TW200806666A - Salts of 8-[(1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy)-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor - Google Patents
Salts of 8-[(1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy)-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor Download PDFInfo
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200806666 九、發明說明: 【發明所屬之技術領域】 本專利申請案大體係關於醫藥學上有用之鹽及製備醫藥 子上有用之鹽的新穎方法。其特定係關於一種合成8_[^_ (3,5-雙-(三氟甲基)苯基)乙氧基甲基]苯基二氮-螺[4,5]癸-2-酮之醫藥學上有用之鹽的新穎方法。 【先前技術】 名為一鼠螺癸酮(根據Bielstein命名法)之8-[{1_(3,5_ 雙_(二氟甲基)苯基)乙氧基卜甲基卜8_苯基'7_二氮-螺 =,5]癸-2_酮,例如 苯基)乙氧基}甲基]-8_苯基-1,7-二氮螺[4,5]癸-2-酮(式I之 化口物)之製備揭示於2〇〇〇年5月i日申請之已公開美國專 利申凊案第2003-0158,173八1號(第173號公開案)中,該申 請案以全文引用之方式併入本文中。200806666 IX. Description of the invention: [Technical field to which the invention pertains] The novel system of the present patent application relates to a pharmaceutically useful salt and a novel method for preparing a salt useful in medicine. Specifically, it relates to a medicine for synthesizing 8_[^_(3,5-bis-(trifluoromethyl)phenyl)ethoxymethyl]phenyldiazo-spiro[4,5]nonan-2-one A novel method of learning useful salts. [Prior Art] 8-[{1_(3,5_bis-(difluoromethyl)phenyl)ethoxymethaneb 8_phenyl'7_), a snail ketone (according to the Bielstein nomenclature) Diazo-spiro =, 5] indol-2-one, such as phenyl)ethoxy}methyl]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one The preparation of the chemical substance of I is disclosed in the published US Patent Application No. 2003-0158, No. 173 (No. 173) filed on May i. The manner of full reference is incorporated herein.
揭示於第173號公開案中之新穎化合物歸類為速激肽化 合物,且為神經肽神經激肽-1受體之拮抗劑(本文簡稱為The novel compounds disclosed in Publication No. 173 are classified as tachykinin compounds and are antagonists of the neuropeptide neurokinin-1 receptor (herein referred to as
之治療劑。揭示於u.s· 5,76〇5〇18(1998)中之Νκ—丨受體拮抗 119709.doc 200806666 劑之一些實例已展示可用於治療疼痛、發炎、偏頭痛及嘔 吐。揭示於美國專利第5,620,989號(1997)及國際公開案第 WO 95/19344號(1995)、第 WO 94/13639號(1994)及第 WO 94/10165號(1994)各者中之其他NK-1受體拮抗劑之額外實 例已展示可用於治療疼痛、傷痛刺激及發炎。受體拮 抗劑之額外實例已描述於以下出版物中:Wu等人,Therapeutic agent. Kappa-丨 receptor antagonism disclosed in u.s. 5, 76〇5〇18 (1998) 119709.doc 200806666 Some examples of agents have been shown to be useful in the treatment of pain, inflammation, migraine and vomiting. Other NK- disclosed in U.S. Patent No. 5,620,989 (1997) and International Publication No. WO 95/19344 (1995), WO 94/13639 (1994), and WO 94/10165 (1994). Additional examples of 1 receptor antagonists have been shown to be useful in the treatment of pain, irritations, and inflammation. Additional examples of receptor antagonists have been described in the following publications: Wu et al.
Tetrahedron 56,3043-3051 (2000); Rombouts 等人, Tetrahedron Letters 42,7397-7399 (2001)及 R0giers 等 人,Tetrahedron 57, 8971-8981 (2001)。 揭示於上述第,173號公開案中之新穎NK-1受體拮抗劑化 合物包括數種新穎二氮螺癸-2-酮(包括式I化合物),據信 其為可用於提供抗嗔心及抗η區吐治療之治療劑。 如第’173號公開案中所報導,藉由TLC及GC/MS技術來 表徵式I之化合物。描述於第,173號公開案中之程序獲得呈 非晶形白色泡沫形式之式I化合物。使游離鹼結晶之重複 _试並未提供結晶物質。 一般而言,已確認為具有治療活性之化合物必須以高純 度形式提供來用於醫藥用途。此外,亦需要提供一定形式 的意欲用於醫藥用途之化合物,該形式可使化合物易於經 處理併入藥劑中,且當併入藥劑中時化合物具有抗化學降 解之足夠穩固之特性且藉此賦予藥劑較長之存放期。 【發明内容】 蓉於前述内容,需要一種治療劑形式,其有助於提供高 度純化形式之治療劑。亦需要一種在處理及儲存之環境條 119709.doc 200806666 件下對於降解而言_之治療劑形式。 本發明有利地提供此等及发 其私的物,在一態樣中本發 月ϋ、鹽形式之式I化合物, 勿其視情況為結晶形式且視情 況併入-或多個溶劑分子,例如結晶單 施例中,化合物!之鹽形式 一貝 Λ係選自順丁烯二酸鹽、甲磺酸 鹽、草酸鹽、苯石黃酸鴎、 ^ | 乙嶒敲鹽、反丁烯二酸鹽、檸檬 酸鹽、酒石酸鹽、破拍献^疏 號轴®文鹽、乳酸鹽、羥基乙酸鹽、1-經Tetrahedron 56, 3043-3051 (2000); Rombouts et al, Tetrahedron Letters 42, 7397-7399 (2001) and R0giers et al, Tetrahedron 57, 8971-8981 (2001). The novel NK-1 receptor antagonist compounds disclosed in the above-mentioned publication No. 173 include several novel diazepyrdin-2-ones (including compounds of formula I) which are believed to be useful for providing anti-caries and A therapeutic agent for the treatment of anti-η area vomiting. The compounds of formula I are characterized by TLC and GC/MS techniques as reported in publication No. 173. The procedure described in the No. 173 publication provides a compound of formula I in the form of an amorphous white foam. Repeating the crystallization of the free base did not provide a crystalline material. In general, compounds which have been identified as having therapeutic activity must be provided in high purity form for medical use. In addition, there is also a need to provide a form of a compound intended for pharmaceutical use that facilitates the incorporation of a compound into a medicament, and which, when incorporated into a medicament, has sufficiently stable properties against chemical degradation and thereby imparts Long shelf life of the drug. SUMMARY OF THE INVENTION In the foregoing, there is a need for a form of therapeutic agent that facilitates the provision of therapeutic agents in highly purified form. There is also a need for a form of therapeutic agent for degradation in the environmental zone of treatment and storage 119709.doc 200806666. The present invention advantageously provides such and whitish, in one aspect, a compound of formula I, in the form of a salt, in the form of a salt, optionally as a crystalline form and optionally incorporated into a solvent molecule, For example, in the single embodiment of the compound, the compound! The salt form of a shellfish is selected from the group consisting of maleate, methanesulfonate, oxalate, barium benzoate, ^ | acetamidine, fumarate, citrate, tartaric acid Salt, broken shots, Xiaouan shaft® salt, lactate, glycolate, 1-jing
基-2-奈甲酸鹽、丙二酸賴 皿㈠L-蘋果酸鹽、馬尿酸鹽及 (1S)樟腦績酸鹽。在一此乾每 二孕乂仏貝她例中,化合物I之鹽形式 為順丁烯二酸鹽。 一本發明之另一態樣提供一種(5S,8S)冬…⑻小(3,5-雙— (-氟甲基)苯基)乙氧基卜曱基卜8_苯基],?·二氮螺[4,5]癸-2-酮之結晶順丁烯二酸鹽形幻鹽形式,其由表丄中所示之 根據繞射角(以2Θ為單位’所有值反映± 〇·2之精確度)、晶 格間距d (以埃為單位)及相對峰強度(,,ri,)表示之χ射線 粉末繞射圖譜來表徵:Base-2-naconate, malonic acid lysate (a) L-malate, horse urate and (1S) oxime acid salt. In the case of her every second pregnant mussel, the salt form of Compound I is maleate. Another aspect of the invention provides a (5S, 8S) winter... (8) small (3,5-bis-(-fluoromethyl)phenyl)ethoxy bromide 8_phenyl],? · Crystalline maleate salt of diazoxide [4,5]nonan-2-one, in the form of a pseudo-salt salt, which is represented by the diffraction angle according to the table (in terms of 2 ' 'all values reflect ± 〇 • The accuracy of 2), the lattice spacing d (in angstroms), and the relative peak intensity (,, ri,) are characterized by the diffraction pattern of the X-ray powder:
表I 繞射角(2Θ 士 0.2) RI 晶格間距(A 土 0.04) 10.0 弱 8.84 13.5 中等 6.55 16.5 中等 5.36 23.5 強 3.79 本發明之另, 一態樣 提供一 種(5S,8S)-8-[{(lR)-l-(3,5,雙 (二氟甲基)苯基)乙氧基卜甲基]_8-苯基d,7_二氮螺[4,5]癸一 119709.doc 200806666 2-酮之結晶順丁烯二酸鹽形式1];鹽,其由表π中所示之根 據繞射角(以2Θ為單位)、晶格間距”(以埃為單位)及相對 峰強度("RI”)表示之X射線粉末繞射圖譜來表徵:Table I diffraction angle (2 0.2 0.2) RI lattice spacing (A soil 0.04) 10.0 weak 8.84 13.5 medium 6.55 16.5 medium 5.36 23.5 strong 3.79 Another aspect of the invention provides a (5S, 8S)-8-[ {(lR)-l-(3,5,bis(difluoromethyl)phenyl)ethoxymethyl]_8-phenyl d,7-diazaspiro[4,5]癸一119709.doc 200806666 2 a ketone crystal maleate form 1]; a salt, which is represented by the diffraction angle (in units of 2 Å), lattice spacing (in angstroms) and relative peak intensity (shown in Table π) "RI") is characterized by an X-ray powder diffraction pattern:
