form; [7'] a (1R,2S)-2- {3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid, or A solvate crystal; [8] The crystal described in [7] or [7'] above, wherein the solvate is a hydrate; [9] The crystal described in [7], [7'] or [8] above The crystal of (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) Phenyl}cyclopropane-1-carboxylic acid monohydrate; [10] As mentioned above [4], [4'], [6], [6'], [7], [7'], [8] and The crystal according to any one of [9], wherein, in the powder X-ray diffraction spectrum, the diffraction is at about 7.0, about 10.7, about 14.0, about 16.3, about 21.5, about 24.9, about 25.9, and about 27.8 degrees Angle (2θ), with at least 2 or more diffraction peaks; [11] As mentioned above [4], [4'], [6], [6'], [7], [7'] and [8] The crystal according to any one of [10], wherein, in the powder X-ray diffraction spectrum, at about 7.0, about 10.7, about 14.0, about 16.3, about 21.5, about 24.9, about 25.9, and about 27.8 degrees Radiation angle (2θ), with diffraction peaks; [12] As mentioned above [4], [4'], [6], [6'], [7], [7'] and [8] to [11] The crystal described in any one, wherein, in the powder X-ray diffraction spectrum, at about 7.0, about 9.4, about 9.7, about 9.9, about 10.6, about 10.7, about 12.5, about 12.8, about 13.4, about 14.0, about 14.2, about 14.8, about 15.2, about 15.4, about 16.3, about 16.9, about 17.4, About 17.8, about 18.4, about 18.6, about 18.7, about 18.9, about 19.2, about 19.6, about 20.1, about 20.3, about 20.5, about 20.8, about 21.0, about 21.5, about 22.3, about 23.0, about 23.4, about 23.8 , about 24.6, about 24.9, about 25.2, about 25.9, about 26.4, about 26.9, about 27.1, about 27.8, about 28.3, about 28.5, about 29.0, about 29.2, about 29.4, about 30.7, about 31.3, about 31.9, about Diffraction angles (2θ) of 32.3, about 33.1, about 33.5, and about 34.4 degrees, with diffraction peaks; [13] as mentioned above [4], [4'], [6], [6'], [7 ], [7'], and the crystal described in any one of [8] to [12], which is characterized by the powder X-ray diffraction spectrum shown in Figure 7; [14] as mentioned in [4], [4' ], [6], [6'], [7], [7'] and any one of [8] to [13], wherein, in differential scanning calorimetry, the initial temperature is about 30 °C or the endothermic peak temperature is about 50 °C; [15] As in the aforementioned [4], [4'], [6], [6'], [7], [7'] and [8] to [14] The crystal described in any item is characterized by the differential scanning calorimetry diagram shown in Figure 8; [16] a kind of (1R,2S)-2-{3-[2,6-dimethyl-4-(2 -phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid in crystalline form; [16'] a (1R,2S)-2 Crystals of -{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid [17] The crystal as described in [7], [7'], [16] or [16'] above, wherein, in the powder X-ray diffraction spectrum, at about 7.7, about 10.3, about 13.4, about 15.5, Diffraction angles (2θ) of about 16.9, about 19.7, about 21.3, and about 22.9 degrees, with at least 2 or more diffraction peaks; [18] As in any one of the aforementioned [7], [16] or [17] The crystal described in item 1, wherein, in the powder X-ray diffraction spectrum, at about 7.7, about 10.3, about 13.4, about 15.5, about 16.9, about 19.7, about 21.3, and about 22.9 degrees of diffraction angle (2θ), having Diffraction peak; [19] The crystal as described in any one of [7], [7'], [16], [16'], [17] and [18], wherein the powder X-ray diffraction spectrum In about 7.0, about 7.7, about 10.3, about 10.5, about 12.2, about 12.6, about 13.4, about 14.2, about 15.5, about 16.2, about 16.7, about 16.9, about 17.3, about 17.9, about 18.2, about 18.6 , about 19.4, about 19.7, about 20.6, about 21.3, about 21.7, about 22.1, about 22.4, about 22.9, about 23.4, about 24.2, about 24.6, about 24.8, about 25.1, about 25.9, about 27.9, about 28.2, about 30.2, and a diffraction angle (2θ) of about 31.3 degrees, with a diffraction peak; [20] As in the aforementioned [7], [7'], [16], [16'] and [17] to [19] The crystals described in any one of the above-mentioned crystals are characterized by the powder X-ray diffraction spectrum shown in Figure 11; The crystal according to any one of [20], wherein the onset temperature is about 69°C or the endothermic peak temperature is about 76°C in differential scanning calorimetry; The crystal described in any one of [16], [16'] and [17] to [21] is characterized by the differential scanning calorimetry diagram shown in Fig. 12; [23] As mentioned above [7], [7] '], [16] or [16'], wherein, in the powder X-ray diffraction spectrum, at about 7.6, about 8.7, about 11.4, about 15.3, about 17.6, about 19.3, about 22.6, and about 26.5 degree of diffraction (2θ), with at least 2 or more diffraction peaks; [24] the crystal described in [7], [7'], [16], [16'] or [23] above, wherein , in the powder X-ray diffraction spectrum, there are diffraction peaks at about 7.6, about 8.7, about 11.4, about 15.3, about 17.6, about 19.3, about 22.6, and about 26.5 degrees of diffraction angle (2θ); [25 ] The crystal described in [7], [7'], [16], [16'], [23] or [24] above, wherein, in the powder X-ray diffraction spectrum, at about 7.6, about 8.1, about 8.7, about 9.1, about 9.7, about 10.6, about 11.0, about 11.4, about 12.1, about 12.5, about 12.9, about 13.0, about 13.7, about 13.9, about 14.6, about 15.3, about 15.9, about 16.0, about 16.3, About 17.0, about 17.3, about 17.6, about 18.1, about 18.6, about 19.3, about 19.8, about 20.1, about 20.4, about 20.7, about 21.1, about 21.4, about 21.7, about 22.2, about 22.6, about 23.0, about 23.5 , about 23.8, about 24.0, about 24.3, about 24.7, about 25.1, about 26.5, about 26.8, about 27.3, about 27.7, about 28.1, Diffraction angles (2θ) of about 28.6, about 28.8, about 29.1, about 29.5, about 30.2, about 30.6, about 31.0, about 32.2, about 33.0, about 33.6, and about 34.5 degrees, with diffraction peaks; [26] The crystal described in any one of [7], [7'], [16], [16'] and [23] to [25] is characterized by the powder X-ray diffraction spectrum shown in Fig. 10 [27] A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(tri A salt of fluoromethyl)phenyl}cyclopropane-1-carboxylic acid, or a solvate thereof; [28] The compound described in [27] above, wherein the salt is a magnesium salt; [29] As in [27] above Or the compound described in [28], which is magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]- 4-(Trifluoromethyl)phenyl}cyclopropane-1-carboxylate]decahydrate; [30] The compound described in any one of the aforementioned [27] to [29], which is in a crystalline form; [30'] A crystal of the compound described in any one of the aforementioned [27] to [29], [31] The crystal of the aforementioned [30] or [30'], wherein, in the powder X-ray diffraction spectrum, At the diffraction angles (2θ) of about 6.8, about 10.2, about 13.6, about 17.0, about 18.6, about 20.1, about 23.9, and about 26.3 degrees, there are at least two or more diffraction peaks; [32] As mentioned above [ 30], [30'] or [31], wherein, in the powder X-ray diffraction spectrum, about 6.8, about 10.2, about 13.6, about 17.0, about 18.6, about 20.1, about 23.9, and about 26.3 [33] The crystal described in any one of [30], [30'], [31] and [32] above, wherein powder X-ray diffraction In the spectrum, at about 6.8, about 8.3, about 10.2, about 12.1, about 12.5, about 12.7, about 13.6, about 14.0, about 15.1, about 15.6, about 16.1, about 16.6, about 17.0, about 17.5, about 17.7, about 18.1, about 18.6, about 19.2, about 20.1, about 21.3, about 21.5, about 21.8, about 22.8, about 23.0, about 23.9, about 24.7, about 25.1, about 25.6, about 26.3, about 28.1, about 28.4, and about 28.9 degree of diffraction angle (2θ), with a diffraction peak; [34] The crystal as described in any one of [30], [30'] and [31] to [33] above, which is characterized in that it is shown in Figure 1 [35] The crystal described in any one of [30], [30'] and [31] to [34] above, wherein, In differential scanning calorimetry, it has an endothermic peak in the range of about 25°C to about 85°C; [36] The crystal as described in any one of the aforementioned [30], [30'] and [31] to [35] , characterized by the differential scanning calorimetry diagram shown in Figure 2; [37] The compound as described in [27] or [28] above, which is a magnesium bis[(1R,2S)-2-{3-[2 ,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate]m hydrate (m represents 4 to 8); [38] The compound described in [37] above, which is in a crystalline form; [38'] A crystal of the compound described in [37] above; [39] The compound described in [38] or [38' above ], wherein, in the powder X-ray diffraction spectrum, there are at least two diffraction angles (2θ) of about 6.8, about 10.2, about 13.7, about 16.1, about 21.7, about 24.3, and about 25.5 degrees The above diffraction peak; [40] The crystal as described in [38], [38'] or [39] above, wherein, in the powder X-ray diffraction spectrum, at about 6.8, about 10.2, about 13.7, about 16.1, Diffraction angles (2θ) of about 21.7, about 24.3, and about 25.5 degrees, with diffraction peaks; [41] as described in any one of the aforementioned [38], [38'], [39] and [40] Crystalline, wherein, in the powder X-ray diffraction spectrum, at about 6.8, about 8.3, about 10.2, about 12.1, about 12.5, about 12.8, about 13.4, about 13.7, about 15.7, about 16.1, about 16.7, about 17.2, about Diffraction angles ( 2θ), with a diffraction peak; [42] The crystal as described in any one of the aforementioned [38], [38'] and [39] to [41], characterized by powder X-ray diffraction as shown in Figure 4 Spectrum; [43] The compound as described in [27] or [28] above, which is magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-benzene ethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate]n hydrate (n represents 4 to 8); [44] as mentioned above [43] The compound described in the crystal form; [44'] A crystal of the compound described in [43] above; [45] The crystal described in [44] or [44'] above, wherein the powder X-ray diffraction spectrum Among them, there are at least two diffraction peaks at the diffraction angles (2θ) of about 6.9, about 10.4, about 13.9, about 16.5, about 18.4, about 19.1, and about 25.6 degrees; [46] As before The crystal described in [44], [44'] or [45], wherein, in the powder X-ray diffraction spectrum, at about 6.9, about 10.4, about 13.9, about 16.5, about 18.4, about 19.1, and about 25.6 degrees The diffraction angle (2θ) has a diffraction peak; [47] The crystal described in any one of [44], [44'], [45] and [46] above, wherein the powder X-ray diffraction spectrum In about 6.9, about 10.2, about 10.4, about 12.5, about 12.9, about 13.9, about 16.0, about 16.5, about 17.5, about 17.7, about 18.0, about 18.4, about 19.1, about 20.5, about 21.3, about 22.7 , about 23.3, about 24.3, about 25.6, about 26.7, about 28.2, and about 29.2 degrees of diffraction angle (2θ), with diffraction peaks; [48] as mentioned above [44][44'] and [45] to The crystal described in any one of [47] is characterized by the powder X-ray diffraction spectrum shown in Figure 5; [49] The compound described in [27] or [28] above, which is a magnesium bis[(1R ,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1 - carboxylate] p hydrate (p represents more than 0 and less than 8); [50] a compound as described in [49] above, which is in a crystalline form; [50'] a crystal of a compound described in [49] above [51] The crystal as described in [50] or [50'] above, wherein, in the powder X-ray diffraction spectrum, at about 7.2, about 10.8, about 14.4, about 16.3, about 21.6, about 22.8, and about 23.7 degree of diffraction angle (2θ), having at least 2 or more diffraction peaks; [52] the crystal as described in [50], [50'] or [51] above, wherein, in the powder X-ray diffraction spectrum, There are diffraction peaks at the diffraction angles (2θ) of about 7.2, about 10.8, about 14.4, about 16.3, about 21.6, about 22.8, and about 23.7 degrees; [53] as mentioned above [50], [50'], The crystal according to any one of [51] and [52], wherein, in the powder X-ray diffraction spectrum, about 7.2, about 8.4, about 10.0, about 10.4, about 10.8, about 11.8, about 12.3, about 13.5, About 13.8, about 13.9, about 14.4, about 15.5, about 16.0, about 16.3, about 16.6, about 17.6, about 18.8, about 19.0, about 20.8, about 21.3, about 21.6, about 22.8, about 23.7, about 26.1, about 27.3 , and a diffraction angle (2θ) of about 28.9 degrees, with a diffraction peak; [54] The crystal described in any one of the aforementioned [50], [50'] and [51] to [53] is characterized by The powder X-ray diffraction spectrum shown in Figure 6; [55] The compound described in [27] above, wherein the salt is dicyclohexylamine salt; [56] The compound described in [27] or [55] above, which is (1R,2S)-2-{3-[2 ,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid dicyclohexylamine salt; [57 ] the compound described in the aforementioned [56], which is in a crystalline form; [57'] a crystal of the compound described in the aforementioned [56]; [58] the crystal described in the aforementioned [57] or [57'], wherein, In the powder X-ray diffraction spectrum, there are at least two diffraction peaks at diffraction angles (2θ) of about 5.9, about 7.9, about 11.4, about 18.8, about 21.2, about 22.7, and about 25.3 degrees; [ 59] The crystal as described in [57], [57'] or [58] above, wherein, in the powder X-ray diffraction spectrum, at about 5.9, about 7.9, about 11.4, about 18.8, about 21.2, about 22.7, and Diffraction angle (2θ) of about 25.3 degrees, with a diffraction peak; [60] The crystal as described in any one of [57], [57'], [58] and [59], wherein the powder X-ray In the diffraction spectrum, at about 5.9, about 6.8, about 7.9, about 8.2, about 11.4, about 11.9, about 13.7, about 15.0, about 15.9, about 17.0, about 17.3, about 17.9, about 18.3, about 18.8, about 19.6 , about 19.9, about 20.4, about 20.7, about 21.2, about 21.5, about 21.9, about 22.7, about 23.9, about 24.3, about 24.7, about 25.3, about 26.8, and about 28.9 degrees of diffraction (2θ), with Diffraction peak; [61] The crystal as described in any one of [57], [57'] and [58] to [60] above, characterized by the powder X-ray diffraction spectrum shown in Figure 13; [ 62] The crystal according to any one of [57], [57'] and [58] to [61] above, wherein, in differential scanning calorimetry, the onset temperature is about 153°C or the endothermic peak temperature is about 155°C; [63] The crystal as described in any one of [57], [57'] and [58] to [62] above, characterized by the differential scanning calorimetry diagram shown in Figure 14; [64] The compound described in [27] above, wherein the salt is calcium salt; [65] The compound described in [27] or [64] above, which is calcium bis[(1R,2S)-2-{3-[2 ,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate]q hydrate (q represents 4 to 8); [66] The compound described in [65] above, which is in a crystalline form; [66'] A crystal of the compound described in [65] above; [67] The compound described in [66] or [66' above ] record A crystal having, in a powder X-ray diffraction spectrum, at least 2 [68] The crystal as described in [66], [66'] or [67] above, wherein, in the powder X-ray diffraction spectrum, at about 7.1, about 10.4, about 12.3, about 14.2 , about 16.8, about 18.6, about 23.3, and about 25.7 degrees of diffraction angle (2θ), with diffraction peaks; [69] as any of the aforementioned [66], [66'], [67] and [68] A described crystal, wherein, in the powder X-ray diffraction spectrum, at about 7.1, about 8.4, about 10.4, about 10.6, about 11.8, about 12.3, about 13.1, about 13.7, about 13.9, about 14.2, about 15.3, About 15.7, about 15.8, about 16.1, about 16.8, about 17.8, about 18.1, about 18.6, about 19.1, about 19.3, about 19.8, about 20.1, about 20.8, about 21.1, about 21.3, about 22.6, about 22.9, about 23.3 , about 23.5, about 24.1, about 24.6, about 24.8, about 25.0, about 25.7, about 26.3, about 27.0, about 27.7, about 28.0, about 28.6, about 29.4, about 29.7, about 30.9, about 31.2, about 31.7, about Diffraction angles (2θ) of 32.2, about 32.4, about 33.1, about 33.3, about 33.5, about 34.0, and about 34.6 degrees, with diffraction peaks; [70] as mentioned above [66], [66'] and [67 ] to [69], characterized by the powder X-ray diffraction spectrum shown in Figure 16; [71] as described in [66], [66'] and [67] to [70] The crystal according to any one of the above, wherein, in differential scanning calorimetry, the onset temperature is about 46°C or the endothermic peak temperature is about 62°C; [72] As mentioned above in [66], [66'] and [67] The crystal according to any one of [71], wherein, in differential scanning calorimetry, the onset temperature is about 74°C or the endothermic peak temperature is about 91°C; [73] as mentioned above in [66], [66'] and the crystal described in any one of [67] to [72], which is characterized by the differential scanning calorimetry diagram shown in Figure 17; [74] A pharmaceutical composition comprising the aforementioned [1] to [73] , [4'], [6'], [7'], [16'], [30'], [38'], [44'], [50'], [57'] and [66'] The compound or crystal described in any one of them and a pharmaceutically acceptable carrier; [75] The pharmaceutical composition as described in [74] above, which is an EP 2 receptor antagonist; [76] The above [74] or [ 75] Recorded medicinal composition [77] The pharmaceutical composition as described in [76] above, wherein the disease caused by the activation of EP2 receptor For endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, chronic pelvic pain syndrome, cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative pain, interstitial Cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic diseases, Hypertension, brain dysfunction, ischemia, cerebral hemorrhage, kidney disease, transplant rejection, atherosclerosis, ischemic heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, Vasculitis, or autoimmune disease; [78] The pharmaceutical composition as described in [76] above, wherein the disease caused by the activation of EP2 receptor is cancer, and the cancer is breast cancer, ovarian cancer, colorectal cancer, lung cancer , prostate cancer, head and neck cancer, lymphoma, uveal melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis /Urethral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (for example, malignant melanoma, etc.), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, Glioblastoma or multiple myeloma; [79] The pharmaceutical composition described in any one of [74] to [78] above, which is formulated with an alkylating agent, a metabolic antagonist, or an anticancer antibiotic Substances, botanicals, hormonal agents, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteosome inhibitors, HDAC inhibitors, and Administration of at least one combination of immunomodulators selected; [80] A method for preventing and/or treating a disease caused by activation of EP 2 receptors, which comprises targeting the For the prevention and/or treatment of diseases, the patients are given an effective amount of the aforementioned [1] to [73], [4'], [6'], [7'], [16'], [30'], [ The compound or crystal described in any one of 38'], [44'], [50'], [57'] and [66']; [81] As mentioned in [1] to [73], [4'] , [6'], [7'], [16'], [30'], [38'], [44'], [50'], [57'] and [66'] A compound or crystal for use in the prevention and/or treatment of diseases caused by the activation of EP 2 receptors; [82] one of the aforementioned [1] to [73], [4'], [6'], [7'], [16'], [30'], [38'], [44'], [50'], [57 '] and [66'], the use of the compound or crystal described in any one of it is used for the manufacture of a preventive and/or therapeutic agent for diseases caused by the activation of EP 2 receptors; [83] an EP 2. A preventive and/or therapeutic agent for a disease in which the receptor is activated, comprising the aforementioned [1] to [73], [4'], [6'], [7'], [16'], [30 '], [38'], [44'], [50'], [57'] and [66'], the compound or crystal. [Example]

