EP1565486A2 - Procede de preparation de l'acetate de glatiramer par le polymerisation d'un anhydride n-carboxy de la l-alanine, l-tyrosine, l-glutamate benzolique et l-lysine benzoloxycarbonyl - Google Patents
Procede de preparation de l'acetate de glatiramer par le polymerisation d'un anhydride n-carboxy de la l-alanine, l-tyrosine, l-glutamate benzolique et l-lysine benzoloxycarbonylInfo
- Publication number
- EP1565486A2 EP1565486A2 EP03775017A EP03775017A EP1565486A2 EP 1565486 A2 EP1565486 A2 EP 1565486A2 EP 03775017 A EP03775017 A EP 03775017A EP 03775017 A EP03775017 A EP 03775017A EP 1565486 A2 EP1565486 A2 EP 1565486A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- protected
- carried out
- lysine
- group
- polypeptide
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
Definitions
- Glatiramer Acetate is a synthetic polypeptide analog of myelin basic protein (MBP), which is a natural component of the myelin sheath. It is also defined in the Physicians' Desk Reference, 56 th Edition 2002 as consisting of acetate salts of synthetic polypeptides, containing four naturally occurring amino acids: namely, L- glutamic acid, L-alanine, L-tyrosine and L-lysine with an average molar fraction of 0.141, 0.427, 0.095 and 0.338 respectively. The average molecular weight is 4,700- 11,000 daltons.
- Glatiramer Acetate is a novel, safe and effective treatment for patients with the exacerbating- remitting form of multiple sclerosis and it is the active ingredient of CopaxoneTM, a medicament used for the treatment of multiple sclerosis.
- the process for the synthesis of Glatiramer Acetate is based on the polymerization of N-carboxyanhydrides of alanine 2, ⁇ -benzyl glutamate 3, N ⁇ -trifluoroacetyl lysine 7 and tyrosine 5, in anhydrous and cancer suspect solvent dioxane at room temperature for 24 hours using diethylamine as initiator (Scheme 2).
- Glatiramer acetate with the required average molecular weight (4.7 to 11 kDa) can be obtained either by chromatography of intermediate 10 containing high molecular weight species and collecting the fractions without the undesired species or by partial acid or enzymatic hydrolysis to remove the high molecular weight species with subsequent purification by dialysis or ultrafiltration. Further methods to obtain Glatiramer Acetate having the required average molecular weight are based on the preparation of the desired species while the amino acids are still protected, followed by deprotection.
- the present invention is directed to a new process for the preparation of a polypeptide designated in the present invention as 1 comprising the following amino acid units in the structure, namely: L-alanine, L-glutamic acid, L- lysine and L-tyrosine randomly arranged in the polypeptide 1, or a pharmaceutically acceptable salt thereof wherein said process, comprises the steps of:
- the advantages of the current process are the result of (i) the novel choice of side chain protection on the glutamic acid and lysine moieties and (ii) the utilization of acetic acid as solvent for the deprotection step thereby permitting the isolation of polypeptide 1 as an acetate salt directly from the reaction mixture without any additional procedures.
- said polymerization is carried out in the presence of an initiator, preferably said initiator comprises at least one of the following: diethylamine, triethylamine and diisopropylamine.
- a process of manufacturing Glatiramer Acetate comprising a single step deprotection of a protected copolymer 6, said protected copolymer 6 comprising a mixture of L- alanine, L-tyrosine, a protected L-glutamate and a protected L-lysine, protected by at least one protecting group, preferably said at least one protecting group is selected from a substituted or unsubstituted ⁇ -benzyl group or a substituted or unsubstituted N ⁇ -benzyloxycarbonyl group or an aryl group, preferably said substituted ⁇ -benzyl group or N ⁇ -benzyloxycarbonyl group is substituted with at least one of the following: Br, CI, NO 2 , OCH 3 .
- said separation and purification of the polypeptide 1 is carried out in a single step, preferably said single step involves a single dialysis against water.
- Protected Copolymer 6 (2.00 g) was dissolved in 40 mL of acetic acid by heating at 80°C under nitrogen. To the yellow solution was added 0.6 g Pd/C (30% wt.) and cyclohexene (5 mL) and then the reaction mixture was stirred at 80°C under nitrogen for 4 hours. The reaction was filtered through celite and the cake was washed with 4 mL of hot acetic acid. After evaporation of the filtrate with 32 mL toluene, a beige solid was obtained (polypeptide 1, 1.4 g, 70%).
- Protected copolymer 6 (5.00 g) was dissolved in 100 mL of acetic acid by heating at 80°C under nitrogen. To the yellow solution was added 1.5 g Pd/C (30% wt.) and 1,4-cyclohexadiene (7.4 mL) and then the reaction mixture was stirred at 80 0 C under nitrogen for 48 hours. The reaction was filtered through celite and the cake washed with 20 mL of hot acetic acid. After evaporation of the filtrate with 32 mL toluene, a beige solid was obtained (polypeptide 1, 2.8 g, 56%).
