SE453748B - (2s,3r)-3-amino-2-hydroxi-4-(4-metoxifenyl)-butanoyl-(s)-leucin - Google Patents
(2s,3r)-3-amino-2-hydroxi-4-(4-metoxifenyl)-butanoyl-(s)-leucinInfo
- Publication number
- SE453748B SE453748B SE8106084A SE8106084A SE453748B SE 453748 B SE453748 B SE 453748B SE 8106084 A SE8106084 A SE 8106084A SE 8106084 A SE8106084 A SE 8106084A SE 453748 B SE453748 B SE 453748B
- Authority
- SE
- Sweden
- Prior art keywords
- hydroxy
- methoxyphenyl
- amino
- acid
- solution
- Prior art date
Links
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000001914 filtration Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 102100032126 Aminopeptidase B Human genes 0.000 description 5
- -1 N-protected 2-oxoethylamine Chemical class 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 108090000449 aminopeptidase B Proteins 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical class CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- ZXHZVSUXSLRNAU-AWEZNQCLSA-N (2s)-4-methyl-2-(4-phenylbutanoylamino)pentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)CCCC1=CC=CC=C1 ZXHZVSUXSLRNAU-AWEZNQCLSA-N 0.000 description 1
- UQRGMQOTEOXNOQ-SJORKVTESA-N (2s,3r)-2-hydroxy-4-(4-methoxyphenyl)-3-(phenylmethoxycarbonylamino)butanoic acid Chemical compound C1=CC(OC)=CC=C1C[C@H]([C@H](O)C(O)=O)NC(=O)OCC1=CC=CC=C1 UQRGMQOTEOXNOQ-SJORKVTESA-N 0.000 description 1
- BKBNTVXNLBNBEC-AMIZOPFISA-N (2s,3r)-3-acetamido-2-hydroxy-2-(4-methoxyphenyl)butanoic acid Chemical compound COC1=CC=C([C@](O)([C@@H](C)NC(C)=O)C(O)=O)C=C1 BKBNTVXNLBNBEC-AMIZOPFISA-N 0.000 description 1
- MOXDUSDNVGWXEY-NEPJUHHUSA-N (2s,3r)-3-acetamido-2-hydroxy-4-(4-methoxyphenyl)butanoic acid Chemical compound COC1=CC=C(C[C@@H](NC(C)=O)[C@H](O)C(O)=O)C=C1 MOXDUSDNVGWXEY-NEPJUHHUSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-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
- MUQYXPVMHCCFJE-UHFFFAOYSA-N 2-amino-2-hydroxy-4-oxobutanoic acid Chemical compound OC(=O)C(O)(N)CC=O MUQYXPVMHCCFJE-UHFFFAOYSA-N 0.000 description 1
- QVPLPSZGHFSYEQ-UHFFFAOYSA-N 2-amino-2-hydroxybutanoic acid Chemical compound CCC(N)(O)C(O)=O QVPLPSZGHFSYEQ-UHFFFAOYSA-N 0.000 description 1
- MNRPCLJIWCLGTR-UHFFFAOYSA-N 2-hydroxy-4-(4-methoxyphenyl)butanoic acid Chemical compound COC1=CC=C(CCC(O)C(O)=O)C=C1 MNRPCLJIWCLGTR-UHFFFAOYSA-N 0.000 description 1
- 125000003974 3-carbamimidamidopropyl group Chemical group C(N)(=N)NCCC* 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 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
- 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 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- MBRRYUQWSOODEO-LBPRGKRZSA-N benzyl (2s)-2-amino-4-methylpentanoate Chemical compound CC(C)C[C@H](N)C(=O)OCC1=CC=CC=C1 MBRRYUQWSOODEO-LBPRGKRZSA-N 0.000 description 1
- DGAUFTRWMCEXLW-UHFFFAOYSA-N benzyl (4,6-dimethylpyrimidin-2-yl)sulfanylformate Chemical compound CC1=CC(C)=NC(SC(=O)OCC=2C=CC=CC=2)=N1 DGAUFTRWMCEXLW-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 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
