200302099 玖、發明說明 (發明說明應敘明：發明所屬之技術領域、先前技術、内容、實施方式及圓式簡單說明） C發明所屬技術領域;j 本發明涉及一組下式化合物的新型鹽，200302099 发明 Description of the invention (The description of the invention should state: the technical field, prior art, contents, embodiments and circular brief description of the invention) C. The technical field to which the invention belongs; j The present invention relates to a group of new compounds of the following formula,
5 及它們在製備藥物化合物中的應用。 【先前技術3 具有上式的苯並氮雜環庚三烯已公開於EP 0733642, EP 0830863，WO00/48601 和 W001/03699。EP 0733642涉 及式（I)的化合物及它們的生理學可接受的鹽，並涉及所述 10 化合物在心臟機能不全方面的應用。EP 0830863， WO00/48601和W001/03699分別涉及上述化合物在改善胃 腸血流、在治療高血壓和在治療和預防由阿黴素及類似抗 癌藥物所引起的心臟損害方面的應用。 優選的苯並氮雜環庚三烯是其中R〗是苯乙基或1-萘基 15 乙基，R2和尺3都是氫，R4是生物不穩定的酯基的化合物。 形成生物不穩定的酯的合適基團包括（Cl-C6)_烷基、在苯 環上被（ci-C6)-烧基或者被連接在兩個相鄰碳原子上的（C2· C6)-亞烧基鏈任選取代的苯基或苯基烧基、在二 氧戊環上被（CrC6)·烷基任選取代的二氧戊環甲基、或在 20 氧甲基上被（CrC6)-烷基任選取代的（c2-c6)-烷酰氧甲基。 當I基團是（CVC6)-烧基時，它優選是非支化的烧 200302099 玖、發明說明 基。在最優選的化合物中，汉4是乙基。 在進一步的藥物和臨床開發過程中，已發現最優選的 化合物有嚴重的缺點，即該化合物是固體泡沫體。爲了確 保來自固體藥劑形式的活性組分具有可重現的、恒定的生 5物利用率，使用活性化合物的均勻和可重現的變體是重要 的。因此，對於源自通常不均勻的材料，例如固體泡沫體 的化合物的可重現性和恒定的生物利用率，總是存在著疑 問。 同樣顯而易見的是，在工業規模上分離固體泡沫體是非常 10困難的。另外，所述化合物幾乎不溶於水，因此製備能夠 用於靜脈注射（IV)的所述化合物的製劑是非常困難的。在 本發明之前，只能由相應的二酸製備IV製劑（見Ep〇733642 的貫知例II)。這思味著用於製劑的化合物必須不同於用 於口服製劑的化合物，而這對於一個藥物化合物來說是不 15希望的。在進一步的開發過程中，已發現單酸的納鹽和卸 鹽在水中的溶解性要好得多，但是這些鹽也只&以固體泡 沫體的形式分離。 C 明内 本發明的目的是提供一種通式⑴化合物的鹽，該化合 20 物的鹽應當滿足如下要求： a) 工業生産規模上易通過結晶或沈澱分離純固體化合 物， b) 在生理流體中有足夠高的溶解性以便製成IV製劑， c) 具有允許用標準輔助化合物和標準設備製備成藥物 200302099 玖、發明說明 製劑的固態性質， d)優選製備過程不會顯著損失手性和化學純度。 這個目的可通過製備上述通式（I)化合物的金屬鹽來實 現，其中金屬離子是鋰離子或二價金屬離子。優選的二價 5金屬鹽是鈣，鎂和鋅鹽。最優選鈣鹽。令人驚奇地，已發 現攻些鹽與EP0733642中提及的鈉鹽和鉀鹽相反，具有非 常需要的性質，如它們能夠以固體（無定形）形式分離，且 在pH 7.4的等滲流體中的溶解性要比相應的酸至少高1〇倍 。而且可以製備二價鹽而不會外消旋。 10 在本發明的另一方面，提供了一種製備金屬鹽，優選5 and their use in the preparation of pharmaceutical compounds. [Prior Art 3 Benzoazepines having the above formula have been disclosed in EP 0733642, EP 0830863, WO00 / 48601 and W001 / 03699. EP 0733642 relates to compounds of formula (I) and their physiologically acceptable salts, and to the use of said compounds for cardiac insufficiency. EP 0830863, WO00 / 48601, and W001 / 03699 relate to the use of the above compounds in improving gastrointestinal blood flow, in treating hypertension, and in treating and preventing heart damage caused by doxorubicin and similar anticancer drugs, respectively. Preferred benzoazacycloheptatrienes are compounds in which R is phenethyl or 1-naphthyl 15 ethyl, R 2 and 3 are both hydrogen, and R 4 is a biologically unstable ester group. Suitable groups to form biolabile esters include (Cl-C6) _alkyl, (ci-C6) -alkyl on the benzene ring, or (C2 · C6) connected to two adjacent carbon atoms -A phenyl or phenylalkenyl group optionally substituted on the alkenylene chain, a dioxolane methyl group optionally substituted with (CrC6) · alkyl on a dioxolane group, or a 20 oxomethyl group ( CrC6) -alkyl optionally substituted (c2-c6) -alkanoyloxymethyl. When the I group is a (CVC6) -alkyl group, it is preferably an unbranched alkyl group. In the most preferred compounds, Han 4 is ethyl. During further pharmaceutical and clinical development, it has been found that the most preferred compound has serious drawbacks, i.e. the compound is a solid foam. In order to ensure a reproducible, constant bioavailability of the active ingredient from the solid pharmaceutical form, it is important to use uniform and reproducible variants of the active compound. Therefore, there are always questions about the reproducibility and constant