以下，藉由實施例詳述本揭示，惟本揭示並非限定於此等者。Hereinafter, the present disclosure will be described in detail through examples, but the present disclosure is not limited thereto.

藉由層析所進行之分離的位置所示之括弧內的溶劑係表示已使用的溶出溶劑或展開溶劑，比率係表示體積比。The solvent in parentheses shown at the position of separation by chromatography means the eluting solvent or developing solvent used, and the ratio means the volume ratio.

NMR的位置所示之括弧內的溶劑係表示測量時使用之溶劑。The solvent in parentheses shown in the position of NMR indicates the solvent used for the measurement.

本說明書中使用的化合物名一般係使用依據IUPAC的規則進行命名之電腦程式、Advanced Chemistry Development公司之ACD/Name(註冊商標)、Openeye Scientific Software公司之Lexichem Toolkit 1.4.2或Perkin Elmer公司之Chemdraw(註冊商標) Ultra、或依據IUPAC命名法所命名者。The compound names used in this specification generally use computer programs named according to the rules of IUPAC, ACD/Name (registered trademark) of Advanced Chemistry Development, Lexichem Toolkit 1.4.2 of Openeye Scientific Software, or Chemdraw of Perkin Elmer ( Registered trademark) Ultra, or those named according to the IUPAC nomenclature.

