DE2954076C2 - - Google Patents
Info
- Publication number
- DE2954076C2 DE2954076C2 DE2954076A DE2954076A DE2954076C2 DE 2954076 C2 DE2954076 C2 DE 2954076C2 DE 2954076 A DE2954076 A DE 2954076A DE 2954076 A DE2954076 A DE 2954076A DE 2954076 C2 DE2954076 C2 DE 2954076C2
- Authority
- DE
- Germany
- Prior art keywords
- aminopeptidase
- compound
- hydroxy
- inhibitory
- amino
- 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.)
- Expired
Links
- 230000002401 inhibitory effect Effects 0.000 description 9
- 102100032126 Aminopeptidase B Human genes 0.000 description 7
- 108090000449 aminopeptidase B Proteins 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 6
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VGGGPCQERPFHOB-UHFFFAOYSA-N Bestatin Natural products CC(C)CC(C(O)=O)NC(=O)C(O)C(N)CC1=CC=CC=C1 VGGGPCQERPFHOB-UHFFFAOYSA-N 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 229950009811 ubenimex Drugs 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- UJXVMAZAIMJQDZ-UHFFFAOYSA-N 2-[(3-amino-2-hydroxybutanoyl)amino]acetic acid Chemical class CC(N)C(O)C(=O)NCC(O)=O UJXVMAZAIMJQDZ-UHFFFAOYSA-N 0.000 description 1
- GAFNVJIFDNKAIU-KOLCDFICSA-N 2-[[(2s,3r)-3-amino-2-hydroxy-4-phenylbutanoyl]amino]acetic acid Chemical compound OC(=O)CNC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 GAFNVJIFDNKAIU-KOLCDFICSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- -1 3-amino-2-hydroxy-butanoyl arginine derivatives Chemical class 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 208000035154 Hyperesthesia Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- DICSXQHGGOAUNU-AWEZNQCLSA-N L-arginine 2-naphthylamide Chemical compound C1=CC=CC2=CC(NC(=O)[C@H](CCCN=C(N)N)N)=CC=C21 DICSXQHGGOAUNU-AWEZNQCLSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 241000970901 Streptomyces olivoreticuli Species 0.000 description 1
- OICQSNDEFNCEAE-UHFFFAOYSA-N [2-(aminodiazenyl)phenyl]methanediazonium Chemical class NN=NC1=CC=CC=C1C[N+]#N OICQSNDEFNCEAE-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
- C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Die Erfindung betrifft den Gegenstand des Patentanspruchs.
Aus der US-PS 40 29 547 ist (2S,3R)-3-Amino-2-hydroxy-4-
phenylbutanoylaminoessigsäure, die auch als Bestatin bezeichnet
wird, als Substanz mit relativ geringer Toxizität
bekannt. Sie wurde von H. Umezawa et al. aus Kultur
filtraten von Streptomyces olivoreticuli als Aminopepti
dase B-Inhibitor isoliert. Diese Verbindung übt eine erhöhte
Wirkung auf die Immunowirkung aus, wie die verzögerte
Hypersthesie, aktiviert den in-vivo-Verteidigungsmechanismus
und zeigt eine inhibierende Wirkung gegenüber Krebs
(vgl. JA-OS 1 17 435/1971). Ferner wird angegeben, daß man von
der Verbindung eine Wirkung als Pharmazeutikum erwartet.
Es ist ferner bekannt, daß verschiedene 3-Amino-2-hydroxy-
butanoylaminoessigsäuren neben Bestatin eine gleiche oder
noch stärker inhibierende Aktivität gegenüber Aminopeptidase
B ausüben als Bestatin.
Aus der DE-OS 28 40 636 sind 3-Amino-2-hydroxy-butanoyl-
arginin-Derivate einschließlich deren optischer Isomere
bekannt. Weiterhin werden hier Syntheseverfahren zur Herstellung
dieser Verbindungen bereitgestellt.
Der Erfindung liegt demnach die Aufgabe zugrunde,
(2S, 3R)-3-Amino-2-hydroxy-4-(4-methoxyphenyl)butanoyl-(S)-leucin
mit einer noch besseren Hemmwirkung gegenüber der Aminopeptidase B
bereitzustellen.
