CN1079474A - 新的抗高血压化合物及它们的制备方法和含它们的药物组合物 - Google Patents
新的抗高血压化合物及它们的制备方法和含它们的药物组合物 Download PDFInfo
- Publication number
- CN1079474A CN1079474A CN92113839A CN92113839A CN1079474A CN 1079474 A CN1079474 A CN 1079474A CN 92113839 A CN92113839 A CN 92113839A CN 92113839 A CN92113839 A CN 92113839A CN 1079474 A CN1079474 A CN 1079474A
- Authority
- CN
- China
- Prior art keywords
- salt
- hexanaphthene
- oxoethyl
- carbonyl
- hydroxylamino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 title claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 206010020772 Hypertension Diseases 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 15
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 150000007530 organic bases Chemical class 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 6
- 239000011575 calcium Substances 0.000 claims abstract description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 4
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims abstract description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 4
- 229940079593 drug Drugs 0.000 claims abstract description 4
- 229930182817 methionine Natural products 0.000 claims abstract description 4
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 4
- 239000011591 potassium Substances 0.000 claims abstract description 4
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 4
- 239000011734 sodium Substances 0.000 claims abstract description 4
- 239000004475 Arginine Substances 0.000 claims abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 3
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 3
- NSOXQYCFHDMMGV-UHFFFAOYSA-N Tetrakis(2-hydroxypropyl)ethylenediamine Chemical compound CC(O)CN(CC(C)O)CCN(CC(C)O)CC(C)O NSOXQYCFHDMMGV-UHFFFAOYSA-N 0.000 claims abstract description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 150000001768 cations Chemical class 0.000 claims abstract description 3
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960001231 choline Drugs 0.000 claims abstract description 3
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims abstract description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 3
- 150000002500 ions Chemical class 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 19
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- -1 alkaline earth metal carbonate Chemical class 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 230000003276 anti-hypertensive effect Effects 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000005204 segregation Methods 0.000 claims description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 2