LC-MS/ELSD係以下述條件進行。 管柱：Waters Triart C 18(粒徑：1.9 x 10 -6m；管柱長：30 x 2.0 mm I.D.)；流速：1.0mL/min；管柱溫度：30℃；移動相(A)：0.1%三氟乙酸水溶液(以下簡稱為TFA)；移動相(B)：0.1%TFA-乙腈溶液；梯度(移動相(A)：記載移動相(B)的比率)：[0分]95：5；[0.1分]95：5；[1.2分]5：95；[1.4分]5：95；[1.41分]95：5；[1.5分]95：5；偵測器：UV(PDA)、ELSD、MS。 LC-MS/ELSD was performed under the following conditions. Column: Waters Triart C 18 (particle size: 1.9 x 10 -6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0mL/min; column temperature: 30°C; mobile phase (A): 0.1 % trifluoroacetic acid aqueous solution (hereinafter referred to as TFA); mobile phase (B): 0.1% TFA-acetonitrile solution; gradient (mobile phase (A): ratio of recorded mobile phase (B)): [0 points] 95:5 ;[0.1 point]95:5;[1.2 point]5:95;[1.4 point]5:95;[1.41 point]95:5;[1.5 point]95:5; detector: UV(PDA), ELSD, MS.

HPLC保持時間表示前述LC-MS/ELSD所記載的條件中的保持時間。The HPLC retention time represents the retention time under the conditions described in the aforementioned LC-MS/ELSD.

粉末X射線繞射譜係藉由以下任一條件而測量。 條件1 裝置：Rigaku製　SmartLab 目標：Cu 電壓：45kV 電流：200mA 掃描速度：30度/min 條件2 裝置：Rigaku製　SmartLab 目標：Cu 電壓：45kV 電流：200mA 掃描速度：2度/min 條件3 裝置：PANalytical製　ENPYREAN 目標：Cu 電壓：45kV 電流：40mA 掃描速度：0.164度/sec The powder X-ray diffraction spectrum is measured by any of the following conditions. Condition 1 Installation: Rigaku SmartLab Target: Cu Voltage: 45kV Current: 200mA Scanning speed: 30 degrees/min Condition 2 Installation: Rigaku SmartLab Target: Cu Voltage: 45kV Current: 200mA Scanning speed: 2 degrees/min Condition 3 Device: ENPYREAN made by PANalytical Target: Cu Voltage: 45kV Current: 40mA Scanning speed: 0.164 degrees/sec

微差掃描熱量測量(DSC)及熱重量測量(TG)係藉由以下任一條件所測量。 條件1 裝置：TA Instruments製　Discovery　DSC 試樣槽：鋁盤 氮氣流量：40mL/min 條件2 裝置：Mettler Toledo製　TGA/DSC　3+ 試樣槽：鋁盤 氮氣流量：40mL/min 條件3 裝置：Mettler Toledo製　DSC822E 試樣槽：鋁盤 氮氣流量：40mL/min 條件4 裝置：Mettler Toledo製　TGA/DSC　3+ 試樣槽：鋁盤 氮氣流量：20mL/min 條件5 裝置：Mettler Toledo製　DSC　3+ 試樣槽：鋁盤 氮氣流量：40mL/min Differential scanning calorimetry (DSC) and thermogravimetric measurement (TG) are measured by any of the following conditions. Condition 1 Device: Discovery DSC by TA Instruments Sample slot: aluminum pan Nitrogen flow: 40mL/min Condition 2 Installation: Mettler Toledo TGA/DSC 3+ Sample slot: aluminum pan Nitrogen flow: 40mL/min Condition 3 Device: Mettler Toledo DSC822E Sample slot: aluminum pan Nitrogen flow: 40mL/min Condition 4 Installation: Mettler Toledo TGA/DSC 3+ Sample slot: aluminum pan Nitrogen flow: 20mL/min Condition 5 Installation: Mettler Toledo DSC 3+ Sample slot: aluminum pan Nitrogen flow: 40mL/min

實施例1：2,6-二甲基-4-(2-苯基乙氧基)安息香酸甲酯 在4-羥基-2,6-二甲基安息香酸甲酯(CAS編號：83194-70-1、2.5g)之N,N-二甲基甲醯胺(10mL)溶液添加碳酸鉀(5.8g)及2-溴乙苯(CAS編號：103-63-9、7.7g)，在80℃攪拌15小時。更且，追加2-溴乙苯(1.4g)及碳酸鉀(1g)並終止攪拌。將反應液以乙酸乙酯與己烷稀釋，以水及飽和食鹽水洗滌，以無水硫酸鈉乾燥後減壓濃縮。將反應液減壓濃縮，將所得之殘渣藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯＝9：1→7：3)進行純化，藉此得到具有以下的物性值之標的化合物(3.3g)。 HPLC保持時間(分鐘)：1.15； MS(ESI, Pos.)：285(M+H) +； 1H-NMR(CDCl3)：δ 2.29, 3.08, 3.88, 4.16, 6.56, 7.11-7.46。 Example 1: 2,6-dimethyl-4-(2-phenylethoxy) methyl benzoate in 4-hydroxy-2,6-dimethyl benzoic acid methyl ester (CAS number: 83194-70 -1, 2.5g) N,N-dimethylformamide (10mL) solution was added potassium carbonate (5.8g) and 2-bromoethylbenzene (CAS number: 103-63-9, 7.7g), at 80 °C and stirred for 15 hours. Furthermore, 2-bromoethylbenzene (1.4 g) and potassium carbonate (1 g) were added and stirring was stopped. The reaction solution was diluted with ethyl acetate and hexane, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3), thereby obtaining the target substance with the following physical properties: Compound (3.3 g). HPLC retention time (minutes): 1.15; MS (ESI, Pos.): 285 (M+H) + ; 1H-NMR (CDCl3): δ 2.29, 3.08, 3.88, 4.16, 6.56, 7.11-7.46.

實施例2：2,6-二甲基-4-(2-苯基乙氧基)安息香酸 在實施例1所製造的化合物(2g)之N-甲基-2-吡咯烷酮(2mL)溶液，添加50%氫氧化鉀水溶液(4mL)在120℃攪拌3小時。將反應液以乙酸乙酯與己烷洗滌，以鹽酸酸化並以乙酸乙酯萃取。將有機層以飽和食鹽水洗滌，以無水硫酸鈉乾燥後減壓濃縮。將獲得的殘渣以己烷進行漿液洗滌，藉此得到具有以下的物性值之標的化合物(0.83g)。 HPLC保持時間(分鐘)：0.98； MS(ESI, Pos.)：271(M+H) +。 Example 2: 2,6-dimethyl-4-(2-phenylethoxy) benzoic acid in N-methyl-2-pyrrolidone (2mL) solution of the compound (2g) produced in Example 1, A 50% aqueous potassium hydroxide solution (4 mL) was added and stirred at 120° C. for 3 hours. The reaction solution was washed with ethyl acetate and hexane, acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was slurry-washed with hexane to obtain the target compound (0.83 g) having the following physical property values. HPLC retention time (min): 0.98; MS (ESI, Pos.): 271 (M+H) + .

實施例3：N-[5-溴-2-(三氟甲基)苯基]-2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺 在實施例2所製造的化合物(1g)及5-溴-2-(三氟甲基)苯胺(CAS編號：703-91-3、1.1g)之乙腈溶液(10mL)，添加N,N-二異丙基乙胺(0.72g)及磷醯氯(0.62g)，在50℃攪拌12小時。在反應液追加磷醯氯(0.12g)並攪拌6小時。將反應液返回室溫後，添加1N氫氧化鈉水溶液(10mL)並攪拌10分鐘。過濾析出的沉澱，以己烷洗滌，藉此獲得具有下述物性值的標的化合物(1.5g)。 HPLC保持時間(分鐘)：1.26； MS(ESI, Pos.)：492(M+H) +。 Embodiment 3: N-[5-bromo-2-(trifluoromethyl)phenyl]-2,6-dimethyl-4-(2-phenylethoxy)benzamide in embodiment 2 The acetonitrile solution (10 mL) of the produced compound (1 g) and 5-bromo-2-(trifluoromethyl)aniline (CAS No.: 703-91-3, 1.1 g) was added to N,N-diisopropyl Ethylamine (0.72g) and phosphoryl chloride (0.62g) were stirred at 50°C for 12 hours. Phosphoryl chloride (0.12 g) was added to the reaction liquid, followed by stirring for 6 hours. After returning the reaction solution to room temperature, 1N aqueous sodium hydroxide solution (10 mL) was added and stirred for 10 minutes. The precipitated precipitate was filtered and washed with hexane to obtain the target compound (1.5 g) having the following physical properties. HPLC retention time (min): 1.26; MS (ESI, Pos.): 492 (M+H) + .

實施例4：N-[5-(5,5-二甲基-1,3,2-二噁唑啉-2-基)-2-(三氟甲基)苯基]-2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺 在實施例3所製造的化合物(500mg)之1,2-二甲氧基乙烷(5mL)溶液，添加雙(新戊基乙醇酸酯)二硼(CAS編號：201733-56-4、459mg)及乙酸鉀(300mg)並脫氣，添加[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀 (II)-二氯甲烷加成物(CAS編號：95464-05-4、83mg)，並在88℃攪拌1.5小時。將反應液以甲基三級丁基醚稀釋，以Cerite(商品名)過濾。將濾液以水洗滌，以無水硫酸鈉乾燥後減壓濃縮。將反應液減壓濃縮，將所得之殘渣藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯＝95：5→1：4)進行純化，藉此得到具有以下的物性值之標的化合物(508mg)。 HPLC保持時間(分鐘)：1.03。 Example 4: N-[5-(5,5-Dimethyl-1,3,2-dioxazolin-2-yl)-2-(trifluoromethyl)phenyl]-2,6- Dimethyl-4-(2-phenylethoxy)benzamide To a solution of the compound (500 mg) produced in Example 3 in 1,2-dimethoxyethane (5 mL), bis(neopentyl glycolate) diboron (CAS number: 201733-56-4, 459 mg ) and potassium acetate (300 mg) and degassed, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane adduct (CAS number: 95464- 05-4, 83 mg), and stirred at 88°C for 1.5 hours. The reaction solution was diluted with methyl tertiary butyl ether, and filtered through Cerite (trade name). The filtrate was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:4), thereby obtaining the target product with the following physical properties: Compound (508 mg). HPLC retention time (min): 1.03.

