FR2627492A1 - New 2' deoxy uridine derivs. - Google Patents
New 2' deoxy uridine derivs. Download PDFInfo
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- FR2627492A1 FR2627492A1 FR8802255A FR8802255A FR2627492A1 FR 2627492 A1 FR2627492 A1 FR 2627492A1 FR 8802255 A FR8802255 A FR 8802255A FR 8802255 A FR8802255 A FR 8802255A FR 2627492 A1 FR2627492 A1 FR 2627492A1
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- uridine
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- MXHRCPNRJAMMIM-BBVRLYRLSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-BBVRLYRLSA-N 0.000 title abstract 2
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 title abstract 2
- 108090000765 processed proteins & peptides Chemical group 0.000 claims abstract description 13
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 125000000539 amino acid group Chemical group 0.000 claims abstract 3
- 229940045145 uridine Drugs 0.000 claims description 29
- 150000001875 compounds Chemical class 0.000 claims description 17
- 150000001413 amino acids Chemical group 0.000 claims description 16
- -1 unsaturated alkyl radical Chemical class 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 125000003412 L-alanyl group Chemical group [H]N([H])[C@@](C([H])([H])[H])(C(=O)[*])[H] 0.000 claims description 6
- 150000005840 aryl radicals Chemical class 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000002062 proliferating effect Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 4
- 108090000526 Papain Proteins 0.000 claims description 3
- 239000004365 Protease Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 238000006911 enzymatic reaction Methods 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 230000003000 nontoxic effect Effects 0.000 claims description 3
- 229940055729 papain Drugs 0.000 claims description 3
- 235000019834 papain Nutrition 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 229940088598 enzyme Drugs 0.000 claims description 2
- 125000000988 D-alanyl group Chemical group N[C@@H](C(=O)*)C 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 2
- 125000003118 aryl group Chemical group 0.000 abstract 2
- 101150009274 nhr-1 gene Proteins 0.000 abstract 2
- 150000003839 salts Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- RZCIEJXAILMSQK-JXOAFFINSA-N TTP Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 RZCIEJXAILMSQK-JXOAFFINSA-N 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 102000006601 Thymidine Kinase Human genes 0.000 description 4
- 108020004440 Thymidine kinase Proteins 0.000 description 4
- 229910001868 water Inorganic materials 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000000172 cytosol Anatomy 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- GSYSFVSGPABNNL-UHFFFAOYSA-N methyl 2-dimethoxyphosphoryl-2-(phenylmethoxycarbonylamino)acetate Chemical group COC(=O)C(P(=O)(OC)OC)NC(=O)OCC1=CC=CC=C1 GSYSFVSGPABNNL-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- TYRGLVWXHJRKMT-MRVPVSSYSA-N (2r)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound OC(=O)[C@@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-MRVPVSSYSA-N 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 0 CC(NC(C(*)=CNC(C1)OC(*)C1O)=O)=O Chemical compound CC(NC(C(*)=CNC(C1)OC(*)C1O)=O)=O 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 125000000030 D-alanine group Chemical group [H]N([H])[C@](C([H])([H])[H])(C(=O)[*])[H] 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 238000010876 biochemical test Methods 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- 238000001953 recrystallisation Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Nouveaux dérivés de l'amino-5'-didéoxy-2'-5'-uridíne, procédé pour les préparer et compositions pharmaceutiques contenant ces composés.New derivatives of amino-5'-dideoxy-2'-5'-uridine, process for their preparation and pharmaceutical compositions containing these compounds.
La présente invention a pour objet de nouveaux dérivés de l'amino-5'-didéoxy-2'-5'-uridine, un procédé pour les préparer et des compositions pharmaceutiques les contenant. The present invention relates to novel amino-5'-dideoxy-2'-5'-uridine derivatives, a process for their preparation and pharmaceutical compositions containing them.
On connaît déjà certains dérivés de la déoxy-2'-uridine. Some derivatives of deoxy-2'-uridine are already known.