Diese Aufgabe wird gemäß Patentanspruch gelöst.
Die DE-OS 26 32 396 betrifft Bestatinderivate und Verfahren
zu ihrer Herstellung. Die hier erwähnten Verbindungen Nr. 21
und Nr. 22, welche die höchste Aktivität der Verbindungen
dieser DE-OS besitzen, weisen IC₅₀-Werte von 0,01 µg/ml
auf, wohingegen die erfindungsgemäße Verbindung einen IC₅₀
von 0,006 µg/ml besitzt. Eine derartig gesteigerte Aktivität
war in Kenntnis des Standes der Technik nicht zu erwarten.
Die erfindungsgemäße Verbindung übt eine inhibierende
Wirkung gegenüber Aminopeptidase B aus, hemmt die Bildung
von Bradykinin und zeigt antiinflammatorische Wirkungen,
so daß sie sich als Pharmazeutika für verschiedene
Krankheiten eignet.
Die Inhibierungswirkung gegenüber der Aminopeptinase B
wird, wie nachfolgend beschrieben durchgeführt.
Die Messung der inhibierenden Wirkung gegenüber Aminopeptidase
B wird nach der Methode durchgeführt, die von Hopsu et
al. (V. K. Hopsu, K. K. Makinen, G. G. Glenner; Archives of
Biochemistry and Biophysics, 114, 557 (1966)) beschrieben
wird, wobei jedoch das Verfahren etwas modifiziert wird.
Eine gemischte Lösung (pH 7,0), die in der Weise hergestellt
worden ist, daß 1,0 ml einer 0,1 m Tris-Chlorwasserstoffsäure
pufferlösung und 0,7 ml einer Lösung, die eine Testprobe enthält,
zu 0,3 ml 0,1 M Arginin-β-naphthylamid zugesetzt
werden, wird auf 37°C während 4 Minuten erhitzt. Anschließend
werden 0,2 ml einer Aminopeptidase B-Lösung, die nach dem
gleichen Enzymreinigungsverfahren wie im Falle des Verfahrens
von Hopsu et al. unter Verwendung von Sephadex® G-100
gereinigt worden ist, zugesetzt und
während 30 Minuten bei 37°C reagieren gelassen. Dann werden
0,6 ml einer 1,0 M Essigsäurepufferlösung (pH 4,2), die
Garnet GBC (o-Aminoazotoluoldiazoniumsalz) in einer Konzentration
von 1,0 mg/ml, sowie Tween® 20 in einer
Konzentration von 1,0% enthält zugesetzt,
worauf man das Ganze während 15 Minuten bei Zimmertemperatur
stehenläßt. Anschließend wird das Absorptionsverhältnis
(a) bei 530 nm gemessen. Das Absorptionsverhältnis
(b) der Blindlösung, in der nur die Pufferlösung verwendet
wird, die keine Probe enthält, wird gleichzeitig
gemessen. Die Inhibierungswirkung gegenüber Aminopeptidase
B wird nach der Beziehung (b-c)/b × 100 berechnet.
Die Inhibierungswirkungen einer jeden Probe bei verschiedenen
Konzentrationen werden nach der vorstehenden Testmethode
ermittelt, wobei die IC₅₀-Werte (50%ige Hemmwerte)
abgeleitet werden. Die Ergebnisse gehen aus der Tabelle I
hervor.
Die erfindungsgemäße Verbindung kann nach den in der
DE-OS 29 47 140 beschriebenen Methoden hergestellt werden.
Die physikalischen und chemischen Eigenschaften der neuen
Verbindung gehen ebenfalls aus der genannten DE-OS hervor.