實施例5：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸乙酯 在實施例4所製造的化合物(488mg)之1,4-二噁烷(5.4mL)溶液，添加(1S,2S)-2-碘環丙烷羧酸乙酯(CAS編號：1629125-76-3、185mg)及2M碳酸銫水溶液(1.2mL)並脫氣，添加氯(2-二環己基膦基-2’,4’,6’-三異丙基聯苯基)(2’-胺基聯苯-2-基)鈀(II)(CAS編號：1310584-14-5、122mg)並在100℃攪拌1.5小時。將反應液以甲基三級丁基醚稀釋，以水洗滌並以無水硫酸鈉乾燥後減壓濃縮。將反應液減壓濃縮，將所得之殘渣藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯＝95：5→0：1)進行純化，藉此得到具有以下的物性值之標的化合物(316mg)。 HPLC保持時間(分鐘)：1.20； MS(ESI, Pos.)：526(M+H) +。 Example 5: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Base}cyclopropane-1-carboxylic acid ethyl ester In 1,4-dioxane (5.4mL) solution of the compound (488mg) produced in Example 4, add (1S,2S)-2-iodocyclopropanecarboxylic acid Ethyl ester (CAS number: 1629125-76-3, 185mg) and 2M cesium carbonate aqueous solution (1.2mL) were degassed, and chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl Biphenyl)(2'-aminobiphenyl-2-yl)palladium(II) (CAS number: 1310584-14-5, 122 mg) and stirred at 100°C for 1.5 hours. The reaction solution was diluted with methyl tertiary butyl ether, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→0:1), thereby obtaining the target substance with the following physical properties: Compound (316 mg). HPLC retention time (min): 1.20; MS (ESI, Pos.): 526 (M+H) + .

實施例6：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸

Figure 02_image011
在實施例5所製造的化合物(500mg)之四氫呋喃(1.5mL)及甲醇(1.5mL)溶液，於冰冷下添加5N氫氧化鈉水溶液(1.5mL)，在50℃攪拌1小時。在反應液添加水並以己烷洗滌。在水層添加5N鹽酸中和，並以甲基三級丁基醚萃取。將獲得的有機層以飽和食鹽水洗滌，以無水硫酸鈉乾燥後減壓濃縮。將反應液減壓濃縮，將所得之殘渣藉由氧化矽凝膠管柱層析(己烷：乙酸乙酯＝95：5→1：1)進行純化，藉此得到具有以下的物性值之標的化合物(395mg)。 型態：非晶質 HPLC保持時間(分鐘)：1.06； MS(ESI, Pos.)：498(M+H) +； 1H-NMR(CDCl3)：δ1.39-1.51, 1.64-1.75, 2.09-2.21, 2.34, 2.62-2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24。 Example 6: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Cyclopropane-1-carboxylic acid
Figure 02_image011
To a solution of the compound (500 mg) produced in Example 5 in tetrahydrofuran (1.5 mL) and methanol (1.5 mL), 5N aqueous sodium hydroxide solution (1.5 mL) was added under ice-cooling, and stirred at 50°C for 1 hour. Water was added to the reaction liquid, followed by washing with hexane. The aqueous layer was neutralized by adding 5N hydrochloric acid, and extracted with methyl tertiary butyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→1:1), thereby obtaining the target product with the following physical properties: Compound (395 mg). Form: amorphous HPLC retention time (min): 1.06; MS (ESI, Pos.): 498 (M+H) + ; 1H-NMR (CDCl3): δ1.39-1.51, 1.64-1.75, 2.09- 2.21, 2.34, 2.62-2.73, 3.10, 4.15-4.21, 6.59, 7.11-7.18, 7.22-7.37, 7.45-7.53, 8.24.

又，本揭示之實施例6係與專利文獻4之實施例18相同的化合物，藉由專利文獻4中記載之方法或本揭示之實施例1至6中記載之方法而獲得的本揭示之實施例6的化合物為非晶質。In addition, Example 6 of the present disclosure is the same compound as Example 18 of Patent Document 4, which is obtained by the method described in Patent Document 4 or the method described in Examples 1 to 6 of the present disclosure. The compound of Example 6 is amorphous.

實施例7：鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　十水合物之結晶(A晶) 在實施例6所製造的化合物(1g)以室溫添加甲醇(1mL)、1mol/L氫氧化鉀水溶液(2.11mL)並使其溶解。其後，將氯化鎂六水合物(225mg)添加於使其溶解於2mL之蒸餾水的溶液，並攪拌6小時間。過濾析出的結晶，藉此得到具有以下的物性值之結晶性固體。 Example 7: Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform base) phenyl} cyclopropane-1-carboxylate] decahydrate crystal (A crystal) The compound (1 g) produced in Example 6 was dissolved by adding methanol (1 mL) and 1 mol/L potassium hydroxide aqueous solution (2.11 mL) at room temperature. Thereafter, magnesium chloride hexahydrate (225 mg) was added to a solution dissolved in 2 mL of distilled water, followed by stirring for 6 hours. The precipitated crystal was filtered to obtain a crystalline solid having the following physical property values.

各別將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖1、DSC圖示於圖2、TG圖示於圖3。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 1 , the DSC pattern is shown in FIG. 2 , and the TG pattern is shown in FIG. 3 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表1。 (1) Powder X-ray Diffraction Spectrum Measurement condition: condition 1 Table 1 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表1]

Figure 02_image016
[Table 1]
Figure 02_image016

(2)微差掃描熱量測量(DSC) 測量條件：條件1 試料量：1.5mg 升溫速度：10℃/min(25至200℃) 吸熱峰：約25℃至約85℃之範圍 (2) Differential Scanning Calorimetry (DSC) Measurement condition: Condition 1 Sample amount: 1.5mg Heating rate: 10°C/min (25 to 200°C) Endothermic peak: range from about 25°C to about 85°C

(3)熱重量測量(TG) 測量條件：條件2 試料量：1.7mg 升溫速度：10℃/min(25至200℃) 顯示約40℃至140℃為止重量損失約15%。 (3) Thermogravimetry (TG) Measurement condition: condition 2 Sample amount: 1.7mg Heating rate: 10°C/min (25 to 200°C) Shows a weight loss of about 15% from about 40°C to 140°C.

實施例8：鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　m水合物(m表示4至8)之結晶(L晶) 將實施例7所製造的化合物(A晶、1mg)在氮氣流下加熱約42℃，藉此得到具有以下的物性值之結晶性固體。 Example 8: Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform Base) phenyl} cyclopropane-1-carboxylate] m hydrate (m represents 4 to 8) crystal (L crystal) The compound (Crystal A, 1 mg) produced in Example 7 was heated at about 42°C under a nitrogen stream to obtain a crystalline solid having the following physical property values.

將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖4。The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 4 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表2。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 1 Table 2 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表2]

Figure 02_image018
[Table 2]
Figure 02_image018

實施例9：鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　n水合物(n表示4至8)之結晶(H晶) 將實施例7所製造的化合物(A晶、1mg)在氮氣流下加熱約48℃，藉此得到具有以下的物性值之結晶性固體。 Example 9: Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform Base) phenyl} cyclopropane-1-carboxylate] n hydrate (n represents 4 to 8) crystal (H crystal) The compound (Crystal A, 1 mg) produced in Example 7 was heated at about 48° C. under nitrogen flow to obtain a crystalline solid having the following physical property values.

將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖5。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 5 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表3。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 1 Table 3 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表3]

Figure 02_image020
[table 3]
Figure 02_image020

實施例10：鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　p水合物(p表示超過0且8以下)之結晶(M晶) 將實施例7所製造的化合物(A晶、1mg)在氮氣流下加熱約67℃，藉此得到具有以下的物性值之結晶性固體。 Example 10: Magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform Base) phenyl} cyclopropane-1-carboxylate] p hydrate (p means more than 0 and less than 8) crystal (M crystal) The compound (Crystal A, 1 mg) produced in Example 7 was heated at about 67° C. under nitrogen flow to obtain a crystalline solid having the following physical property values.

將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖6。The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 6 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表4。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 1 Table 4 shows the results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα ray.

[表4]

Figure 02_image022
[Table 4]
Figure 02_image022

實施例11：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　一水合物之結晶(C晶) 在實施例6所製造的化合物(50mg)，在室溫添加乙酸(750μL)及蒸餾水(250μL)，使其溶解。於此添加蒸餾水(500μL)。攪拌的同時，進行20℃至60℃之加熱及冷卻至20℃，並以每分0.1℃之速度重複10次。其後，少量添加實施例7所製造的化合物，在室溫放置10天。過濾析出的結晶，藉此得到具有以下的物性值之結晶性固體。 Example 11: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Cyclopropane-1-carboxylic acid monohydrate crystal (C crystal) The compound (50 mg) produced in Example 6 was dissolved by adding acetic acid (750 μL) and distilled water (250 μL) at room temperature. Distilled water (500 μL) was added here. While stirring, heating at 20° C. to 60° C. and cooling to 20° C. were repeated 10 times at a speed of 0.1° C. per minute. Thereafter, a small amount of the compound produced in Example 7 was added, and it was left to stand at room temperature for 10 days. The precipitated crystal was filtered to obtain a crystalline solid having the following physical property values.

各別將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖7、DSC圖示於圖8、TG圖示於圖9。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 7 , the DSC pattern is shown in FIG. 8 , and the TG pattern is shown in FIG. 9 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表5。 (1) Powder X-ray Diffraction Spectrum Measurement condition: condition 1 Table 5 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表5]

Figure 02_image024
[table 5]
Figure 02_image024

(2)微差掃描熱量測量(DSC) 測量條件：條件1 試料量：2.3mg 升溫速度：10℃/min(0至250℃) 第一吸熱峰：起始溫度約30℃、峰溫度約50℃ 第二吸熱峰：起始溫度約70℃、峰溫度約77℃ (2) Differential Scanning Calorimetry (DSC) Measurement condition: Condition 1 Sample amount: 2.3mg Heating rate: 10°C/min (0 to 250°C) The first endothermic peak: the initial temperature is about 30°C, and the peak temperature is about 50°C The second endothermic peak: the initial temperature is about 70°C, and the peak temperature is about 77°C

(3)熱重量測量(TG) 測量條件：條件2 試料量：3.6mg 升溫速度：10℃/min(25至250℃) 顯示60℃至120℃為止之重量損失約2.9%。 (3) Thermogravimetry (TG) Measurement condition: Condition 2 Sample amount: 3.6mg Heating rate: 10°C/min (25 to 250°C) It shows that the weight loss from 60°C to 120°C is about 2.9%.

實施例12：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(B晶) 將實施例11所製造的化合物(C晶、1mg)在室溫、濕度0%之氛圍下，放置10分鐘以上，藉此得到具有以下的物性值之結晶性固體。 Example 12: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Crystalline of Cyclopropane-1-Carboxylic Acid (Crystal B) The compound (C crystal, 1 mg) produced in Example 11 was left at room temperature under an atmosphere of 0% humidity for 10 minutes or more to obtain a crystalline solid having the following physical properties.

將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖10。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 10 .