bioavailability of compounds derived from materials that are usually non-uniform, such as solid foams. It is also obvious that it is very difficult to separate solid foams on an industrial scale. In addition, the compound is hardly soluble in water, so it is very difficult to prepare a formulation of the compound that can be used for intravenous injection (IV). Prior to the present invention, IV formulations could only be prepared from the corresponding diacids (see EP II 733642). This means that the compound used in the formulation must be different from the compound used in the oral formulation, which is not desirable for a pharmaceutical compound. During further development, it has been found that the mono-acid sodium salt and desalted salt have much better solubility in water, but these salts are also separated only in the form of solid foams. C. The purpose of the present invention is to provide a salt of a compound of the general formula VII. The salt of the compound 20 should meet the following requirements: a) On a commercial scale, it is easy to separate pure solid compounds by crystallization or precipitation, b) In physiological fluids High enough solubility to make IV preparations, c) Solid state properties that allow preparation of drugs with standard auxiliary compounds and standard equipment 200302099 发明, invention description formulations, d) preferred preparation process without significant loss of chirality and chemical purity . This object can be achieved by preparing a metal salt of the compound of the above general formula (I), wherein the metal ion is a lithium ion or a divalent metal ion. Preferred divalent 5-metal salts are calcium, magnesium and zinc salts. Most preferred is a calcium salt. Surprisingly, it has been found that these salts, in contrast to the sodium and potassium salts mentioned in EP0733642, have highly desirable properties, such as their ability to separate in solid (amorphous) form, and in isotonic fluids at pH 7.4 The solubility is at least 10 times higher than the corresponding acid. And divalent salts can be prepared without racemization. 10 In another aspect of the invention, there is provided a method for preparing a metal salt, preferably
Li+或二價 Ca2+、Mg2%tZn2+鹽的方法。 令人驚奇地，已經發現在室溫下，式j化合物的鋰鹽 和二價金屬鹽在諸如環己烷、甲苯、甲基叔丁基醚和乙酸 乙醋之類的弱極性非質子溶劑中的溶解性非常好。 15 通過將所需金屬的氫氧化物或合適的鹽與式I化合物 在上述弱極性非質子溶劑中的溶液或漿液混合，可以容易 地獲得本發明的鹽類。或者，當所需金屬的氫氧化物或鹽 的溶解度不足以開始進行反應時，可以向所述有機溶劑的 溶液或漿液中加入少量的水，並且所加的水可以通過共沸 20蒸餾除去。在這種情況下，必須選擇和水形成共沸物的非 極性非質子溶劑。對於氫氧化物溶解性非常不好的金屬， 可以將該金屬以乙氧化物（例如Mg(〇Et)2)或混合氫氧化物/ 碳酸鹽（3Zn(OH)2.2ZnC〇3)的形式加入。上述方法中優選 的溶劑疋甲基叔丁基醚或乙酸乙酯。當已經在溶液中獲得 200302099 玖、發明說明 了所述鹽時，可以通過如下步驟進行分離：首先通過共彿 蒸餾除去仍然存在的水，隨後和沈澱劑混合。沈澱劑定義 爲第二種液體，該液體被加入到溶液中以降低溶解化合物 的溶解度，引起該化合物的沈澱/結晶並使産物的産率最 5大化。這兩種液體（原始溶劑和所加的沈澱劑）能夠以任意 比例彼此完全互溶是必要的。（這種方法也用於通過加入 與水互溶的有機溶劑來降低無機鹽在水溶液中的溶解度 (ALFASSI Ζ·Β·等，AlChE J. 1984U74-6; MYDLARZ J_ 等，J· Chem. Eng· Data 1989,丛 124-6; MULLIN J.W·等， 10 chem· Eng· Process· 1989,丛，93-9)。本發明範圍内的沈澱 劑的實例爲線性烴。優選的沈澱劑是線性c4_Ci()烴。最優 選的沈殿劑是正己烧。 因爲在所有的情況下所述鹽都是以非晶態沈澱物形式 分離的，該沈澱物在所有情況下似乎都是均勻的，有時需 15要進行真正的結晶步驟以提高必須滿足嚴格要求的活性化 合物的純度。令人驚奇的是，已經發現式合物的s-a-甲 基苄基胺鹽非常適合用於這些化合物的純化，例如所述鹽 是晶體，並且可以從有機溶劑中以高産率進行重結晶，所 述有機溶劑優選是醇如乙醇或異丙醇。因此，本發明還涉 20 及式1化合物的S-a-甲基苄基胺鹽。因爲s-a-甲基苄基胺似 乎毋性太大不能使用’因此所述鹽只適合用作純化步驟中 的中間體。 可以通過向式I化合物在乙醇或異丙醇或其他合適醇 中的溶液中加入S-a-曱基节基胺來製備式I化合物的S-a·曱 200302099 玫、發明說明 基节基胺鹽。該溶液靜置冷卻後，所述鹽將從溶液中結晶 出來（根據濃度）。 可以按照現有技術的配方工藝來配製本發明的藥學可 接受的鹽。可以使用常用製劑，例如片劑、膠囊或栓劑。 5 這些藥物製劑可以用已知的方法製備，例如直接壓縮、造 粒、擠出、模制，採用常規的固體賦形劑，例如填充劑如 纖維素、乳糖和澱粉，粘合劑如纖維素和聚乙烯基吼咯烷 嗣（PVP)，崩解劑如澱粉和交聯pvp，滑動劑（glidiants)如膠 體一氧化石夕’潤滑劑如硬脂酸鎂，或者常規的液體和半固 10體賦形劑，例如聚乙二醇、蓖麻油衍生物、甘油三酯和石 蠟。