- 239000012267 brine Substances 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 235000013905 glycine and its sodium salt Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NMHMNPHRMNGLLB-UHFFFAOYSA-N phloretic acid Chemical compound OC(=O)CCC1=CC=C(O)C=C1 NMHMNPHRMNGLLB-UHFFFAOYSA-N 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 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
453 748 2 OH R1 - CH2 - CH - CH - CONHCHCOUH (VII) NH 2 R4 Rs vari R1 betecknar naftyl eller en grupp med formeln I R7 vari R6 och R7 var för sig betecknar väte; halogen, hydroxi, C1-C6-alkoxi, C1-C5- alkyl eller fenyl och vari R4 betecknar C3-C4-alkyl eller 3-guanidinopropyl, vari karboxylgruppen tidigare kan ha skyddats, om så erfordras, med C1-C6-alkyl eller bensyl och skyddsgruppen sedan avlägsnats, lämpligen genom katalytisk hydre- ring i närvaro av palladümßvart, som kännetecknas av följande steg: (A) en N-skyddad 2-oxoetylamin med den generella formeln R1 - f _ cue - az (I) 0 vari RI har ovan angiven betydelse och R2 betecknar lägre alkylkarbonylamíno som kan innehålla en halogenatom, ben- soylamíno, bensyloxíkarbonylamino,'ftalimino eller lägre alkoxikarbonylamino, reageras med glyoxylsyra eller dess ester med den generella formeln Hc _ cooR3 (II) 0 vari R3 betecknar väte eller C1-C6-alkyl, för att bilda en treo-3-skyddad amino- 2-hydroxi-4-oxosmörsyra eller estrar därav med den generella formeln ou H - ha - cooag (111) \_..
R1-(í- 0 Z-(S 2 vari R1, R2 och R3 har ovan angiven betydelse; (B) ovanstående förening reduceras därefter, lämpligen med metalliskt natrium eller metalliskt litium i flytande ammoniak eller med surt zink eller tenn eller genom katalytisk hydreríng, till en treo-3-skyddad amino-2-hydroxismörsyra eller estrar därav med den generella formeln _ on g_,¿T g a1 - cnz -_çH _ ca - cooR3 (lv) ° q , -- 453 748 vari R1, R2 och R3 har ovan angiven betydelse; (C) ovanstående förening utsätts därefter, om så erfordras, för följande steg a) optisk uppdelning, lämpligen med hjälp av en optiskt aktivçt-fenyletylamin eller brucin, och/eller b) avlägsnande av aminoskyddsgruppen, lämpligen genom hydrolys med saltsyra, och omvandling av föreningen till treo-3-amino-2-hydroxismörsyra med den generella formeln on I - on - en - coon (v) R'2 R1 ~ CH2 vari R'2 betecknar amino eller den skyddade aminogruppen, och (D) ovanstående förening kondenseras därefter på konventionellt sätt, för att bilda en peptidbindning, lämpligen enligt ett karbodiimidförfarande eller aktiv esterförfarande, såsom N-hydroxisuccinimidesterförfarandet, med en aminoättiksyra med den generella formeln Ra nnz _ en - coon (vx) vari R4 har ovan angiven betydelse.
Den nya föreningen (2S,3R)-3-amino-2-hydroxi-4-(4-metoxifenyl)- -butyryl-(S)-leucin, samt även fysiologiskt icke toxiska salter därav, exempelvis salter av klorvätesyra och ättiksyra, har inhi- berande effekt pâ aminopeptidas B, inhiberar bildandet av brady- kinin och uppvisar antiinflammatorisk effekt och kan förväntas bli ett användbart farmaceutiskt läkemedel för olika sjukdomar.
Inhiberande effekt på aminopeptidas B Testmetod: I Undersökningen av den aminopeptidas B-inhiberande effekten ut-H 'fördes enligt den metod som beskrivits av Hopsu et al., varvid processen dock var något modifierad ¿V.K.Hopsu, K.K.Makinen, G.G.