C'est ainsi qu'ont été décrits des dérivés de la déoxy2'-uridine substitués en position 5, et répondant à la formule chimique générale suivante
dans laquelle R est un radical alkyle saturé ou insature ayant de 1 à 4 atomes de carbone, un radical aryle ou un halogène, lesdits radicaux alkyle et aryle pouvant comporter au moins un substituant halogène.Thus, derivatives of deoxy-2-uridine substituted in the 5-position, and corresponding to the following general chemical formula, have been described.
in which R is a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms, an aryl radical or a halogen radical, said alkyl and aryl radicals possibly comprising at least one halogen substituent.
On connaît également, notamment par le brevet américain 4,093,716 l'amino-5'-didéoxy-2t-5'-méthyl-5-uridine de formule
qui est présenté comme inhibiteur potentiel du virus de l'herpès.US Pat. No. 4,093,716 also discloses amino-5'-dideoxy-2t-5'-methyl-5-uridine of formula
which is presented as a potential inhibitor of the herpes virus.
La préparation de ce composé est décrite dans un article d'Horwitz et al, dans la revue "The Journal of American Chemical Society 27 3045, (1962)". The preparation of this compound is described in an article by Horwitz et al, in the journal "The Journal of the American Chemical Society 27 3045, (1962)".
La présente invention concerne une nouvelle classe de dérivés de l'amino-5'-didéoxy-2'-5'-uridine répondant à la formule générale suivante
dans laquelle . R représente un radical alkyle saturé ou insaturé ayant de 1 à 4. The present invention relates to a novel class of amino-5'-dideoxy-2'-5'-uridine derivatives having the following general formula
in which . R represents a saturated or unsaturated alkyl radical having from 1 to 4.
atomes de carbone, un radical aryle ou un halogène, lesdits
radicaux alkyle ou aryle pouvant comporter au moins un
substituant halogène ; et . R' représente un reste d'acide aminé ou de peptide comportant
de deux à six acides aminés.carbon atoms, an aryl radical or a halogen, said
alkyl or aryl radicals which may comprise at least one
halogen substituent; and. R 'represents an amino acid or peptide residue comprising
from two to six amino acids.
Il a en effet été découvert que ces nouveaux dérivés possèdent la propriété pharmacologique intéressante d'être des inhibiteurs de la thymidine kinase foetale présente dans les tissus cancéreux humains et sont ainsi des inhibiteurs de la synthèse de l'ADN des cellules cancéreuses en voie de prolifération. It has been discovered that these novel derivatives possess the valuable pharmacological property of being inhibitors of fetal thymidine kinase present in human cancerous tissues and thus inhibit the synthesis of the DNA of proliferating cancer cells. .
Ces nouveaux produits se présentent, suivant la structure de l'acide aminé ou du peptide précité, sous la forme D ou L. These new products are, according to the structure of the amino acid or the aforementioned peptide, in the D or L form.
Le procédé général pour la préparation des composés selon l'invention de formule
dans laquelle R et R' sont définis comme ci-dessus, comporte la réaction, par voie chimique ou par voie enzymatique d'un dérivé aminé en position 5' répondant à la formule générale
dans laquelle R a la même signification que dans la formule I, avec un acide aminé ou un peptide comportant de deux à six acides aminés.The general process for the preparation of the compounds according to the invention of formula
in which R and R 'are defined as above, comprises the reaction, chemically or enzymatically, of a 5'-amino derivative corresponding to the general formula
wherein R has the same meaning as in formula I, with an amino acid or a peptide having from two to six amino acids.