- 239000002184 metal Substances 0.000 abstract description 2
- 239000002220 antihypertensive agent Substances 0.000 abstract 1
- 229940127088 antihypertensive drug Drugs 0.000 abstract 1
- 239000003999 initiator Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 229960004756 ethanol Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000005526 G1 to G0 transition Effects 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 238000000711 polarimetry Methods 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000003821 enantio-separation Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000005987 sulfurization reaction Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- QKIVRALZQSUWHH-SFYZADRCSA-N (1s,2r)-2-[[2-(hydroxyamino)-2-oxoethyl]-methylcarbamoyl]cyclohexane-1-carboxylic acid Chemical compound ONC(=O)CN(C)C(=O)[C@@H]1CCCC[C@@H]1C(O)=O QKIVRALZQSUWHH-SFYZADRCSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229950010375 idrapril Drugs 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
与金属和有机碱生成的(+)-(1S,2R)-2-[[N-
(2-羟氨基-2-氧代乙基)-N-甲基-氨基]羰基]环己
烷-1-羧酸的新的盐,它们由下例通式表示。
其中R和R1结合在一起代表二阶阳离子选自
钙、乙二胺和其它药物上可接受的阳离子或有机碱,
或者如果R1=H+,R代表钠、钾、咪唑基、赖氨酸、胆
碱、二乙醇胺、精氨酸或组氨酸。它们具有ACE—抑
制活性,因此它们可作为抗高血压药物的活性成分使
用。
它们的制备方法,优选的包括在加氢催化剂存在
下在加氢条件下,用苄基保护的起始物酸与适宜的水
合物、碳酸盐或有机碱的反应。
Description
本发明涉及新的具有抗高血压活性的(+)-(1S,2R)-2-〔[N-(2-羟氨基-2-氧代乙基)-N-甲基-氨基]羰基〕环己烷-1-羧酸与金属和有机碱形成的盐,它们的制备方法和它们在药物上的应用,该盐由通式(Ⅰ)表示:
基中如果R和R1结合在一起时,它们代表二价阳离子其选自于钙、乙二胺和其它药物上可接受的阳离子或有机碱,或者如果R1+H+,则R代表钠、钾、咪唑基、赖氨酸、胆碱、二乙醇胺、精氨酸、组氨酸。在欧洲专利申请89106304.2中公开了(+)-(1S,2R)-2-[[N-(2羟氨基-2-氧代乙基)-N-甲基-氨基]羰基]环己烷-1-羧酸1,(D、C、I、Idrapril)化合物作为新的ACE-抑制剂,其具有抗高血压活性。
此酸当在通常的湿度和温度环境条件下暴露在空气中时易发生自动分解过程,产生明显与治疗使用不相容的杂质。该降解过程也可通过保存在以上条件下的酸的温度的上升而加速。
现已发现并为本发明的主要目的是根据本发明,如上定义的新盐不会发生前述的自动分解和降解过程。
从以下的实验数据可知本发明的盐,尤其是经彻底净化后的盐在通常的环境条件下稳定的化合物。另外这种盐就自身保存或包含(在固体状态)在用于治疗使用所提供的药物制剂(片剂、丸剂、胶囊、冻干的组合物等)中,都可随保存时间的延长而保持不发生变化。这些盐在药品中的应用可避免采用昂贵的保护方法否则这些保护方法就得用于上述酸的储存和它们转化成药物制剂的过程中。
本发明化合物的制备基于的方法特征在于将选自于(+)-(1S,2R)-2-[[N-(2-(2-苄基-羟氨基-2-氧代乙基)N-甲基-氨基]羰基]环己烷-1-羧酸2和(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸1的化合物与选自本发明定义的水合物和碱金属、碱土金属的碳酸盐或其它适宜盐的化合物、还有有机碱,在有机溶剂或其与水的混合物中进行反应,在反应物2作为起始原料的方法中反应还同时伴随有在适宜的加氢催化剂存在下,在大气压力下用氢气使苄基保护基团氢解,上述方法是以最后离析所需的酸的盐而完成的反应。
下列合成路线说明了本发明的方法。
其中Q为所述氢氧化物或碱金属盐或钙盐或有机碱。
在以上定义的方法中,优选的加氢催化剂为以碳为载体的Pd,但PtO2,Ph/Al2O3和阮内镍也可使用。
对于有机溶剂,除了甲醇和乙醇外,还可以是丙醇、四氢呋喃和二噁烷。
下列实施例仅是说明并不限制本发明范围,它解释了本发明化合物的特殊方面和化学-物理性质。
实施例1
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基-氨基]羰基]环己烷-1-羧酸钙盐。
在氮气氛下,向剧烈搅拌的在水(152ml)中的15.2g氢氧化钙悬浮液中加入溶于甲醇(1150ml)中的75g(+)-(1S,2R)-2-[[N-2-苄基羟氨基-2-氧代乙基)N-甲基氨基]羰基]环己烷-1-羧酸2的溶液,并在20℃氮气氛下持续搅拌20分钟。
