1284039 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、實施方式及圖式簡單說明) 【發明所屬之技術領域】 本發明涉及一組下式化合物的新型鹽，1284039 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明
5 及它們在製備藥物化合物中的應用。 t先前技術】 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， 冒000/48601和冒001/03699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!是苯乙基或丨-萘基 15 乙基，R2和R3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（CrC6)-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· c0)-亞烷基鏈任選取代的苯基或苯基-(c^Q)-烷基、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（Ci-C：6)-烧基任選取代的（c2-c6)-烧醜氧曱基。 當R4基團是（crC6)-烷基時，它優選是非支化的烷 1284039 玖、發明說明 基。在最優選的化合物中，R4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EP0733642 的實施例II)。這意味著用於IV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，已發現單酸的鈉鹽和鉀 鹽在水中的溶解性要好得多，但是這些鹽也只能以固體泡 沫體的形式分離。 C 明内容】 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， 幻具有允許用標準輔助化合物和標準設備製備成藥物 1284039 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 現這些鹽與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10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. t Prior Art] Benzazepines having the above formula are 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 10 compounds in cardiac insufficiency. EP 0830863, 冒 000/48601 and 001/03699 respectively relate to the use of the above compounds for improving gastrointestinal blood flow, for treating hypertension and for treating and preventing heart damage caused by doxorubicin and similar anticancer drugs. A preferred benzazepine is a compound wherein R! is phenethyl or fluorenyl-naphthyl 15 ethyl, R2 and R3 are both hydrogen, and R4 is a biolabile ester group. Suitable groups for the formation of biolabile esters include (CrC6)-alkyl groups, (Ci-C6)-alkyl groups on the phenyl ring or (c2·c0)-ya groups attached to two adjacent carbon atoms. An alkyl group optionally substituted phenyl or phenyl-(c^Q)-alkyl, dioxolane methyl optionally substituted by (CrC6)-alkyl on dioxolane, or at 20 oxygen (c2-c6)-burning oxime-oxyl group optionally substituted on the methyl group by (Ci-C:6)-alkyl. When the R4 group is (crC6)-alkyl, it is preferably an unbranched alkane 1284039. In the most preferred compounds, R4 is ethyl. In further pharmaceutical and clinical development processes, the most preferred compounds have been found to have serious drawbacks, i.e., the compound is a solid foam. In order to ensure a reproducible, constant biomass utilization of the active ingredient from the solid dosage form, it is important to use uniform and reproducible variants of the active compound. Therefore, there is always a doubt about the reproducibility and constant bioavailability of compounds derived from generally non-uniform materials, such as solid foams. It is also apparent that it is very difficult to separate solid foams on an industrial scale. Further, the compound is hardly soluble in water, and therefore preparation of a preparation of the compound which can be used for intravenous injection (IV) is very difficult. Prior to the present invention, IV formulations were only prepared from the corresponding diacids (see Example II of EP0733642). This means that the compound used for the IV preparation must be different from the compound used for the oral preparation, which is not desirable for a pharmaceutical compound. During further development, it has been found that the sodium and potassium salts of monoacids are much more soluble in water, but these salts can only be separated as solid foams. C. The object of the present invention is to provide a salt of the compound of the formula (1), which salt should satisfy the following requirements: a) separation of pure solid compounds by crystallization or precipitation on an industrial scale, b) in physiological fluids There is a sufficiently high solubility to make an IV formulation, which allows for the preparation of the drug 1284039 by standard auxiliary compounds