(1)粉末X射線繞射譜 測量條件：條件2 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表6。 (1) Powder X-ray Diffraction Spectrum Measurement condition: condition 2 Table 6 shows the results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα ray.

[表6]

Figure 02_image026
[Table 6]
Figure 02_image026

實施例13：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(D晶) 將實施例11所製造的化合物(C晶、1mg)在氮氣流下於約45℃加熱，藉此得到具有以下的物性值之結晶性固體。 Example 13: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Crystals of Cyclopropane-1-Carboxylic Acid (Crystal D) The compound (crystal C, 1 mg) produced in Example 11 was heated at about 45° C. under a nitrogen stream to obtain a crystalline solid having the following physical property values.

各別將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖11、DSC圖示於圖12。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 11 , and the DSC pattern is shown in FIG. 12 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表7。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 1 Table 7 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表7]

Figure 02_image028
[Table 7]
Figure 02_image028

(2)微差掃描熱量測量(DSC) 測量條件：條件1 試料量：1.0mg 升溫速度：10℃/min(25至250℃) 第一吸熱峰：起始溫度約39℃、峰溫度約42℃(認為源自實施例11所製造的化合物的峰) 第二吸熱峰：起始溫度約69℃、峰溫度約76℃ (2) Differential Scanning Calorimetry (DSC) Measurement condition: condition 1 Sample amount: 1.0mg Heating rate: 10°C/min (25 to 250°C) First endothermic peak: Onset temperature about 39°C, peak temperature about 42°C (peak derived from the compound produced in Example 11) The second endothermic peak: the initial temperature is about 69°C, and the peak temperature is about 76°C

實施例14：(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽之結晶(E晶) 在實施例6所製造的化合物(100mg)，在室溫添加甲基三級丁基醚(1mL)，使其溶解。於此添加二環己胺(44μL)。在室溫下攪拌3天，過濾析出的結晶，藉此得到具有以下的物性值之結晶性固體。屬於本實施例化合物之二環己胺鹽，與其他鹽相比，可作為純度高之結晶而被析出，故有用於作為製造中間體。 1H-NMR(DMSO-d6)：δ 9.94, 7.56-7.54, 7.45, 7.34-7.30, 7.25-7.21, 6.68, 4.22-4.18, 3.05-3.02, 2.74-2.66, 2.42-2.36, 2.31, 1.96-1.90, 1.81-1.78, 1.66-1.62, 1.55-1.52, 1.42-1.38, 1.22-1.00。 Example 14: (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)benzene Crystal of dicyclohexylamine salt of dicyclohexylamine cyclopropane-1-carboxylate (crystal E) To the compound (100 mg) produced in Example 6, methyl tertiary butyl ether (1 mL) was added at room temperature and dissolved. To this was added dicyclohexylamine (44 μL). After stirring at room temperature for 3 days, the precipitated crystal was filtered to obtain a crystalline solid having the following physical property values. The dicyclohexylamine salt belonging to the compound of this example can be precipitated as crystals with higher purity than other salts, so it is useful as a production intermediate. 1H-NMR(DMSO-d6): δ 9.94, 7.56-7.54, 7.45, 7.34-7.30, 7.25-7.21, 6.68, 4.22-4.18, 3.05-3.02, 2.74-2.66, 2.42-2.36, 2.31, 1.96-1.90, 1.81-1.78, 1.66-1.62, 1.55-1.52, 1.42-1.38, 1.22-1.00.

各別將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖13、DSC圖示於圖14、TG圖示於圖15。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 13 , the DSC pattern is shown in FIG. 14 , and the TG pattern is shown in FIG. 15 .

(1)粉末X射線繞射譜 測量條件：條件3 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表8。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 3 Table 8 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表8]

Figure 02_image030
[Table 8]
Figure 02_image030

(2)微差掃描熱量測量(DSC) 測量條件：條件5 試料量：4.88mg 升溫速度：10℃/min(25至300℃) 吸熱峰：起始溫度約153℃、峰溫度約155℃ (2) Differential Scanning Calorimetry (DSC) Measurement condition: condition 5 Sample amount: 4.88mg Heating rate: 10°C/min (25 to 300°C) Endothermic peak: the initial temperature is about 153°C, and the peak temperature is about 155°C

(3)熱重量測量(TG) 測量條件：條件4 試料量：7.17mg 升溫速度：10℃/min(25至300℃) 顯示155℃至300℃為止之重量損失約21%。 (3) Thermogravimetry (TG) Measurement condition: Condition 4 Sample amount: 7.17mg Heating rate: 10°C/min (25 to 300°C) It shows that the weight loss from 155°C to 300°C is about 21%.

實施例15：鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　q水合物(q表示4至8)之結晶(F晶) 在實施例6所製造的化合物(300mg)，添加氫氧化鈣(22.3mg)、異丙醇(1.2mL)及蒸餾水(300mL)，在室溫攪拌3天。過濾析出的粉末，在室溫減壓乾燥。在該粉末(10mg)中添加蒸餾水(40μL)。在25℃攪拌7天。過濾析出的結晶，藉此得到具有以下的物性值之結晶性固體。 Example 15: Calcium bis[(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoroform base) phenyl} cyclopropane-1-carboxylate] q hydrate (q means 4 to 8) crystal (F crystal) Calcium hydroxide (22.3 mg), isopropanol (1.2 mL) and distilled water (300 mL) were added to the compound (300 mg) produced in Example 6, and stirred at room temperature for 3 days. The precipitated powder was filtered and dried under reduced pressure at room temperature. Distilled water (40 µL) was added to this powder (10 mg). Stir at 25°C for 7 days. The precipitated crystal was filtered to obtain a crystalline solid having the following physical property values.

各別將以下述條件所測量之該結晶的粉末X射線繞射譜圖示於圖16、DSC圖示於圖17、TG圖示於圖18。The powder X-ray diffraction pattern of the crystal measured under the following conditions is shown in FIG. 16 , the DSC pattern is shown in FIG. 17 , and the TG pattern is shown in FIG. 18 .

(1)粉末X射線繞射譜 測量條件：條件1 將藉由使用了Cu-Kα線之粉末X射線繞射譜法而得的繞射角(2θ)(度)及相對強度(%)之結果示於表9。 (1) Powder X-ray Diffraction Spectrum Measurement condition: Condition 1 Table 9 shows the results of diffraction angle (2θ) (degrees) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[表9]

Figure 02_image032
[Table 9]
Figure 02_image032

(2)微差掃描熱量測量(DSC) 測量條件：條件2 試料量：3.6mg 升溫速度：10℃/min(25至250℃) 第一吸熱峰：起始溫度約46℃、峰溫度約62℃ 第二吸熱峰：起始溫度約74℃、峰溫度約91℃ (2) Differential Scanning Calorimetry (DSC) Measurement condition: condition 2 Sample amount: 3.6mg Heating rate: 10°C/min (25 to 250°C) The first endothermic peak: the initial temperature is about 46°C, and the peak temperature is about 62°C The second endothermic peak: the initial temperature is about 74°C, and the peak temperature is about 91°C

(3)熱重量測量(TG) 測量條件：條件2 試料量：3.6mg 升溫速度：10℃/min(25至250℃) 顯示25℃至120℃為止之重量損失約10.6%。 (3) Thermogravimetry (TG) Measurement condition: condition 2 Sample amount: 3.6mg Heating rate: 10°C/min (25 to 250°C) It shows that the weight loss from 25°C to 120°C is about 10.6%.

物理化學的實施例1：吸濕性評估 在以下條件實施等溫吸附曲線測量(DVS)。將實施例7、實施例11及實施例15記載之化合物以下述條件進行測量。 Physicochemical Example 1: Hygroscopicity Evaluation Isotherm adsorption curve measurement (DVS) was carried out under the following conditions. The compounds described in Example 7, Example 11 and Example 15 were measured under the following conditions.

(條件) 裝置：DVS Intrinsic 測量溫度：25℃ 測量範圍：相對濕度0至95%或5至95% 測量間隔：相對濕度5% (condition) Installation: DVS Intrinsic Measuring temperature: 25°C Measuring range: 0 to 95% or 5 to 95% relative humidity Measurement interval: relative humidity 5%

本評估之結果如圖19所示，確認出與實施例15記載之化合物比較，實施例7記載之化合物及實施例11記載之化合物吸濕性低。The results of this evaluation are shown in FIG. 19 , and it was confirmed that the compound described in Example 7 and the compound described in Example 11 were lower in hygroscopicity than the compound described in Example 15.

物理化學的實施例2：化學穩定性試驗 在條件1之保管條件下，針對實施例7及實施例11中記載之化合物的化學穩定性進行探討。保存後，藉由HPLC算出各條件下保存樣品之殘存率(%)相對於-20℃保存樣品之面積百分率。 Physical and Chemical Example 2: Chemical Stability Test Under the storage conditions of Condition 1, the chemical stability of the compounds described in Example 7 and Example 11 was examined. After storage, calculate the residual rate (%) of the sample stored under each condition by HPLC relative to the area percentage of the sample stored at -20°C.

＜保存條件及期間＞ 條件1　60℃：1個月：粉碎 各樣品之比較對象係保存於-20℃。 ＜Conditions and period of storage＞ Condition 1 60°C: 1 month: pulverized The comparison object of each sample was stored at -20°C.

[結果] 以條件1保存後之實施例7及實施例11所記載之化合物樣品中，化合物殘存率(%)係100%。 [result] In the compound samples described in Example 7 and Example 11 stored under Condition 1, the compound remaining rate (%) was 100%.

藥理實驗例1：使用***素受體(prostanoid receptor)表現細胞的EP 2拮抗活性測量實驗 Pharmacological Experiment Example 1: EP 2 Antagonism Activity Measurement Experiment Using Prostanoid Receptor Expressing Cells

依照Nishigaki等人的方法(FEBS Letters，第364卷，第339-341頁，1995年)，調製表現人EP 2受體的CHO細胞，將在CELLBANKER2(日本全藥工業股份有限公司製)中涷結保存成1.5x10 7cells/mL/vial者供予實驗將細胞解涷，使其以成為5x10 5cells/mL的方式懸浮於檢測培養基(assay medium)(D-PBS containing 1mmol/L IBMX，2μmol/L Diclofenac)。對細胞懸浮液(10μL)單獨添加最終濃度10nmol/L的PGE 2，或添加同時含有此與實施例6記載之化合物的溶液(10μL)而使反應開始，在室溫反應1小時後，依照cAMP Gs Dynamic kit(CISBIO公司製)所記載之方法，定量細胞內的cAMP量。 According to the method of Nishigaki et al. (FEBS Letters, vol. 364, pp. 339-341, 1995), CHO cells expressing the human EP 2 receptor were prepared and prepared in CELLBANKER2 (manufactured by Zenyaku Kogyo Co., Ltd.). Those whose results were stored at 1.5x10 7 cells/mL/vial were used for experiments. The cells were lysed and suspended in assay medium (D-PBS containing 1mmol/L IBMX, 2μmol /L Diclofenac). Add PGE 2 with a final concentration of 10 nmol/L to the cell suspension (10 μL) alone, or add a solution (10 μL) containing the compound described in Example 6 at the same time to start the reaction. After reacting at room temperature for 1 hour, according to cAMP The amount of cAMP in cells was quantified by the method described in Gs Dynamic kit (manufactured by CISBIO).