在加入的15g 10% Pd/碳悬浮于152ml水中之后,在20℃用压力为1Atm的起始H2使产物进行加氢3小时。
当氢吸收停止(约吸收了5000ml)时,过滤催化剂并用水/甲醇(1/1)混合物(300ml)洗涤,将滤液与洗涤液合并在40℃真空下浓缩直到除去所有甲醇。
这样得到的悬浮液用200ml甲醇处理两次,除去之后仍在40℃真空下除去所有溶剂。
最后的悬浮液在0-4℃冷却20小时,过滤沉淀物并在滤器上用70ml 0-4℃预冷却水洗涤。
得到55g化合物3(产率85%),象牙色固体,具有下列化学物理性质:
熔点>250℃
[α]20D=+35.3°(C=1,H2O)
重金属<30PPm
硫化灰=40.6%(基于得到的产物)
C5(EDTA)=11.7%
K.F.=7.8%
乙醇=400PPm
TLC:固定相Merck F254硅胶板
流动相nBuOH/AcOH/H2O=6/2/2
单元点在Rf=0.7
HPLC:Nucleosil柱C135/u(250×4.6)
洗脱液CH3CN/H3PO40.1%=20/80
流速0.8ml/min
波长=214nm
注射20ml 0.01% CH3CN/H2O溶液=20/80
产物的手性纯度通过HPLC在手性柱上分析手性柱AGP
洗脱液CH3CN/PH=4.1的缓冲液=1/99
流速0.7ml/min
波长=214nm
注射20u 0.01% CH3CN/H2溶液=1/99
化学纯度:总杂质=0.5%
旋光纯度>98%
实施例2
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸钙盐
在氮气流和剧烈搅拌下,向在1500ml水中的15.2g氢氧化钙悬浮液中加入50g(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸1,混合物在20℃下进一步剧烈搅拌60分钟。
过滤(在滤纸上)所得到的轻悬浮液,在40℃真空下浓缩滤液至200ml。在0-4℃冷却24小时后,过滤沉淀产物并在滤器上用50ml0-4℃预冷却水洗涤。
得到48.2g化合物3(产率84%),象牙色固体,具有下列性质:
熔点>250℃
[α]20D=+34.8°(C=1,H2O)
Ca(EDTA)=10.1%(基于得到的产物)
K.F.=9.04%
TLC固定相Merck F254硅胶板
流动相nBuOH/AcOH/H2O=6/2/2
单元点
HPLC:分析及手性色谱在前述实施例1的条件下进行
化学纯度:总杂质=1.0%
旋光纯度>98%
实施例3
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸钠盐
在20℃搅拌下,将70g化合物2加入溶于95%乙醇(1050ml)的7.6g氢氧化钠中。
在氮气氛下,向溶液中加入悬浮于35ml水中的7g 10% Pd/碳并在20℃下用压力为1Am的起始H2加氢3小时。当氢吸收停止(4850ml)时,过滤催化剂并用95%乙醇(150ml)洗涤两次。
将滤液与洗涤液合并在30℃真空下挥发直至少量体积。两次向剩余物中加入200ml丙酮并再浓缩直至少量体积。然后用丙酮(200ml)稀释,过滤沉淀物并在滤器上用丙酮(100ml)洗涤。
得到56g化合物4,为吸湿的白色固体,具有下列化学-物理性质:
[α]30D=+26.0(C=1,H2O)
重金属<20PPm
硫化灰=19%(基于得到的产物)
K.F.=2.5%
乙醇=1.1%
丙酮=5.8%
TLC:固定相Merck F254硅胶板
流动相nBuOH/AcOH/H2O=6/2/2
单元点R.f.=0.7
HPLC:分析和手性色谱在前述实施例1条件下进行
化学纯度:总杂质=2.0%
旋光纯度>95%
实施例4
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸L-赖氨酸盐在搅拌下,向在95%乙醇(725ml)中的化合物2溶液中加入溶于水138ml的21g的赖氨酸。
在氮气氛下,向此溶液中加入5g 10% Pd/碳并在20℃下用压力为1Atm的起始H2加氢3小时。
当氢吸收停止(吸收了3600ml H2)时,在滤纸上过滤催化剂并用无水乙醇(150ml)洗涤两次。
将滤液与洗涤液合并在30℃真空下浓缩至干,两次向剩余物加入丙酮(200ml),然后在真空下除去挥发部分。
往得到的剩余物中再加入丙酮(200ml),过滤并在滤器上用丙酮(100ml)洗涤。
得到49g化合物5,为吸湿的白色固体。
HPLC分析在实施例1中的条件下进行:杂质总量为4%
实施例5
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸钾盐
适当变换反应物,按与实施例4相同方法进行制备。得到强吸湿的白色固体,具有以下化学-物理性质:
TLC:固定相Merck F254硅胶板
流动相nBuOH/AcOH/H2O=6/2/2
单元点R.f.=0.7
HPLC:分析和手性色谱在实施例1中的条件下进行。
化学纯度:总杂质=4.0%
旋光纯度>90%
实施例6
(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸咪唑盐
适当变换反应物,按与实施例4相同方法进行制备,得到吸湿的树脂状产物。
HPLC分析在实施例1中的条件下进行:杂质=10%
将已得到的可称量的和可物理定性的固体状化合物1和实施例1和3的化合物根据以下方法时行试验,认为在60℃空气中具有相对稳定性。
在预定的时间,将2g物质放入60℃恒温炉中。
进行HPLC分析,测定化合物的纯度和可能的杂质。
仪器:水600E多溶剂释放系统
可旋转的吸收率测试仪水484
注射孔20μ
积分水745数据软件
Nucleosil柱C185μ(250×4.6)
流动相CH3CN/H3PO40.01%=20/80
