NO178028B - Fremgangsmåte ved fremstilling av 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre samt derivater derav - Google Patents
Fremgangsmåte ved fremstilling av 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre samt derivater derav Download PDFInfo
- Publication number
- NO178028B NO178028B NO904404A NO904404A NO178028B NO 178028 B NO178028 B NO 178028B NO 904404 A NO904404 A NO 904404A NO 904404 A NO904404 A NO 904404A NO 178028 B NO178028 B NO 178028B
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- Prior art keywords
- thiazolidine
- carboxylic acid
- pyroglutamyl
- derivatives
- formula
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 9
- -1 L-pyroglutamyl Chemical group 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 abstract description 8
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 abstract description 5
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- DZLNHFMRPBPULJ-UHFFFAOYSA-N thioproline Chemical class OC(=O)C1CSCN1 DZLNHFMRPBPULJ-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- DZLNHFMRPBPULJ-GSVOUGTGSA-N D-thioproline Chemical compound OC(=O)[C@H]1CSCN1 DZLNHFMRPBPULJ-GSVOUGTGSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachlorophenol Chemical compound OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 3
- RMHPSSGICDJKDR-VKHMYHEASA-N (2s)-5-oxopyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCC(=O)N1 RMHPSSGICDJKDR-VKHMYHEASA-N 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 1
- LHJGJYXLEPZJPM-UHFFFAOYSA-N 2,4,5-trichlorophenol Chemical compound OC1=CC(Cl)=C(Cl)C=C1Cl LHJGJYXLEPZJPM-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- SQRLNYSSTHJCIU-JEDNCBNOSA-N ethyl (4r)-1,3-thiazolidine-4-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)[C@@H]1CSCN1 SQRLNYSSTHJCIU-JEDNCBNOSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06173—Dipeptides with the first amino acid being heterocyclic and Glp-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Thiazole And Isothizaole Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av L-pyroglutaminsyre eller derivater derav av formel (III), hvor R^ er hydrogen, C^- Cq alkyl, C3-C7 cykloalkyl eller C2~C6 alkylkarbonyl.
Italiensk patent 1.202.426 beskriver L-tiazolidin-4-karboksylsyre med immuno-modulerende, ^ antitoksisk, anti-inflamma-torisk, antioksyderende og anti-eldende aktivitet, hvilken forbindelse fremstilles ved å starte fra en L-pyroglutaminsyre-reaktiv ester eller fra syrekloridet og L-tiazolidin-4-karboksylsyre.
Mer spesielt innbefatter nevnte prosess bruk av f.eks. hver av de reaktive estere av L-pyroglutaminsyre med pentaklor-fenol, pentafluorfenol, 2,4,5-triklorfenol, N-hydroksysuccinimid, N-hydroksyftalimid, som omsettes med L-tiazolidin-4-karboksylsyre i aprotiske oppløsningsmidler, i nærvær av tertiære baser, eller av L-pyroglutaminsyreklorid som omsettes med L-tiazolidin-4-karboksylsyre i et alkalisk medium.
Italiensk patentsøknad nr. 19.401 A/89 beskriver 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre-derivater med til-svarende farmakologiske egenskaper, hvilke derivater fremstilles ifølge analoge prosesser som starter fra L-pyroglutaminsyre-reaktive estere eller amider og alkoholer eller aminer.
Nevnte fremgangsmåter lider av enkelte ulemper, f.eks. bruk av toksiske forbindelser såsom halofenoler, dårlig stabili-tet av L-pyroglutaminsyre-estere med N-hydroksysuccinimid og N-hydroksyftalimid, utilfredsstillende utbytte, stor ustabilitet og vanskeligheter ved håndteringen av L-pyro-glutamylklorid.
Fremgangsmåten ifølge foreliggende oppfinnelse gjør det mulig å overvinne ovenfor nevnte ulemper og å fremstille disse forbindelser lettere, i større utbytte og uten bruk av toksiske og/eller ustabile intermediater.
Fremgangsmåten ifølge oppfinnelsen er særpreget ved å omsette en forbindelse av formel (I)
hvor:
Hl er hydrogen eller C^- Cq alkyl, og X er OH eller Cl, med en forbindelse av formel (II)
hvor:
R3 er hydrogen eller C3-C9 trialkylsilyl, med det forbehold at når X er OH, utføres reaksjonen i nærvær av et kondensa-sjonsmiddel. Slike kondensasjonsmidler kan være dicykloheksylkarbodiimid, diisopropylkarbodiimid eller basiske karbodiimider i aprotiske oppløsnignsmidler såsom dioxan, tetrahydrofuran, etylacetat, dimetylformamid, dimetylsulfok-syd, diklormetan, heksametylfosfortriamid eller blandinger derav, for å gi et 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre-derivat av formel (III)
hvor Ri kar ovenfor nevnte betydninger, hvilket derivat (III) eventuelt kan omdannes til 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre i meget godt utbytte under mildt sure eller basiske hydrolysebetingelser.