Les composés de forme L sont préparés de préférence par réaction enzymatique du dérivé aminé de formule II avec un acide aminé ou un peptide de forme L ou DL, en présence d'une enzyme choisie parmi la papaine et la chymopapaine, la réaction étant effectuée à une température d'environ 10 à environ 700C en milieu acide. Dans ces conditions, il y a réaction entre la fonction amine du dérivé aminé en 5' et la fonction acide libre de l'acide aminé ou du peptide, étant entendu que les fonctions amines dudit acide aminé ou peptide sont préalablement bloquées à l'aide de réactifs connus tels que le benzyloxycarbonyle, le t-butoxycarbonyle ou le fluorénométhyloxycarbonyle. The compounds of L-form are preferably prepared by enzymatic reaction of the amino derivative of formula II with an amino acid or a peptide of L or DL form, in the presence of an enzyme chosen from papain and chymopapaine, the reaction being carried out at a temperature of about 10 to about 700C in acidic medium. Under these conditions, there is reaction between the amine function of the 5 'amino derivative and the free acid function of the amino acid or of the peptide, it being understood that the amine functions of said amino acid or peptide are previously blocked using known reagents such as benzyloxycarbonyl, t-butoxycarbonyl or fluoromethyloxycarbonyl.
Les composés de forme L, D ou DL peuvent également être préparés en utilisant un procédé purement chimique. Compounds of L, D or DL form can also be prepared using a purely chemical process.
La présente invention concerne également des compositions pharmaceutiques, notamment à activité d'inhibiteur de la synthèse de l'ADN des cellules cancéreuses en voie de prolifération, caractérisées en ce qu'elles contiennent, à titre d'ingrédient actif, au moins l'un des composés définis précédemment de formule générale I, en association avec un véhicule ou support non-toxique pharmaceutiquement acceptable. The present invention also relates to pharmaceutical compositions, in particular with activity of inhibitor of the synthesis of the DNA of proliferating cancer cells, characterized in that they contain, as active ingredient, at least one previously defined compounds of general formula I in association with a pharmaceutically acceptable non-toxic carrier or carrier.
L'invention sera illustrée plus en détail par les exemples non-limitatifs suivants
Exemple 1 : Voie enzymatique
Synthèse de N-(L-alanyl)-amino-5'-didéoxy-2' ,5'-méthyl-5-uridine
Example 1 Enzymatic Route
Synthesis of N- (L-alanyl) -amino-5'-dideoxy-2 ', 5'-methyl-5-uridine
Dans un tricol de 100 ml équipé d'une agitation magnétique, d'un thermomètre et d'un réfrigérant, on introduit successivement - 16 ml de soude normale - 3,57 g de (N-benzyloxycarbonyl)-L-alanine (0,016 mole) - 3,86 g d'amino-5'-didéoxy-2',5'-méthyl-5-uridine (0,016 mole) - 188 mg de chlorhydrate de L-cystéine dissous dans 2,4 ml d'eau
distillée - 20 ml de solution tampon citrique pH : 5
Le milieu réactionnel dont le pH est 8,98 est chauffé à 500C à a partir de 300C, le mélange est limpide. In a 100 ml three-necked flask equipped with a magnetic stirrer, a thermometer and a condenser, 16 ml of normal sodium hydroxide are introduced successively (3.57 g of (N-benzyloxycarbonyl) -L-alanine (0.016 mol). 3.86 g of amino-5'-dideoxy-2 ', 5'-methyl-5-uridine (0.016 mol) - 188 mg of L-cysteine hydrochloride dissolved in 2.4 ml of water
distilled - 20 ml of citric buffer solution pH: 5
The reaction medium whose pH is 8.98 is heated at 500C to 300C, the mixture is clear.
A 500C, on additionne une solution de 3,6 g de papaine (2,9 UI/mg) dans 8 ml d'eau. Le pH évolue lentement vers 8,41. At 500C, a solution of 3.6 g of papain (2.9 IU / mg) in 8 ml of water is added. The pH slowly changes to 8.41.
Par addition d'acide citrique en poudre (m = 1,2 g) on amène le pH à 4,6 et laisse sous vive agitation pendant 24 h. By adding citric acid powder (m = 1.2 g) the pH is brought to 4.6 and stirred vigorously for 24 hours.
La réaction terminée, on refroidit le milieu réactionnel, filtre et lave le précipité à l'eau. The reaction is complete, the reaction medium is cooled, filtered and the precipitate is washed with water.