and standard equipment, the solid state properties of the formulation, d) the preferred preparation process without significant loss of chirality and chemical purity . This object can be attained by preparing a metal salt of the above compound of the formula (I) wherein the metal ion is a lithium ion or a divalent metal ion. Preferred divalent 5 metal salts are the calcium, magnesium and zinc salts. Most preferred are calcium salts. Surprisingly, it has been found that these salts, in contrast to the sodium and potassium salts mentioned in EP0733642, have very desirable properties, such as their ability to be isolated in solid (amorphous) form and in isotonic fluids at pH 7.4. The solubility is at least 10 times higher than the corresponding acid. Moreover, divalent salts can be prepared without racemization. In another aspect of the invention, there is provided a method of preparing a metal salt, preferably
Li+或二價Ca2+、Mg2+或Zn2+鹽的方法。 令人驚奇地，已經發現在室溫下，式I化合物的鋰鹽 和二價金屬鹽在諸如環己烷、曱苯、甲基叔丁基醚和乙酸 乙酯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(OEt)2)或混合氫氧化物/ 碳酸鹽（3Zn(0H)2-2ZnC03)的形式加入。上述方法中優選 的溶劑是甲基叔丁基醚或乙酸乙酯。當已經在溶液中獲得 1284039 玖、發明說明 了所述鹽時，可以通過如下步驟進行分離··首先通過共沸 瘵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/結晶並使産物的產率最 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 Z.B.等，AlChE J. 1984,拉，874-6; MYDLARZ J. 等，J· Chem. Eng. Data 1989, 11，124-6; MULLIN J.W·等， 10 Chem. Eng. Process. 1989, 269 93-9)。本發明範圍内的沈殿 劑的實例爲線性烴。優選的沈澱劑是線性c4_ClG烴。最優 選的沈澱劑是正己烷。 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I化合物的S-a_曱 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 2〇 及式I化合物的S-a-甲基苄基胺鹽。因爲S-a-曱基苄基胺似 乎毒性太大不能使用，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-甲基苄基胺來製備式I化合物的S-a-曱 1284039 玖、發明說明 基f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吡咯烷 酮（PVP)，崩解劑如澱粉和交聯pvp，滑動劑（glidiants)如膠 體二氧化矽，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 2〇 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1〜800 mg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 1284039 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4〇my| 5 極性非質子溶劑中。加入約U當篁的金屬試劑’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。卷 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、液加入己烧中’當形成固體產物時，用過遽收 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 全屈 試劑Μ 溶劑 M的數量 (gXmmo) 溶劑量 (ml) 烷量 -Inil) 固艘 粉太 I Ca(OH)2 MTBE 0.67 (9.0) 40 80 I Mgi+ Mg(OEt)2 MTBE 1.25 00.9) 40 130 103 固體 粉太 I ~Zx^~ 3Ζη(ΟΗ)2· 2Zn(C03)2 MTBE 1.05 (10.9) 115 235 95 固體 粉太 I Li+ LiOH MTBE 0.4 (16.7) 160 130 85 固體 粉東 I K+ KOH MTBE 1.02 (18.3) 95 235 98 固體 泡沫體 I Na十 NaOH MTBE 1.02 07.8) 95 235 89 固體 泡沫體 Π Ca(OH)2 EtOAc 0.56 (7.6) 75 235 87 固體 粉末 15 *化合物I = (3S>3-[[[l<2R)^(乙氧羰基>4·苯基丁基]環戊基]羰基]氨基]·2,3,4,5·四氩-2-氧 代-1Η-1-苯並氮雜環庚三烯小乙酸。 *化合物Π = [S<R*，S*)]-3-[[[H2·(乙氧羰基>4<1-萘基)丁基]環戊基]羰基]氨基]-2,3,4,5-四 氣-2·氧-1H-1-苯並氮雜環庚三烯·!_乙酸。 11 20 1284039 玖、發明說明 表2總結了所製備的鹽的性質。化合物含量用HPLC法 測定（MACHEREY-NAGELNucleosil 100-5 C18-HD柱，使 用從5%B到100%B的梯度體系，洗脫液A是ρΗ=5·1的磷酸 緩衝液，洗脫液Β是和10%洗脫液Α混合的乙腈）。對於部 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 物* 鹽中的 金屬 化合物含量 (%rel) _金屬含量^ (%W/W) 理論金屬含量 (%W/W) 在弱極性非質 子有機溶蛐中 的溶解唐 溶解性 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 *> 丨匕合物I=(3S>3-[[[1<2R)«2·(乙氧羰基)>4-苯J ‘丁基]環戊基]羰基]氨基]-2,3,4,5-四氫-2-氧 代-1H-1-苯並氮雜環庚三嫦-1-乙酸。 10 *化合物II = [S<R*，S*)]-3-[[[l-[2·(乙氧羰基萘基)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 1284039 玖、發明說明 實施例2、（3S)-3-[[[l-(2R)-2-(乙氧魏基)·4-苯基丁基]環戊 基]^基]氨基]-2,3,4,5-四氫_2_氧代•苯並氮雜環庚三 烯-1-乙酸的S-α-甲基苄基胺鹽的製備 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-1H-1-苯並氮雜環庚三 烯-1-乙酸溶解在90ml無水乙醇中。在2〇〜25〇c下加入41g S-ct-甲基苄基胺。將自然形成的晶體漿液加熱至4(Γ(：,並 攪拌1小時。待冷卻至〇〜5它後，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 10 。第一批收集到19g(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 雜環庚三烯-1-乙酸的S-a-甲基苄基胺鹽。 實施例3、（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 15 烯-1-乙酸鈣鹽的製備 向30g (3S)-3-[[[H2R)-2-(乙氧羰基）冬苯基丁基]環戊 基]羰基]氨基]-2,3,4,5-四氫-2-氧代-111-1-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，授拌所 20 得的混合物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 1284039 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。