表II 繞射角(2Θ 士 〇·2) RI 晶格間距(A 土 0.04) 4.8 中等 8.47 12.0 強 7.38 24.5 強 3.64 28.9 中等 ’寬 3.08 本發明之另一態樣提供一 -種(5S,8S)-8-[{(lR)-l_(3,5-雙- (三氟甲基)苯基)乙氧基}_f 基l·8-苯基-l,7-二氮螺[4,5]癸- 2-酮之結晶甲石黃酸鹽 形式I鹽,其由表III中所示之根據繞 射角(以2Θ為單位)、' 晶袼間距”d’’(以埃為單位)及相對峰強 度(’’RI”)表不之X射線粉末繞射圖譜來表徵: 表III 繞射角(2Θ ± 0.2) RI 晶格間距(A 土 0.04) 7.3 強 12.17 10.2 強 8.69 22.7 強 3.92 28.9 強 3.08 本發明之另一態樣提供一種 (三a曱基)苯基)乙氧基}_甲基]_8_苯基二氮螺[4,5;]癸_ 2,之結晶甲磺酸鹽形式„鹽,其由表1¥中所示之根據繞 射角(以2Θ為單位)、晶格間距”d”(以埃為單位)及相對峰強 H9709.doc 200806666 度("RI”)表不之X射、線粉末繞射圖譜來表徵: 表IV 繞射角(2Θ 士 0.2) RI 晶格間距(人± 0.04) 6.2 中等 14.20 9.6 中等 9.24 19.9 極強 4.46 21.2 強 4.19 本發明之另一態樣提供一種(58,88)_8-[{(1幻_1_(3,5_雙_ (三氟甲基)苯基)乙氧基卜甲基]_8-苯基4,^二氮螺[4,5]癸· 2-酮之結晶甲磺酸鹽形式出鹽 ’其由表V中所示之根據繞 射角(以2Θ為單位)、 晶袼間距1 dπ (以埃為單位)及相對峰強 度(nRIn)表示之X射線粉末繞射圖譜來表徵: 表V 繞射角(2Θ ± 0.2) RI 晶格間距(Α 士 0.04) 4.7 強 18.62 9.5 中等 9.26 19.2 極強 4.63 20.9 中等, 寬 4.25 本發明之另一態樣提供一種 (三氟甲基)苯基)乙氧基卜曱基]I苯基],7-二氣螺[4,5]癸_ 2^之結晶草酸鹽,其由表^中所示之根據繞射角(以^ 為單位)、晶袼間距"d”(以埃為單位)及相對峰強度(,,幻”)表 示之X射線粉末繞射圖譜來表徵:Table II Diffraction angle (2Θ士〇·2) RI Lattice spacing (A soil 0.04) 4.8 Medium 8.47 12.0 Strong 7.38 24.5 Strong 3.64 28.9 Medium 'Width 3.08 Another aspect of the invention provides one-of-a-kind (5S, 8S )-8-[{(lR)-l_(3,5-bis-(trifluoromethyl)phenyl)ethoxy}_fyl l·8-phenyl-l,7-diazaspiro[4, 5] 癸- 2-ketone crystalline carbamate Form I salt, which is shown in Table III according to the diffraction angle (in units of 2 Å), 'crystal spacing' d'' (in angstroms) And the relative peak intensity (''RI') is not characterized by the X-ray powder diffraction pattern: Table III diffraction angle (2Θ ± 0.2) RI lattice spacing (A soil 0.04) 7.3 strong 12.17 10.2 strong 8.69 22.7 strong 3.92 28.9 Strong 3.08 Another aspect of the present invention provides a (tria-indenyl)phenyl)ethoxy}-methyl]-8-phenyldiazospiro[4,5;]癸_ 2, a crystalline form A Sulfonate form „salt, which is shown by the diffraction angle (in 2Θ), lattice spacing “d” (in angstroms) and relative peak intensity H9709.doc 200806666 degrees (" ;RI") not X-ray, line powder diffraction map Signs: Table IV diffraction angle (2 0.2 0.2) RI lattice spacing (human ± 0.04) 6.2 medium 14.20 9.6 medium 9.24 19.9 extremely strong 4.46 21.2 strong 4.19 Another aspect of the invention provides a (58, 88) _8- Crystallization of [{(1 illusion_1_(3,5_bis-(trifluoromethyl)phenyl)ethoxy)methyl]_8-phenyl 4,^diazaspiro[4,5]indole-2-one The methanesulfonate salt is formed as an X-ray powder represented by the diffraction angle (in units of 2 Å), the spacing of the wafers in 1 dπ (in angstroms), and the relative peak intensity (nRIn) shown in Table V. The diffraction pattern is used to characterize: Table V diffraction angle (2Θ ± 0.2) RI lattice spacing (Α0.04) 4.7 strong 18.62 9.5 medium 9.26 19.2 extremely strong 4.63 20.9 medium, width 4.25 Another aspect of the invention provides one ( Trifluoromethyl)phenyl)ethoxydimethyl]Iphenyl], 7-dioxaspiro[4,5]癸_ 2^ crystalline oxalate, which is represented by the diffraction angle according to the table X-ray powder diffraction pattern (in units of ^), wafer spacing "d" (in angstroms) and relative peak intensity (, illusion):
表VI 119709.doc -10- 200806666 繞射角(2Θ 土 0.2) RI 晶格間距(人± 0·04) 5.6 弱,寬 12.37 19.8 中等 4.84 21.0 中等 4.57 22.8 中等 4.18 本發明之另一態樣提供一種(5S,8S)-8-[{(;lR)_l-(3,5-雙-(三氟甲基)苯基)乙氧基}-甲基]-8-苯基-l,7-二氮螺[4,5]癸-2-酮之結晶乙磺酸鹽,其由表VII中所示之根據繞射角(以 2Θ為單位)、晶格間距"d’’(以埃為單位)及相對峰強度(nRI’’) 表示之X射線粉末繞射圖譜來表徵:Table VI 119709.doc -10- 200806666 Diffraction angle (2 Θ soil 0.2) RI lattice spacing (human ± 0·04) 5.6 weak, width 12.37 19.8 medium 4.84 21.0 medium 4.57 22.8 medium 4.18 Another aspect of the invention provides (5S,8S)-8-[{(;lR)_l-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-methyl]-8-phenyl-l,7 a crystalline ethanesulfonate salt of diaziro[4,5]nonan-2-one, which is represented by the diffraction angle (in units of 2 Å) and lattice spacing "d'' X-ray powder diffraction pattern represented by angstrom unit and relative peak intensity (nRI''):
表VII 繞射角(2Θ 土 0.2) RI 晶格間距(A 土 0.04) 11.4 中等 7.73 12.8 中等 6.90 20.0 強 4.44 21.2 中等 4.18 本發明進一步提供各自含有選自 順丁烯二酸鹽形式I及 II、甲磺酸鹽形式I、II及ΙΠ、乙磺酸鹽及草酸鹽之 (5 3,83)-8-[{(111)-1-(3,5-雙-(三氟甲基)苯基)乙氧基卜曱 基]-8-苯基-1,7-二氮螺[4,5]癸-2-酮(式I化合物)結晶鹽形式 之醫藥組合物,及使用含有一或多種式〗化合物之結晶鹽 形式之藥劑治療及/或預防σ惡心及π區吐之方法。 【實施方式】 (5S,8S)I[{(1R)小(3,5 —雙-(三氟曱基)苯基)乙氧基卜甲 119709.doc -11 - 200806666 基]冬苯基-1,7-二氮螺[4,5]癸_2_酮⑷之化合物)之鹽形式 ΗTable VII diffraction angle (2 Θ 0.2) RI lattice spacing (A soil 0.04) 11.4 medium 7.73 12.8 medium 6.90 20.0 strong 4.44 21.2 medium 4.18 The present invention further provides that each of them is selected from the group consisting of maleic acid forms I and II, (5 3,83)-8-[{(111)-1-(3,5-bis-(trifluoromethyl)) mesylate form I, II and hydrazine, ethanesulfonate and oxalate A pharmaceutical composition in the form of a crystalline salt of phenyl)ethoxy bromide]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one (compound of formula I), and the use of one or more A method of treating a compound in the form of a crystalline salt of a compound and/or preventing sputum nausea and π-region vomiting. [Embodiment] (5S, 8S) I[{(1R) small (3,5-bis-(trifluoromethyl)phenyl)ethoxy bromide 119709.doc -11 - 200806666 base] winter phenyl- Salt form of 1,7-diazaspiro[4,5]indole-2-one (4)
提供一種有益於治療噁心及嘔吐之藥物。儘管本發明之 化合物可用於提供對由任何原因引起之噁心及嘔吐的抗噁 心及抗喔吐治療’但據信式]:之化合物將最有效用於提供 對與化學療法治療、輻射治療相關及手術後期内出現之噁 心及/或嘔吐的抗噁心及/或抗嘔吐治療。另外,與有益於 &供有用藥劑之化合物的游離驗形式相比較,本文所揭示 之鹽形式具有與其在極性溶劑中之改良溶解度相關的處理 優點。此外,甲苯磺酸鹽、鹽酸鹽、蘋果酸鹽、甲磺酸 鹽、草酸鹽、苯磺酸鹽及乙磺酸鹽之各者具有一或多種結 晶形式,該等結晶形式提供與化合物之非晶形形式相比較 具有以下優點之形式的式][化合物··較低雜質含量及更一 致之產品品質,亦即包括更一致之顏色、溶解速率及處理 易度的更一致之物理特徵;以及併入藥劑中時更長期之穩 定性。 如下文詳細描述,可藉由檢測各別鹽形式之特徵性X射 線繞射圖譜(見圖1、2及9至13)、特徵性紅外線光譜(見圖4 及6)及分析性差示掃描熱量測定(DSC)溫譜圖(圖7及8)中之 一或多者而容易地將本文所述之各式I化合物之結晶鹽形 式彼此區別且與非晶形形式區別。 119709.doc -12- 200806666 如上式11中所示,本發明者出乎意料地發現式i之二氮螺 癸-2-酮含有足夠鹼度之環胺氮而使其可經由選自苯磺酸、 乙磺酸及曱磺酸之無機酸質子化(分別形成式j化合物之苯 磺酸鹽、乙磺酸鹽及甲磺酸鹽)。亦出乎意料地發現式 二氮螺癸-2-酮可經由選自蘋果酸、草酸、反丁烯二酸、酒 石酸、檸檬酸、琥珀酸、乳酸、羥基乙酸、丙二酸、丨·羥 基-2-萘甲酸、順丁烯二酸、馬尿酸及樟腦磺酸之有機酸質 子化而分別形成式I化合物之蘋果酸鹽、草酸鹽、反丁烯 二酸鹽、酒石酸鹽、檸檬酸鹽、琥珀酸鹽、乳酸鹽、羥基 乙酸鹽、丙二酸鹽、丨_羥基萘甲酸鹽、順丁烯二酸鹽、 馬尿酸鹽及樟腦磺酸鹽。此外,已發現選自順丁烯二酸 鹽、甲磺酸鹽、草酸鹽、苯磺酸鹽及乙磺酸鹽形式之酸性 鹽可以結晶固體之形式提供,該結晶固體之晶體結構(對 於經質子化式I化合物之各分子而言)視情況包括一或多個 溶劑分子,例如甲苯、己烷或乙腈。 本發明之鹽提供許多在物理特性方面超過游離鹼之驚人 優點’例如研磨、微米尺寸化及溶解化合物之能力。該鹽 之較佳結晶形式係選自順丁烯二酸鹽及甲磺酸鹽形式。已 發現此等鹽除具有所需溶解度及處理特徵外亦具熱力學穩 定性’從而以易於併入藥劑且在多種環境條件下穩定之鹽 形式提供式I化合物。 如吾人所知,當治療劑在約pH 1至約pH 7之pH範圍内具 有小於約10 mg/ml之水溶解度時,其通常展示較差吸收速 率。此外’當口服投藥時,治療劑在此pH範圍内展示小於 119709.doc 13 200806666 約1 mg/ml之溶解度,由於溶解度與吸收在經口服投藥藥 d中係相關的’因此通常該等試劑展示受溶解速率限制^ 吸收因此’對於提供經設計帛以傳遞作為治療劑之 化合物的口服投蘂游4 ^ 又梁形式之樂劑而言,此等鹽之改良溶 特性係重要的。如下文詳細描述,除此等所需改良溶解度 特性以外’所選之鹽展㈣外_之物理特性。 又 般而口化合物鹽係由式j化合物及選自草酸 稀二酸、甲續酸、苯績酸、乙續酸、反丁稀二酸'私 ,:酒石酸、破轴酸、乳酸、經基乙酸、,…蔡; 酉二Γ—酸、•果酸、馬尿酸及樟腦·酸之酸根據以下程 序來製備: & 0在擾摔下,將0·1 §之量的式1化合物(大約〇2 福叫及當量(亦即G.2 mMGl)經選擇之酸溶解 納於容器中之約3ml無水乙醇中; 、 ⑴在連續授拌下,將無水乙趟逐滴添加至混合 直至其變得渾濁; 出)將恰好足以传運、、欢、主 曰 使渾渴也、凊之量的無水乙醇添加至渾 濁混合物中(通常為數滴); V) ㈨停ΐ㈣且以含有排氣孔之㈣覆蓋容器,且靜 置容器歷時24至48小時,期間固體沉殿;" 靜置時間結束時,藉由過攄回收固體, :,且接著首先在空氣中乾燥約!至㈣小;: …且接著在周圍溫度下於室内真空下 燥隔夜而獲得式I化合物之鹽。 一二氡 I19709.doc -14- 200806666 對於一些gg a —氣向S ’根據以下通用程序來製備各種晶體之 ^谷劑合物形式。M丄、 措由根據上述程序反應性結晶,或使首先 利用上述通用# & 序以非晶形物質形式沉澱且隨後藉由添加 非晶形鹽之赞、、右曰# 旦 7 ’夜日日種而結晶之鹽再結晶所製備的鹽之樣本 量入小瓶内,诵赍炎% t Λ 、吊為、、、勺10 mg至約50 mg。將足以完全浸沒 二體之里的,谷劑添加至小瓶中,該溶劑係選自乙醇、異丙 酉予、乙腈、、田 、f本、乙酸乙酯、二氯甲烷及己烷。將固 體及溶劑在周圍條件下攪拌足以提供溶劑合物晶體之時 丫 4如約7天。當已製備溶劑合物晶體時,將懸浮溶劑 合^日體之樣本滴於供粉末χ射線繞射分光計中使用之樣 本固疋裔上且風乾。#著根據本文所述之程序藉由X射線 光譜法來分析此等樣本。 分析程序 藉由或夕種包括X射線粉末繞射光譜法(PXRD)、紅外 線光碏法(IR)及拉曼光譜法(Raman)之技術來表徵各式Η匕 合物之結晶鹽形式。亦藉由差示掃描熱量測定(DSC)來分 析及/或藉由包括溶解度研究及穩定性研究之物理方法來 進一步表徵所選擇之化合物〗之鹽形式。 X射線粉末繞射光譜法 使用以下程序之一獲得樣本之X射線粉末繞射光譜。對 於根據上述程序所製備之溶劑合物,在Rigaku上根據以下 程序進行分析。 對於使用Rigaku Miniflex分光計分析所得樣本時,使用 以下程序(PXRD方法〇。將由PXRD方法〗分析之樣品輕輕 119709.doc -15- 200806666 衣在低月厅、为析盤上。樣品暴露於周圍溫度及濕度之室内 裒i兄下RlgakU刀光什裝備有六個分析盤轉料架,其使樣 品以54啊旋轉,從而將所研究樣本中晶體之較佳定向降 至最低。Rigaku分光計亦裝備不使用Κα2遽波器之銅〖以輻 射源。分光計亦裝備可變發散狹缝及G 3随接收狹縫。自 2.0至4〇。20執行掃描範圍。使用對於lu平面之Cu〖Μ峰 驗證儀器校準。掃描期間’經〇.6秒之步進時間的步長為 〇.〇2度。使用Jade P1US(版本5〇26)分析軟體完成數據分 析。使用Savitzky-Golay拋物線濾波器使丨i個點之數據形 成平滑曲線。通常,,d"間距值精確在± 〇 〇4八内。 對於一些樣本而言,使用2〇〇2年製造之Bruker D8繞射 计獲付X射線粉末繞射光譜學分析(pxRD方法H)。huker 繞射計具有利用G0BEL光束聚焦鏡及具有固定徑向素抽狹 縫之PSD錢器之平行光學㈣。Bruker繞射計與Ant〇n Paar TTK450溫度台一起使用。