Claims (1)
- (2S, 3R)-3-Amino-2-hydroxy-4-(4-methoxyphenyl)butanoyl-(S)- leucin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14550978A JPS5572151A (en) | 1978-11-25 | 1978-11-25 | Threo-(2rs)-3-amino-2-hydroxy-4-oxo-4-phenylbutyric acid, its ester, and their preparation |
| JP15315778A JPS5579353A (en) | 1978-12-13 | 1978-12-13 | Preparation of (2s,3r)-3-amino-2-hydroxy-4- phenylbutanoylaminoacetic acid and its intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2954076C2 true DE2954076C2 (de) | 1988-02-25 |
Family
ID=26476602
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE2954076A Expired DE2954076C2 (de) | 1978-11-25 | 1979-11-22 | |
| DE19792947140 Granted DE2947140A1 (de) | 1978-11-25 | 1979-11-22 | Verfahren zur herstellung von threo-3-amino-2-hydroxybutanoyl- aminoessigsaeure |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19792947140 Granted DE2947140A1 (de) | 1978-11-25 | 1979-11-22 | Verfahren zur herstellung von threo-3-amino-2-hydroxybutanoyl- aminoessigsaeure |
Country Status (13)
| Country | Link |
|---|---|
| US (3) | US4281180A (de) |
| AR (1) | AR227636A1 (de) |
| AU (1) | AU530362B2 (de) |
| CA (3) | CA1182125A (de) |
| CH (3) | CH653669A5 (de) |
| DE (2) | DE2954076C2 (de) |
| DK (1) | DK162288C (de) |
| ES (1) | ES486572A1 (de) |
| FR (3) | FR2442227A1 (de) |
| GB (2) | GB2090595B (de) |
| IT (2) | IT1194593B (de) |
| NL (2) | NL188162C (de) |
| SE (3) | SE452888B (de) |
Families Citing this family (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4370318A (en) * | 1980-07-07 | 1983-01-25 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Bestatin-related compounds as immunopotentiator |
| JPS5767516A (en) * | 1980-09-24 | 1982-04-24 | Microbial Chem Res Found | Novel analgesic agent |
| GB2094786B (en) * | 1981-03-04 | 1985-09-11 | Ici Plc | Herbicidal and fungicidal amide derivatives |
| JPS58110553A (ja) * | 1981-12-24 | 1983-07-01 | Microbial Chem Res Found | ベスタチンのγ型結晶及びその製造法 |
| JPS606647A (ja) * | 1983-06-17 | 1985-01-14 | Microbial Chem Res Found | アルフアメニン及びその関連化合物と合成法 |
| JPS62205095A (ja) * | 1986-03-04 | 1987-09-09 | Toyo Jozo Co Ltd | 新生理活性物質アルドスタチンおよびその製造法 |
| US4681972A (en) * | 1986-09-16 | 1987-07-21 | Warner-Lambert Company | Separation of diastereomers |
| US4871870A (en) * | 1987-03-16 | 1989-10-03 | Biomeasure, Inc. | Immunomodulators and method of making same |
| IT1216104B (it) * | 1988-03-16 | 1990-02-22 | Zambon Spa | Peptidi ad attivita' farmaceutica. |
| IT1217567B (it) * | 1988-05-11 | 1990-03-30 | Zambon Spa | Processo diastereoselettivo per la preparazione di intermedi utili per la sintesi di derivati peptidici |
| JPH0759507B2 (ja) * | 1989-02-23 | 1995-06-28 | 日本化薬株式会社 | 骨髄異形成症候群治療剤 |
| NL9101380A (nl) * | 1991-08-13 | 1993-03-01 | Dsm Nv | Werkwijze voor de bereiding van een alfa-aminozuur, de overeenkomstige ester en amide. |
| US5455353A (en) * | 1993-03-24 | 1995-10-03 | Hoffmann-La Roche Inc. | 4-(benzyl-2-oxo-oxazolidin-5 ylmethyl)N tertbutyl-decahydroisoquinoline-3-carboxamides |
| US5656603A (en) * | 1995-05-31 | 1997-08-12 | Loyola University Of Chicago | Aminopeptidase P inhibitors and uses thereof |