過濾分離固體產物，並用5〇ml己烷洗 滌。乾燥後獲得25.6g灰白色自由流動的粉末。 b-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=2.2, 6.6, 7.6)，7·19 (2H，dddd，J=〇.6，1.7, 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(1Η，dd，J=7.2和 10.8)，4·01(1Η，dd，J=7.1 和 10 1〇·8)，3.33(1H，ddd，J=8.0, 13·2, 13·7)，2·57(1Η，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(1Η，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=l.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一6.7, 9.6, 13.6)，2.02-1.42 (8H，m)，1.21 (3H，dd，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-(1-萘基）丁基]環戊基]羰基]氨基]-2,3,4,5-四氫-氧代-1H-1-20 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[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-乙酸溶於190ml MTBE中。加入 45ml乙醇和4.5g S-a-甲基苄基胺。在4°C貯存4天並每天攪 14 1284039 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Π即[S-(1^*，8*)]-3-[[[1-[2-(乙氧叛基）-4-(1-秦基）丁基]知►戍基]数基 ]氨基]-2,3,4,5-四氫-氧代-1Η·1_苯並氮雜環庚三烯-1_乙酸 5 的S-α-曱基苄基胺鹽。 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-111-1-苯並氮雜環庚 二婦-1-乙酸舞鹽的製備 在攪拌下，在 15分鐘内，向 10g[S_(R*，S*)]-3-[[[l-[2-( 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50ml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，5〇艺，ι2〇毫巴 )後’獲得7.4g自由流動的粉末。 h-NMR: 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 1284039 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=1.5 和 8)，7·13 (1H，三重雙峰，J=1.5, 8, 8)，4.48 (1H，d，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)。 【圖式簡單說明】 無 10 【圖式之主要元件代表符號表】 無 16A method of Li+ or a divalent Ca2+, Mg2+ or Zn2+ salt. Surprisingly, it has been found that at room temperature, the lithium and divalent metal salts of the compounds of formula I are in weakly polar aprotic solvents such as cyclohexane, toluene, methyl t-butyl ether and ethyl acetate. The solubility in is very good. The salts of the present invention can be readily obtained by mixing a hydroxide or a suitable salt of the desired metal with a solution or slurry of the compound of formula I in the above weakly polar aprotic solvent. Alternatively, when the solubility of the hydroxide or salt of the desired metal is insufficient 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 which forms an azeotrope with water must be selected. For a metal having very poor hydroxide solubility, the metal may be added in the form of an ethoxylate (for example, Mg(OEt)2) or a mixed hydroxide/carbonate (3Zn(0H)2-2ZnC03). The preferred solvent in the above process is methyl tert-butyl ether or ethyl acetate. When 1284039 已经 has been obtained in the solution, and the salt is described by the invention, the separation can be carried out by the following steps: First, the water still present is removed by azeotropic distillation, followed by mixing with the precipitating agent. The precipitant is defined as a second liquid which is added to the solution to lower the solubility of the dissolved compound, causing precipitation/crystallization of the compound and maximizing the yield of the product. It is necessary that the two liquids (the original solvent and the added precipitant) are completely miscible with each other in an arbitrary ratio. (This method is also used to reduce the solubility of inorganic salts in aqueous solutions by the addition of water-miscible organic solvents (ALFASSI ZB et al, AlChE J. 1984, ed., 874-6; MYDLARZ J. et al., J. Chem. Eng Data 1989, 11, 124-6; MULLIN JW et al, 10 Chem. Eng. Process. 