另外可以加入防腐劑，例如對羥基苯甲酸酯類，和乳 化劑如聚山梨酸酯。 本發明的藥物可接受的鹽適合作爲大型哺乳動物，特別 是人類的用藥，用於治療心力衰竭和促進特別是心力衰竭 15的患者的排尿和鈉尿排泄，用於改善胃腸血流，治療高血 壓以及治療和預防由阿黴素及類似抗癌藥物引起的心臟損 害。爲實現該目的，可以以腸胃外給藥，特別是靜脈注射 ’口服或栓劑給藥的藥物形式使用本發明的化合物。所用 劑量可以因人而異，並根據被治療的狀況的性質、所用的 20特定物質以及給藥方式而變化。對於大型哺乳動物，特別 是人類而言，以活性物質含量爲單劑卜綱呵的藥物形 式給藥一般是合適的。 【實施方式3 下列的實施例只是爲了更詳細地舉例說明本發明，因 10 200302099 玖、發明說明 此這些實施例在任何方面都不構成對本發明範圍的限制。 實施例 實施例1、製備式I化合物金屬鹽的一般程式。 將約15 mmol酸形式的活性物質溶解或懸浮在40ml弱 5 極性非質子溶劑中。加入約1.2當量的金屬試劑，該試劑 溶於水或與活性化合物所用溶劑相同的溶劑中。在某些情 況下，必須加入水以啓動反應。通過共沸蒸餾除去水。當 金屬試劑不是氫氧化物或乙氧化物時，將溶劑全部除去， 接著重新溶解在40〜160ml的原始弱極性非質子溶劑中， 10 隨後過濾以除去未反應的金屬試劑和任選的所形成的其他 鹽。將濾液加入己烷中，當形成固體産物時，用過濾器收 集産物。當形成焦油或油狀物時，將大部分溶劑輕輕傾倒 出去，並蒸發掉剩餘溶劑以獲得固體泡沫體。 表1、兩種活性物質的不同鹽的製備 化合 物* 鹽中的 金屬 金屬 試劑M 溶劑 M的數量 (g)(mmo) 溶劑量 (ml) 己烧量 (ml) 産率 (%) 結果 I Ca2+ Ca(OH)2 MTBE 0.67 (9.0) 40 80 95 固體 粉末 I Mg2+ Mg(OEt)2 MTBE 1.25 00.9) 40 130 103 固體 粉末 I Zn2+ 3Zn(OH)2· 2Zn(C〇3)2 MTBE 1.05 (10.9) 115 235 95 固體 粉末 I Li+ LiOH MTBE 0.4 (16.7) 160 130 85 固體 粉末 I r KOH MTBE 1.02 (18.3) 95 235 98 固體 泡沫體 I Na+ NaOH MTBE 1.02 07.8) 95 235 89 固體 泡沫體 Π Ca2+ Ca(OH)2 EtOAc 0.56 (7.6) 75 235 87 固體 粉末 15 *化合物I = (3S>3-[[[l-(2R)-2-(乙氧羰基>4-苯基丁基]環戊基]羰基]氨基]-2,3,4,5-四氫-2-氧 代-1H-1-苯並氮雜環庚三烤-1·乙酸。 *化合物II = [S-(R*，S*)]-3-[[[l-p-(乙氧羰基)冰(1-萘基)丁基]環戊基]羰基]氨基]_2,3,4,5_四 氫-2·氧-1H-1·苯並氮雜環庚三烯小乙酸。 11 200302099 玖、發明說明 表2總結了所製備的鹽的性質。化合物含量用Hpi^e& 測定（MACHEREY-NAGELNucleosil 100-5 C18-HD；j：主，彳吏 用從5%B到100%B的梯度體系，洗脫液A是ρΗ=5·1的碟酉变 缓衝液，洗脫液Β是和10%洗脫液Α混合的乙腈）。對於_ 5 ，金屬含量用乙二胺四乙酸二鈉鹽配位滴定法測定，對於 其他金屬，金屬含量用原子發射光譜（AES)測定。 表2、表1製備的鹽的性能 化合 鹽中的 化合物含量 金屬含量 理論金屬含量 在弱極 子有機溶劑中 的溶解庶 溶解性 物* 金屬 (% rel) (%W/W) (%W/W) I Ca2+ 99.8 3.8 3.6 可溶 ------- 可溶 I Mg2+ 99.6 2.4 2.2 可溶 —-—. 可溶 I Zn2+ 99.9 7.0 5.8 可溶 ----- 可溶 I Li+ 88.0 1.6 1.3 可溶 —-— 易溶 I K+ 78.4 7.5 6.8 不溶 易溶 I Na+ 84.7 4.3 4.1 不溶 易溶 Π Ca2+ n.d. 3.4 3.3 可溶 可溶 *化合物I =(3S>3-[[[l<2R)-2·(乙氧羰基M·苯基丁基]環戊基]羰基]氨基]-2,3,4,5-四氫-2-氧 代-1H-1-苯並氮雜環庚三烯小乙酸。 10 *化合物II = [S-(R*，S*)]-3-[[[l-[2»(乙氧羰基M*(l-萘基)丁基]環戊基]羰基]氨基]-2,3,4,5-四 氫-2-氧代-1H-1-苯並氮雜環庚三烯小乙酸。 n.d.=未測定 從表2可以看到，作爲固體粉末分離出來的Li、Ca、 15 Mg和Zn鹽可溶解在弱極性非質子溶劑中。這些溶劑的實 例有乙酸乙酯，甲苯，環己烷和甲基叔丁基醚。這些化合 物還可溶解在極性非質子溶劑中，例如THF，丙酮，乙腈 ，DMF和DMSO。鹽中測得的金屬含量稍高於理論量，但 這在這些類型的後處理和分析中是正常的。在和一價強鹼 20 性氫氧化物成鹽的過程中，會發生活性物質的降解，導致 最終鹽中的低化合物含量。 12 200302099 玖、發明說明 貫施例2、（38)-3-[[[1-(21〇-2-(乙氧羰基）_4-苯基丁基]環戊 基]羰基]氨基]-2,3,4,5-四氫-2-氧代-1H-1-苯並氮雜環庚三 烯-1-乙酸的S-α-曱基苄基胺鹽的製備 將18g (3S)-3-[[[l-(2R)_2-(乙氧羰基）_4_苯基丁基]環戊 5基]羰基]氨基>2,3,4,5-四氫-2-氧代·ιη-1-苯並氮雜環庚三 烯-1·乙酸溶解在90ml無水乙醇中。在20〜25°C下加入4.lg S-a-甲基苄基胺。將自然形成的晶體漿液加熱至4(rc，並 攪拌1小時。待冷卻至〇〜5°C後，再攪拌4小時，過濾收集 晶體’用40ml冷無水乙醇洗滌，45°C下在真空烘箱中乾燥 1〇 。第一批收集到19g(3S)-3-[[[l-(2R)-2-(乙氧羰基）冰苯基 丁基]環戊基]羰基]氨基]·2,3,4,5·四氫-2-氧代-1H-1-苯並氮 雜環庚二稀-1·乙酸的S-a-甲基节基胺鹽。 實施例3、（3S)-3-[[[l-(2R)-2-(乙氧羰基）-4-苯基丁基]環戊 基]幾基]氨基]-2,3,4,5-四氫-2-氧代-1H-1·苯並氮雜環庚三 15 烯·1-乙酸鈣鹽的製備 向30g (3S)-3-[[[l-(2R)-2-(乙氧羰基）-4-苯基丁基]環戊 基]羰基]氨基]-2,3,4,5-四氫-2-氧代_1Η-1·苯並氮雜環庚三 烯-1-乙酸的S-a-甲基苄基胺鹽在120ml甲基叔丁基醚 (MTBE)中的溶液中，加入100ml 1M鹽酸水溶液，擾拌所 20 仔的混合物10分鐘。分離各層，並用15ml水洗條有機層至 少3次，直至PH高於5。加入2g 95% Ca(OH)2，加熱回流混 合物至55°C。當30分鐘後懸浮液數量不明顯減少時，加入 0.5ml水。通過脫水器（Dean-stark設備）回流混合物2小時。 2小時後，餾出液完全澄清而反應混合物有一點渾濁。將 13 200302099 玖、發明說明 混合物冷卻至30_35°C，並通過在線過濾器在30分鐘之内 加到240ml己烷中。過濾分離固體産物，並用50ml己烷洗 滌。乾燥後獲得25.6g灰白色自由流動的粉末。 