CZ262796A3 - Cyclosylated n-protected analogs of dalargin and process for preparing thereof - Google Patents
Cyclosylated n-protected analogs of dalargin and process for preparing thereof Download PDFInfo
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- CZ262796A3 CZ262796A3 CZ962627A CZ262796A CZ262796A3 CZ 262796 A3 CZ262796 A3 CZ 262796A3 CZ 962627 A CZ962627 A CZ 962627A CZ 262796 A CZ262796 A CZ 262796A CZ 262796 A3 CZ262796 A3 CZ 262796A3
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- dalargin
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- hydrogen
- dalargine
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- GDPHPXYFLPDZGH-XBTMSFKCSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[2-[[(2r)-2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)NC(=O)CNC(=O)[C@@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 GDPHPXYFLPDZGH-XBTMSFKCSA-N 0.000 title claims abstract description 14
- 108700029992 Ala(2)-Arg(6)- enkephalin-Leu Proteins 0.000 title description 6
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 phenylacetyl Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000000126 substance Substances 0.000 abstract description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 abstract description 3
- 239000004744 fabric Substances 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 4
- 239000004475 Arginine Substances 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 238000006206 glycosylation reaction Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- CJWJLFIFVCIAJU-HNEXDWKRSA-N (2S,3R,4S,5R,6R)-2-(2-chloroethylsulfanyl)-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@@H](SCCCl)[C@H](O)[C@@H](O)[C@H]1O CJWJLFIFVCIAJU-HNEXDWKRSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010073038 Penicillin Amidase Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
X-Tyr(OY)-D-Ala-Gly-Phe-Leu-ArgOHÍZ), kde X znamená fenylacetyl nebo terč. butyloxykarbonyl; Y je vodík v případě, že Z je 4-(Obeta-D-galaktopyranosyl-D-deoxy-1 -N-amin í oglucitol (látky I, II) nebo thiogalaktosyl, T jestliže Z je vodík (látky III, IV). Látky obecnét CO ho vzorce I se připraví tak, že na N-chráněné analogy dalarginu se působí redukujícím cukrem v přítomnosti kyanborohydridu sodného (látky I a II) nebo chlorethylthiogalaktopyranosidem (látky III a IV).X-Tyr (OY) -D-Ala-Gly-Phe-Leu-ArgOHI 2), where X is phenylacetyl or a target. butyloxycarbonyl; Y is hydrogen when Z is 4- (Obeta-D-galactopyranosyl-D-deoxy-1) -N-amine oglucitol (substances I, II) or thiogalactosyl, T if Z is hydrogen (substances III, IV). General Fabrics The CO of formula I is prepared so that it is N-protected dalargin analogs are treated with reducing sugar in the presence of sodium cyanoborohydride (substances I and II) or chloroethylthiogalactopyranoside (substances III and IV).
Description
(57) Anotace:(57)
X-Tyr(OY)-D-Ala-Gly-Phe-Leu-ArgOHÍZ), kde X znamená fenylacetyl nebo terč. butyloxykarbonyl; Y je vodík v případě, že Z je 4-(Obeta-D-galaktopyranosyl-D-deoxy-1 -N-amin í oglucitol (látky I, II) nebo thiogalaktosyl,X-Tyr (OY) -D-Ala-Gly-Phe-Leu-ArgOHIZ) where X is phenylacetyl or tert. butyloxycarbonyl; Y is hydrogen when Z is 4- (Obeta-D-galactopyranosyl-D-deoxy-1-N-aminoglucitol (compounds I, II) or thiogalactosyl,
T jestliže Z je vodík (látky III, IV). Látky obecnét CO ho vzorce I se připraví tak, že na N-chráněné analogy dalarginu se působí redukujícím cukrem v přítomnosti kyanborohydridu sodného (látky I a II) nebo chlor ethyl thio galaktopyranosidem (látky III a IV).T if Z is hydrogen (compounds III, IV). The compounds of formula I are prepared by treating the N-protected analogues of dalargine with a reducing sugar in the presence of sodium cyanoborohydride (compounds I and II) or chloroethyl thio galactopyranoside (compounds III and IV).