又，實施例6記載之化合物的拮抗劑作用(IC 50值)係以相對於PGE 2單獨會顯示次最大(submaximal)的cAMP產生作用的濃度亦即10nM的反應之抑制率的方式算出，而求出IC 50值。 In addition, the antagonistic action ( IC50 value) of the compound described in Example 6 was calculated as the inhibition rate of the reaction at 10 nM, which is the concentration at which PGE 2 alone exhibits a submaximal (submaximal) cAMP production action, and Find the IC50 value.

由上述藥理實驗可知，實施例6記載之化合物具有強力的EP 2受體拮抗活性。 It can be seen from the above pharmacological experiments that the compound described in Example 6 has strong EP 2 receptor antagonistic activity.

[表10] 實施例No. EP2_IC50(μm) 6 0.0009 [Table 10] Example No. EP2_IC50(μm) 6 0.0009

藥理實驗例2：小鼠大腸癌細胞株CT26的同種移植模型中之抗腫瘤效果 以屬於小鼠大腸癌細胞株之CT26的同種移植模型來評估實施例6記載之化合物的抗腫瘤效果。CT26係使用含有10vol%的已不活化的胎牛血清(Fetal Bovine Serum；FBS)、100units/mL的青黴素(Penicillin)及100μg/mL的鏈黴素(Streptomycin)之RPMI-1640培養基在CO 2培養箱內進行培養。在移植當天，將培養上清液移除，將CT26以磷酸緩衝液(以下簡稱為PBS)洗後，予以回收。將回收的CT26懸浮於PBS，作為移植用細胞。在麻醉情況下，對雌性Balb/C小鼠(日本Charles River股份有限公司)的右側背部皮下移植30萬個移植用細胞。移植4天後，將該小鼠依介質群及實施例6記載之化合物群這2群各平分10例。就介質及化合物A而言，係將10mg/kg之實施例6記載的化合物以移植第4天為1次、移植第5天至移植第25天期間內為1天2次的方式對小鼠重複投予。腫瘤體積(mm 3)係使用電子卡尺來測量腫瘤的短徑及長徑，並以下述的數學式1算出腫瘤體積。此外，投予期間中，於腫瘤形成有潰瘍的小鼠係從該時點後續的評估中排除。 [數學式1] 腫瘤體積=[(短徑) 2×長徑]/2 Pharmacological Experimental Example 2: Anti-tumor Effects of Mouse Colorectal Cancer Cell Line CT26 Allograft Model The anti-tumor effect of the compound described in Example 6 was evaluated in an allograft model of mouse colorectal cancer cell line CT26. CT26 was cultured in RPMI-1640 medium containing 10vol% inactivated fetal bovine serum (Fetal Bovine Serum; FBS), 100 units/mL of penicillin (Penicillin) and 100 μg/mL of streptomycin (Streptomycin) in CO 2 Cultivate in the box. On the day of transplantation, the culture supernatant was removed, and CT26 was recovered after being washed with phosphate buffered solution (hereinafter abbreviated as PBS). The recovered CT26 was suspended in PBS and used as cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right back of female Balb/C mice (Charles River Japan Co., Ltd.). Four days after transplantation, the mice were equally divided into 10 cases each according to the vehicle group and the compound group described in Example 6. For the vehicle and compound A, 10 mg/kg of the compound described in Example 6 was administered to the mice once on the 4th day of transplantation, and twice a day from the 5th day of transplantation to the 25th day of transplantation. Dosing was repeated. The tumor volume (mm 3 ) was measured by using an electronic caliper to measure the short axis and long axis of the tumor, and the tumor volume was calculated according to the following mathematical formula 1. In addition, mice with ulcerations in tumor formation during the administration period were excluded from subsequent evaluation at that time point. [Mathematical formula 1] Tumor volume = [(short diameter) 2 × long diameter]/2

其結果，實施例6記載之化合物具有腫瘤增殖的抑制作用。實施例6記載之化合物投予群在移植第25天之腫瘤體積如圖20所示，相對介質投予群的有利的變小。As a result, the compound described in Example 6 has an inhibitory effect on tumor growth. The tumor volume of the compound-administered group described in Example 6 on the 25th day of transplantation was favorably smaller than that of the vehicle-administered group, as shown in Fig. 20 .

[製劑例][Preparation example]

製劑例1 藉由常規方法將以下各成分混合後製錠，而獲得在一錠中含有10mg之活性成分的錠劑1萬錠。 ・(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　一水合物之結晶(A晶)　　　　　               …100g ・羧甲纖維素鈣(崩壊劑)　　                              …20g ・硬脂酸鎂(潤滑劑)　　　　　　　　               …10g ・微結晶纖維素　　　　　　　　　　　　　   …870g Preparation example 1 Tablets were prepared by mixing the following ingredients by a conventional method to obtain 10,000 tablets containing 10 mg of the active ingredient in one tablet. ・(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl} ring Crystal of propane-1-carboxylic acid monohydrate (crystal A) …100g ・Carmellose calcium (disintegrant) ...20g ・Magnesium stearate (lubricant) ...10g ・Microcrystalline cellulose …870g

製劑例2 藉由常規方法將以下各成分混合後，以濾塵器過濾，在安瓿中各填充5ml，在高壓釜中加熱滅菌，而獲得1安瓿中含有20mg活性成分之安瓿1萬根。 ・(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　一水合物之結晶(A晶)　　                       …200g ・甘露醇　　　　　　　　　　　　　　    …20g ・蒸餾水　　　　　　　　　　　　　　　 …50L (產業上之可利用性) Preparation example 2 After mixing the following ingredients by a conventional method, filter them with a dust filter, fill 5ml each in ampoules, heat and sterilize them in an autoclave, and obtain 10,000 ampoules containing 20mg of the active ingredient in 1 ampoule. ・(1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl} ring Crystal of propane-1-carboxylic acid monohydrate (crystal A) …200g ・Mannitol …20g ・Distilled water …50L (industrial availability)

化合物I對於EP 2受體具有拮抗活性，故有效於起因於EP 2受體之活性化之疾病的預防及/或治療。此外，本揭示之鹽、溶劑合物、及/或結晶有用作為醫藥品原藥。 Compound I has antagonistic activity against EP 2 receptors, and thus is useful for the prevention and/or treatment of diseases caused by activation of EP 2 receptors. In addition, the salts, solvates, and/or crystals of the present disclosure are useful as pharmaceutical raw materials.