h-NMR: δ = 7.29 (1H，dd，J=2.2 和 8.1)，7·28 (1H， 5 ddd，J=2.0, 6.6, 8.1)，7·25 (1H，dd，J=2.0和 7.6)，7.19 (1H， ddd，J=2.25 6.6, 7.6)，7.19 (2H，dddd，J=0.6, 1.7, 7.5, 7·8)， 7.13 (1H，dd，J=1.3和 7·5)，7·10 (2H，ddd，J=1.3, 2.1，7.8)， 4.39 (1H，d，J=16.9)，4.28 (1H，dd，J=8.1 和 11.7)，4·28 (1H， d，J=16.9)，4.07(1H，dd，J=7.2和 10.8)，4·01(1Η，dd，J=7.1 和 10 1〇·8)，3·33(1Η，ddd，J=8,0, 13.2, 13.7)，2.57(1H，ddd，J=1.2, 7·1，13.7)，2.52(1H，dd，J=5.9和 9.6)，2.49 (1H，dd，J=6.7和 9.4)，2.31(1H，dddd，J=3.3, 5.1，9·2,9·3)，2·29 (1H，dddd， J=7.1，8.1，13.1，13.2)，2.03 (1H，dddd，J=1.2，8.0，11.7, 13.1)，2.0 (1H，dd，J=9.3 和 14.2)，1.82 (1H，dd，J=3.3 和 15 14.2)，1.82 (1H，ddd，J=5.9，9.4，13.6)，1·70 (1H，ddd， J=6.7, 9.6, 13.6)，2.02-1.42 (8H，m)，1.21 (3H，dd5 J=7.1 和 7.2)。 實施例4、化合物II即[S-(R*，S*)]-3-[[[l-[2-(乙氧羰基）_4_ (卜萘基）丁基]環戊基]羰基]氨基]-2,3,4,5·四氫-氧代·— 2〇 苯並氮雜環庚三烯-1-乙酸的S-α-甲基苄基胺鹽的製備 將21g化合物II即乙氧羰基）_ 4-(1-萘基）丁基]環戊基]羰基]氨基]-2,3,4,5-四氫-氧代-1Η· 1-苯並氮雜環庚三烯·1·乙酸溶於19〇ml ΜΤΒΕ中。加入 45ml乙醇和4.5g S-a-曱基苄基胺。在4°C貯存4天並每天擾 14 200302099 玖、發明說明 拌一次後，過濾收集晶體，用80ml MTBE洗滌，在真空烘 箱中於45 °C乾燥。第一批收集到19g化合物II即[s-(R*，S*)]-3-[[[l-[2-(乙氧羰基）-4-(1-萘基）丁基]環戊基憤基 ]氨基]-2,3,4,5-四氫-氧代-1H-1-苯並氮雜環庚三烯-1-乙酸 5 的S-α-甲基苄基胺鹽。 實施例 5、[S-(R*，S*)]-3-[[[l-[2-(乙氧羰基）-4-(1-萘基）丁基 ]環戊基]羰基]氨基]-2,3,4,5-四氫-氧代-1H-1-苯並氮雜環庚 三烯-1-乙酸鈣鹽的製備 在攪拌下，在 15分鐘内，向 10g[S-(R*，S*)]-3-[[|>|>( 10 乙氧羰基）-4-(1-萘基）丁基]環戊基]羰基]氨基]-2,3,4,5-四 氫-氧代-1H-1-苯並氮雜環庚三烯-1-乙酸的s-a-甲基苄基胺 鹽在80ml甲基叔丁基醚（MTBE)和60ml水中形成的多相混 合物中加入4.4ml 36%的鹽酸水溶液，在室溫下攪拌所得 混合物1.5小時。分離各層，有機層用50mi水洗滌兩次。 15將有機層濃縮成油’加入15ml乙酸乙酯，將所得溶液再次 濃縮成油。用80ml乙酸乙酯再次溶解該油，並加入2ml水 。加入 0.56g 95% Ca(OH)2,通過脫水器（Dean-Stark 設備） 回流混合物4小時。過濾溶液，並將溶液體積減少到4〇ml 。將溶液冷卻至30-35 °C，在30分鐘内加到250ml冷己烷 20 (10°C)中，在l〇°C下再攪拌30分鐘。過濾分離固體産物， 用l〇ml己烷洗滌兩次。真空乾燥（18小時，5〇t，ι2〇毫巴 )後’獲得7.4g自由流動的粉末。 tNMR: δ = 7·99 (1H，寬雙峰，J=8)，7.88 (1H，dd， J=l_5和 8)，7·73 (1H，寬雙峰，J==8)，7 56_7 44 (2H，m)，7 37 15 200302099 玖、發明說明 (1H，t，J=8)，〜7.36 (NH，d，J=8)，7.31 (1H，dd，J=1.5和 8)， 7.29 (1H，d，J=8)，7·24 (1H，三重雙峰，J=1.5，8, 8)，7·21 (1H，dd，J二 1.5 和 8)，7.13 (1H，三重雙峰，J=1.5, 8, 8)，4.48 (1H，d5 J=16)，4·23 (1H，雙三重峰，J=8，8，12)，4.14-3.99 5 (3H，m)，3.56 (1H，三重雙峰，J=8，13，13)，3.02-2.96 (2H， m)，2.5-2.34 (2H，m)，2.2-1.74 (8H，m)，1.6-1.24 (6H，m)， 1.20 (3H，t，J=6)。 I：圖式簡單說明3 無 10 【圖式之主要元件代表符號表】 無 16Li + or divalent Ca2 +, Mg2% tZn2 + salt method. Surprisingly, lithium and divalent metal salts of compounds of formula j have been found in weakly polar aprotic solvents such as cyclohexane, toluene, methyl tert-butyl ether and ethyl acetate at room temperature. The solubility is very good. 15 The salts of the present invention can be easily obtained by mixing a hydroxide or a suitable salt of the desired metal with a solution or slurry of a compound of formula I in the above-mentioned weakly polar aprotic solvent. Alternatively, when the hydroxide or salt of the desired metal has insufficient solubility to start the reaction, a small amount of water may be added to the solution or slurry of the organic solvent, and the added water may be removed by azeotropic distillation. In this case, a non-polar aprotic solvent that forms an azeotrope with water must be selected. For metals with very poor hydroxide solubility, this metal can be added in the form of ethoxide (such as Mg (〇Et) 2) or mixed hydroxide / carbonate (3Zn (OH) 2.2ZnC03) . The preferred solvents in the above method are methyl tert-butyl ether or ethyl acetate. When 200302099 has been obtained in solution and the salt is described in the invention, it can be separated by the following steps: First, the co-foss distillation is used to remove the remaining water, and then it is mixed with the precipitation agent. A precipitating agent is defined as a second liquid which is added to the solution to reduce the solubility of the dissolved compound, causing precipitation / crystallization of the compound and maximizing the yield of the product. It is necessary that these two liquids (the original solvent and the added