1989, 269 93-9). Examples of sedatives within the scope of the invention are linear hydrocarbons. Preferred precipitants are linear c4_ClG Hydrocarbon. The most preferred precipitant is n-hexane. Since in all cases the salt is isolated as an amorphous precipitate, the precipitate appears to be homogeneous in all cases, sometimes requiring 15 A true crystallization step is carried out to increase the purity of the active compound which must meet stringent requirements. Surprisingly, it has been found that the S-a-mercaptobenzylamine salt of the compound of formula I is very suitable for the purification of these compounds, for example The salt is crystalline and can be recrystallized from an organic solvent in a high yield, preferably an alcohol such as ethanol or isopropanol. Thus, the present invention also relates to a Sa-methyl group of a compound of formula I Benzylamine salt because of Sa-mercaptobenzyl The amine appears to be too toxic to be used, so the salt is only suitable for use as an intermediate in the purification step. Sa-methylbenzyl can be added to a solution of a compound of formula I in ethanol or isopropanol or other suitable alcohol. The amine is used to prepare Sa-曱1284039 化合物 of the compound of formula I, and the invention describes the base f-amine salt. After the solution is allowed to stand for cooling, the salt will crystallize out from the solution (depending on the concentration). The pharmaceutically acceptable salts of the present invention are formulated. Commonly used preparations such as tablets, capsules or suppositories can be used. 5 These pharmaceutical preparations can be prepared by known methods such as direct compression, granulation, extrusion, molding, and conventional use. Solid excipients such as fillers such as cellulose, lactose and starch, binders such as cellulose and polyvinylpyrrolidone (PVP), disintegrants such as starch and crosslinked pvp, gliders such as colloidal Cerium oxide, a lubricant such as magnesium stearate, or conventional liquid and semi-solid excipients such as polyethylene glycol, castor oil derivatives, triglycerides and paraffins. Preservatives, for example, parabens, and emulsifiers such as polysorbates. The pharmaceutically acceptable salts of the invention are suitable for use as large mammals, particularly humans, for the treatment of heart failure and for the promotion of especially heart Urination and sodium urinary 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. For this purpose, parenteral administration is possible. The compounds of the present invention are used, especially in the form of pharmaceuticals for intravenous, oral or suppository administration. The dosages employed may vary from person to person and will vary depending upon the nature of the condition being treated, the particular substance employed, and the mode of administration. For large mammals, especially humans, it is generally suitable to administer a pharmaceutical form in a single dose of from 1 to 800 mg. [Embodiment 3] The following examples are intended to illustrate the invention in more detail, and are not intended to limit the scope of the invention in any way. EXAMPLES Example 1. General procedure for the preparation of metal salts of the compounds of formula I. Approximately 15 mmol of the active form of the acid form is dissolved or suspended in a 4 〇 my| 5 polar aprotic solvent. A metal reagent of about U is added. The reagent is dissolved in water or the same solvent as the solvent used for the active compound. In some cases, water must be added to initiate the reaction. Water is removed by azeotropic distillation. When the metallization reagent is not a hydroxide or ethoxylate, the solvent is completely removed, and then redissolved in 40 to 160 ml of the original weakly polar aprotic solvent, 10 followed by filtration to remove the unreacted metal reagent and optionally formed. Other salt. The filtrate and liquid are added to the hexane. When the solid product is formed, the product is collected with hydrazine. When a 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 Compound * Metal full-refraction reagent in salt 数量 Number of solvent M (gXmmo) Solvent amount (ml) Alkane-Inil) Solid powder too I Ca(OH)2 MTBE 0.67 (9.0) 40 80 I Mgi+ Mg(OEt)2 MTBE 1.25 00.9) 40 130 