Glennerj Archives of Biochemistry and Biophysics,_ll4, S57 (1966L7. 453 748 En blandad lösning (pH 7,0), framställd genom tillsats av 1,0 ml av en 0,1 M buffertlösning av tris-klorvätesyra och 0,7 ml av en lösning innehållande en testsubstans till 0,3 ml 0,1 mM arginin-B-- naftylamid, värmdes vid 37°C under 4 minuter. Därefter tillsattes 0.2 ml av en aminopeptidas B-lösning. renad med hjälp av samma enzym- renihgsprocess som processen enligt Hopsu et al. under användning aV 3ePhadex G-100 (registrerat varumärke). och det hela fick reagera vid 37°C under 30 minuter. Därefter tillsattes 0,6 ml av en 1,0 M buffertlösning av ättiksyra (pH 4,2) inne- hållande Garnet GBC (o-amínoazotoluendiazoniumsalt) i en koncent- ration av 1,0 mg/ml och innehållande Tween 20 (registrerat varu- märke) i en koncentration av l,0%, och blandninqen fick stå under 15 minuter vid rumstemperatur varefter absorptionen (a) vid S30 nm mättes. Absorptionen (b) för blindprovet, som endast bestod av buffertlösning utan någon testsubstans, mättes samtidigt, och inhiberingsgraden för aminopeptidas B beräknades såsom (b-a)/b x 100. ' , Resultat: Inhiberingsgraden för varje testsubstans vid olika koncentra- tioner fastställdes med hjälp av ovanstående testmetod, och på basis därav bestämdes den 50%-iga inhiheringsgraden (IC50). Re- sultaten visas i tabell 1.
Tabell 1 ¿ - F_f>'.r_efl_ias ICSO (few/ml) I (25,3R1-3-amino-2-hydroxi-4-(4-metoxifenyl) butyryl-(S)-leucin 0,006 § Uppfinningen kommer i det föbíande att beskrivas i form av ett -,'_' specifikt exempel. _ V Exemggl _ X ' u) Franstallnlng av tree-(2128)-B-acetylaminø-2-hydrvxi-4- -°xo-4-(4-metoxifenylïsmörsyrfl n 453 748 N-lë-ox°-2-(4-metox1feny11ety17a=eeam1a (a2,a q, o,4oo m°1), 95,8 9 (l,l4 mol) natriumvätekarbonat och 66,3 g (0,720 mol) qlyoxylsyramonohydrat löstes 1 en blandning av 700 ml metanol och 200 ml vatten. När lösningen fick reagera vid 50-60°C var reaktionen avslutad efter 4 timmar. Reaktionsblandninfien koncent- rerades till torrhet under reducerat tryck. Återstoden löstes i vatten och tvättades därefter med etylacetat. Vattenfasen inr ställdes med klorvätesyra på pH l-2. Utfällda kristaller uppsam- lades genom filtrering, tvättades med vatten och torkades i vakuum.
Treo-(ZRS)L3-acetylamino-2-hydroxi-4~oxo-4-(4-metoxifenyl)smör- syra ernö11s. Uchy:e= 102,3 g (91.os). up. 193 - 19s°c (sönder- aenungz. ann-spektrum (anse-as: 5 = 1.9 man; cníco). 3.8 (s,3H; CH3-0), 4.5 (d,H,J = 4Hz; C§-OH), 5.7 (dd, H; C§fNH), 7.1, 7.9 (a,a,zn,2u,J = 9 az; -<<:;:>>-). (2) Framställning av treo-(2RS)-3-acetylamino-2-hydroxi-4- -(4-metoxifenyl)smörsyra Treo-(ZRS)-3-acetylamino-2-hydroxi-4-oxo-4-(4-metoxifenyl)- smörsyra (30,0 g, 0,107 mol) löstes 1 300 ml metanol och 1,50 q 5% palladium-på-kol tillsattes. När lösningen reducerades i en autoklav vid en temeratur av 40°C och vid ett vätgastryck av 25 kg/cmz var reaktionen avslutad efter ca 3 timmar.