無none

圖1表示鎂　雙[(1R,2S)-2-{3-[2，6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物之結晶(A晶)之粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖2表示鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物之結晶(A晶)之微差掃描熱量測量(DSC)圖(縱軸表示熱通量(W/g)、橫軸表示溫度(℃))。 圖3表示鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物之結晶(A晶)之熱重量測量(TG)圖(縱軸表示重量(%)、橫軸表示溫度(℃))。 圖4表示鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]m水合物(m表示4至8)之結晶(L晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖5表示鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]n水合物(n表示4至8)之結晶(H晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖6表示鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]p水合物(p表示超過0且8以下)之結晶(M晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖7表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(C晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖8表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(C晶)之微差掃描熱量測量(DSC)圖(縱軸表示熱通量(W/g)、橫軸表示溫度(℃))。 圖9表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(C晶)的熱重量測量(TG)圖(縱軸表示重量(%)、橫軸表示溫度(℃))。 圖10表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(B晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖11表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(D晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖12表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶(D晶)的微差掃描熱量測量(DSC)圖(縱軸表示熱通量(W/g)、橫軸表示溫度(℃))。 圖13表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸二環己胺鹽之結晶(E晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖14表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸二環己胺鹽之結晶(E晶)的微差掃描熱量測量(DSC)圖(縱軸表示熱通量(W/g)、橫軸表示溫度(℃))。 圖15表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸二環己胺鹽之結晶(E晶)的熱重量測量(TG)圖(縱軸表示重量(%)、橫軸表示溫度(℃))。 圖16表示鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]q水合物(q表示4至8)之結晶(F晶)的粉末X射線繞射譜圖(縱軸表示強度(counts)、橫軸表示2θ(度))。 圖17表示鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]q水合物(q表示4至8)之結晶(F晶)的微差掃描熱量測量(DSC)圖(縱軸表示熱通量(W/g)、橫軸表示溫度(℃))。 圖18表示鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]q水合物(q表示4至8)之結晶(F晶)的熱重量測量(TG)圖(縱軸表示重量(%)、橫軸表示溫度(℃))。 圖19表示(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物之結晶(C晶)、鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]　十水合物之結晶(A晶)、及鈣　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]q水合物(q表示4至8)之結晶(F晶)的等溫吸附曲線(縱軸表示重量變化率(%)、橫軸表示相對濕度(RH)(%))。 圖20係顯示小鼠大腸癌細胞株CT26的同種移植模型中之化合物I之抗腫瘤效果的圖。 Figure 1 shows the magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl )Phenyl}cyclopropane-1-carboxylate] decahydrate crystal (crystal A) powder X-ray diffraction spectrum (the vertical axis represents the intensity (counts), the horizontal axis represents 2θ (degrees)). Figure 2 represents the magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl )Differential scanning calorimetry (DSC) diagram of crystallization (A crystal) of phenyl} cyclopropane-1-carboxylate] decahydrate (vertical axis represents heat flux (W/g), horizontal axis represents temperature ( °C)). Figure 3 shows magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl ) phenyl}cyclopropane-1-carboxylate] decahydrate crystal (crystal A) thermogravimetry (TG) diagram (vertical axis represents weight (%), horizontal axis represents temperature (°C)). Figure 4 represents the magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl ) phenyl} cyclopropane-1-carboxylate] m hydrate (m represents 4 to 8) crystal (L crystal) powder X-ray diffraction spectrum (vertical axis represents intensity (counts), horizontal axis represents 2θ (Spend)). Figure 5 shows the magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl ) phenyl} cyclopropane-1-carboxylate] n hydrate (n represents 4 to 8) crystal (H crystal) powder X-ray diffraction spectrum (vertical axis represents intensity (counts), horizontal axis represents 2θ (Spend)). Figure 6 shows that magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl )Phenyl}cyclopropane-1-carboxylate]p hydrate (p represents more than 0 and less than 8) powder X-ray diffraction spectrum (vertical axis indicates intensity (counts), horizontal axis) of crystal (M crystal) Indicates 2θ (degrees)). Figure 7 shows (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Powder X-ray diffraction spectrum of cyclopropane-1-carboxylic acid monohydrate crystal (crystal C) (the vertical axis represents the intensity (counts), and the horizontal axis represents 2θ (degrees)). Figure 8 shows (1R,2S)-2-{3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Differential scanning calorimetry (DSC) diagram of cyclopropane-1-carboxylic acid monohydrate crystal (crystal C) (vertical axis represents heat flux (W/g), horizontal axis represents temperature (°C)). Figure 9 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }The thermogravimetry (TG) diagram of cyclopropane-1-carboxylic acid monohydrate crystal (crystal C) (the vertical axis represents weight (%), and the horizontal axis represents temperature (°C)). Figure 10 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Powder X-ray diffraction spectrum of cyclopropane-1-carboxylic acid crystal (crystal B) (the vertical axis represents the intensity (counts), and the horizontal axis represents 2θ (degrees)). Figure 11 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Powder X-ray diffraction spectrum of cyclopropane-1-carboxylic acid crystal (D crystal) (the vertical axis represents the intensity (counts), and the horizontal axis represents 2θ (degrees)). Figure 12 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Differential scanning calorimetry (DSC) diagram of cyclopropane-1-carboxylic acid crystal (crystal D) (vertical axis represents heat flux (W/g), horizontal axis represents temperature (°C)). Figure 13 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl } Powder X-ray diffraction spectrum of cyclopropane-1-carboxylic acid dicyclohexylamine salt crystal (E crystal) (the vertical axis represents the intensity (counts), and the horizontal axis represents 2θ (degrees)). Figure 14 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl Differential scanning calorimetry (DSC) diagram of cyclopropane-1-carboxylic acid dicyclohexylamine salt crystal (E crystal) (vertical axis represents heat flux (W/g), horizontal axis represents temperature (°C)) . Figure 15 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }The thermogravimetric (TG) diagram of the crystal of cyclopropane-1-carboxylic acid dicyclohexylamine salt (E crystal) (the vertical axis represents weight (%), and the horizontal axis represents temperature (°C)). Figure 16 shows calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl ) phenyl}cyclopropane-1-carboxylate]q hydrate (q represents 4 to 8) crystal (F crystal) powder X-ray diffraction spectrum (vertical axis represents intensity (counts), horizontal axis represents 2θ (Spend)). Figure 17 shows calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl )Differential scanning calorimetry (DSC) figure of the crystal (F crystal) of phenyl}cyclopropane-1-carboxylate]q hydrate (q represents 4 to 8) (vertical axis represents heat flux (W/g ), the horizontal axis represents the temperature (°C)). Figure 18 shows calcium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl ) phenyl} cyclopropane-1-carboxylate] q hydrate (q represents 4 to 8) of the crystallization (F crystal) thermogravimetry (TG) figure (vertical axis represents weight (%), horizontal axis represents temperature (°C)). Figure 19 represents (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl }Cyclopropane-1-carboxylic acid monohydrate crystal (C crystal), magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy base) benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate] decahydrate crystal (crystal A), and calcium bis[(1R,2S)-2- {3-[2,6-Dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate]q The adsorption isotherm curve of the hydrate (q represents 4 to 8) crystal (F crystal) (the vertical axis represents the weight change rate (%), and the horizontal axis represents the relative humidity (RH) (%)). Fig. 20 is a graph showing the antitumor effect of compound I in the homograft model of mouse colorectal cancer cell line CT26.

Claims (40)