轄射源為銅(κα)。發散狹 縫固定為0.6醜。Bruker繞射計使用頂部裝載黃銅塊樣本 固定器。使用PSD快速掃描自4.〇。至39.9。進行掃描。為獲 得繞射圖_,將樣品裝載於樣本固定器上且以玻璃顯㈣ 載片調平。在關濕度下且不經氮氣沖洗且不在真空下, 將樣本室溫度設定為饥、机㈣代。使用雲母鮮驗 證儀器校準。掃描期間’經G.U1G秒之步進時間的步長 為0.013度至G.G2度。使用由Bruker⑧提供s〇cabim⑧編寫 之EVA分析軟體版本".ο」完成數據分析。#由軟體使〇ι 至0 · 1 5之數據形成平滑曲線。 H9709.doc -16- 200806666 除根據上述程序所製備之彼等溶劑合物樣本以外,使用 於X射線粉末繞射(’’PXRD”)分析之樣本經歷最低限度之製 備以防止任何形式變化。將樣本顆粒輕輕裝入樣本固定器 以確保其形成平滑表面且不會結塊在一起。對於根據上述 程序製備之溶劑合物樣本之外的樣本,不使用溶劑、乾燥 或其他製備步驟。 紅外線光譜法 利用衰減全反射(ATR)紅外線光譜法使用裝備有Avatar Smart Miracle衰減全反射(ATR)樣本室之Nicolet Instruments NEXUS 670 FTIR來表徵樣本。利用以下參數 收集光譜:DTGS KBr偵側器;KBr光束分光器;掃描範 圍:600 cm-1至4000 cnT1 ;縫隙設定:100 ;解析度:2 ; 每樣本掃描100次。藉由收集背景光譜,接著將參考標準 或顆粒樣本(通常為3 mg至5 mg之樣本)置於ATR晶體上且 根據废商建議以儀器之壓力臂對樣本施力來進行分析。接 著利用廠商專有軟體,以背景與樣品光譜比率之形式獲得 樣品(參考或樣本)之光譜。 拉曼光譜法 利用兩種程序之一來進行拉曼光譜法(Raman)。以高解 析度模式在 Thermo Electron Nicolet Almega Dispersive拉 曼分光計上進行程序I拉曼分析。樣本容納於NMR樣本管 内,且在以下條件下獲得光譜:掃描範圍:4000 cm “至90 cm·1 ;曝光時間·· 1.0秒;100次樣本及100次背景曝光; 785 nm激發雷射/100%功率位準/平行雷射偏振;每毫米格 119709.doc -17- 200806666 柵1200行;100微米狹縫;照相機溫度:-50°C。 在設定為 50倍放大率之Thermo Electron Nicolet Almega 拉曼顯微鏡上進行程序II拉曼分析。藉由將少量化合物置 於顯微鏡載片上且不使用蓋玻片來製備樣本,且在以下條 件下獲得光譜:掃描範圍3481 cm·1至96 cnT1 ;低解析度; 曝光時間:5.0秒;10次樣本及10次背景曝光;780 nm激 發雷射(去偏振)/100%功率位準;每毫米格栅1200行;25 微米針孔;照相機溫度:-48°C。 差示掃描熱量測定 利用TA Instruments之調變差示掃描熱量計(DSC)進行熱 量測定研究。在l〇°C/min·之加熱速率下,於40 ml/min之 氮氣流動速率下在開口鋁盤中進行DSC掃描。 藉由將過量化合物置於所關注溶劑之等分試樣中且使漿 液在所選溫度條件下(通常為周圍溫度)平衡來進行溶解度 測試。當溶劑為水時,以鹽酸及氫氧化鈉將pH調節至所需 值。當漿液混合物已平衡時,將過量固體自上清液離心 (水)或過濾(所有其他溶劑)出來,且利用經稀釋上清液等 分試樣之HPLC分析來定量已溶解之化合物量。使用醫藥 級溶劑。 藉由將精確稱重之式I化合物之鹽形式樣本置於聚乙烯 袋内對所關注鹽形式之等分試樣進行化學穩定性測試。將 裝入袋内之樣本封入配備有金屬帽之纖維板管内,該等纖 維板管在指定濕度及溫度條件下儲存指定時間。藉由使小 瓶内容物溶解且利用HPLC分析定量溶解物之量來進行分 119709.doc -18- 200806666 析。若有特定註釋,則在已提及之條件下將等分試樣儲存 於封蓋琥珀色小瓶中來代替聚乙烯袋。 實例 如下所述製備式I化合物之順丁烯二酸鹽、甲綠酸踏、 乙磺酸鹽及草酸鹽形式。如下文詳細描述,亦藉由包括X 射線粉末繞射光譜法、紅外線光譜法及拉曼光譜法之多種 光譜技術來表徵各式I化合物之鹽形式。分析所選擇之_ 形式之穩定性、溶解度及其他改良物理特性,對於某些踏 而言其包括差示掃描熱量測定(DSC)分析。除非另外規 定,否則根據2000年5月1日申請之申請中之公開美國專利 申請案第2003-0158,173 A1號(第173號公開案)(其以全文引 用之方式併入本文中)中所揭示之程序來製備用於製備本 文所述之鹽之(5S,8S)-8-[{(lR)-l-(3,5-雙_(三氟甲基)苯基) 乙氧基}-曱基]-8-苯基-1,7-二氮螺[4,5]癸-2-酮(式ϊ之化合 物)。所有反應性結晶、再結晶及製漿程序均在規定級(除 非另外規定通常為醫藥級或食品級)之市售溶劑中進行且 以公認標準形式使用(除非另外規定)。 式I化合物之順丁烯二酸鹽 根據上述用於製備式I化合物之鹽之通用程序,藉由將i g(2 mmol)式I化合物溶解於4 ml甲基第三丁基醚(MTBE)中 且將其與1當量溶於4 ml異丙醇中之順丁烯二酸一起擾拌 來製備式I化合物之非晶形順丁烯二酸鹽。根據上文所述 之通用I桌私序’猎由將以上所製備之非晶形順丁烯二酸 鹽在乙腈或乙酸異丙酯中製成漿液來製備式^化合物之順 H9709.doc -19- 200806666 丁烯二酸鹽形式1鹽。利用上述程序藉由x-射線、紅外線 及拉曼光譜法來表徵且藉由Dsc來分析式〗化合物之順丁烯 一酸鹽形式I。圖1說明順丁烯二酸鹽形式〗鹽之又射線粉末 、v〇射光Μ。下表VIII列出圖1中所示之χ射線粉末繞射光譜 之12個特徵峰,其根據以2Θ度數(〇2θ)表示之繞射角、以埃 (Α)為單位之相應”d”間距來表示,且在相鄰列中以下列符 號表不信號之相對強度: S=強,M=中等,W=:弱, V=極且,D=擴散:Provide a drug that is beneficial for the treatment of nausea and vomiting. Although the compounds of the present invention are useful for providing anti-nausea and anti-obesity treatment for nausea and vomiting caused by any cause, 'the formula is believed to be the most effective for providing treatments related to chemotherapy, radiation therapy and Anti-nausea and/or anti-vomiting treatment for nausea and/or vomiting that occurs later in the surgery. In addition, the salt forms disclosed herein have the processing advantages associated with improved solubility in polar solvents as compared to free assay forms of compounds useful for <RTIgt; Further, each of the tosylate, the hydrochloride, the malate, the methanesulfonate, the oxalate, the besylate, and the ethanesulfonate has one or more crystalline forms, and the crystalline forms provide the compound The amorphous form has a more consistent physical character than a formula having the following advantages: a compound · a lower impurity content and a more consistent product quality, that is, a more consistent color, dissolution rate, and ease of handling; And longer term stability when incorporated into the agent. As described in detail below, the characteristic X-ray diffraction pattern (see Figures 1, 2 and 9 to 13), the characteristic infrared spectrum (see Figures 4 and 6), and the analytical differential scanning heat can be detected by detecting individual salt forms. The crystalline salt forms of the various compounds of formula I described herein are readily distinguished from each other and from the amorphous form by determining one or more of the (DSC) thermograms (Figs. 7 and 8). 119709.doc -12- 200806666 As shown in the above formula 11, the inventors have unexpectedly discovered that the diazepyr-2-one of the formula i contains a cyclic amine nitrogen of sufficient basicity such that it can be selected from the group consisting of benzenesulfonate The inorganic acids of acid, ethanesulfonic acid and sulfonic acid are protonated (forms the besylate, ethanesulfonate and methanesulfonate of the compound of formula j, respectively). It has also unexpectedly been found that the diazepam-2-one can be selected from the group consisting of malic acid, oxalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, lactic acid, glycolic acid, malonic acid, and hydrazine. The organic acids of -2-naphthoic acid, maleic acid, hippuric acid and camphorsulfonic acid are protonated to form malate, oxalate, fumarate, tartrate, citric acid, respectively, of the compound of formula I Salt, succinate, lactate, glycolate, malonate, hydrazine-hydroxynaphthoate, maleate, hippurate and camphor sulfonate. Furthermore, it has been found that an acid salt selected from the group consisting of maleic acid salt, methanesulfonate, oxalate, benzenesulfonate and ethanesulfonate can be provided in the form of a crystalline solid, the crystal structure of which By protonation of each molecule of the compound of formula I) optionally includes one or more solvent molecules such as toluene, hexane or acetonitrile. The salts of the present invention provide a number of surprising advantages over physical properties in terms of physical properties, such as milling, micron sizing, and ability to dissolve compounds. The preferred crystalline form of the salt is selected from the group consisting of maleic acid salts and methanesulfonate salts. These salts have been found to have thermodynamic stability in addition to the desired solubility and handling characteristics to provide a compound of formula I in a salt form which is readily incorporated into the agent and which is stable under a variety of environmental conditions. As is known, when the therapeutic agent has a water solubility of less than about 10 mg/ml in a pH range from about pH 1 to about pH 7, it typically exhibits a poor rate of absorption. In addition, when administered orally, the therapeutic agent exhibits a solubility of less than 119709.doc 13 200806666 of about 1 mg/ml in this pH range, since solubility is related to absorption in the oral administration d. Limited by dissolution rate ^ Absorption Thus, the improved solubility characteristics of such salts are important for providing oral administrations that are designed to deliver compounds that are therapeutic agents. As described in detail below, in addition to these desired improved solubility characteristics, the physical properties of the selected salt exhibits (4). The compound of the formula is a compound of the formula j and is selected from the group consisting of oxalic acid dibasic acid, methyl benzoic acid, benzoic acid, ethyl benzoic acid, and butyl succinic acid, tartaric acid, tartaric acid, lactic acid, and thiol Acetic acid, ..., Cai; bismuth-acid, • fruit acid, hippuric acid, and camphor acid acid are prepared according to the following procedure: & 0 under the scrambling, the compound of formula 1 in an amount of 0·1 § About 〇2 blessing and equivalent (ie, G.2 mMGl) the selected acid