precipitant) be completely miscible with each other in any ratio. (This method is also used to reduce the solubility of inorganic salts in aqueous solutions by adding organic solvents that are miscible with water (ALFASSI Z · Β · et al., AlChE J. 1984U74-6; MYDLARZ J_ et al., J. Chem. Eng · Data 1989, plex 124-6; MULLIN JW. Et al., 10 chem. Eng. Process 1989, plex, 93-9). Examples of precipitants within the scope of the present invention are linear hydrocarbons. Preferred precipitants are linear c4_Ci () Hydrocarbons. The most preferred Shen Dian agent is hexane. Because in all cases the salt is separated as an amorphous precipitate which appears to be homogeneous in all cases. A true crystallization step is performed to increase the purity of the active compounds that must meet stringent requirements. Surprisingly, the sa-methylbenzylamine salts of formula compounds have been found to be very suitable for the purification of these compounds, such as the salts Are crystals and can be recrystallized from organic solvents in high yields, preferably organic alcohols such as ethanol or isopropanol. Therefore, the present invention also relates to Sa-methylbenzylamines of 20 and compounds of formula 1 Salt. Because sa-methylbenzylamine It is too large to be used 'so the salts are only suitable as intermediates in the purification step. Sa-fluorenyl can be added to a solution of a compound of formula I in ethanol or isopropanol or another suitable alcohol Amine to prepare Sa · 200302099 of compound of formula I. Description of the invention: Selenium amine salt. After the solution is left to cool, the salt will crystallize (depending on concentration) from the solution. The pharmaceutically acceptable salts of the present invention are formulated. Common formulations such as tablets, capsules or suppositories can be used. 5 These pharmaceutical formulations can be prepared by known methods, such as direct compression, granulation, extrusion, molding, using conventional Solid excipients, such as fillers such as cellulose, lactose, and starch, binders such as cellulose and polyvinylpyrrolidine (PVP), disintegrants such as starch and crosslinked pvp, glidants Such as colloidal nitric oxide 'lubricants such as magnesium stearate, or conventional liquid and semi-solid 10-body excipients such as polyethylene glycol, castor oil derivatives, triglycerides and paraffin waxes. Alternatively, Preservatives, such as parabens, and emulsifiers, such as polysorbates. The pharmaceutically acceptable salts of the present invention are suitable for use in large mammals, especially humans, for the treatment of heart failure and the promotion of heart effort in particular Urination and sodiumuria excretion in patients with failure 15 for improving gastrointestinal blood flow, treating hypertension, and treating and preventing heart damage caused by doxorubicin and similar anticancer drugs. To achieve this, parenteral administration In particular, the compounds of the present invention are used in a pharmaceutical form for intravenous or oral or suppository administration. The dosage used may vary from person to person and varies depending on the nature of the condition being treated, the 20 specific substances used, and the mode of administration. For large mammals, especially humans, the administration of a single dose of Bu Gang Ha with the active substance content is generally suitable. [Embodiment 3] The following examples are only for illustrating