| CA2312385A1 (en) * | 1999-06-22 | 2000-12-22 | Daiso Co., Ltd. | Process for producing erythro-3-amino-2-hydroxybutyric acid derivatives |
| JP2005029470A (ja) * | 2001-06-21 | 2005-02-03 | Japan Energy Electronic Materials Inc | 新規ノルスタチン誘導体 |
| ES2602826T3 (es) * | 2009-05-28 | 2017-02-22 | Novartis Ag | Derivados aminobutíricos sustituidos como inhibidores de neprilisina |
| MA33364B1 (fr) | 2009-05-28 | 2012-06-01 | Novartis Ag | Dérivés aminobutyriques substitués en tant qu'inhibiteurs de néprilysine |
| JO2967B1 (en) | 2009-11-20 | 2016-03-15 | نوفارتس ايه جي | Acetic acid derivatives of carbamoyl methyl amino are substituted as new NEP inhibitors |
| CN101891647B (zh) * | 2010-03-15 | 2012-12-19 | 浙江普洛康裕制药有限公司 | 一种乌苯美司的制备方法 |
| ME02295B (me) * | 2010-12-15 | 2016-02-20 | Theravance Biopharma R&D Ip Llc | Inhibitori neprilizina |
| CN102391145B (zh) * | 2011-08-31 | 2014-07-02 | 深圳万乐药业有限公司 | 一种乌苯美司中间体的光学异构体的拆分方法 |
| AP2015008621A0 (en) | 2013-02-14 | 2015-07-31 | Novartis Ag | Substituted bisphenyl butanoic nep 'neutral endopeptidase' inhibitors |
| WO2014126972A1 (en) | 2013-02-14 | 2014-08-21 | Novartis Ag | Substituted bisphenyl butanoic acid derivatives as nep inhibitors with improved in vivo efficacy |
| CN103360277A (zh) * | 2013-04-01 | 2013-10-23 | 上海信谊万象药业股份有限公司 | 一种乌苯美司重结晶的方法 |
| CN103333089A (zh) * | 2013-06-20 | 2013-10-02 | 深圳万乐药业有限公司 | N-[(2s,3r)-4-苯基-3-苄基-3-苄氧甲酰氨基-2-羟基丁酰]-l-亮氨酸苄酯的晶型及其制备方法 |
| CN106117075B (zh) * | 2016-01-14 | 2020-06-12 | 上海信谊万象药业股份有限公司 | 一种新型乌苯美司重结晶方法 |
| EP3481799A1 (de) * | 2016-07-05 | 2019-05-15 | Novartis AG | Neues verfahren für frühe sacubitrilzwischenprodukte |
| CN106631880B (zh) * | 2016-08-01 | 2018-06-01 | 四川青木制药有限公司 | 一种乌苯美司δ晶型及其制备方法 |
| CN106831473B (zh) * | 2017-02-22 | 2019-07-16 | 江西瑞雅药业有限公司 | 3-酰胺基-4-(2’-烷氧基-4-联苯基)丁酸衍生物及其制备方法、药物组合物 |
| AU2022376563A1 (en) | 2021-11-01 | 2023-12-07 | Alkahest, Inc. | Benzodioxane modulators of leukotriene a4 hydrolase (lta4h) for prevention and treatment of aging-associated diseases |
| CN115784918A (zh) * | 2022-11-24 | 2023-03-14 | 四川青木制药有限公司 | 一种高纯度乌苯美司中间体的制备方法 |
| CN115594606A (zh) * | 2022-12-16 | 2023-01-13 | 成都傲科新技术有限责任公司（Cn） | 苏式-2-羟基-3-乙酰氨基-4-苯基羰基丁酸不对称合成方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2632396A1 (de) * | 1975-07-22 | 1977-02-03 | Microbial Chem Res Found | Bestatinderivate und verfahren zu ihrer herstellung |
| DE2840636A1 (de) * | 1977-09-21 | 1979-03-29 | Microbial Chem Res Found | Peptide, verfahren zu ihrer herstellung und ihre therapeutische verwendung |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2242086A1 (en) * | 1973-09-03 | 1975-03-28 | Aries Robert | Antibacterial, antiviral dihydroxy butyric acid derivs - active against Gram-positive and -negative cocci and bacilli |
| US4179573A (en) * | 1974-07-01 | 1979-12-18 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid |
| US4029547A (en) * | 1974-07-01 | 1977-06-14 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Biologically active substance, bestatin, and production thereof |
| US4052449A (en) * | 1974-07-01 | 1977-10-04 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Biologically active substance, bestatin, and production thereof |
| US4189604A (en) * | 1975-07-22 | 1980-02-19 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Bestatin |