is dissolved in about 3 ml of absolute ethanol in the container; (1) under continuous mixing, anhydrous hydrazine is added dropwise until it is mixed. Become turbid; out) will be just enough to transport, the joy, the main sputum to make thirst, the amount of anhydrous ethanol added to the turbid mixture (usually a few drops); V) (n) stop ΐ (four) and contain vents (4) Covering the container, and the container is allowed to stand for 24 to 48 hours, during which the solid sinks the temple; " At the end of the rest time, the solid is recovered by passing through, :, and then first dried in the air about! ~ (4) small; : ... and then dried overnight in an indoor vacuum at ambient temperature to obtain a salt of a compound of formula I. One or two 氡 I19709.doc -14- 200806666 For some gg a - gas direction S ', various crystalline forms of the granules were prepared according to the following general procedure. M丄, the reaction is reactively crystallized according to the above procedure, or is first precipitated in the form of an amorphous substance by the above-mentioned general-purpose & and then by adding an amorphous salt, and right 曰# 旦 7 'Night day A sample of the salt prepared by recrystallization of the salt of the crystal is placed in a vial, 10% to about 50 mg of sputum. The granules are added to a vial sufficient to completely immerse the dimer, and the solvent is selected from the group consisting of ethanol, isopropylidene, acetonitrile, field, f, ethyl acetate, dichloromethane, and hexane. The solid and solvent are stirred under ambient conditions to provide a solvate crystal such as about 7 days. When a solvate crystal has been prepared, a sample of the suspension solvent is dropped on a sample for use in a powder X-ray diffraction spectrometer and air dried. #分析分析的分析分析的分析。 X-ray spectroscopy was used to analyze these samples according to the procedures described herein. Analytical Procedures The crystalline salt forms of the various chelates are characterized by techniques such as X-ray powder diffraction spectroscopy (PXRD), infrared ray diffraction (IR), and Raman spectroscopy (Raman). The salt form of the selected compound is further characterized by differential scanning calorimetry (DSC) and/or by physical methods including solubility studies and stability studies. X-ray powder diffraction spectroscopy The X-ray powder diffraction spectrum of the sample was obtained using one of the following procedures. For the solvate prepared according to the above procedure, the analysis was carried out on Rigaku according to the following procedure. For the analysis of the sample obtained using the Rigaku Miniflex spectrometer, the following procedure was used (PXRD method 〇. The sample analyzed by the PXRD method was lightly 119709.doc -15-200806666 on the low moon hall, on the plate. The sample was exposed to the surrounding The temperature and humidity of the indoor 裒i brother RlgakU knife light is equipped with six analysis disk transfer rack, which makes the sample rotate at 54 ah, thus the preferred orientation of the crystal in the sample under study is minimized. Rigaku spectrometer also Equipped with copper without Κα2 chopper 〖with radiation source. Spectrometer is also equipped with variable divergence slit and G 3 with receiving slit. From 2.0 to 4 〇. 20 performs scanning range. Use Cu for lu plane Μ The peak verifies the calibration of the instrument. During the scan, the step size of the step of 6 seconds is 〇.〇2 degrees. The data analysis is performed using the Jade P1US (version 5〇26) analysis software. The Savitzky-Golay parabolic filter is used. The data of 丨i points form a smooth curve. Usually, the d" spacing value is accurate within ± 〇〇 4 8 . For some samples, the X-ray powder is obtained using a Bruker D8 diffractometer manufactured in 2 〇〇 2 years. Diffraction spectrum Learning analysis (pxRD method H). The huker diffractometer has parallel optics (4) using a G0BEL beam focusing mirror and a PSD money device with a fixed radial sampling slit. The Bruker diffractometer is used with the Ant〇n Paar TTK450 temperature stage. The source of the nucleus is copper (κα). The divergence slit is fixed at 0.6 ug. The Bruker diffractometer uses a top loaded brass block sample holder. Use PSD to quickly scan from 4. 〇 to 39.9. Photograph_, the sample is loaded on the sample holder and leveled with the glass display (four). The sample chamber temperature is set to hunger, machine (four) generation under the humidity and without nitrogen purge and not under vacuum. Fresh calibration instrument calibration. During the scanning period, the stepping time of G.U1G seconds is 0.013 degrees to G.G2 degrees. Data analysis is performed using the EVA analysis software version ".ο" written by Bruker8 s〇cabim8 The data from 软ι to 0 · 1 5 is formed by the software to form a smooth curve. H9709.doc -16- 200806666 In addition to the solvate samples prepared according to the above procedure, it is used for X-ray powder diffraction ('' PXRD") sample of analysis Subject to minimal preparation to prevent any form of change. Gently load the sample particles into the sample holder to ensure that they form a smooth surface and do not clump together. For samples other than the solvate samples prepared according to the above procedure, Solvent, drying or other preparative steps were used. Infrared spectroscopy The samples were characterized using attenuated total reflectance (ATR) infrared spectroscopy using a Nicolet Instruments NEXUS 670 FTIR equipped with an Avatar Smart Miracle Attenuated Total Reflection (ATR) sample chamber. The spectra were collected using the following parameters: DTGS KBr side detector; KBr beam splitter; scan range: 600 cm-1 to 4000 cnT1; gap setting: 100; resolution: 2; 100 scans per sample. By collecting the background spectrum, a reference standard or particle sample (usually a sample of 3 mg to 5 mg) is placed on the ATR crystal and analyzed by applying pressure to the sample using the pressure arm of the instrument according to the waste recommendation. The spectrum of the sample (reference or sample) is then obtained as a background to sample spectral ratio using vendor proprietary software. Raman spectroscopy Raman spectroscopy (Raman) is performed using one of two procedures. Program I Raman analysis was performed on a Thermo Electron Nicolet Almega Dispersive Raman spectrometer in a high resolution mode. The sample was housed in an NMR sample tube and the spectra were obtained under the following conditions: scan range: 4000 cm "to 90 cm·1; exposure time · 1.0 second; 100 samples and 100 background exposures; 785 nm excitation laser / 100 % power level / parallel laser polarization; 119709.doc -17- 200806666 per millimeter grid 1200 rows; 100 micron slit; camera temperature: -50 ° C. Thermo Electron Nicolet Almega pull set at 50 times magnification Procedure II Raman analysis was performed on a Man microscope. Samples were prepared by placing a small amount of the compound on a microscope slide without using a coverslip, and the spectra were obtained under the following conditions: scan range 3481 cm·1 to 96 cnT1; low resolution Exposure time: 5.0 seconds; 10 samples and 10 background exposures; 780 nm excitation laser (depolarization) / 100% power level; 1200 lines per mm grid; 25 micron pinhole; camera temperature: -48 °C. Differential Scanning Calorimetry Thermal analysis was performed using a TA Instruments modulated differential scanning calorimeter (DSC) at a nitrogen flow rate of 40 