the present invention in more detail. Therefore, these 2003 embodiments do not limit the scope of the present invention in any way. Examples Example 1. General procedure for preparing metal salts of compounds of formula I. About 15 mmol of the active substance in acid form is dissolved or suspended in 40 ml of a weak 5 polar aprotic solvent. About 1.2 equivalents of a metal reagent is added, which is dissolved in water or the same solvent as the solvent used for the active compound. In some cases, water must be added to start the reaction. Water was removed by azeotropic distillation. When the metal reagent is not hydroxide or ethoxide, the solvent is completely removed, and then re-dissolved in 40 to 160 ml of the original weakly polar aprotic solvent, 10 followed by filtration to remove unreacted metal reagent and optional formed Of other salts. The filtrate was added to hexane, and when a solid product was formed, the product was collected with a filter. When tar or oil is formed, most of the solvent is gently poured out, and the remaining solvent is evaporated to obtain a solid foam. Table 1. Preparation of different salts of two active substances. Compounds * Metal metal reagent M in salt Amount of solvent M (g) (mmo) Amount of solvent (ml) Amount burned (ml) Yield (%) Result I Ca2 + Ca (OH) 2 MTBE 0.67 (9.0) 40 80 95 Solid powder I Mg2 + Mg (OEt) 2 MTBE 1.25 00.9) 40 130 103 Solid powder I Zn2 + 3Zn (OH) 2 2Zn (C〇3) 2 MTBE 1.05 (10.9 ) 115 235 95 solid powder I Li + LiOH MTBE 0.4 (16.7) 160 130 85 solid powder I r KOH MTBE 1.02 (18.3) 95 235 98 solid foam I Na + NaOH MTBE 1.02 07.8) 95 235 89 solid foam Π Ca2 + Ca ( OH) 2 EtOAc 0.56 (7.6) 75 235 87 Solid powder 15 * Compound I = (3S> 3-[[[l- (2R) -2- (ethoxycarbonyl> 4-phenylbutyl) cyclopentyl ] Carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzoazepine-1.acetic acid. * Compound II = [S- (R *, S *)]-3-[[[lp- (ethoxycarbonyl) ice (1-naphthyl) butyl] cyclopentyl] carbonyl] amino] _2,3,4,5_tetrahydro-2 · oxy- 1H-1. Benzoazepine triene small acetic acid. 11 200302099 玖, Description of the invention Table 2 summarizes the properties of the prepared salts. The compound content is Hpi ^ e & (MACHEREY-NAGEL Nucleosil 100-5 C18-HD; j: Master, the official uses a gradient system from 5% B to 100% B, the eluent A is a dish change buffer with ρΗ = 5.1 Liquid B is acetonitrile mixed with 10% eluent A). For _5, the metal content is determined by ethylenediaminetetraacetic acid disodium salt complexometric titration. For other metals, the metal content is determined by atomic emission spectroscopy (AES) Table 2. Table 1. Properties of the salts prepared. Compound content in the salt. Metal content. Theoretical metal content. Dissolution in weak polar organic solvents. Soluble matter * Metal (% rel) (% W / W) (% W / W) I Ca2 + 99.8 3.8 3.6 Soluble ------- Soluble I Mg2 + 99.6 2.4 2.2 Soluble -----. Soluble I Zn2 + 99.9 7.0 5.8 Soluble --- Soluble I Li + 88.0 1.6 1.3 Soluble —-— I K + 78.4 7.5 6.8 Insoluble I Na + 84.7 4.3 4.1 Insoluble and soluble Π Ca2 + nd 3.4 3.3 Soluble and soluble * Compound I = (3S > 3-[[[l < 2R) -2 · (Ethoxycarbonyl M · phenylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzoazepinetriene small Acetic acid. 10 * Compound II = [S- (R *, S *)]-3-[[[l- [2 »(Ethoxycarbonyl M * (l-naphthyl) butyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzoazacycloheptatriene small acetic acid. Nd = Not determined From Table 2, it can be seen that Li separated