Spesielt har det overraskende blitt funnet at kun etyl-esteren av L-tiazolidin-4-karboksylsyre gjorde det mulig å erholde meget gode utbytter, mens andre estere, såsom metyl-eller isopropylestere, gav dårlige resultater. Den gunstige effekt av etylester II er uavhengig av typen av pyrogluta-minsyrederivat av formel I.
De følgende eksempler illustrerer oppfinnelsen ytterligere.
Eksempel 1
En oppløsning av 16,78 g (0,084 mol) av etyl-L-tiazolidin-4-karboksylat hydroklorid i 33 ml vann behandles med 16,78 g kaliumkarbonat og ekstraheres med 40 ml etylacetat. Oppløsningen omrøres og avkjøles til 0-5°C, derpå tilsettes til dette 19,2 g (0,093 mol) dicykloheksylkarbodiimid oppløst i 20 ml etylacetat samt 12 g (0,093 mol) L-pyroglutaminsyre. Reaksjonsblåndingen omrøres i 1 time ved 0-5°C, derpå i 12 timer ved romtemperatur, dicykloheksylurea filtreres fra, filtratet inndampes under vakuum, og det oljeaktige residuum, inneholdende etyl-3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylat tas opp i 25 ml vann. 3,73 g natriumhydroksyd oppløst i 13,3 ml vann tilsettes den resul-terende oppløsning. Etter 30 minutter surgjøres reaksjons-blandingen med konsentrert saltsyre ved 0-5°C, filtreres derpå under vask med litt kaldt vann og tørkes for å erholde 17,8 g (87,6%) av 3-(L-pyroglutamyl)-L-tiazolidin-4-
karboksylsyre, smp. 193-194"C.
Eksempel 2
23 g (0,1 mol) L-N-butoksykarbonylpyroglutaminsyre (E. Schroder og E. Klinger, Ann. Chem., 673, 1964, 202) og 16,1 g (0,1 mol) etyl-L-tiazolidin-4-^karboksylat oppløses i 150 ml THF, oppløsningen omrøres ved 0-5°C, 21 g (0,105 mol) dicykloheksylkarbodiimid tilsettes og oppslemmingen omrøres ved romtemperatur i 15 timer. Dicykloheksylurea filtreres, det gjenværende filtrat inndampes under vakuum og det oljeaktige residuum oppbevares i 40 ml vann. Til oppløs-ningen settes 6,6 g kaliumhydroksyd i litt vann i løpet av 30 minutter ved 15-20°C, pH justeres til 2 med saltsyre ved 0-5°C og etter 2 timer filtreres og tørkes den utfelte L-pyroglutamyl-L-tiazolidin-4-karboksylsyre, som gir 88%, smp. 193-4°C.
I tabell I er som sammenligningsforbindelser angitt resultatene erholdt ved bruk av metyl-, n-propyl- og isopropyl-estere av L-tiazolidin-H-karboksylsyre under samme betingelser som i eksempel 1 og 2 oppsummert.
Claims (2)
1. Fremgangsmåte ved fremstilling av 3-(L-pyroglutamyl)- L-tiazolidin-4-karboksylsyre samt derivater derav av formel
hvor Ri er hydrogen, C± - C6 alkyl, C3 - C7 cykloalkyl, eller C2 - Cg alkylkarbonyl,
karakterisert ved å omsette en forbindelse av formel (I)
hvor R1 har samme betydninger som angitt ovenfor og X er OH eller Cl, med en forbindelse av formel (II)
hvor R3 er hydrogen eller C3 - C9 trialkylsilyl, med det forbehold at når X=OH, utføres reaksjonen i nærvær av et kondensasj onsmiddel.