ml/min at a heating rate of 10 °C/min. In the open aluminum plate DSC scanning. Solubility testing is performed by placing excess compound in an aliquot of the solvent of interest and equilibrating the slurry under selected temperature conditions (usually ambient temperature). When the solvent is water, hydrochloric acid and hydrogen are used. Sodium oxide adjusts the pH to the desired value. When the slurry mixture is equilibrated, excess solids are centrifuged (water) from the supernatant or filtered (all other solvents) and HPLC is applied to the aliquot of the diluted supernatant. Analysis to quantify the amount of dissolved compound. A pharmaceutical grade solvent was used. Chemical stability tests were performed on aliquots of the salt form of interest by placing a precisely weighed sample of the salt form of the compound of formula I in a polyethylene bag. The sample contained in the bag is sealed in a fiberboard tube equipped with a metal cap, which is stored under specified humidity and temperature for a specified time. By dissolving the contents of the vial and analyzing the amount of dissolved matter by HPLC analysis 119709.doc -18- 200806666 Analysis. If there are specific notes, store the aliquot in a capped amber vial under the conditions mentioned in place of the polyethylene bag. EXAMPLES The maleic acid salt, the chloroformic acid tartrate, the ethanesulfonate salt and the oxalate salt form of the compound of formula I are prepared as follows, as described in detail below, also by including X-ray powder diffraction spectroscopy, infrared spectroscopy. Various spectral techniques of Raman spectroscopy and Raman spectroscopy to characterize the salt forms of the various compounds of formula I. Analyze the stability, solubility and other improved physical properties of the selected form, including differential scanning calorimetry for certain steps (DSC) analysis, unless otherwise specified, in accordance with the disclosure of U.S. Patent Application Serial No. 2003-0158, No. 173, No. 173, filed on May 1, 2000. The procedure disclosed in the present invention) is used to prepare (5S,8S)-8-[{(lR)-l-(3,5-bis-(trifluoromethyl))benzene for the preparation of the salts described herein. Ethyloxy}-indenyl]-8-phenyl-1,7-diazaspiro[4,5]nonan-2-one (a compound of the formula). All reactive crystallization, recrystallization, and pulping procedures are carried out in commercially available solvents at specified grades (unless otherwise specified as pharmaceutical or food grade) and are used in recognized standard form (unless otherwise specified). The maleic acid salt of the compound of formula I is prepared by dissolving ig (2 mmol) of a compound of formula I in 4 ml of methyl tert-butyl ether (MTBE) according to the general procedure described above for the preparation of a salt of a compound of formula I The amorphous maleate salt of the compound of formula I was prepared by scrambling it with 1 equivalent of maleic acid dissolved in 4 ml of isopropanol. According to the general I table private sequence described above, the preparation of the compound of the formula is prepared by slurrying the amorphous maleate prepared above in acetonitrile or isopropyl acetate. H9709.doc -19 - 200806666 Butenoic acid salt form 1 salt. The maleic acid salt form I of the compound of the formula was characterized by x-ray, infrared and Raman spectroscopy using the above procedure and by Dsc. Figure 1 illustrates the gamma-ray, v-ray ray of the maleate salt form. Table VIII below lists 12 characteristic peaks of the diffraction spectrum of the X-ray powder shown in Figure 1, which are based on the diffraction angle expressed in 2 Θ (〇 2θ), and the corresponding "d" in angstroms (Α). The spacing is expressed, and the relative strength of the signal is indicated by the following symbols in adjacent columns: S = strong, M = medium, W =: weak, V = pole, and D = diffusion:
表 VIII 繞射角 (°2Θ ± 0.2^ d間距 (Α, ± 〇·〇4) 相對強度 9.06 9.75 W 10.0 8.84 W 13.5 6.55 Μ 16.5 5.36 Μ 18.0 4.91 Μ 18.8 4.72 Γ Μ 19.9 1 4.46 Μ 20.2 4.39 Μ 21.7 4.08 Μ 23.5 3.79 S 24.3 3.65 Μ 25.3 3.52 Μ 在表vm中所示之式1化合物之順丁烯二酸鹽形式I鹽的 特徵峰中,8個最具特徵性之峰為在繞射角等於9.%、 1〇·〇、13.5、16.5、18.0、後2、23.5及24.3(以。2以單位) 處出現之Φ,且4個最具特徵性之峰為在繞射角等於 10·0、13·5 ' 16·5及23.5(以。2Θ為單位)處出現之峰。 圖3說明使用上述程序所獲得之幻化合物之結晶順丁歸 119709.doc -20- 200806666 二酸鹽形式I鹽形式的透射紅外線光譜。表IX列出圖3中所 說明之光譜的12個最具特徵性之峰,且在相鄰列中使用以 下符號表示所列各峰之相對吸收強度:S=強,M==中等, 3 =寬,V=極,弱。Table VIII Diffraction angle (°2Θ ± 0.2^ d spacing (Α, ± 〇·〇4) Relative strength 9.06 9.75 W 10.0 8.84 W 13.5 6.55 Μ 16.5 5.36 Μ 18.0 4.91 Μ 18.8 4.72 Γ Μ 19.9 1 4.46 Μ 20.2 4.39 Μ 21.7 4.08 Μ 23.5 3.79 S 24.3 3.65 Μ 25.3 3.52 中 Of the characteristic peaks of the maleate form I salt of the compound of formula 1 shown in Table vm, the 8 most characteristic peaks are at the diffraction angle Equal to 9.%, 1〇·〇, 13.5, 16.5, 18.0, 2, 23.5, and 24.3 (in .2 in units) where Φ occurs, and the 4 most characteristic peaks are at a diffraction angle equal to 10 · Peaks appearing at 0, 13·5 '16·5 and 23.5 (in units of .2Θ). Figure 3 illustrates the crystals of the phantom compound obtained using the above procedure. cis gui 119709.doc -20- 200806666 diacid salt Transmission infrared spectroscopy in the form of Form I salt. Table IX lists the 12 most characteristic peaks of the spectrum illustrated in Figure 3, and the following symbols are used in adjacent columns to indicate the relative absorption intensities of the listed peaks: S = Strong, M== medium, 3 = wide, V=polar, weak.
表IX 吸收峰 波數 (cm1) 相對強度 1 1695 S 1576 WB 3 1379 MB 4 1319 Μ ~ 5 1276 S 6 1183 S 7 1117 SB 8 1900 ~ S 9 866 10 767 "s ~ 11 682 Is ~ ' 12 644 ^SB ~ Μ穴付傲性之 峰為在 1695、1319、1276、1183、1117、则、866 及⑻ 公分倒數(cm-1)處出現之峰,且4個最具特徵性之峰為在 1695、1276、1117及 682 cnT1 處出現之峰。 圖4說明使用上述程序所獲得之幻化合物之結晶順 二酸鹽形式1鹽形式的拉曼光譜。下表X列出圖4中所1明 之光譜的12個最具特徵性之散射峰(以公分倒數,c: 示)’且在相鄰列中以下列爲骑本— 下列付號表不所列各峰之相對吸收 強度.S,,M=中等,w=弱,v=極,b=寬。 119709.doc -21 - 200806666 表xTable IX Absorption peak wave number (cm1) Relative intensity 1 1695 S 1576 WB 3 1379 MB 4 1319 Μ ~ 5 1276 S 6 1183 S 7 1117 SB 8 1900 ~ S 9 866 10 767 "s ~ 11 682 Is ~ ' 12 644 ^SB ~ The peak of the acupoint is the peak appearing at 1695, 1319, 1276, 1183, 1117, then, 866 and (8) centimeters (cm-1), and the four most characteristic peaks are Peaks appearing at 1695, 1276, 1117, and 682 cnT1. Figure 4 illustrates the Raman spectrum of the crystalline cisacid form 1 salt form of the phantom compound obtained using the above procedure. Table X below lists the 12 most characteristic scattering peaks of the spectrum shown in Figure 4 (reciprocal in centimeters, c:) and the following columns are in the adjacent columns - the following payment tables are not The relative absorption intensities of the columns are .S,, M = medium, w = weak, v = pole, b = width. 119709.doc -21 - 200806666 Table x
散射♦ 波數 相對強度 Λ ---- icitT1) 1 r% " 1694 MB λ 1--- J^20_ MB Λ ^380 MB 4 1203 M 5 c "· ---— T〇36 ~ WB 6 1002 s 7 〇 ---- 728 M 〇 9 ^ 620 Y T WR 10 ^ 1¾ VV JJ WB 11 'τη MB 12 '^ 752 ' SB 在表X中所不之特徵峰中,化合物之8個最具特徵性之峰 為在 1694、1620、138〇、1203 處出現之峰’且4個最具特徵性之峰為在162G、1380、 1002及728 cmf1處出現之峰。Scattering ♦ Relative strength of wave number Λ ---- icitT1) 1 r% " 1694 MB λ 1--- J^20_ MB Λ ^380 MB 4 1203 M 5 c "· ---- T〇36 ~ WB 6 1002 s 7 〇---- 728 M 〇9 ^ 620 YT WR 10 ^ 13⁄4 VV JJ WB 11 'τη MB 12 '^ 752 ' SB Among the characteristic peaks in Table X, the 8 of the compounds are the most The characteristic peaks are peaks appearing at 1694, 1620, 138, and 1203' and the four most characteristic peaks are peaks appearing at 162G, 1380, 1002, and 728 cmf1.