流速0.9ml/min
测试仪:波长214nm
样品制备:将20mg样品物质溶于100ml H2O/CH3CN 80/20
注射 20μ
在这些条件下的滞留时间为r.t.=.7.9min
结果列于表1,在第一栏中为酸(1)化合物的数据,其它的数据都是按相同方法试验所得的。
本发明的盐在适当的用量比例内在实践上与酸1化合物效力和活性持续时间都是可比较的。
通过按表2所列的实验结果将酸(1)化合物与实施例1的钙盐比较,从实验上证明了具有等同药理作用。
表2
本发明的盐构成了用于制备口服和胃肠外使用的药物组合物的活性组分。
这种组合物和制剂用已知的药物技术和使用通常的赋形剂,载体和溶剂来制备。
分别观察口服给药用量25至150mgs/天和胃肠外给药量2.5-25mgs/天的情况。
Claims (10)
1、稳定的(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)N-甲基氨基]羰基]环己烷-1-羧酸盐,由通式(Ⅰ)表示:
其中如果R和R1结合在一起,它们代表二价阳离子其选自于钙、乙二胺和其它药物上可接受的阳离子或有机碱,或者如果R1=H+,R代表钠、钾、咪唑基、赖氨酸、胆碱、二乙醇胺、精氨酸或组氨酸。
2、权利要求1的盐,特征在于它们具有ACE-抑制活性。
3、权利要求1式(Ⅰ)盐的制备方法,特征在于将选自(+)-(1S,2R)-2-[[N-(2-苄基羟氨基-2-氧代乙基)N-甲基氨基]羰基]环己烷-1-羧酸2和(+)-(1S,2R)-2-[[N-(2-羟氨基-2-氧代乙基)-N-甲基氨基]羰基]环己烷-1-羧酸1与选自本发明定义的水合物和碱金属、碱土金属的碳酸盐或其它适宜盐的化合物、还有有机碱,在有机溶剂或其与水的混合物中进行反应,在反应物2作为起始原料的方法中,反应还伴随有在加氢催化剂存在下在大气压下用氢气使苄基保护基团氢解的反应,上述方法是以最后离析所需的酸1盐而完成。
4、根据权利要求3的方法,特征在于酸2与选自水合物、碱金属或碱土金属碳酸盐或有机碱化合物的混合物在加氢催化剂存在下在大气压下与氢气进行了反应。
5、权利要求3的方法,特征在于所说的碱土金属是钙。
6、权利要求3的方法,特征在于所说的碱金属选自钠和钾。
7、权利要求3的方法,特征在于所的加氢催化剂是以碳为载体的钯。
8、权利要求3的方法,其所说的有机溶剂选自丙醇、四氢呋喃和二噁烷。
9、药物组合物,特征在于它含有作为活性成份的权利要求1的盐,还有通常的赋形剂和载体。
10、根据权利要求9的药物组合物,特征在于它具有抗高血压活性。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT91A003448 | 1991-12-23 | ||
ITMI913448A IT1252708B (it) | 1991-12-23 | 1991-12-23 | Sali stabili dell'acido (+)-(1r,2s)-2((n-(2-idrossilammino-2-ossoetil)-n-metilammino)carbonil)cicloesan-1-carbossilico,ad attivita' ace inibitrice, procedimento per la loro preparazione e composizioni farmaceutiche che li contengono. |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1079474A true CN1079474A (zh) | 1993-12-15 |
Family
ID=11361409
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN92113839A Pending CN1079474A (zh) | 1991-12-23 | 1992-12-23 | 新的抗高血压化合物及它们的制备方法和含它们的药物组合物 |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0575572A1 (zh) |
JP (1) | JPH06506002A (zh) |
CN (1) | CN1079474A (zh) |
AU (1) | AU657591B2 (zh) |
BG (1) | BG98050A (zh) |
BR (1) | BR9205652A (zh) |
CA (1) | CA2104372A1 (zh) |
CZ (1) | CZ379692A3 (zh) |
EE (1) | EE9400006A (zh) |
FI (1) | FI933685A (zh) |
HR (1) | HRP921454A2 (zh) |
HU (1) | HUT69287A (zh) |
IT (1) | IT1252708B (zh) |
LV (1) | LV10426B (zh) |
MA (1) | MA22749A1 (zh) |
MX (1) | MX9207543A (zh) |
NZ (1) | NZ245547A (zh) |
PL (1) | PL169086B1 (zh) |
PT (1) | PT101156A (zh) |
RU (1) | RU2079489C1 (zh) |
SI (1) | SI9200409A (zh) |
SK (1) | SK379692A3 (zh) |
TN (1) | TNSN92117A1 (zh) |
WO (1) | WO1993013056A1 (zh) |
YU (1) | YU110892A (zh) |