一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之溶劑合物。A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) Solvate of phenyl}cyclopropane-1-carboxylic acid. 如請求項1所述之化合物，其中，該溶劑合物係水合物。The compound according to claim 1, wherein the solvate is a hydrate. 如請求項1或2所述之化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸一水合物。The compound as described in claim 1 or 2, which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]- 4-(Trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid monohydrate. 一種如請求項1至3中任一項所述之化合物的結晶。A crystal of the compound as described in any one of claims 1 to 3. 如請求項4所述之結晶，其中，粉末X射線繞射譜中，在約7.0、約10.7、約14.0、約16.3、約21.5、約24.9、約25.9、及約27.8度之繞射角(2θ)，具有繞射峰。The crystal as claimed in claim 4, wherein, in the powder X-ray diffraction spectrum, the diffraction angles at about 7.0, about 10.7, about 14.0, about 16.3, about 21.5, about 24.9, about 25.9, and about 27.8 degrees ( 2θ), with diffraction peaks. 如請求項4或5所述之結晶，其中，粉末X射線繞射譜中，在約7.0、約9.4、約9.7、約9.9、約10.6、約10.7、約12.5、約12.8、約13.4、約14.0、約14.2、約14.8、約15.2、約15.4、約16.3、約16.9、約17.4、約17.8、約18.4、約18.6、約18.7、約18.9、約19.2、約19.6、約20.1、約20.3、約20.5、約20.8、約21.0、約21.5、約22.3、約23.0、約23.4、約23.8、約24.6、約24.9、約25.2、約25.9、約26.4、約26.9、約27.1、約27.8、約28.3、約28.5、約29.0、約29.2、約29.4、約30.7、約31.3、約31.9、約32.3、約33.1、約33.5、及約34.4度之繞射角(2θ)，具有繞射峰。The crystal as described in Claim 4 or 5, wherein, in the powder X-ray diffraction spectrum, at about 7.0, about 9.4, about 9.7, about 9.9, about 10.6, about 10.7, about 12.5, about 12.8, about 13.4, about 14.0, about 14.2, about 14.8, about 15.2, about 15.4, about 16.3, about 16.9, about 17.4, about 17.8, about 18.4, about 18.6, about 18.7, about 18.9, about 19.2, about 19.6, about 20.1, about 20.3, About 20.5, about 20.8, about 21.0, about 21.5, about 22.3, about 23.0, about 23.4, about 23.8, about 24.6, about 24.9, about 25.2, about 25.9, about 26.4, about 26.9, about 27.1, about 27.8, about 28.3 , about 28.5, about 29.0, about 29.2, about 29.4, about 30.7, about 31.3, about 31.9, about 32.3, about 33.1, about 33.5, and about 34.4 degrees of diffraction angle (2θ), with diffraction peaks. 如請求項4至6中任一項所述之結晶，其特徵為圖7所示之粉末X射線繞射譜圖。The crystal according to any one of claims 4 to 6 is characterized by the powder X-ray diffraction spectrum shown in FIG. 7 . 如請求項4至7中任一項所述之結晶，其中，微差掃描熱量測量中，起始溫度為約30℃或吸熱峰溫度為約50℃。The crystal according to any one of claims 4 to 7, wherein, in differential scanning calorimetry, the onset temperature is about 30°C or the endothermic peak temperature is about 50°C. 如請求項4至8中任一項所述之結晶，其特徵為圖8所示之微差掃描熱量測量圖。The crystal according to any one of Claims 4 to 8 is characterized by the differential scanning calorimetry diagram shown in FIG. 8 . 一種(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸之結晶。A (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl)phenyl} ring Crystals of propane-1-carboxylic acid. 如請求項10所述之結晶，其中，粉末X射線繞射譜中，在約7.7、約10.3、約13.4、約15.5、約16.9、約19.7、約21.3、及約22.9度之繞射角(2θ)，具有繞射峰。The crystal as claimed in claim 10, wherein, in the powder X-ray diffraction spectrum, the diffraction angles at about 7.7, about 10.3, about 13.4, about 15.5, about 16.9, about 19.7, about 21.3, and about 22.9 degrees ( 2θ), with diffraction peaks. 如請求項10或11所述之結晶，其中，粉末X射線繞射譜中，在約7.0、約7.7、約10.3、約10.5、約12.2、約12.6、約13.4、約14.2、約15.5、約16.2、約16.7、約16.9、約17.3、約17.9、約18.2、約18.6、約19.4、約19.7、約20.6、約21.3、約21.7、約22.1、約22.4、約22.9、約23.4、約24.2、約24.6、約24.8、約25.1、約25.9、約27.9、約28.2、約30.2、及約31.3度之繞射角(2θ)，具有繞射峰。The crystal as claimed in claim 10 or 11, wherein, in the powder X-ray diffraction spectrum, at about 7.0, about 7.7, about 10.3, about 10.5, about 12.2, about 12.6, about 13.4, about 14.2, about 15.5, about 16.2, about 16.7, about 16.9, about 17.3, about 17.9, about 18.2, about 18.6, about 19.4, about 19.7, about 20.6, about 21.3, about 21.7, about 22.1, about 22.4, about 22.9, about 23.4, about 24.2, The diffraction angles (2θ) of about 24.6, about 24.8, about 25.1, about 25.9, about 27.9, about 28.2, about 30.2, and about 31.3 degrees have diffraction peaks. 如請求項10至12中任一項所述之結晶，其特徵為圖11所示之粉末X射線繞射譜圖。The crystal according to any one of claims 10 to 12 is characterized by the powder X-ray diffraction spectrum shown in FIG. 11 . 如請求項10至13中任一項所述之結晶，其中，微差掃描熱量測量中，起始溫度為約69℃或吸熱峰溫度為約76℃。The crystal according to any one of claims 10 to 13, wherein, in differential scanning calorimetry, the onset temperature is about 69°C or the endothermic peak temperature is about 76°C. 如請求項10至14中任一項所述之結晶，其特徵為圖12所示之微差掃描熱量測量圖。The crystal according to any one of Claims 10 to 14 is characterized by the differential scanning calorimetry diagram shown in FIG. 12 . 一種化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸的鹽、或其溶劑合物。A compound which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4-(trifluoromethyl) A salt of phenyl}cyclopropane-1-carboxylic acid, or a solvate thereof. 如請求項16所述之化合物，其中，鹽係鎂鹽。The compound as claimed in claim 16, wherein the salt is a magnesium salt. 如請求項16或17所述之化合物，其係鎂　雙[(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸鹽]十水合物。The compound as described in claim 16 or 17, which is magnesium bis[(1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzoyl Amine]-4-(trifluoromethyl)phenyl}cyclopropane-1-carboxylate] decahydrate. 一種請求項16至18中任一項所述之化合物的結晶。A crystal of the compound described in any one of claims 16 to 18. 如請求項19所述之結晶，其中，粉末X射線繞射譜中，在約6.8、約10.2、約13.6、約17.0、約18.6、約20.1、約23.9、及約26.3度之繞射角(2θ)，具有繞射峰。The crystal as claimed in claim 19, wherein, in the powder X-ray diffraction spectrum, the diffraction angles at about 6.8, about 10.2, about 13.6, about 17.0, about 18.6, about 20.1, about 23.9, and about 26.3 degrees ( 2θ), with diffraction peaks. 如請求項19或20所述之結晶，其中，粉末X射線繞射譜中，在約6.8、約8.3、約10.2、約12.1、約12.5、約12.7、約13.6、約14.0、約15.1、約15.6、約16.1、約16.6、約17.0、約17.5、約17.7、約18.1、約18.6、約19.2、約20.1、約21.3、約21.5、約21.8、約22.8、約23.0、約23.9、約24.7、約25.1、約25.6、約26.3、約28.1、約28.4、及約28.9度之繞射角(2θ)，具有繞射峰。The crystal as claimed in claim 19 or 20, wherein, in the powder X-ray diffraction spectrum, at about 6.8, about 8.3, about 10.2, about 12.1, about 12.5, about 12.7, about 13.6, about 14.0, about 15.1, about 15.6, about 16.1, about 16.6, about 17.0, about 17.5, about 17.7, about 18.1, about 18.6, about 19.2, about 20.1, about 21.3, about 21.5, about 21.8, about 22.8, about 23.0, about 23.9, about 24.7, The diffraction angles (2θ) of about 25.1, about 25.6, about 26.3, about 28.1, about 28.4, and about 28.9 degrees have diffraction peaks. 如請求項19至21中任一項所述之結晶，其特徵為圖1所示之粉末X射線繞射譜圖。The crystal according to any one of claims 19 to 21 is characterized by the powder X-ray diffraction spectrum shown in FIG. 1 . 如請求項19至22中任一項所述之結晶，其中，微差掃描熱量測量中，在約25℃至約85℃之範圍內，具有吸熱峰。The crystal as claimed in any one of claims 19 to 22, wherein, in differential scanning calorimetry, there is an endothermic peak in the range of about 25°C to about 85°C. 如請求項19至23中任一項所述之結晶，其特徵為圖2所示之微差掃描熱量測量圖。The crystal according to any one of claims 19 to 23 is characterized by the differential scanning calorimetry diagram shown in FIG. 2 . 如請求項16所述之化合物，其係(1R,2S)-2-{3-[2,6-二甲基-4-(2-苯基乙氧基)苯甲醯胺]-4-(三氟甲基)苯基}環丙烷-1-羧酸　二環己胺鹽。The compound as described in claim 16, which is (1R,2S)-2-{3-[2,6-dimethyl-4-(2-phenylethoxy)benzamide]-4- (Trifluoromethyl)phenyl}cyclopropane-1-carboxylic acid dicyclohexylamine salt. 一種請求項25所述之化合物的結晶。A crystal of the compound described in Claim 25. 如請求項26所述之結晶，其中，粉末X射線繞射譜中，在約5.9、約7.9、約11.4、約18.8、約21.2、約22.7、及約25.3度之繞射角(2θ)，具有繞射峰。The crystal according to claim 26, wherein, in the powder X-ray diffraction spectrum, at about 5.9, about 7.9, about 11.4, about 18.8, about 21.2, about 22.7, and about 25.3 degrees of diffraction angle (2θ), Has a diffraction peak. 如請求項26或27所述之結晶，其中，粉末X射線繞射譜中，在約5.9、約6.8、約7.9、約8.2、約11.4、約11.9、約13.7、約15.0、約15.9、約17.0、約17.3、約17.9、約18.3、約18.8、約19.6、約19.9、約20.4、約20.7、約21.2、約21.5、約21.9、約22.7、約23.9、約24.3、約24.7、約25.3、約26.8、及約28.9度之繞射角(2θ)，具有繞射峰。The crystal according to claim 26 or 27, wherein, in the powder X-ray diffraction spectrum, at about 5.9, about 6.8, about 7.9, about 8.2, about 11.4, about 11.9, about 13.7, about 15.0, about 15.9, about 17.0, about 17.3, about 17.9, about 18.3, about 18.8, about 19.6, about 19.9, about 20.4, about 20.7, about 21.2, about 21.5, about 21.9, about 22.7, about 23.9, about 24.3, about 24.7, about 25.3, The diffraction angles (2θ) of about 26.8 and about 28.9 degrees have diffraction peaks. 如請求項26至28中任一項所述之結晶，其特徵為圖13所示之粉末X射線繞射譜圖。The crystal according to any one of Claims 26 to 28 is characterized by the powder X-ray diffraction spectrum shown in FIG. 13 . 如請求項26至29中任一項所述之結晶，其中，微差掃描熱量測量中，起始溫度為約153℃或吸熱峰溫度為約155℃。The crystal according to any one of claims 26 to 29, wherein, in differential scanning calorimetry, the onset temperature is about 153°C or the endothermic peak temperature is about 155°C. 如請求項26至30中任一項所述之結晶，其特徵為圖14所示之微差掃描熱量測量圖。The crystal according to any one of Claims 26 to 30 is characterized by the differential scanning calorimetry diagram shown in FIG. 14 . 一種醫藥組成物，其係含有請求項1至31中任一項所述之化合物或結晶與藥學上可接受之載體。A pharmaceutical composition, which contains the compound or crystal described in any one of claims 1 to 31 and a pharmaceutically acceptable carrier. 如請求項32所述之醫藥組成物，其係EP 2受體拮抗劑。 The pharmaceutical composition according to claim 32, which is an EP 2 receptor antagonist. 如請求項32或33所述之醫藥組成物，其係起因於EP 2受體之活性化之疾病的預防及/或治療劑。 The pharmaceutical composition according to claim 32 or 33, which is a preventive and/or therapeutic agent for diseases caused by activation of EP2 receptor . 如請求項34所述之醫藥組成物，其中，起因於EP 2受體之活性化之疾病為子宮內膜症、子宮肌瘤、月經過多、腺肌症、月經困難症、慢性骨盆痛症候群、癌症、炎症性疼痛、神經因性疼痛、頭痛、偏頭痛、術後疼痛、間質性膀胱炎、平滑肌瘤、過敏性大腸症候群、阿茲海默氏症、帕金森氏症、肌萎縮性側索硬化症、多發性硬化症、風濕病、骨關節炎、痛風、過敏性疾病、高血壓、腦機能障礙、缺血、腦溢血、腎疾病、移植排斥反應、粥狀動脈硬化症、缺血性心疾病、尋常性痤瘡、氣喘、***炎、腎絲球性腎炎、類肉瘤病、血管炎、或自體免疫疾病。 The pharmaceutical composition according to claim 34, wherein the disease caused by activation of the EP2 receptor is endometriosis, uterine fibroids, menorrhagia, adenomyosis, dysmenorrhea, and chronic pelvic pain syndrome , cancer, inflammatory pain, neuropathic pain, headache, migraine, postoperative pain, interstitial cystitis, leiomyoma, irritable bowel syndrome, Alzheimer's disease, Parkinson's disease, muscular atrophy Lateral sclerosis, multiple sclerosis, rheumatism, osteoarthritis, gout, allergic disease, hypertension, brain dysfunction, ischemia, cerebral hemorrhage, kidney disease, transplant rejection, atherosclerosis, Blood heart disease, acne vulgaris, asthma, prostatitis, glomerulonephritis, sarcoidosis, vasculitis, or autoimmune disease. 如請求項34所述之醫藥組成物，其中，起因於EP 2受體之活性化之疾病為癌症，癌症為乳癌、卵巢癌、大腸癌、肺癌、***癌、頭頸部癌、淋巴瘤、葡萄膜黑色素瘤、胸腺瘤、間皮瘤、食道癌、胃癌、十二指腸癌、肝細胞癌、膽管癌、膽囊癌、胰臟癌、腎細胞癌、腎盂/尿道癌、膀胱癌、陰莖癌、睪丸癌、子宮癌、***癌、外陰癌、皮膚癌(例如，惡性黑色素瘤等)、惡性骨腫瘤、軟組織肉瘤、軟骨肉瘤、白血病、骨髓發育不良症候群、神經膠質母細胞瘤或多發性骨髓瘤。 The pharmaceutical composition as described in Claim 34, wherein the disease caused by the activation of EP2 receptor is cancer, and the cancer is breast cancer, ovarian cancer, colorectal cancer, lung cancer, prostate cancer, head and neck cancer, lymphoma, grape Membranous melanoma, thymoma, mesothelioma, esophageal cancer, gastric cancer, duodenal cancer, hepatocellular carcinoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, renal cell carcinoma, renal pelvis/urethral cancer, bladder cancer, penile cancer, testicular cancer , uterine cancer, vaginal cancer, vulvar cancer, skin cancer (eg, malignant melanoma, etc.), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, glioblastoma, or multiple myeloma. 如請求項32至36中任一項所述之醫藥組成物，其係與由烷基化劑、代謝拮抗劑、抗癌性抗生物質、植物性製劑、荷爾蒙劑、鉑化合物、拓樸異構酶抑制劑、激酶抑制劑、抗CD20抗體、抗HER2抗體、抗EGFR抗體、抗VEGF抗體、蛋白質體抑制劑、HDAC抑制劑、及免疫調整藥選擇之至少1種以上組合投予。The pharmaceutical composition according to any one of claims 32 to 36, which is composed of alkylating agent, metabolic antagonist, anticancer antibiotic, botanical preparation, hormone agent, platinum compound, topoisomer Enzyme inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteosome inhibitors, HDAC inhibitors, and immunomodulators are administered in combination. 一種起因於EP 2受體之活性化之疾病的預防及/或治療方法，其係包含向需要起因於EP 2受體之活性化之疾病的預防及/或治療的患者投予有效量的請求項1至31中任一項所述之化合物或結晶。 A method for preventing and/or treating diseases caused by activation of EP2 receptors , comprising a request for administering an effective amount to a patient in need of prevention and/or treatment of diseases caused by EP2 receptors activation The compound or crystal according to any one of Items 1 to 31. 如請求項1至31中任一項所述之化合物或結晶，其係使用於起因於EP 2受體之活性化之疾病的預防及/或治療。 The compound or crystal according to any one of claims 1 to 31, which is used for the prevention and/or treatment of diseases caused by the activation of EP2 receptor . 一種請求項1至31中任一項所述之化合物或結晶的用途，其係用於製造起因於EP 2受體之活性化之疾病的預防及/或治療劑。 A use of the compound or crystal according to any one of claims 1 to 31 for the manufacture of a preventive and/or therapeutic agent for diseases caused by activation of EP2 receptor .
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