圖7 口兒明自使用上述程序所獲得之式ι化合物之結晶順丁 烯-酸鹽形式I鹽形式的差示掃描熱量測定分析獲得之D s C 溫譜圖。參看圖7,DSC溫譜圖含有集中在大約赋處之 寬吸熱。 ⑼,叫8-[{(1R)邻,5_雙_(三氟甲基)苯基)乙氧基卜甲 基]冬苯基_1,7_:氮螺[4,5]癸相之順丁烯:酸鹽形式Π 鹽(式I化合物之順丁稀二酸鴎 形式11鹽)由使用上述非晶形 鹽製備程序沉澱之式I化合物 初之順丁烯二酸鹽來製備。因 此,根據本文所述之漿液製備 、, k用私序將如上所述製備之 百先沉澱之順丁烯二酸鹽在甲 伐甲本中製成漿液而獲得式^匕 119709.doc -22. 200806666 合物之結晶順丁烯二酸鹽形式π鹽。 參看圖2、5、6及8,使特徵峰程序藉由X-射線、紅外線 及拉曼光譜法來表徵且藉由DSC來分析式I化合物之順丁婦 二酸鹽形式II鹽。下表XI列出圖2中所示之X射線粉末繞射 光譜之12個特徵峰,其根據以20度數(。20)表示之繞射角、 以埃(Α)為單位之相應”d"間距及以下列符號表示之信號相 對強度(nRI·’): S=強,M=中等,弱,V二極且,D =擴散 列出:Figure 7 is a graph showing the D s C thermogram obtained by differential scanning calorimetry analysis of the crystalline cis-butene-acid salt form I salt form of the compound of the formula ι obtained using the above procedure. Referring to Figure 7, the DSC thermogram contains a broad endotherm focused on approximately the assignment. (9), called 8-[{(1R) o,5_bis-((trifluoromethyl)phenyl)ethoxymethyl]-t-phenylphenyl-1,7_:aziro[4,5]pyrene The olefinic acid salt form (the cis succinate form 11 salt of the compound of formula I) is prepared from the maleic acid salt of the compound of formula I which is precipitated using the amorphous salt preparation procedure described above. Therefore, according to the preparation of the slurry described herein, k is prepared by slurrying the maleic acid salt prepared as described above in the acetaminophen to obtain the formula: 匕 119709.doc -22 . 200806666 Crystalline maleate form π salt. Referring to Figures 2, 5, 6 and 8, the characteristic peak program is characterized by X-ray, infrared and Raman spectroscopy and the cis-butane salt form II salt of the compound of formula I is analyzed by DSC. Table XI below lists 12 characteristic peaks of the X-ray powder diffraction spectrum shown in Figure 2, which are based on the diffraction angle expressed in degrees (20) and the corresponding "d" in angstroms (Α). Spacing and signal relative strength (nRI·') expressed by the following symbols: S = strong, M = medium, weak, V dipole and D = diffusion listed:
表XI 繞射角 (°2Θ ± 0.2) d間距 (A,土 0.04) 相對強度 4.8 18.47 Μ 9.5 9.26 Μ 10.5 8.45 Μ 12.0 7.38 S 15.1 5.88 Μ 17.5 5.07 Μ 20.0 4.44 MB 20.3 4.38 MB 22.8 3.89 MB 24.0 3.70 M 24.5 3.64 S 28.9 3.08 MB -------------——1 在表XI中所示之式][化合物之結晶順丁烯二酸鹽形式U鹽 的特徵峰中,8個最具特徵性之峰為在繞射角(以。2Θ為單 位)等於4.8、9.5、10.5、12.0、15.1、175、24.5及28.9處 出現之峰,且4個最具特徵性之峰為在繞射角(以。20為$ 位)等於4·8、12.0、24.5及28.9處出現之峰。 圖5次明使用上述程序獲得之式丨化合物之結晶順丁烯二 119709.doc -23 - 200806666 酸鹽形式11鹽形式的透射紅外線光譜。下表ΧΠ列出圖5中 所說明之紐的12個最具特徵性之峰,且在相鄰列中使用 下列符號表示所列各峰之相對吸收強度:s=強,μ=中 等,弱,Β =寬,v=極。Table XI Diffraction angle (°2Θ ± 0.2) d spacing (A, soil 0.04) Relative strength 4.8 18.47 Μ 9.5 9.26 Μ 10.5 8.45 Μ 12.0 7.38 S 15.1 5.88 Μ 17.5 5.07 Μ 20.0 4.44 MB 20.3 4.38 MB 22.8 3.89 MB 24.0 3.70 M 24.5 3.64 S 28.9 3.08 MB -------------——1 In the characteristic peaks of the U salt of the crystalline maleate form of the compound shown in Table XI] The eight most characteristic peaks are those at diffraction angles (in .2 )) equal to 4.8, 9.5, 10.5, 12.0, 15.1, 175, 24.5, and 28.9, and the four most characteristic peaks. It is the peak appearing at the diffraction angle (in bits of .20 for $bit) equal to 4·8, 12.0, 24.5, and 28.9. Figure 5 shows the transmission of infrared spectroscopy of the salt form of the salt form of the oxime compound obtained by the above procedure using the above procedure butyl 119709.doc -23 - 200806666. The table below lists the 12 most characteristic peaks of the nucleus illustrated in Figure 5, and uses the following symbols in adjacent columns to indicate the relative absorption intensities of the listed peaks: s = strong, μ = medium, weak, Β = width, v = pole.
表XIITable XII
吸收峰 (cnT1) 相對強度 1 1687 ~~ S 2 145Γ~ ~~ Μ 3 Τ434~ ~~ MB 4 1382~ S 5 ~1342 Μ 6 1277 ~~ S 7 Il68 ~~ SB 8 1124 ^VB 9 *897 ~~ 10 863 S 11 766 M 12 682 S 在表XII中所示之特徵峰中,化合物之8個最具特徵性之 峰為在 1687、1277、1168、1124、897、863、766及 682公 分倒數(cm·1)處出現之峰,且4個最具特徵性之峰為在 1687、1277、1124及 682 cnT1 處出現之峰。 圖ό說明使用上述程序獲得之式I化合物之結晶順丁稀二 酸鹽形式II鹽形式的拉曼光譜。下表ΧΠΙ列出圖6中所說明 之光譜的12個最具特徵性之散射峰(以公分倒數,cnr1表 示),且在相鄰列中使用下列符號表示所列各峰之相對強 度· 強,M=中等,弱,極,B=寬。 119709.doc -24- 200806666Absorption peak (cnT1) Relative intensity 1 1687 ~~ S 2 145Γ~ ~~ Μ 3 Τ434~ ~~ MB 4 1382~ S 5 ~1342 Μ 6 1277 ~~ S 7 Il68 ~~ SB 8 1124 ^VB 9 *897 ~ ~ 10 863 S 11 766 M 12 682 S Among the characteristic peaks shown in Table XII, the 8 most characteristic peaks of the compound are reciprocal at 1687, 1277, 1168, 1124, 897, 863, 766 and 682 cm. The peak appearing at (cm·1), and the four most characteristic peaks are the peaks appearing at 1687, 1277, 1124, and 682 cnT1. BRIEF DESCRIPTION OF THE DRAWINGS The Raman spectrum of the crystalline cis-succinate form II salt form of the compound of formula I obtained using the above procedure is illustrated. The table below lists the 12 most characteristic scattering peaks of the spectrum illustrated in Figure 6 (represented by the reciprocal of the cent, cnr1), and the following symbols are used in adjacent columns to indicate the relative intensity of the listed peaks. M = medium, weak, polar, B = wide. 119709.doc -24- 200806666
表 XIII 散射峰 — 'ϊϊ (cm4) 相對強度 1 Τ700 ~ΜΒ 2 ^1623 "mb 3 ^454~~' WB MB ~~ 4 ] 5 ~ 1|84~~~ ^202~' MB — ^ 6 1003~— "s ^— 7 〇 ~~ "m ^ 8 9 10 Λ Λ J04 ~~~ |m ~ ^621 ~ — [M ^ 519 WB 11 ^281 ~~~ "mb 12 1?1 在表XIII中所示之特徵峰中,化合物之8個最具特徵性 281 cm·1處出現之峰,且4個最具特徵性之峰為在Mu、 1384、1003及281 cm·1處出現之峰。 圖8說明使用上述程序對式化合物之結晶順丁稀二酸鹽 形式II鹽形式之分析的差示掃描熱量測定溫譜圖。參看圖 8,溫譜圖含有集中在大約155。〇處之吸熱尖峰。 式I化合物之甲磺酸鹽 藉由將1 g(2 mmolJSJ化合物及丨當量甲磺酸溶解於恰 好足以溶解此等起始物質之量的無水乙醇(通常為約4 mi) 中,隨後添加大約30 ml無水***來製備(58,88)_8-[{(111)-1-(3,5-雙-(三氟甲基)苯基)乙氧基卜甲基]苯基_1,7_二氮 螺[4,5]癸-2-酮之結晶甲磺酸鹽(式:[化合物之甲磺酸鹽形式 I鹽)。藉由以通風蓋覆蓋混合物,在周圍條件下靜置丨至2 天之時段使式I化合物之甲磺酸鹽形式〗鹽之晶體沉澱。藉 119709.doc -25- 200806666 由使用真空過濾收集此等晶體,將其以無水乙_洗滌且在 室内真空下乾燥來製備此等晶體用於X-射線繞射分析。 藉由X射線粉末繞射光譜法來判別式I化合物之結晶甲磺 酸鹽形式1鹽。圖9說明式I化合物之甲磺酸鹽形式I鹽之x 射線粕末繞射光譜。下表XIV列出圖9中所示之X射線粉末 ⑺射光瑨之12個特徵峰,其根據以2Θ度數表示之繞射 角、以埃(Α)為單位之相應”d”間距列出,且在下一欄中以 下列符號表示所出示各列峰之相對強度(實):8=強,· 中專’ W-弱’ V=極且,擴散:Table XIII Scattering Peaks - 'ϊϊ (cm4) Relative Intensity 1 Τ700 ~ΜΒ 2 ^1623 "mb 3 ^454~~' WB MB ~~ 4 ] 5 ~ 1|84~~~ ^202~' MB — ^ 6 1003~— "s ^— 7 〇~~ "m ^ 8 9 10 Λ Λ J04 ~~~ |m ~ ^621 ~ — [M ^ 519 WB 11 ^281 ~~~ "mb 12 1?1 Among the characteristic peaks shown in Table XIII, the eight most characteristic peaks of the compound at 281 cm·1, and the four most characteristic peaks are at Mu, 1384, 1003, and 281 cm·1. The peak that appears. Figure 8 illustrates a differential scanning calorimetry thermogram of the analysis of the crystalline cis-succinate salt form II salt form of the compound using the procedure described above. Referring to Figure 8, the thermogram contains a concentration of approximately 155. The heat absorbing peak of the cockroach. The mesylate salt of the compound of formula I is prepared by dissolving 1 g (2 mmol of JSJ compound and hydrazine equivalent methanesulfonic acid in absolute ethanol (usually about 4 mi) in an amount sufficient to dissolve the starting materials, followed by addition. Preparation of (58,88)_8-[{(111)-1-(3,5-bis-(trifluoromethyl)phenyl)ethoxymethyl]phenyl_1,7_2 from 30 ml of anhydrous diethyl ether Crystalline methanesulfonate of the snail [4,5]nonan-2-one (formula: [methanesulfonate form I salt of the compound). The mixture is allowed to stand under ambient conditions to 2 by covering the mixture with a venting cap. The crystals of the mesylate salt of the compound of formula I were precipitated over a period of time. These crystals were collected by vacuum filtration using 119709.doc -25-200806666, which was washed with anhydrous ethyl acetate and dried under vacuum in a room. These crystals are prepared for X-ray diffraction analysis. The crystalline mesylate salt form 1 salt of the compound of formula I is discriminated by X-ray powder diffraction spectroscopy. Figure 9 illustrates the mesylate salt form of the compound of formula I. X-ray diffraction diffraction spectrum of salt. Table XIV below lists 12 characteristic peaks of the X-ray powder (7) radiant 图 shown in Figure 9, which is expressed in terms of 2 Θ. The angle of incidence, the corresponding "d" spacing in angstroms (Α) is listed, and the relative intensity of each column peak is shown in the following column with the following symbols: 8 = strong, · secondary school 'W-weak ' V= extremely, diffusion:
表XIVTable XIV
特中:示之式1化合物之甲續酸鹽形式1鹽形式的 =峰中,8個最具特徵性之峰為在 荨於7.3、10.2、12·9、 勹早位) 現之峰,且4個最具特徵‘之:9二22.7、24.G及28·9處出 等於7.3' Π).2、22.7及為在繞射角(以。⑼為單位) 8·9處出現之峰。 根據上述用於製備式1化合物之鹽之通用程序,藉由们 H9709.doc ' 26 - 200806666 g(2 mmol)式I化合物溶解於4 ml甲基第三丁基醚幻中 且將其與丨當量溶於4 ml異丙醇中之甲磺酸—起攪拌來製 備式Η匕合物之非晶形甲磺酸鹽。藉由真空過渡分離此非 :¾形物質。式I化合物之甲磺酸鹽之兩種額外結晶形式可 藉由漿液結晶自此非晶形物質來製備。 口此根據本文所述之製漿程序,藉由將如上所述製備 之非晶形甲磺酸鹽在等體積混合之乙酸乙_與己烷混合溶 劑中製成漿液來製備(5S,8S)|[{(1R)小(3,5_雙_(三氟甲 基)苯基)乙氧基}_甲基]_8_苯基],7_二氮螺同之 甲,、酉夂皿幵/式II鹽(式I化合物之甲績酸鹽形式Η鹽)。根據 上述PXRD方法][藉由χ射線粉末繞射光譜法來分析式工化合 物之甲磺酸鹽形式„鹽形式之晶體。下表χν列出圖1〇中所 示之X射線粉末繞射光譜之12個特徵峰之繞射角(以2θ度數 (2Θ)表不)、以埃(Α)為單位之相應"d,,間距,且在相鄰列 中以下列符號表示所列各峰之相對強度(,,ri") : s=強,· 中等,弱,V=極且,D,散:In particular, the peak of the salt form of the compound of formula 1 is shown in the form of the salt form of the salt form, and the eight most characteristic peaks are the peaks at 7.3, 10.2, 12.9, and 勹. And the four most characteristic 's: 9 2 22.7, 24.G and 28.9 are equal to 7.3' Π). 2, 22.7 and appear at the diffraction angle (in units of (9)) 8·9 peak. According to the above general procedure for the preparation of the salt of the compound of the formula 1, by H9709.doc ' 26 - 200806666 g (2 mmol) of the compound of the formula I is dissolved in 4 ml of methyl tert-butyl ether and it is combined with hydrazine The methanesulfonic acid equivalently dissolved in 4 ml of isopropanol was stirred to prepare an amorphous mesylate salt of the formula. This non-3⁄4-shaped substance is separated by a vacuum transition. Two additional crystalline forms of the mesylate salt of the compound of formula I can be prepared from the amorphous material by crystallization of the slurry. According to the pulping procedure described herein, (5S, 8S) is prepared by slurrying the amorphous mesylate salt prepared as described above in an equal volume of a mixed solvent of ethyl acetate and hexane. [{(1R) small (3,5-bis-(trifluoromethyl)phenyl)ethoxy}_methyl]_8_phenyl], 7-diaza snail with a, 酉夂 幵/Formula II salt (formula salt of the compound of formula I). According to the above PXRD method] [analyze the mesylate form of the formula compound by the χ ray powder diffraction spectroscopy „ salt form crystal. The following table χ ν lists the X-ray powder diffraction spectrum shown in Fig. 1〇 The diffraction angle of the 12 characteristic peaks (indicated by 2θ degrees (2Θ)), the corresponding "d, spacing in angstroms (Α), and the relative symbols in the adjacent columns are represented by the following symbols Strength (,, ri") : s=strong, · medium, weak, V=polar and D, scattered:
表XVTable XV
繞^射角 (°2Θ ±〇.2) d間距 1^±0.04) 相對強度 __6.2 __14.20 Μ __9.24 Μ 10.0 __8.87 W 12.4 _7.16 MB __14.3 6.18 WB __5.85 WB __4.46 VS ---2D _ _ 4.19 S __22Ό _4.03 M 119709.doc -27- 200806666Winding angle (°2Θ ±〇.2) d spacing 1^±0.04) Relative strength __6.2 __14.20 Μ __9.24 Μ 10.0 __8.87 W 12.4 _7.16 MB __14.3 6.18 WB __5. 85 WB __4.46 VS ---2D _ _ 4.19 S __22Ό _4.03 M 119709.doc -27- 200806666
22.7 — Μ 23.6 -376_ MB 2^8 MB 在表Xv中所不之式1化合物之甲磺酸鹽形式II鹽形式的 特斂峰中,8個最具特徵性之峰為在繞射角(以〇2Θ為單位) 等於 6.2、9.6、12.4、19.9、21.2、22.7、23.6 及 24·8 處出 現之峰,且4個最具特徵性之峰為在繞射角(以。2Θ為單位) 等於6.2、9.6、19.9及21.2處出現之峰。 藉由將10 g如上所述製備之非晶形甲磺酸鹽溶解於經加 溫至40 C之溫度時恰好足以溶解該鹽之量的曱苯中且使溶 液冷至室溫來製備^心“卜^以^幻心-^^雙气三氟甲基) 苯基)乙氧基卜甲基]-8-苯基_丨,7_二氮螺[4,5]癸-2_酮之甲磺 酸鹽形式111鹽形式(式I化合物之甲磺酸鹽形式III鹽形 式)°藉由X射線粉末繞射光譜法來表徵式I化合物之甲石黃 酸鹽形式111鹽。圖11說明結晶曱磺酸鹽形式III鹽之X射線 粉末繞射光譜。下表XVI列出圖11中所示之X射線粉末繞 射光譜之12個特徵峰,列出其以2Θ度數(°2Θ)表示之繞射 角、以埃(Α)為單位之相應,,d”間距,且在相鄰列中以下列 符號表示所列峰之相對強度("RI”): S=強,中等,w= 弱’ V=極且,B =寬:22.7 — Μ 23.6 -376_ MB 2^8 MB Of the specific peaks of the mesylate salt form II salt form of the compound of formula 1 in Table Xv, the eight most characteristic peaks are at the diffraction angle ( In 〇2Θ, it is equal to the peaks at 6.2, 9.6, 12.4, 19.9, 21.2, 22.7, 23.6, and 24·8, and the four most characteristic peaks are at the diffraction angle (in .2Θ) Equal to the peaks appearing at 6.2, 9.6, 19.9, and 21.2. By preparing 10 g of the amorphous mesylate salt prepared as described above, it is prepared by dissolving in an amount of toluene which is sufficient to dissolve the salt at a temperature of 40 C and allowing the solution to cool to room temperature.卜^以^幻心-^^bis-trifluoromethyl)phenyl)ethoxymethyl]-8-phenyl-indole, 7-diazaspiro[4,5]indole-2-one Salt form 111 salt form (methanesulfonate form III salt form of the compound of formula I) ° Characterization of the formazin form 111 salt of the compound of formula I by X-ray powder diffraction spectroscopy. Figure 11 illustrates crystallization 曱X-ray powder diffraction spectrum of the sulfonate form III salt. Table XVI lists 12 characteristic peaks of the X-ray powder diffraction spectrum shown in Fig. 11, which are listed as 2 turns (° 2 Θ). The angle of incidence, in angstroms (Α), d' spacing, and the relative intensity of the listed peaks in the adjacent columns ("RI"): S = strong, medium, w = weak V=polar and B=width:
表XVI 繞射角 (〇2^±0^ d間距 f A, 土 〇·〇4) 相對強度 4.7 18.62 S ~ 8.0 11.10 W 9.5 9.26 Μ — 17.4 -----— 5.09 WD — 119709.doc -28- 200806666Table XVI diffraction angle (〇2^±0^d spacing f A, soil 〇·〇4) Relative strength 4.7 18.62 S ~ 8.0 11.10 W 9.5 9.26 Μ — 17.4 ------ 5.09 WD — 119709.doc - 28- 200806666
在表XVI中所示之式1化合物之甲磺酸鹽形式πι鹽形式的 特被峰中’ 8個最具特徵性之峰為在繞射角(以。2Θ為單位) 等於(7、9.5、18.6、192、2〇9、221、241及257處出 現之峰,且4個最具特徵性之峰為在繞射角(以。2Θ為單位) 等於(7、9.5、19·2及2〇·9處出現之峰。 式I化合物之草酸鹽 根據上述通用程序,將!當量 (三氟甲基)苯基)乙氧基卜甲基]_8_苯基=1,7_二氮螺[4,5]癸_ 2-酮之化合物(式〗化合物)與丨當量草酸之混合物溶解於無 水乙醇中,向混合物中添加足夠的無水***以誘發渾濁出 現,將額外乙醇滴定至混合物中直至溶液回復為澄清狀 態,且將溶液靜置48小時直至草酸鹽形式【鹽之晶體沉 殿’藉此來製備式I化合物之草酸鹽。接著藉由真空過據 收集式I化合物之草酸鹽形式I鹽形式之晶體且風乾。 圖12說明式I化合物之草酸鹽形式I鹽形式之叉射線粉末 繞射光譜。下表XVII列出圖12中所示之X射線粉末繞射光 错之11個特徵峰的以2Θ度數(。20)表示之繞射角、以埃(a) 為單位之相應”d"間距,且在相鄰列中使用下列符號表八 所列各峰之相對強度(nRI") ·· S二強,中等,弱,v== 119709.doc -29- 200806666In the special peak of the mesylate salt form of the compound of formula 1 shown in Table XVI, the 'eight most characteristic peaks are at the diffraction angle (in units of .2 )) equal to (7, 9.5). Peaks appearing at 18.6, 192, 2〇9, 221, 241, and 257, and the four most characteristic peaks are at the diffraction angle (in units of .2 )) equal to (7, 9.5, 19·2 and The peak of the compound of formula I. The oxalate salt of the compound of formula I according to the above general procedure, equivalence (equivalent (trifluoromethyl)phenyl)ethoxymethyl]_8_phenyl=1,7-diaza snail A mixture of [4,5]癸_2-ketone compound (formula compound) and an equivalent of oxalic acid is dissolved in absolute ethanol, and sufficient anhydrous ether is added to the mixture to induce turbidity, and additional ethanol is titrated into the mixture until The solution returned to a clear state and the solution was allowed to stand for 48 hours until the oxalate form [crystal salt of the salt] was used to prepare the oxalate salt of the compound of formula I. The oxalic acid of the compound of formula I was then collected by vacuum. Crystals in the form of a salt form I salt and air dried. Figure 12 illustrates the cross-section of the oxalate salt form I salt of the compound of formula I Powder diffraction spectrum. Table XVII below shows the diffraction angle of 11 characteristic points (.20) of 11 characteristic peaks of the X-ray powder diffraction optical error shown in Fig. 12, in units of angstroms (a). "d" spacing, and use the relative intensity of the peaks listed in Table 8 in the adjacent columns (nRI") ·· S is strong, medium, weak, v== 119709.doc -29- 200806666