CZ 2627-96CZ 2627-96
Glykosylované N-chránéné analogy přípravy dalarginu a způsob jejichGlycosylated N-protected analogues for the preparation of dalargin and a method thereof
Oblast technikyTechnical field
Vynález se týká glykosylovaných N-chráněných analogů dalarginu a způsobu jejich přípravy.The invention relates to glycosylated N-protected analogues of dalargin and a process for their preparation.
Dosavadní stav technikyBACKGROUND OF THE INVENTION
Funkční skupiny dalarginu jako hydroxyl tyrosinu, jeho koncová amino skupina a quanidylová skupina argininu jsou cílem glykosylačních modifikací. Možnosti modifikace dalarginu cukernými zbytky nejsou zdaleka vyčerpány a to nejen s ohledem na přítomnost karboxylu (Š.Horvát et. al. Helv.Chim.Ácta 74, 951-955, 1991) a jeho modifikace glykosidy či insercí aminokyseliny s další modifikovatelnou funkční skupinou do původní struktury peptidu (R.Polt et al. J.Amer,Chem. Soc. 114, 10249- 1992). Použitím reduktivní aminace, přístupu který je zacílen na modifikace NH2 či NH skupiny v guanidylové skupině argininu se sice nezmenšuje počet možných produktů na ( ve srovnání s glykosylací provedenou v dalarginu s halogenalkylthioglykosidem), dva monoglykosylované a jeden diglykosylovaný a ani separace jednotlivých produktů nemusí být především po preparativní stránce jednoduchou záležitostí. Ve snaze po jednoznačnosti reakce byly autory připraveny dva N-chráněné analogy dalarginu, Boc-dalargin a Pac-dalargin. Boc(Benzyloxykarbonyl) a Pac (Fenylacetyl)-deriváty dalarginu účinně blokují primární amino skupinu tyrosinu a jsou odstranitelné za různých podmínek, kyselinou trifluorvodíkovou skupina Boc a enzymově katalysovanou hydrolysou (penicilinamidohydrolasa) skupina PacDalargin functional groups such as hydroxyl tyrosine, its terminal amino group, and the quanidyl group of arginine are targets of glycosylation modifications. The possibilities of modification of dalargin by sugar residues are far from exhausted, not only due to the presence of carboxyl (Š.Horvát et. Al. Helv.Chim.Acta 74, 951-955, 1991) and its modification by glycosides or by insertion of amino acids with another modifiable functional group into original peptide structures (R.Polt et al. J.Amer, Chem. Soc. 114, 10249-1992). Using reductive amination, an approach aimed at modifying the NH 2 or NH group in the guanidyl group of arginine does not reduce the number of possible products to (compared to glycosylation carried out in dalargine with haloalkylthioglycoside), two monoglycosylated and one diglycosylated, and even product separation especially from a preparatory point of view. In an effort to clarify the reaction, the authors prepared two N-protected analogues of dalargin, Boc-dalargin and Pac-dalargin. Boc (Benzyloxycarbonyl) and Pac (Phenylacetyl) dalargin derivatives effectively block the primary amino group of tyrosine and are removable under various conditions, with Boc trifluoric acid and enzymatically catalysed hydrolysis (penicillin amidohydrolase) Pac group
z tyrosiňu. Tento přístup dává možnost přípravy derivátů dalarginu glykosylovaných na guanidylové skupině argininu v posici 6.of tyrosine. This approach gives the possibility to prepare dalargin derivatives glycosylated at the guanidyl group of arginine at position 6.