ZA (1) | ZA9210004B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114845603A (zh) * | 2020-04-27 | 2022-08-02 | 卡特-霍夫曼有限责任公司 | 用于柜的门移动系统 |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1264860B1 (it) * | 1993-06-21 | 1996-10-17 | Guidotti & C Spa Labor | Derivati di acidi cis- e trans-2(((2-(isdrossiammino)-2-ossoetil)- alchilammino)carbonil)cicloesancarbossilici |
US5639746A (en) * | 1994-12-29 | 1997-06-17 | The Procter & Gamble Company | Hydroxamic acid-containing inhibitors of matrix metalloproteases |
FR2817241B1 (fr) | 2000-11-30 | 2003-03-07 | Cebal | Tube aluminium avec embout secable |
AU2007302670A1 (en) * | 2006-09-28 | 2008-04-10 | Merck & Co., Inc. | Amine base salts of SAHA and polymorphs thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1224627B (it) * | 1988-04-12 | 1990-10-04 | Guidotti & C Spa Labor | Ammidi di acidi ciclometilen_1,2_dicarbossilici adattivita' terapeutica, procedimenti per la loro preparazione e composizioni farmaceutiche che le contengono. |
-
1991
- 1991-12-23 IT ITMI913448A patent/IT1252708B/it active IP Right Grant
-
1992
- 1992-12-12 WO PCT/EP1992/002903 patent/WO1993013056A1/en not_active Application Discontinuation
- 1992-12-12 AU AU30871/92A patent/AU657591B2/en not_active Ceased
- 1992-12-12 HU HU9302389A patent/HUT69287A/hu unknown
- 1992-12-12 BR BR9205652A patent/BR9205652A/pt not_active Application Discontinuation
- 1992-12-12 CA CA002104372A patent/CA2104372A1/en not_active Abandoned
- 1992-12-12 RU RU9293052414A patent/RU2079489C1/ru active
- 1992-12-12 EP EP92924726A patent/EP0575572A1/en not_active Withdrawn
- 1992-12-12 JP JP5511398A patent/JPH06506002A/ja active Pending
- 1992-12-21 SK SK3796-92A patent/SK379692A3/sk unknown
- 1992-12-21 NZ NZ245547A patent/NZ245547A/en unknown
- 1992-12-21 CZ CS923796A patent/CZ379692A3/cs unknown
- 1992-12-22 MA MA23040A patent/MA22749A1/fr unknown
- 1992-12-22 HR HR921454A patent/HRP921454A2/hr not_active Application Discontinuation
- 1992-12-22 SI SI9200409A patent/SI9200409A/sl unknown
- 1992-12-23 PT PT101156A patent/PT101156A/pt not_active Application Discontinuation
- 1992-12-23 YU YU110892A patent/YU110892A/sh unknown
- 1992-12-23 ZA ZA9210004A patent/ZA9210004B/xx unknown
- 1992-12-23 CN CN92113839A patent/CN1079474A/zh active Pending
- 1992-12-23 TN TNTNSN92117A patent/TNSN92117A1/fr unknown
- 1992-12-23 PL PL92297118A patent/PL169086B1/pl unknown
- 1992-12-23 MX MX9207543A patent/MX9207543A/es unknown
- 1992-12-23 LV LVP-92-358A patent/LV10426B/lv unknown
-
1993
- 1993-08-18 BG BG98050A patent/BG98050A/bg unknown
- 1993-08-20 FI FI933685A patent/FI933685A/fi not_active Application Discontinuation
-
1994