2. Fremgangsmåte ifølge krav 1, karakterisert ved at kondensas j onsmidlet er valgt fra gruppen omfattende dicykloheksylkarbodiimid og karbonyldiimidazol.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22003A IT1239029B (it) | 1989-10-12 | 1989-10-12 | Processo per la preparazione dell'acido 3-(l-piroglutamil)-l- tiazolidin-4-carbossilico e suoi derivati. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO904404D0 NO904404D0 (no) | 1990-10-11 |
| NO904404L NO904404L (no) | 1991-04-15 |
| NO178028B true NO178028B (no) | 1995-10-02 |
| NO178028C NO178028C (no) | 1996-01-10 |
Family
ID=11190043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO904404A NO178028C (no) | 1989-10-12 | 1990-10-11 | Fremgangsmåte ved fremstilling av 3-(L-pyroglutamyl)-L-tiazolidin-4-karboksylsyre samt derivater derav |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US5110936A (no) |
| EP (1) | EP0422566B1 (no) |
| JP (1) | JP2813450B2 (no) |
| KR (1) | KR100195895B1 (no) |
| AT (1) | ATE121420T1 (no) |
| AU (1) | AU644379B2 (no) |
| CA (1) | CA2027341C (no) |
| DE (2) | DE69018755T2 (no) |
| DK (1) | DK0422566T3 (no) |
| ES (1) | ES2028766T3 (no) |
| FI (1) | FI95271C (no) |
| GR (1) | GR910300072T1 (no) |
| HU (1) | HU210213B (no) |
| IE (1) | IE67047B1 (no) |
| IL (1) | IL95949A (no) |
| IT (1) | IT1239029B (no) |
| NO (1) | NO178028C (no) |
| ZA (1) | ZA908097B (no) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1230706B (it) * | 1989-02-10 | 1991-10-29 | Poli Ind Chimica Spa | Derivati dell'acido 3 piroglutamoil tiazolidin 4 carbossilico e loro proprieta' farmacologiche. |
| IT1237998B (it) * | 1990-01-23 | 1993-06-21 | Poli Ind Chimica Spa | Acido 3-l-(5-tioxo-l-prolil)tiazolidin-4-carbossilico e derivati, loro preparazione e composizioni farmaceutiche che li contengono |
| IT1270017B (it) * | 1994-09-27 | 1997-04-16 | Poli Ind Chimica Spa | "sintesi quantitativa dell'acido 3-(l-piroglutamil)-l-tiazolidin-4- carbossilico e suoi derivati" |
| CA2263764A1 (en) * | 1996-09-06 | 1998-03-12 | Michael John Martinelli | Process and novel intermediates |
| JP2010537984A (ja) * | 2007-08-28 | 2010-12-09 | イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ | ポリペプチドおよび蛋白質の化学合成のための方法および中間体 |
| CN102167727B (zh) * | 2011-01-29 | 2013-05-15 | 浙江金立源药业有限公司 | 一种匹多莫德的合成方法 |
| WO2016112977A1 (en) | 2015-01-15 | 2016-07-21 | Polichem S.A. | Di-pidotimod benzathine and solid forms thereof |
| KR101642445B1 (ko) * | 2016-01-11 | 2016-07-26 | (주)남양통신 | 수상태양광 발전장치용 계류장치 |
| CN107383162A (zh) * | 2017-07-06 | 2017-11-24 | 成都美域高制药有限公司 | 一种匹多莫德的制备方法 |
| CN108640912A (zh) * | 2018-06-19 | 2018-10-12 | 广州大光制药有限公司 | 一种匹多莫德的工业化规模制备方法 |
| CN111233854A (zh) * | 2019-12-30 | 2020-06-05 | 常州寅盛药业有限公司 | 一种匹多莫德杂质的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1202426B (it) * | 1987-01-26 | 1989-02-09 | Poli Ind Chimica Spa | Derivato di acido tiazolidin-4-carbossilico,sua preparazione e composizioni farmaceutiche che lo contengono |
-
1989
- 1989-10-12 IT IT22003A patent/IT1239029B/it active IP Right Grant
-
1990
- 1990-10-08 DE DE69018755T patent/DE69018755T2/de not_active Expired - Fee Related
- 1990-10-08 DK DK90119271.6T patent/DK0422566T3/da active
- 1990-10-08 EP EP90119271A patent/EP0422566B1/en not_active Expired - Lifetime
- 1990-10-08 IE IE359990A patent/IE67047B1/en not_active IP Right Cessation
- 1990-10-08 DE DE199090119271T patent/DE422566T1/de active Pending
- 1990-10-08 ES ES90119271T patent/ES2028766T3/es not_active Expired - Lifetime
- 1990-10-08 AT AT90119271T patent/ATE121420T1/de not_active IP Right Cessation
- 1990-10-09 ZA ZA908097A patent/ZA908097B/xx unknown
- 1990-10-09 US US07/594,313 patent/US5110936A/en not_active Expired - Lifetime
- 1990-10-10 IL IL9594990A patent/IL95949A/en not_active IP Right Cessation
- 1990-10-10 KR KR1019900015999A patent/KR100195895B1/ko not_active IP Right Cessation
- 1990-10-11 CA CA002027341A patent/CA2027341C/en not_active Expired - Fee Related
- 1990-10-11 HU HU906417A patent/HU210213B/hu not_active IP Right Cessation
- 1990-10-11 AU AU64521/90A patent/AU644379B2/en not_active Ceased
- 1990-10-11 NO NO904404A patent/NO178028C/no unknown
- 1990-10-11 FI FI905011A patent/FI95271C/fi active IP Right Grant
- 1990-10-12 JP JP2275100A patent/JP2813450B2/ja not_active Expired - Fee Related
-
1991
- 1991-11-15 GR GR91300072T patent/GR910300072T1/el unknown
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