Podstata vvnálezuThe essence of the invention
Předmětem vynálezu jsou glykosylované N-chráněné analogy dalarginu obecného vzorce IThe present invention provides glycosylated N-protected dalargine analogs of Formula I
OY zOY z
X-Tyr-D-Ala-Gly-Phe-Leu-ArgOH (I) kde X znamená fenylacetyl nebo terč. butyloxykarbonyl ,*X-Tyr-D-Ala-Gly-Phe-Leu-ArgOH (I) wherein X is phenylacetyl or a target. butyloxycarbonyl, *
Y je vodík v případě, že Z jeY is hydrogen when Z is
4- (O-beta-D-galaktopyranosyl-D-deoxy-l-N-aminoglucitol (látky I,II), nebo thiogalaktosyl, jestliže Z je vodík (látky III, IV).4- (O-beta-D-galactopyranosyl-D-deoxy-1-N-aminoglucitol (I, II), or thiogalactosyl when Z is hydrogen (III, IV).
Látky obecného vzorce I se připraví tak, že se na N-chráněné analogy dalarginu působí redukujícím cukrem v přítomnosti kyanborohydridu sodného (látky I a II) nebo chloroethylthiogalaktopyranosidem (látky III a IV).Compounds of formula I are prepared by treating N-protected analogues of dalargine with a reducing sugar in the presence of sodium cyanoborohydride (compounds I and II) or chloroethylthiogalactopyranoside (compounds III and IV).
S výhodou se látky I a II připraví tak, že na Pac dalargin, prekursor látky i, či na Boc dalargin, prekursor látky II, rozpuštěné v koncentraci 1-20 nM (v 50% EtOH) v pufru o neutrálním pH se působí redukujícím cukrem (10-50 mg/ml) v přítomnosti kyanborohydridu scidného (10 mg/ml) při 37°C po dobu 24 hodin. Po ukončení glykosylace se reakce zastaví okyselením, například 50% kyselinou octovou. Látky III a IV se připraví tak, že na prekursory Fenylacetyl- či terč.butyloxykarbonyl dalargin se působí chloroethylthiogalaktopyranosidem. Isolace reakčních produktů se provádí s výhodou separací na molekulovém sítě.Preferably, compounds I and II are prepared by treating a Pac dalargin, a precursor of i, or Boc dalargin, a precursor of II, dissolved in a concentration of 1-20 nM (in 50% EtOH) in a neutral pH buffer with a reducing sugar (10-50 mg / ml) in the presence of scidium cyanoborohydride (10 mg / ml) at 37 ° C for 24 hours. Upon completion of glycosylation, the reaction is stopped by acidification, for example with 50% acetic acid. Compounds III and IV are prepared by treating the precursors of phenylacetyl or tert-butyloxycarbonyl dalargine with chloroethylthiogalactopyranoside. The isolation of the reaction products is preferably carried out by separation on a molecular network.
VIN
Příklady provedení vynálezuDETAILED DESCRIPTION OF THE INVENTION
Příklad 1.Example 1.
N-Fenylacetyl dalargin (5mg) byl rozpuštěn v 1 ml fysiologického roztoku obsahujícího 50% EtOH 0,05 M Na-fosfát, pH 7,5. K roztoku bylo přidáno 30 mg laktosy a 10 mg kyanborohydridu sodného. Směs byla ponechána 24 hod při 37°C a reakce poté zastavena okyselením 50% kys. octovou. Reakční směs byla dělena na koloně Biogelu P-2 (1,5 x 45cm), který byl v rovnováze s 0,05M NH4HCO3. Kolona byla eluována stejným roztokem kyselého uhličitanu amonného rychlostí 8 ml/hod, frakce byly jímány po 2 ml.Během eluce byla monitorována přítomnost peptidů (280 nm) a volného cukru (Duboiš et al. Anal.Chem. 18, 350, 1956). Glykosylované deriváty dalarginu byly separovány HPLC a jejich přítomnost sledována hmotovou spektroskopií, kapilární elektroforesou a biol. testem GPI.N-Phenylacetyl dalargin (5mg) was dissolved in 1 ml of physiological saline containing 50% EtOH 0.05 M Na-phosphate, pH 7.5. 30 mg of lactose and 10 mg of sodium cyanoborohydride were added to the solution. The mixture was left at 37 ° C for 24 hours and then quenched by acidification with 50% acetic acid. The reaction mixture was separated on a Biogel P-2 column (1.5 x 45cm) that was equilibrated with 0.05M NH 4 HCO 3 . The column was eluted with the same ammonium bicarbonate solution at a rate of 8 ml / h, fractions were collected by 2 ml. During the elution, the presence of peptides (280 nm) and free sugar was monitored (Dubois et al. Anal.Chem. 18, 350, 1956). Glycosylated derivatives of dalargin were separated by HPLC and their presence monitored by mass spectroscopy, capillary electrophoresis and biol. GPI test.