103 Solid powder too I ~Zx^~ 3Ζη(ΟΗ)2· 2Zn(C03)2 MTBE 1.05 (10.9) 115 235 95 Solid powder too I Li+ LiOH MTBE 0.4 (16.7) 160 130 85 Solid powder East I K+ KOH MTBE 1.02 (18.3) 95 235 98 Solid foam I Na ten NaOH MTBE 1.02 07.8) 95 235 89 Solid foam Π Ca(OH)2 EtOAc 0.56 (7.6) 75 235 87 Solid powder 15 *Compound I = (3S>3-[[[l<2R)^(ethoxycarbonyl>4·phenylbutyl]cyclopentyl]carbonyl]amino]·2, 3,4,5·tetraar-2-oxo-1Η-1-benzoazepines. *Compound Π = [S<R*,S*)]-3-[[[H2 (Ethoxycarbonyl>4<1-naphthyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetras-2-oxy-1H-1-benzodiazepine Heptanetriene·!-acetic acid. 11 20 1284039 发明, description of the invention Table 2 summarizes the properties of the prepared salts. The content of the compound was determined by HPLC (MACHEREY-NAGEL Nucleosil 100-5 C18-HD column, using a gradient system from 5% B to 100% B, and the eluent A was a phosphate buffer of ρΗ=5.1, and the eluent was Β It is acetonitrile mixed with 10% eluent. For Part 5, the metal content was determined by coordination titration with ethylenediaminetetraacetic acid disodium salt. For other metals, the metal content was determined by atomic emission spectroscopy (AES). Properties of the salts prepared in Table 2 and Table 1 Compounds * Content of metal compounds in the salt (% rel) _ Metal content ^ (% W / W) Theoretical metal content (% W / W) in weakly polar aprotic organic solvents Solubility Tang Cao 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 soluble I K+ 78.4 7.5 6.8 Insoluble soluble I Na+ 84.7 4.3 4.1 Insoluble easily soluble Π Ca2+ nd 3.4 3.3 Soluble soluble*> Hydrate I=(3S>3-[[[1<2R)«2·(ethoxycarbonyl)>4-benzene J 'butyl]cyclopentyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine heptatrione-1-acetic acid. 10 *Compound II = [S<R*,S*)]-3-[[[l-[2·(ethoxycarbonylnaphthyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4 , 5-tetrahydro-2-oxo-1H-1·benzazepines. N.d. = not determined From Table 2, it can be seen that Li, Ca, 15 Mg and Zn salts separated as solid powders can be dissolved in a weakly polar aprotic solvent. Examples of such solvents are ethyl acetate, toluene, cyclohexane and methyl tert-butyl ether. These compounds can also be dissolved in polar aprotic solvents such as THF, acetone, acetonitrile, DMF and DMSO. The metal content measured in the salt is slightly higher than the theoretical amount, but this is normal in these types of post-treatment and analysis. In the process of forming a salt with a monovalent strong base 20 hydroxide, degradation of the active substance occurs, resulting in a low compound content in the final salt. 12 1284039 发明, invention description Example 2, (3S)-3-[[[l-(2R)-2-(ethoxy Wei)) 4-phenylbutyl]cyclopentyl]]yl]amino] Preparation of S-α-methylbenzylamine salt of -2,3,4,5-tetrahydro-2-oxo-benzoxazepine-1-acetic acid 18g (3S)-3- [[[l-(2R)-2-(ethoxycarbonyl)_4_phenylbutyl]cyclopenta-5yl]carbonyl]amino]-2,3,4,5•tetrahydro-2-oxo-1H 1--1-Benzazepine-1-acetic acid was dissolved in 90 ml of absolute ethanol. 41 g of S-ct-methylbenzylamine was added at 2 Torr to 25 Torr. The naturally formed crystal slurry was heated to 4 (Γ, and stirred for 1 hour. After cooling to 〇~5, it was stirred for another 4 hours, and the crystals were collected by filtration, washed with 40 ml of cold absolute ethanol, and vacuum at 45 °C. Dry in an oven. 10. The first batch collected 19 g of (3S)-3-[[[l-(2R)-2-(ethoxycarbonyl)-4.phenylbutyl]cyclopentyl]carbonyl]amino]. Sa-methylbenzylamine salt of 2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetic acid. Example 3, (3S)- 3-[[[l-(2R)-2-(ethoxycarbonyl)-4-phenylbutyl]cyclopentyl]carbonyl]amino]·2,3,4,5-tetrahydro-2-oxo Preparation of -1H-1-benzoxazepine-15-en-1-acetate calcium salt to 30 g of (3S)-3-[[[H2R)-2-(ethoxycarbonyl)-t-phenylphenyl] ring Sa-methylbenzylamine salt of amyl]carbonyl]amino]-2,3,4,5-tetrahydro-2-oxo-111-1-benzoazepine-1·acetic acid To a solution of 120 ml of methyl tert-butyl ether (MTBE), 100 ml of a 1 M aqueous hydrochloric acid solution was added, and the mixture obtained in 20 was stirred for 10 minutes. The layers were separated, and the organic layer was washed with 15 ml of water at least 3 times until the pH was higher than 5. 