Katalysatorn avlägsnades genom filtrering och filtratet koncent- rerades vid reducerat tryck. Till återstoden sattes 100 ml etyl- acetat och utfällda kristaller uppsamlades genom filtrering, tvättades med etylacetat och torkades i vakuum. Treo-(2RS)-3- -acetyl-amino-2-hydrox1-4-(4-metoxifenyl)smörsyra erhölls. utbyte 26.5 g (9z.1s1. smp. 101.5 - 1o9°c. nun-spektrum (cr3coop).j' gå = 2.3 ts. an; cu3-co), 3.1 (a, zu, J=anz; cnz), 4.o (s, sa; cn3:o), 4.6 (a, n, J-znz; eg-on), 1.0, 1.3 (a, a, za, za, J=9n=;“ -@-). 453 748 (3) Franställning av S(-)-l-fenyletylaminsaltet av (2S,3R)-3- -acetylamino-2-hydroxi-4-(4-metoxifenyl)smörsyra Treo-(ZRS)-3-acetylamino-2-hydroxi-4-(4-metoxifenyl)SmörSYra (l0,0 g, 37,0 mmol) och 4,8 g (37,0 mmol) S(-)-I-fenyletylamin löstes under värmning'i 75 ml etanol. Lösningen fick sedan svalna till rumstemperatur. Utfällda kristaller uppsamlades genom filtre- ring, tvättades med en liten kvantitet etanol och torkades i vakuum. 4,56 kristaller erhölls. fqlš° + s2,1° (c = 1,9, netanon .
Kristallerna (4,50 g) löstes i 30 ml etanol under värmning och lösningen fick svalna till rumstemperatur. Utfällda kristaller uppsamlades genom filtrering, tvättades med en liten kvantitet etanol och torkades. S(-)-l-fenyletylaminsaltet av (2S,3R)-3- -acetyl-amino-2-hydroxi-(4-metoxifenyl)smörsyra erhölls. utbym 4,24 g sm. f 194-19s°c ['q]åo + 32,8° (c = 0,5, metanol) (4) Pramställning av (28,3R)-3-acetylamino-2-hydroxi-4-(4- -metoxifenyl)smörsyra S(-)-fenyletylaminsaltet av (2S,3R)-2-acety1amino-2-hydroxi-4- -(4metoxifenyl)smörsyra (2,79 g, 7,20 mmol) sattes till 15 ml 0,5N vattenlösning av natriumhydroxid och S(-)-l-fenyletylaminen estraherades 3 gånger och varje gång med 15 ml etylacetat.
Vattenfasen separerades och inställdes med l-normal saltsvra på pH l-2, samt koncentrerades till torrhet vid reducerat tryck.
Till återstoden sattes 20 ml aceton, olösliga föreningar avlägs- nades genom filtrering och filtratet koncentrerades sedan till. jtorrhet vid reducerat tryck. Etylacetat (30 ml) sattes till âterq. 'stoden. Utfällda kristaller uppsamlades genom filtrering, tvätta- des med etylacetat och torkades i vakuum. (2S,3R)-3jacetvlamino- ' -2-hydroxi-4-(4-metoxifenyl)smbrsyra erhölls. A (utbyta 1,32 g (san) lujšzs» 21,1° (c = 1,1, metanol) 453 748 (S) Framställning av (28,3R)-3-amino-2-hydroxi-4-(4-metoxi- feny1)smörsyra (25.3R)-3-acetylamino-2-hydroxi-4-(4-metoxifenyl)smörsyra (4.89 g, 18,3 mmol) sattes till en blandning av 22 ml 2,SN saltsyra och 22 ml dioxan. När lösninaen värmdes vid 60°C var reaktionen avslutad efter 8 timmar.