as a solid powder , Ca, 15 Mg and Zn salts are soluble in weakly polar aprotic solvents. Examples of these solvents are ethyl acetate, toluene, cyclohexane and methyl tert-butyl ether. These compounds are also soluble in polar aprotic solvents Medium, such as THF, acetone, acetonitrile, DMF, and DMSO. The measured metal content in the salt is slightly higher than the theoretical amount, but this is normal in these types of post-treatment and analysis. In the case of monovalent strong base 20 During the process of the oxide to form a salt, degradation of the active substance will occur, resulting in a low content of compounds in the final salt. 12 200302099 发明, Description of the Invention Implementation Example 2, (38) -3-[[[1- (21〇- 2- (ethoxycarbonyl) _4-phenylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxo-1H-1-benzoazepine Preparation of S-α-fluorenylbenzylamine salt of ene-1-acetic acid 18g (3S) -3-[[[[l- (2R) _2- (ethoxycarbonyl) _4 _Phenylbutyl] cyclopentyl 5yl] carbonyl] amino > 2,3,4,5-tetrahydro-2-oxo · ιη-1-benzoazepinetriene-1 · acetic acid is dissolved in 90ml of absolute ethanol. Add 4.lg Sa-methylbenzylamine at 20 ~ 25 ° C. Heat the naturally occurring crystal slurry to 4 ° C and stir for 1 hour. After cooling to 0 ~ 5 ° C After stirring for 4 hours, the crystals were collected by filtration, washed with 40 ml of cold absolute ethanol, and dried in a vacuum oven at 45 ° C. 10. The first batch collected 19 g (3S) -3-[[[l- (2R)- 2- (ethoxycarbonyl) glacial phenylbutyl] cyclopentyl] carbonyl] amino] · 2,3,4,5 · tetrahydro-2-oxo-1H-1-benzoazepine Sa-methylbenzylamine salt of -1. Acetic acid. Example 3, (3S) -3-[[[l- (2R) -2- (ethoxycarbonyl) -4-phenylbutyl] cyclopentane [Amino] Amino] Amino] -2,3,4,5-tetrahydro-2-oxo-1H-1 · benzoazepinetri 15ene · 1-acetic acid calcium salt Preparation to 30g (3S) -3-[[[l- (2R) -2- (ethoxycarbonyl) -4-phenylbutyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-2-oxy To a solution of the Sa-methylbenzylamine salt of 1Η-1Η-benzoazepinetriene-1-acetic acid in 120 ml of methyl tert-butyl ether (MTBE), add 100 Mix 1 ml of a 1M aqueous hydrochloric acid solution and stir the mixture for 20 minutes. Separate the layers and wash the strips with 15 ml of water at least 3 times until the pH is higher than 5. Add 2 g of 95% Ca (OH) 2 and heat to reflux the mixture to 55 ° C. When the number of suspensions does not decrease significantly after 30 minutes, 0.5 ml of water is added. The mixture was refluxed through a dehydrator (Dean-stark apparatus) for 2 hours. After 2 hours, the distillate was completely clear and the reaction mixture was slightly cloudy. 13 200302099 30, description of invention The mixture was cooled to 30-35 ° C and added to 240 ml of hexane through an in-line filter in 30 minutes. The solid product was isolated by filtration and washed with 50 ml of hexane. After drying, 25.6 g of an off-white free-flowing powder was obtained. h-NMR: δ = 7.29 (1H, dd, J = 2.2 and 8.1), 7.28 (1H, 5 ddd, J = 2.0, 6.6, 8.1), 7.25 (1H, dd, J = 2.0 and 7.6) ), 7.19 (1H, ddd, J = 2.25 6.6, 7.6), 7.19 (2H, dddd, J = 0.6, 1.7, 7.5, 7.8), 7.13 (1H, dd, J = 1.3 and 7.5), 7 · 10 (2H, ddd, J = 1.3, 2.1, 7.8), 4.39 (1H, d, J = 16.9), 4.28 (1H, dd, J = 8.1 and 11.7), 4.28 (1H, d, J = 16.9), 4.07 (1H, dd, J = 7.2 and 10.8), 4.01 (1Η, dd, J = 7.1 and 10 10.8), 3.33 (1Η, ddd, J = 8, 0, 13.2, 13.7), 2.57 (1H, ddd, J = 1.2, 7.1, 13.7), 2.52 (1H, dd, J = 5.9 and 9.6), 2.49 (1H, dd, J = 