- 1994-05-23 EE EE9400006A patent/EE9400006A/xx unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114845603A (zh) * | 2020-04-27 | 2022-08-02 | 卡特-霍夫曼有限责任公司 | 用于柜的门移动系统 |
Also Published As
Publication number | Publication date |
---|---|
PT101156A (pt) | 1994-06-30 |
YU110892A (sh) | 1996-01-08 |
CA2104372A1 (en) | 1993-06-24 |
LV10426A (lv) | 1995-02-20 |
CZ379692A3 (en) | 1993-09-15 |
HUT69287A (en) | 1995-09-28 |
JPH06506002A (ja) | 1994-07-07 |
ITMI913448A1 (it) | 1993-06-23 |
HRP921454A2 (en) | 1995-02-28 |
RU2079489C1 (ru) | 1997-05-20 |
HU9302389D0 (en) | 1993-11-29 |
SK379692A3 (en) | 1995-04-12 |
WO1993013056A1 (en) | 1993-07-08 |
BR9205652A (pt) | 1994-05-03 |
ITMI913448A0 (it) | 1991-12-23 |
ZA9210004B (en) | 1993-12-13 |
NZ245547A (en) | 1995-12-21 |
BG98050A (bg) | 1994-04-29 |
AU3087192A (en) | 1993-07-28 |
AU657591B2 (en) | 1995-03-16 |
LV10426B (en) | 1995-08-20 |
PL297118A1 (en) | 1993-09-06 |
EP0575572A1 (en) | 1993-12-29 |
TNSN92117A1 (fr) | 1993-06-08 |
EE9400006A (et) | 1995-12-15 |
MA22749A1 (fr) | 1993-07-01 |
FI933685A0 (fi) | 1993-08-20 |
SI9200409A (en) | 1993-09-30 |
PL169086B1 (pl) | 1996-05-31 |
MX9207543A (es) | 1993-08-01 |
IT1252708B (it) | 1995-06-26 |
FI933685A (fi) | 1993-08-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1845917A (zh) | 3-[(2-{[4-(已氧基羰基氨基-亚氨基-甲基)-苯氨基]-甲基}-1-甲基-1 h-苯并咪唑-5-羰基)-吡啶-2-基-氨基]-丙酸乙酯-甲磺酸酯及其作为药物的用途 | |
CN1030920C (zh) | 孕二烯酮糠酸酯-水合物的制备方法 | |
CN1243779C (zh) | 具有y形分支的亲水性聚合物衍生物、其制备方法、与药物分子的结合物以及包含该结合物的药物组合物 | |
CN1023788C (zh) | 一种可吸性沉淀二氧化硅的制造方法 | |
CN1289515C (zh) | 不对称(转移)氢化催化剂 | |
CN1151845C (zh) | 含有晶体学稳定的无定形头孢茵素的组合物及其制备方法 | |
CN1024658C (zh) | 炔属不饱和化合物的羰基化方法 | |
CN1071323C (zh) | 缩肽衍生物或其盐的制造方法 | |
CN1527814A (zh) | 氧化氮合酶抑制剂磷酸盐 | |
CN1527834A (zh) | 制备二膦类化合物的方法及其应用 | |
CN1080288A (zh) | 酰氨基吲哚衍生物 | |
CN1079474A (zh) | 新的抗高血压化合物及它们的制备方法和含它们的药物组合物 | |
CN1660920A (zh) | 末端连接ω-氨基酸的聚乙二醇酸或活性酯及制法和应用 | |
CN1575199A (zh) | 相容性-多相有机溶剂系统 | |
CN1037266C (zh) | 喹啉衍生物的富马酸盐及其制法和其药物组合物 | |
CN1289482C (zh) | 氨氯地平的有机酸盐 | |
CN101065387A (zh) | 含磷酰胆碱基的化合物及其制备方法 | |
CN1079960A (zh) | 不对称氢化 | |
CN1125057C (zh) | 缩酚酸环肽衍生物的新型晶体及其制备方法 | |
CN1184213C (zh) | N-(1(s)-乙氧基羰基-3-苯基丙基)l-丙氨酸n-羧酸酐的结晶方法 | |
CN1198735A (zh) | 苯磺酰胺衍生物以及它们的制备和在医领域中的应用 | |
CN1068117A (zh) | 具有肾素抑制性质的杂环化合物它的制备方法及其用途 | |
CN1067055A (zh) | 3-头孢-4-羧酸-1-(2,2-二甲基丙酰氧基)乙酯非对映体的结晶性酸加成盐 | |
CN1077890C (zh) | 作为多巴胺d2激动剂的4-氨基乙氧基-吲哚衍生物 | |
CN1743320A (zh) | 糖精阴离子的离子液体及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C01 | Deemed withdrawal of patent application (patent law 1993) | ||
WD01 | Invention patent application deemed withdrawn after publication |