Reaktionslösningen koncentrerades vid reducerat tryck till torr- het. Återstoden löstes 1 vatten och koncentrerades åter till torr- het vid reducerat tryck. Återstoden löstes 1 20 ml vatten och olösliga föreningar avlägsnades genom filtrerina. Vattenfasen inställdes därefter på pH 5-6 med 2N vattenlösning av natrium- hydroxid och kyldes 1 ett isbad. Utfällda kristaller uppsamlades genom filtrering, tvättades med vatten och torkades 1 vakuum. (25,3RL-3-amino-2-hydroxi-4-(4-metoxifenyl)smörsyra erhölls.
Z'u;7š° + 2s.9° (c_; 1. N Hcl). smp- 230- ntbyte= 3.26 g (79.6 s). 3.2 (aa, zu; 232°c (sönaeraelning). nun-spektrum (cF3c00D) 6 = CH21, 3.9 (s, 3H: CH3), 4.2 (multi, H; Cfi-NH2). 4-3 (är H: J = 4:12; cg-on), 7.1, 7.3 (d. d. 2H, 23. J = 9112: /__\ 1- (6) Framställning av (2S,3R)-3-bensyloxikarbonylamino-2- hydroxi-4-(4-metoxifenyl)smörsyra (23,3R)-3-amino-2-hydroxi-4-(4-metoxifenyl)smörsyra (2,70 g, 12,0 mmol), 2,52 ml (l8,0 mmol) trietylamin och 3,95 g (l4,4 mmol) bensyl-S-4,6-dimetylpyrimidin-2-yl-tiokarbonat löstes i en lösningsmedelblandning av 12 ml vatten och 12 ml dioxan.
Reaktionen var avslutad efter omröring över natten vid rumstempe- ratur. Reaktionslösnlngen koncentrerades vid reducerat tryck för avdestillering av dioxanen. Till återstoden sattes 50 ml vatten _och lösningen tvättades 2 gânåer, varje aång med 50 m1~etylacetatÄ Vattënfasen justerades med utspädd saltsyra till pH 1-2Ä Utfällda -"- Ioljellknande produkter eitrañerades 2 gånger, varje gång med 50 ml -etylacetat. Extrakten sammanfördes, tvåttades 3 aånger.med 50 ml av en vattenlösning av natriumklorid varje gåna, och torkades sedan över vattenfritt natriumsulfat. 453 748 Natriumsulfatet avlägsnades genom filtrering. Filtratet koncent- rerades under reducerat tryck och återstoden triturerades med petroleumeter. Separerade kristaller uppsamlades genom filtrering, tvättades med petroleumeter och torkades i vakuum. (2S,3R)-3- -bensyloxikarbonylaminQ-2-hydroxi-4-(4-metoxifenyl)smörsyra er- hölls. uubyte= 3.25 g 05.42). smp. iso - 1s2°c [G 138 + a7.1° (c = 1, aeuksyra). nun-spektrum (nMso-dß) 6 = 2.8 (d, zu, J - anz; cmz-cx), 3.7 (s, an; C113) 4.0 (d. n, J - znz; cg-oa), 4.1 (multi, n, cg-Nn), s.o (s, zn; cnz-c), 7.1 (multi, inn; Q., Q... øch NH). (7) Framställning av (25,3R)-3-bensyloxikarbonylamino-2- hydroxi-4-(4-metoxifenyl)butyryl-(S)-leucin-bensylester (28,3RL-3-bensyloxikarbonylamino-2-hydroxi-4-(4-metoxifenyl)- smörsyra (l,44 g, 4,00 mmol), 1,91 g (4,80 mmol) av p-toluensulfon- syrasaltet av bensyl-(S)-leucinat och 0,65 g (4,8 mmol) l-hydroxi- bensotriazol löstes i 23 ml tetrahydrofuran. Under kylning i ett is/saltbad sattes 0,67 ml (4,8 mol) trietylamin och 0,99 g (4,8 mmol) dicyklohexylkarbodiimid till lösningen, som fick reagera över natten.