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Gastroenterology & Hepatology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Peptides Or Proteins (AREA)
- Polyamides (AREA)
Abstract
L'invention concerne un procédé de préparation d'un polypeptide désigné dans l'invention comme 1, constitué, dans la structure, des unités d'acides aminés suivantes: L-alanine, acide L-glutamique, L-lysine et L-tyrosine agencés aléatoirement dans le polypeptide 1, ou dans des sels pharmaceutiquement acceptables de ce polypeptide. Ledit procédé consiste : a) à polymériser un mélange de N-carboxyanhydrides de L-alanine, L-tyrosine, L-glutamate protégé et L-lysine protégé afin d'obtenir un copolymère 6 protégé ou un sel de ce copolymère (formule (I)) ; b) à déprotéger le copolymère 6 (ou un sel de ce copolymère) afin de produire le polypeptide 1 ou un sel pharmaceutiquement acceptable de celui-ci en une seule étape (formule (II)) ; c) à séparer et à purifier le polypeptide 1 (ou un sel pharmaceutiquement acceptable de celui-ci) afin d'obtenir un polypeptide 1 purifié. (formule (III)).
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA2411786 | 2002-11-13 | ||
| CA002411786A CA2411786C (fr) | 2002-11-13 | 2002-11-13 | Methode de preparation de polypeptide 1 |
| US10/326,994 US7049399B2 (en) | 2002-11-13 | 2002-12-24 | Process for the preparation of polypeptide 1 |
| US326994 | 2002-12-24 | ||
| PCT/CA2003/001744 WO2004043995A2 (fr) | 2002-11-13 | 2003-11-13 | Procede de preparation de polypeptide 1 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1565486A2 true EP1565486A2 (fr) | 2005-08-24 |
Family
ID=32313425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP03775017A Withdrawn EP1565486A2 (fr) | 2002-11-13 | 2003-11-13 | Procede de preparation de l'acetate de glatiramer par le polymerisation d'un anhydride n-carboxy de la l-alanine, l-tyrosine, l-glutamate benzolique et l-lysine benzoloxycarbonyl |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP1565486A2 (fr) |
| AU (1) | AU2003283152A1 (fr) |
| WO (1) | WO2004043995A2 (fr) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2349033T3 (es) | 2001-12-04 | 2010-12-22 | Teva Pharmaceutical Industries, Ltd. | Procedimientos para la medida de la actividad del acetato de glatiramer. |
| SI1797109T1 (sl) | 2004-09-09 | 2016-07-29 | Yeda Research And Development Co., Ltd. | Zmesi polipeptidov, sestavki, ki jih vsebujejo, in postopki za njihovo pripravo ter njihove uporabe |
| ATE536363T1 (de) * | 2004-09-09 | 2011-12-15 | Teva Pharma | Verfahren zur herstellung von mischungen von trifluoroacetyl-glatirameracetat bei verwendung von hydrobromsäure |
| WO2006050122A1 (fr) | 2004-10-29 | 2006-05-11 | Sandoz Ag | Procedes de preparation d'un glatiramere |
| AU2006211510B8 (en) * | 2005-02-02 | 2011-04-21 | Teva Pharmaceutical Industries, Ltd. | Process for producing polypeptide mixtures using hydrogenolysis |
| SI2046817T1 (sl) * | 2006-07-05 | 2010-04-30 | Momenta Pharmaceuticals Inc | Izboljšani postopek za pripravo kopolimera-1 |
| WO2008157697A2 (fr) | 2007-06-21 | 2008-12-24 | Momenta Pharmaceuticals, Inc. | Dosage de copolymère |
| EP2173766A1 (fr) | 2007-07-31 | 2010-04-14 | Natco Pharma Limited | Procédé de préparation de l'acétate de glatiramer (copolymère-1) |
| EP2277050B2 (fr) | 2008-04-16 | 2022-09-28 | Momenta Pharmaceuticals, Inc. | Analyse de compositions copolymères d'acides aminés |
| ES2612001T4 (es) | 2009-08-20 | 2018-02-07 | Yeda Research & Development Company, Ltd. | Terapia de baja frecuencia con acetato de glatirámero |
| USRE49251E1 (en) | 2010-01-04 | 2022-10-18 | Mapi Pharma Ltd. | Depot systems comprising glatiramer or pharmacologically acceptable salt thereof |
| US8759302B2 (en) | 2010-03-16 | 2014-06-24 | Teva Pharmaceutical Industries, Ltd. | Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis |
| NZ609938A (en) | 2010-10-11 | 2015-11-27 | Teva Pharma | Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate |
| WO2013009885A2 (fr) | 2011-07-11 | 2013-01-17 | Momenta Pharmaceuticals, Inc. | Evaluation de diéthylamide de copolymère |
| JP2014530819A (ja) | 2011-10-10 | 2014-11-20 | テバ ファーマシューティカル インダストリーズ リミティド | 酢酸グラチラマーに対する臨床的応答性を予測するために有用な一塩基多形 |
| CA3050086A1 (fr) | 2017-03-26 | 2018-10-04 | Mapi Pharma Ltd. | Systemes de depot de glatiramere pour le traitement de formes progressives de sclerose en plaques |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL36670A (en) * | 1971-04-21 | 1974-09-10 | Sela M | Therapeutic basic copolymers of amino acids |
-
2003
- 2003-11-13 EP EP03775017A patent/EP1565486A2/fr not_active Withdrawn
- 2003-11-13 WO PCT/CA2003/001744 patent/WO2004043995A2/fr not_active Application Discontinuation
- 2003-11-13 AU AU2003283152A patent/AU2003283152A1/en not_active Abandoned
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2004043995A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004043995A2 (fr) | 2004-05-27 |
| AU2003283152A8 (en) | 2004-06-03 |
| WO2004043995A3 (fr) | 2004-10-07 |
| AU2003283152A1 (en) | 2004-06-03 |
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| DAX | Request for extension of the european patent (deleted) | ||
| 17Q | First examination report despatched |
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