Přiklad 2.Example 2.
N-terc.butyloxykarbonyl dalargin (5 mg) byl zpracován postupem uvedeným v příkladě 1. Separační a analytické methody byly identické s příkladem 1.N-tert-butyloxycarbonyl dalargine (5 mg) was treated as described in Example 1. Separation and analytical methods were identical to Example 1.
Příklad 3.Example 3.
N-Fenylacetyl dalargin (5 mg) byl rozpuštěn ve 2 ml 0,1 M NaHC03 (obsahujícím 50% EtOH) a smíchán se 2 ml roztoku 2-chloroethyl l-thio-p-D-galaktopyranosidu (50 mg ve 2 ml 0,1 M NaHC03 ) a reakční směs ponechána inkubovat při 37° c*po 18 hodin. Po skončení inkubace bylo pH roztoku upraveno přidáním pevného NaHCO3 na hodnotu 6,0. Reakční směs byla dělena a analysována, jak je uvedeno v příkladě 1.N-Phenylacetyl dalargine (5 mg) was dissolved in 2 ml of 0.1 M NaHCO 3 (containing 50% EtOH) and mixed with 2 ml of a solution of 2-chloroethyl 1-thio-β-D-galactopyranoside (50 mg in 2 ml of 0.1 M NaHCO 3 ) and the reaction mixture was allowed to incubate at 37 ° C * for 18 hours. After the incubation was completed, the pH of the solution was adjusted to 6.0 by addition of solid NaHCO 3 . The reaction mixture was separated and analyzed as in Example 1.
iand
Příklad 4.Example 4.
N-terc.butyloxykarbonyl dalargin (5 mg) byl zpracován jak je uvedeno v příkladě 3.N-tert-butyloxycarbonyl dalargine (5 mg) was treated as described in Example 3.
Průmyslová využitelnost $ ' . ' tIndustrial Applicability $ '. 't
( Látky podle vynálezu lze využít v základním výzkumu, ve farmaceutickém průmyslu a ve zdravotnictví. (The substances according to the invention can be used in basic research, in the pharmaceutical industry and in health care.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ962627A CZ262796A3 (en) | 1996-09-09 | 1996-09-09 | Cyclosylated n-protected analogs of dalargin and process for preparing thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CZ962627A CZ262796A3 (en) | 1996-09-09 | 1996-09-09 | Cyclosylated n-protected analogs of dalargin and process for preparing thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CZ262796A3 true CZ262796A3 (en) | 1998-03-18 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ962627A CZ262796A3 (en) | 1996-09-09 | 1996-09-09 | Cyclosylated n-protected analogs of dalargin and process for preparing thereof |
Country Status (1)
| Country | Link |
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| CZ (1) | CZ262796A3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091177A1 (en) | 2007-01-18 | 2008-07-31 | Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' | Exenatide and dalargin-based medicinal preparation for treating pancreatic diabetes |
-
1996
- 1996-09-09 CZ CZ962627A patent/CZ262796A3/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008091177A1 (en) | 2007-01-18 | 2008-07-31 | Otkrytoe Aktsionernoe Obschestvo 'otechestvennye Lekarstva' | Exenatide and dalargin-based medicinal preparation for treating pancreatic diabetes |
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