\. Separerad dicyklohexylkarbamid filtrerades av och filtratet kon- centrerades under reducerat tryck. Återstoden löstes i 40 ml etylacetat och olösliga produkter frånseparerades genom filtre- ring ännu en gång och tvättades med etylacetat. Fi1tratet.och tvättlösningen sammanfördes och tvättades med 0,5N saltsyra 2 gånger, med en vattenlösning av natriumklorid 3 gånger, med 5%-ig vattenlösning av natriumvätekarbonat 2 gånger och därefter medlen vatteñlösning av koksalt 3 gånger, och torkades sedan över vettenfritt natriumsulfat.
Natrlumsulfatet fránseparerades genom filtrering och filtratet koncentrerades under reducerat tryck. Återstoden triturerades med n-hexan och utfälldä kristaller uppsamlades aenom filtrering, 453 748 tvättades med n-hexan øch torkades i vakuum. BensY1e5tefn av (ZS,3R)-3-bensyloxikarbonylamino-2-hydroxi-4-(4-metoxifenY17' butyryl-(S)-leucin erhölls. utbyte 2.21 q (9s,2 z). Smp- 124 ' l26°C~ ¿'u_;š;8 + 21_5° (C = 1, ätcixsyra). una-spektrum (cnc13) 6 - 0.9 (d. 6H, J = SH=fi (C§¿)2CH) 2.9 (a, 2H, J = anz; cn-cnz-Ar), 3.7 (S, sn; CH3-0). 5.0, 5.1 (s, S, za, za: CE: -OCOCHI CH2'°°°NH) 5_5 (<3, H, J = 932; NH), 'TfO (multi, EH; och NH). (8) Framställning av (25, 3R)-3-amino-2-hYÖr°Xi“4'(4'met°xi" fenyl)butyryl-(S)-leflßifl Bensylestern av (25,3R)-3-bensyloxikarbonylaminø-2-hydroxi-4- _(4-metox1fenyl)butyryl~(S)-leucin (l,69 G, 3,00 mmol) löstes i so ml ss:-19 atuiksyra. En xatalytisk mängd pallßdiumfivflrt till' sattes och väte infördes under atmosfärtryck i lösningen- När den katalytiska reduktionen avslutats i rumstemperatur efter 4,5 timmar frånseparerades palladiumsvart 9en°m filtrering °°h filtratet 1n¿un5taâe5 noggrant till torrhet under reducerat tryck.
Till återstoden sattes 20 ml aceton. Utfällda kristaller upp- samlades genom filtrering och tvättades sedan med aceton, var- efter torkades i vakuum. (ZS,3R)-3-amino-2-hydroxi-4*(4-metoki>% fenyllbutyryl-(S)-leucin erhölls. utbyte 0.95 g (94 s). smp. 228 - 2a1°c (sönaerae1n1ng>. ['«_7âå8 - 12.s° (C = 1, annixsyra).
NMR-spektrum (CF3C0OD1 6 = 1.1 (d, GH, J = 5Hz; (CH3)2CH[, 3,q_(d, zu, J = vnz; caz-Ari, 4.0 ts, an; cn3«ç), “" _ 4.1 (multi. H; cg-NHZ1, 4.7 (multi, H; eg-uni' 4.8 (a, n,'J = 4nz; eg-on). 1.o,_v.3 (a, a, za, J ¿_9az,' G 1ê;>a)« . H -i_
Claims (1)
1. 453 748 I 10 Patentkrav (2S,3R)-3-amino-2-hydroxi-4-(4-metoxifenyï)-butanoyï-(S)-ïeucin.