2 g of 95% Ca(OH) 2 was added and the mixture was heated to reflux to 55 °C. When the amount of the suspension did not decrease significantly after 30 minutes, 0.5 ml of water was added. The mixture was refluxed by a dehydrator (Dean-Stark apparatus) for 2 hours. After 2 hours, the distillate was completely clarified and the reaction mixture was slightly cloudy. 13 1284039发明, Invention Description The mixture was cooled to 30-35 ° C and added to 240 ml of hexane over 30 minutes through an in-line filter. The solid product was isolated by filtration and washed with 5 mL of hexanes. Flowing powder. b-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=2.2, 6.6, 7.6), 7·19 (2H, dddd, J=〇.6, 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 (1Η, dd, J=7.2 and 10.8), 4·01 (1Η, dd, J=7.1 and 10 1〇·8), 3.33 (1H, ddd) , J=8.0, 13·2, 13·7), 2.57 (1Η, 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 (1Η, 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=l.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,dd,J=7.1 and 7·2) . Example 4, Compound II is [S-(R*,S*)]-3-[[[l-[2-(ethoxycarbonyl)-4-(1-naphthyl)butyl]cyclopentyl] Preparation of S-α-methylbenzylamine salt of carbonyl]amino]-2,3,4,5-tetrahydro-oxo-1H-1-20 benzazepine-1-acetic acid 21g of compound II is [S-(R*,S*)]_3-[[[l-[2-(ethoxycarbonyl)-4-(1-naphthyl)butyl]cyclopentyl]carbonyl]amino] -2,3,4,5-Tetrahydro-oxo-1H-1-benzazepine-1-acetic acid was dissolved in 190 ml of MTBE. 45 ml of ethanol and 4.5 g of S-a-methylbenzylamine were added. Store at 4 ° C for 4 days and stir 14 1284039 每天 per day. Description After mixing once, the crystals were collected by filtration, washed with 80 ml of MTBE, and dried at 45 ° C in a vacuum oven. The first batch of 19 g of compound was collected [S-(1^*,8*)]-3-[[[1-[2-(ethoxyxo)-4-(1-methyl))butyl] S-α-mercaptobenzylidene of the amino group]amino]-2,3,4,5-tetrahydro-oxo-1Η·1_benzoazepine-1 -acetic acid 5 Base amine salt. Example 5, [S-(R*,S*)]-3-[[[l-[2-(ethoxycarbonyl)-4-(1-naphthyl)butyl]cyclopentyl]carbonyl]amino] Preparation of -2,3,4,5-tetrahydro-oxo-111-1-benzoazepine-2 -acetic acid dance salt with stirring, in 10 minutes, to 10 g [S_(R *,S*)]-3-[[[l-[2-( 10 ethoxycarbonyl)-4-(1-naphthyl)butyl]cyclopentyl]carbonyl]amino]-2,3,4, Sa-methylbenzylamine salt of 5-tetrahydro-oxo-1H-1-benzazepine-1-acetic acid formed in 80 ml of methyl tert-butyl ether (MTBE) and 60 ml of water To the 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 mL water. 15 The organic layer was concentrated to an oil, 15 ml of ethyl acetate was added, and the obtained solution was again concentrated to oil. The oil was redissolved in 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 through a dehydrator (Dean-Stark apparatus) for 4 hours. The solution was filtered and the solution volume was reduced to 4 〇 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 an additional 30 minutes. The solid product was isolated by filtration and washed twice with 1 mL of hexane. After drying in vacuo (18 hours, 5 〇 art, ι 2 〇 mbar), 7.4 g of free-flowing powder was obtained. h-NMR: 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 1284039 玖, invention description (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, triplet doublet, J=1.5, 8, 8), 7.21 (1H, dd, J=1.5 and 8), 7·13 (1H , triple doublet, J=1.5, 8, 8), 4.48 (1H, d, J=16), 4.23 (1H, double triplet, J=8,8,12), 4·14·3·99 5 (3H,m), 3.56 (1H, triplet 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). [Simple description of the diagram] None 10 [The main components of the diagram represent the symbol table] None 16