| CA1066304A (en) * | 1975-09-12 | 1979-11-13 | Yani Christidis | Process for manufacturing n-acyl derivatives of hydroxyarylgycines and novel products resulting therefrom |
| FR2351952A1 (fr) * | 1975-09-12 | 1977-12-16 | Nobel Hoechst Chimie | Procede de fabrication de derives n-acyles de glycines a substituees par des radicaux aromatiques |
| JPS609487B2 (ja) * | 1976-03-26 | 1985-03-11 | 財団法人微生物化学研究会 | 免疫制癌剤 |
| US4105789A (en) * | 1976-05-10 | 1978-08-08 | E. R. Squibb & Sons, Inc. | Carboxyalkylacylamino acids |
| GB1540019A (en) * | 1977-06-01 | 1979-02-07 | Microbial Chem Res Found | Bestatin derivatives |
| FR2393788A2 (fr) * | 1977-06-10 | 1979-01-05 | Microbial Chem Res Found | Derives de bestatine |
| US4243678A (en) * | 1977-12-30 | 1981-01-06 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Acylhydrocarbylaminoalkanoic acids, compositions and uses |
-
1979
- 1979-11-22 IT IT27487/79A patent/IT1194593B/it active
- 1979-11-22 AU AU53115/79A patent/AU530362B2/en not_active Ceased
- 1979-11-22 GB GB8200496A patent/GB2090595B/en not_active Expired
- 1979-11-22 ES ES486572A patent/ES486572A1/es not_active Expired
- 1979-11-22 AR AR278992A patent/AR227636A1/es active
- 1979-11-22 CH CH6192/83A patent/CH653669A5/de not_active IP Right Cessation
- 1979-11-22 GB GB7940413A patent/GB2037754B/en not_active Expired
- 1979-11-22 FR FR7928830A patent/FR2442227A1/fr active Granted
- 1979-11-22 CA CA000340428A patent/CA1182125A/en not_active Expired
- 1979-11-22 DE DE2954076A patent/DE2954076C2/de not_active Expired
- 1979-11-22 CH CH5649/81A patent/CH653687A5/de not_active IP Right Cessation
- 1979-11-22 DK DK496379A patent/DK162288C/da active
- 1979-11-22 DE DE19792947140 patent/DE2947140A1/de active Granted
- 1979-11-22 SE SE7909655A patent/SE452888B/sv not_active IP Right Cessation
- 1979-11-22 CH CH10433/79A patent/CH650265A5/de not_active IP Right Cessation
- 1979-11-22 NL NLAANVRAGE7908510,A patent/NL188162C/xx not_active IP Right Cessation
- 1979-11-23 US US06/096,693 patent/US4281180A/en not_active Expired - Lifetime
-
1980
- 1980-05-12 FR FR8010563A patent/FR2449078A1/fr active Granted
- 1980-11-28 US US06/211,035 patent/US4391986A/en not_active Expired - Lifetime
-
1981
- 1981-07-10 FR FR8113611A patent/FR2483409B1/fr not_active Expired
- 1981-10-06 NL NL8104545A patent/NL8104545A/nl not_active Application Discontinuation
- 1981-10-14 SE SE8106084A patent/SE453748B/sv not_active IP Right Cessation
- 1981-12-15 IT IT8125614A patent/IT1211147B/it active
- 1981-12-31 US US06/336,492 patent/US4453003A/en not_active Expired - Lifetime
-
1982
- 1982-06-14 CA CA000405157A patent/CA1170667A/en not_active Expired
- 1982-08-24 CA CA000410051A patent/CA1167464A/en not_active Expired
-
1984
- 1984-07-31 SE SE8403931A patent/SE466200B/sv not_active IP Right Cessation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2632396A1 (de) * | 1975-07-22 | 1977-02-03 | Microbial Chem Res Found | Bestatinderivate und verfahren zu ihrer herstellung |
| DE2840636A1 (de) * | 1977-09-21 | 1979-03-29 | Microbial Chem Res Found | Peptide, verfahren zu ihrer herstellung und ihre therapeutische verwendung |
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