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 (2)
| Publication Number | Publication Date |
|---|---|
| SE8106084L SE8106084L (sv) | 1981-10-14 |
| SE453748B true SE453748B (sv) | 1988-02-29 |
Family
ID=26476602
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7909655A SE452888B (sv) | 1978-11-25 | 1979-11-22 | Sett att framstella treo-3-amino-2-hydroxibutanoylaminoettiksyror |
| SE8106084A SE453748B (sv) | 1978-11-25 | 1981-10-14 | (2s,3r)-3-amino-2-hydroxi-4-(4-metoxifenyl)-butanoyl-(s)-leucin |
| SE8403931A SE466200B (sv) | 1978-11-25 | 1984-07-31 | Treo-3-skyddad amino-2-hydroxi-4-oxosmoersyra eller dess ester samt ett saett foer framstaellning daerav |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE7909655A SE452888B (sv) | 1978-11-25 | 1979-11-22 | Sett att framstella treo-3-amino-2-hydroxibutanoylaminoettiksyror |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| SE8403931A SE466200B (sv) | 1978-11-25 | 1984-07-31 | Treo-3-skyddad amino-2-hydroxi-4-oxosmoersyra eller dess ester samt ett saett foer framstaellning daerav |
Country Status (13)
| Country | Link |
|---|---|
| US (3) | US4281180A (sv) |
| AR (1) | AR227636A1 (sv) |
| AU (1) | AU530362B2 (sv) |
| CA (3) | CA1182125A (sv) |
| CH (3) | CH650265A5 (sv) |
| DE (2) | DE2947140A1 (sv) |
| DK (1) | DK162288C (sv) |
| ES (1) | ES486572A1 (sv) |
| FR (3) | FR2442227A1 (sv) |
| GB (2) | GB2090595B (sv) |
| IT (2) | IT1194593B (sv) |
| NL (2) | NL188162C (sv) |
| SE (3) | SE452888B (sv) |
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 |
| DE3276110D1 (en) * | 1981-03-04 | 1987-05-27 | Ici Plc | Amide derivatives, processes for preparing them, their use as fungicides and pesticidal compositions containing them |
| 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 |
| EP2435402B1 (en) | 2009-05-28 | 2016-04-13 | Novartis AG | Substituted aminobutyric derivatives as neprilysin inhibitors |
| CN103896796B (zh) * | 2009-05-28 | 2016-04-27 | 诺华股份有限公司 | 作为脑啡肽酶抑制剂的取代的氨基丙酸衍生物 |
| 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 |
| US8586536B2 (en) * | 2010-12-15 | 2013-11-19 | Theravance, Inc. | Neprilysin inhibitors |
| 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 |
| US9102635B2 (en) | 2013-02-14 | 2015-08-11 | Novartis Ag | Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy |
| CU24330B1 (es) | 2013-02-14 | 2018-03-13 | Novartis Ag | Derivados del ácido 4-((1,1) bifenil-4-il)-3-(3-fosfonopropanamido) butanoico, activos como inhibidores de nep (endopeptidasa neutral) |
| 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 |
| CN109415308B (zh) * | 2016-07-05 | 2022-09-06 | 诺华股份有限公司 | 用于早期沙卡布曲中间体的新方法 |
| 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 |
| CN115784918B (zh) * | 2022-11-24 | 2024-10-15 | 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 |
Family Cites Families (14)
| 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 |
| 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 |
| US4179573A (en) * | 1974-07-01 | 1979-12-18 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | (2S,3R)-3-amino-2-hydroxy-4-phenylbutanoic acid |
| GB1510477A (en) * | 1975-07-22 | 1978-05-10 | Microbial Chem Res Found | Peptides and to amino acid intermediates thereof |
| US4189604A (en) * | 1975-07-22 | 1980-02-19 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Bestatin |
| 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 |
| NL7609939A (nl) * | 1975-09-12 | 1977-03-15 | Nobel Hoechst Chimie Societe A | Werkwijze voor de bereiding van n-acylhydroxyaryl- glycinen. |
| 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 |
| JPS6026099B2 (ja) * | 1977-09-21 | 1985-06-21 | 財団法人微生物化学研究会 | ペプチド、その酸附加塩およびその製造法 |