6.7 and 9.4), 2.31 ( 1H, dddd, J = 3.3, 5.1, 9.2, 9 · 3), 2 · 29 (1H, dddd, J = 7.1, 8.1, 13.1, 13.2), 2.03 (1H, dddd, J = 1.2, 8.0, 11.7, 13.1), 2.0 (1H, dd, J = 9.3 and 14.2), 1.82 (1H, dd, J = 3.3 and 15 14.2), 1.82 (1H, ddd, J = 5.9, 9.4, 13.6), 1.70 (1H, ddd, J = 6.7, 9.6, 13.6), 2.02-1.42 (8H, m), 1.21 (3H, dd5 J = 7.1 and 7.2). Example 4 Compound II [S- (R *, S *)]-3-[[[l- [2- (ethoxycarbonyl) _4- (bnaphthyl) butyl] cyclopentyl] carbonyl] amino]- Preparation of 2,3,4,5 · Tetrahydro-oxo · -20 Benzazepine-1-acetic acid S-α-methylbenzylamine salt 21 g of compound II is ethoxycarbonyl ) 4- (1-naphthyl) butyl] cyclopentyl] carbonyl] amino] -2,3,4,5-tetrahydro-oxo-1Η · 1-benzoazepine · 1 -Acetic acid was dissolved in 190 ml MTBE. 45 ml of ethanol and 4.5 g of S-a-fluorenylbenzylamine were added. Store at 4 ° C for 4 days and disturb each day. 14 200302099 99, description of the invention After mixing once, the crystals are collected by filtration, washed with 80ml MTBE, and dried in a vacuum oven at 45 ° C. The first batch collected 19g of compound II, which is [s- (R *, S *)]-3-[[[l- [2- (ethoxycarbonyl) -4- (1-naphthyl) butyl] cyclopentane S-α-methyl] amino] -2,3,4,5-tetrahydro-oxo-1H-1-benzoazepinetriene-1-acetic acid S-α-methylbenzylamine salt 5. Example 5. [S- (R *, S *)]-3-[[[l- [2- (ethoxycarbonyl) -4- (1-naphthyl) butyl] cyclopentyl] carbonyl] amino ] -2,3,4,5-Tetrahydro-oxo-1H-1-benzoazacycloheptatriene-1-acetic acid calcium salt Under stirring, to 15 g [S- (R *, S *)]-3-[[| > | > (10 ethoxycarbonyl) -4- (1-naphthyl) butyl] cyclopentyl] carbonyl] amino] -2,3, The sa-methylbenzylamine salt of 4,5-tetrahydro-oxo-1H-1-benzoazepinetriene-1-acetic acid is formed in 80 ml of methyl tert-butyl ether (MTBE) and 60 ml of water To the heterogeneous mixture was added 4.4 ml of a 36% aqueous hydrochloric acid solution, and the resulting mixture was stirred at room temperature for 1.5 hours. The layers were separated and the organic layer was washed twice with 50 mi of water. 15 The organic layer was concentrated to an oil ', 15 ml of ethyl acetate was added, and the resulting solution was concentrated to an oil again. The oil was dissolved again with 80 ml of ethyl acetate and 2 ml of water was added. 0.56 g of 95% Ca (OH) 2 was added, and the mixture was refluxed for 4 hours through a dehydrator (Dean-Stark apparatus). The solution was filtered and the volume of the solution was reduced to 40 ml. The solution was cooled to 30-35 ° C, added to 250 ml of cold hexane 20 (10 ° C) over 30 minutes, and stirred at 10 ° C for another 30 minutes. The solid product was isolated by filtration and washed twice with 10 ml of hexane. After vacuum drying (18 hours, 50 t, 20 mbar), 7.4 g of a free-flowing powder were obtained. tNMR: δ = 7.99 (1H, broad doublet, J = 8), 7.88 (1H, dd, J = l_5 and 8), 7.73 (1H, broad doublet, J == 8), 7 56_7 44 (2H, m), 7 37 15 200302099 玖, description of the invention (1H, t, J = 8), ~ 7.36 (NH, d, J = 8), 7.31 (1H, dd, J = 1.5 and 8), 7.29 (1H, d, J = 8), 7.24 (1H, triple doublet, J = 1.5, 8, 8), 7.21 (1H, dd, J two 1.5 and 8), 7.13 (1H, triple Doublet, J = 1.5, 8, 8), 4.48 (1H, d5 J = 16), 4.23 (1H, double triplet, J = 8, 8, 12), 4.14-3.99 5 (3H, m) , 3.56 (1H, triple doublet, J = 8, 13, 13), 3.02-2.96 (2H, m), 2.5-2.34 (2H, m), 2.2-1.74 (8H, m), 1.6-1.24 (6H , M), 1.20 (3H, t, J = 6). I: Brief description of the drawing 3 None 10 [Representative symbol table of the main components of the drawing] None 16