極,B=寬且,D=擴散: 表 XVIIPole, B = wide and D = diffusion: Table XVII
在表XVII中所V之式I化合物之草酸鹽形式J鹽形式的特 徵峰中,8個最具特徵性之峰為在繞射角(以。2β為單位)等 於 5.6、9.2、U.9、19.8、21.〇、21 5、22 8及 23 8處出現 之峰’且4個最具特徵性之峰為在繞射角(以。⑼為單位)等 於5.6、19·8、21.0及22.8處出現之峰。 式I化合物之乙磺酸鹽 將1當量(5S,8S)-8-[{(1R)-l-(3,5-雙_(三氟甲基)苯基)乙 氧基}-甲基]-8-苯基— π二氮螺[4,5]癸·2晒(式【化合物)與 1當量乙磺酸之混合物溶解於無水乙醇中,向混合物中添 加足夠的無水乙_以誘發渾濁出%,將額外乙醇滴定至混 合物中直至溶液回復為澄清狀態,且將溶液靜置48小時直 至式1化合物之乙續酸鹽形式1鹽形式之晶體沉殿,藉此來 製備式I化合物之乙磺酸鹽。藉由真空過濾收集乙磺酸鹽 形式I鹽之晶體且風乾。 119709.doc -30- 200806666 圖13說明式I化合物之乙磺酸鹽形式I鹽形式之χ射線粉 末繞射光譜。下表χνπ中列出圖13中所示之X射線粉末繞 射光譜之12個最具特徵性之峰的以20度數(。20)表示之繞射 角、以埃(Α)為單位之相應,,d”間距,且在相鄰列中以下列 符號表示所列各峰的之相對強度("RI”)·· 強,中等, 弱,v=極,寬且,擴散:Among the characteristic peaks of the oxalate form J salt form of the compound of formula I in Table XVII, the eight most characteristic peaks are at the diffraction angle (in units of .2β) equal to 5.6, 9.2, U. 9, 19.8, 21.〇, 21 5, 22 8 and 23 8 peaks appear and 4 of the most characteristic peaks are at the diffraction angle (in units of (9)) equal to 5.6, 19·8, 21.0 And the peak that appeared at 22.8. The ethanesulfonate salt of the compound of formula I will have 1 equivalent of (5S,8S)-8-[{(1R)-l-(3,5-bis-(trifluoromethyl)phenyl)ethoxy}-methyl ]-8-Phenyl-π-diazaspiro[4,5]癸·2 drying (a mixture of the formula [compound) and 1 equivalent of ethanesulfonic acid is dissolved in absolute ethanol, and sufficient anhydrous B is added to the mixture to induce The turbidity is %, the additional ethanol is titrated into the mixture until the solution returns to a clear state, and the solution is allowed to stand for 48 hours until the crystal of the compound of the formula 1 is in the form of a salt of the salt form, thereby preparing the compound of the formula I The ethanesulfonate. The crystals of the ethanesulfonate Form I salt were collected by vacuum filtration and air dried. 119709.doc -30- 200806666 Figure 13 illustrates the x-ray diffraction spectrum of the sulfonate salt form I salt of the compound of formula I. The following table χνπ lists the diffraction angles expressed by 20 degrees (.20) of the 12 most characteristic peaks of the X-ray powder diffraction spectrum shown in Fig. 13 in units of angstroms (Α). ,, d" spacing, and the relative intensity of the listed peaks in the adjacent columns ("RI")·· strong, medium, weak, v=polar, wide and diffuse:
表 XVIIITable XVIII
繞射角 (°2Θ 士 0.2) d間距 (A, ± 0.04) 相對強度 7.1 12.37 WB 9.9 8.89 WD 11.4 7.73 Μ 12.2 7.27 W 12.8 6.90 Μ 16.6 5.33 WD 18.3 4.84 Μ 19.4 4.57 Μ 20.0 4.44 S 20.5 4.32 W 21.2 4.18 Μ 22.0 4.04 WD 特欲峰中’ 8個最具特徵性之峰為在繞射角(以,為單位) 等於 9·9、11·4、12·8、16·6、18 3、2〇 〇、212及 22 〇處出 =之峰,且4個最具特徵性之峰為在繞射角(以。別為單 專於U.4、12.8、20,0及21.2處出現之峰。 【圖式簡單說明】 人L1表示式1化合物之結晶順丁稀二酸鹽形式ι(曱苯溶劑 ° )之特徵性X射線粉末繞射圖讀,[縱車由:強度(cps, H9709.do, ”31- 200806666 計數(平方根));橫軸:2Θ(度)]。 圖2表示式I化合物之結晶順丁 人物^处 作二酸鹽形式π(乙腈溶劑 口物)之特徵性X射線粉末繞射 耵圖瑨,[縱軸:強度(CPS, °卞數(平方根));橫軸·· 2Θ(度)]。 圖3表示式I化合物之結晶順丁 入私w 』席二酸鹽形式1(甲苯溶劑 口 )之特徵性紅外線光譜,[縱輛· # u ^ 站· ϋ 袖·透射率(百分數);橫 釉·波數(cm·1);]。 二酸鹽形式1(甲苯溶劑 拉曼位移(公分倒數); 二酸鹽形式11(乙腈溶劑 •透射率(百分數);橫 圖4表示式I化合物之結晶順丁稀 合物)之特徵性拉曼光譜,[橫軸: 縱轴:與背景相比之相對強度]。 圖5表示式I化合物之結晶順丁婦 合物)之特徵性紅外線光譜,[縱軸 軸:波數(cnT1)]。 -圖6表示式ϊ化合物之結晶順丁烯二酸鹽形式π(乙腈溶劑 二物)之特欲性拉哭光譜,[橫轴:拉曼位移(公分倒數); 縱軸·與背景相比之相對強度]。 人圖7表不式ζ化合物之結晶順丁烯二酸鹽形式1(甲苯溶劑 。物)之特徵性差不掃描熱量測定溫譜圖,[縱軸··熱流量 (eal/sec/g);橫軸:溫度(攝氏度。 圖8表不式I化合物之結晶順丁烯二酸鹽形式^(乙腈溶劑 口物)之特徵性差示掃描熱量測定溫譜圖,[縱軸:熱流量 (Cal/sec/g);橫軸:溫度(攝氏度)]。 圖9表示式I化合物之結晶甲磺酸鹽形式][(自乙酸乙酯/己 烧混合溶劑結晶)之特徵性X射線粉末繞射圖譜,[縱軸: 119709.doc -32- 200806666 強度(CPS,計數(平方根));橫軸·· 2Θ(度)]。 圖10表示式I化合物之結晶甲石黃駿鹽形式Η (自甲苯結晶) 之特徵性X射線粉末繞射圖譜,[縱軸:強度(cps,計數 (平方根));橫軸:2Θ(度)]。 圖11表示式I化合物之結晶曱磺酸鹽形式ΠΙ(自甲苯結晶) 之特徵性X射線粉末繞射圖譜,[縱軸:強度(cps,計數 (平方根));橫軸:2Θ(度)]。 圖12表不式I化合物之結晶草酸鹽形式之特徵性X射線粉 末繞射圖譜,[縱輪:強度(cps,計數(平方根));橫轴: 2Θ(度)]。 圖13表示式1化合物之結晶乙磺酸鹽形式之特徵性X射線 粉末繞射圖譜,[縱缸·故,斗叙 I釉·強度(CPS,叶數(平方根));橫 軸:2Θ(度)]。 119709.doc -33 -Diffraction angle (°2Θ0.2) d spacing (A, ± 0.04) Relative strength 7.1 12.37 WB 9.9 8.89 WD 11.4 7.73 Μ 12.2 7.27 W 12.8 6.90 Μ 16.6 5.33 WD 18.3 4.84 Μ 19.4 4.57 Μ 20.0 4.44 S 20.5 4.32 W 21.2 4.18 Μ 22.0 4.04 WD Special peaks 'The eight most characteristic peaks are at the diffraction angle (in units) equal to 9·9, 11·4, 12·8, 16·6, 18 3, 2 〇〇, 212 and 22 〇 = = = peak, and the four most characteristic peaks are at the diffraction angle (to be a single peak for U.4, 12.8, 20, 0 and 21.2) [Simple description of the diagram] Human L1 represents the characteristic X-ray powder diffraction pattern of the crystalline cis-succinate form of the compound of formula 1 (m-benzene solvent °), [vertical vehicle: strength (cps, H9709) .do, "31-200806666 count (square root)); horizontal axis: 2 Θ (degrees)]. Figure 2 shows the characteristic of the compound of formula I as a diacid salt form π (acetonitrile solvent) X-ray powder diffraction pattern 瑨, [vertical axis: intensity (CPS, ° 卞 (square root)); horizontal axis · · 2 Θ (degrees)]. Figure 3 shows the crystal of the compound of formula I Intrinsic infrared spectrum of the succinate form 1 (toluene solvent port), [longitudinal · # u ^ station · 袖 sleeve · transmittance (percent); horizontal glaze · wave number (cm · 1); Diacid form 1 (toluene solvent Raman shift (cm reciprocal); diacid form 11 (acetonitrile solvent • transmittance (percent); cross-section 4 shows the crystalline cis-butyl compound of formula I) Raman spectroscopy, [horizontal axis: vertical axis: relative intensity compared to background] Figure 5 shows the characteristic infrared spectrum of the crystalline cis-but compound of the compound of formula I, [vertical axis: wave number (cnT1) )] - Figure 6 shows the deliberate tearing spectrum of the crystalline maleate form of the formula ϊ (acetonitrile solvent), [horizon axis: Raman shift (reciprocal reciprocal); vertical axis · and The relative strength of the background is compared with the background. Figure 7 shows the characteristic difference of the crystalline maleate form 1 (toluene solvent) of the compound of the formula, and does not scan the calorimetric thermogram, [vertical axis··heat flow (eal/sec/g); horizontal axis: temperature (degrees Celsius) Figure 8 shows the crystalline maleate form of the compound of formula I^( Characteristic differential scanning calorimetry thermogram of nitrile solvent), [vertical axis: heat flux (Cal/sec/g); horizontal axis: temperature (degrees Celsius)]. Figure 9 shows the crystalline methanesulfonic acid of the compound of formula I. Characteristic X-ray powder diffraction pattern of salt form][(crystallized from ethyl acetate/hexane mixed solvent), [vertical axis: 119709.doc -32-200806666 intensity (CPS, count (square root)); horizontal axis· · 2Θ (degrees)]. Figure 10 is a graph showing the characteristic X-ray powder diffraction pattern of the crystalline form of the compound of the formula I, yttrium yttrium (crystallized from toluene), [vertical axis: intensity (cps, count (square root)); horizontal axis: 2 Θ (degrees)] . Figure 11 shows a characteristic X-ray powder diffraction pattern of the crystalline oxime sulfonate form of the compound of formula I (crystallized from toluene), [vertical axis: strength (cps, count (square root)); horizontal axis: 2 Θ (degrees) ]. Figure 12 shows a characteristic X-ray powder diffraction pattern of the crystalline oxalate form of the compound of formula I, [longitudinal: strength (cps, count (square root)); horizontal axis: 2 Θ (degrees)]. Figure 13 is a graph showing the characteristic X-ray powder diffraction pattern of the crystalline ethanesulfonate salt form of the compound of Formula 1, [longitudinal cylinder, rug, strength (CPS, number of leaves (square root)); horizontal axis: 2 Θ ( degree)]. 119709.doc -33 -
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