| 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 FR FR7928830A patent/FR2442227A1/fr active Granted
- 1979-11-22 NL NLAANVRAGE7908510,A patent/NL188162C/xx not_active IP Right Cessation
- 1979-11-22 CA CA000340428A patent/CA1182125A/en not_active Expired
- 1979-11-22 GB GB8200496A patent/GB2090595B/en not_active Expired
- 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 AR AR278992A patent/AR227636A1/es active
- 1979-11-22 AU AU53115/79A patent/AU530362B2/en not_active Ceased
- 1979-11-22 ES ES486572A patent/ES486572A1/es not_active Expired
- 1979-11-22 DE DE2954076A patent/DE2954076C2/de not_active Expired
- 1979-11-22 CH CH10433/79A patent/CH650265A5/de not_active IP Right Cessation
- 1979-11-22 CH CH5649/81A patent/CH653687A5/de not_active IP Right Cessation
- 1979-11-22 GB GB7940413A patent/GB2037754B/en not_active Expired
- 1979-11-22 DK DK496379A patent/DK162288C/da active
- 1979-11-22 CH CH6192/83A patent/CH653669A5/de 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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| SE453748B (sv) | (2s,3r)-3-amino-2-hydroxi-4-(4-metoxifenyl)-butanoyl-(s)-leucin | |
| Zervas et al. | Studies on arginine peptides. I. Intermediates in the synthesis of N-terminal and C-terminal arginine peptides | |
| Nishizawa et al. | Synthesis and structure-activity relations of bestatin analogs, inhibitors of aminopeptidase B | |
| US4165311A (en) | Addition compound of dipeptide derivative and amino acid derivative | |
| RS50470B (sr) | Inhibitori ćelijske adhezije | |
| US4173562A (en) | Process for the preparation of α-L-aspartyl-L-phenylalanine methyl ester | |
| US7935818B2 (en) | Process for the preparation and purification of valgancyclovir hydrochloride | |
| DE2218120A1 (de) | N-geschützte Aminosäuren und Peptide | |
| FR2622581A1 (fr) | Nouveaux derives de l-proline, leur preparation et leurs applications biologiques | |
| UA77756C2 (uk) | Спосіб одержання периндоприлу високої чистоти і проміжних продуктів, корисних у його синтезі | |
| FI95271C (sv) | Förfarande för att framställa 3-(L-pyroglutamyl)-L-tiazolidin-4-karboxylsyra och dess N-substituerade derivat | |
| JPS6026099B2 (ja) | ペプチド、その酸附加塩およびその製造法 | |
| SE452318B (sv) | Aminosyror till anvendning som mellanprodukter vid framstellning av bestatiner | |
| US4490386A (en) | Phosphate salts of 1-[2-[(1-alkoxycarbonyl-3-aralkyl)-amino]-1-oxoalkyl]octahydro-1H-indole-2-carboxylic acids, preparation of, and medical compositions thereof | |
| US4432896A (en) | Derivatives of hippuryl-L-phenylalanine | |
| IE42785B1 (en) | L-3-(3,4-dihydroxyphenyl)-2-methyl-alanine peptides | |
| US4257939A (en) | Peptide derivative | |
| Taylor et al. | Thallium in organic synthesis. XII. Improved syntheses of the 1-acyloxy-2 (1H)-pyridone class of active esters | |
| US3532736A (en) | Novel amino acid protecting group | |
| NO309479B1 (no) | Fremgangsmåte for fremstilling av (1S-(1R*,2S*,3R*))-N-(4- morfolinylsulfonyl)-L-fenylalanyl-3-(2-amino-4-tiazolyl)-N-((1- cykloheksylmetyl)-2,3-dihydroksy-5-metylheksyl)-L-alaninamid | |
| US3280098A (en) | Process of producing peptides and products obtained thereby | |
| EP0129163B1 (en) | Arphamenine and its related compounds, a process for their preparation and their use as medicaments | |
| CA2166246A1 (en) | Process of producing .alpha.-l-aspartyldipeptide amide derivatives | |
| IE65530B1 (en) | Process for the synthesis of optically active aminoacids | |
| DE2416355A1 (de) | Direkte synthese von dopaminaminosaeureamiden |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| NUG | Patent has lapsed |
Ref document number: 8106084-0 Effective date: 19920604 Format of ref document f/p: F |