Après séchage à 60 C sous vide, on obtient 4,3 g de
N-[(N-benzyloxycarbonyl)-L-alanyl]-amino-5'-didéoxy-2',5'-méthyl-5- uridine.After drying at 60 ° C. under vacuum, 4.3 g of
N - [(N-benzyloxycarbonyl) -L-alanyl] -amino-5'-dideoxy-2 ', 5'-methyl-5-uridine.
La purification est effectuée par cristallisation dans 50 ml de méthanol. The purification is carried out by crystallization in 50 ml of methanol.
m = 3,9 g Rdt = 55% Pureté :95%
Ce composé est mis en solution dans le méthanol et hydrogéné en présence de 400 mg de charbon palladié à 10 %.m = 3.9 g Yield = 55% Purity: 95%
This compound is dissolved in methanol and hydrogenated in the presence of 400 mg of 10% palladium on carbon.
Après filtration du catalyseur et concentration du solvant, on reprend le résidu par l'éther éthylique et filtre-le précipité obtenu. After filtration of the catalyst and concentration of the solvent, the residue is taken up in ethyl ether and the precipitate obtained is filtered off.
On obtient après séchage 7,9 mmoles de N-(L-alanyl)amino-5'-didéoxy-2',5'-méthyl-5-uridine (Rdt : 90 %). La recristallisation dans 20 ml ce méthanol du produit précédent conduit à 7,11 mmoles du composé désiré optiquement pur (B 1245) m = 2,21 g Rdt global : 44 % , F = 190-1930C (Thermovar)
[αD20 = -28 5 (C = 0,5 MeOH) ; IR (KBR) : 1670cm-l (C=0); 1275 cm-1, 1580 cm-1, 3250 cm-1 (N - H). RMN (200 MHz, CD3OD) : 1,30 (3H, d, Me ala) ; 1,90 (3H, s, Me) ; 2,22 à 2,28 (2H, m,
C-2'-H) ; 3,47 à 3,51 (3H, m, C-5'-H, C-ala-H) 3,90 à 3',92 (1H, m, C-4'-H) ; 4,25 à 4,27 (1H, m, C-3'-H) ; 6,18 (1H, t, C-1'-H) ; 7,49 (1H, s, C-6-H).After drying, 7.9 mmol of N- (L-alanyl) amino-5'-dideoxy-2 ', 5'-methyl-5-uridine (yield: 90%) are obtained. Recrystallization from this product in 20 ml of this product gives 7.11 mmol of the desired optically pure compound (B 1245) m = 2.21 g Overall yield: 44%, mp = 190-1930 ° C. (Thermovar)
[α D20 = -28 (C = 0.5 MeOH); IR (KBR): 1670cm -1 (C = O); 1275 cm -1, 1580 cm -1, 3250 cm -1 (N - H). NMR (200 MHz, CD3OD): 1.30 (3H, d, Me ala); 1.90 (3H, s, Me); 2.22 to 2.28 (2H, m,
C-2'-H); 3.47-3.51 (3H, m, C-5'-H, C-ala-H) 3.90-3 ', 92 (1H, m, C-4'-H); 4.25 to 4.27 (1H, m, C-3'-H); 6.18 (1H, t, C-1'-H); 7.49 (1H, s, C-6-H).
Exemple 2 : Voie chimique
Synthèse de N-(D-alanyl)-amino-5'-didéoxy-2',5'-méthyl-5-uridine
Synthesis of N- (D-alanyl) -amino-5'-dideoxy-2 ', 5'-methyl-5-uridine
Dans un tricol de 100 ml équipé d'une agitation magnétique, d'un thermomètre et d'une garde de chlorure de calcium, on introduit
o - 20 ml de dichlorométhane sec (tamis-4 A) - 893 mg de (N-benzyloxycarbonyl)-D-alanine (4 mmoles) - 0,6 ml de triéthylamine (4,3 mmoles)
On refroidit la solution obtenue à -50C et ajoute 0,4 ml de chloroformiate d'éthyle (4,2 mmoles).In a three-necked 100 ml equipped with a magnetic stirrer, a thermometer and a guard of calcium chloride, it introduces
o - 20 ml of dry dichloromethane (4 A sieve) - 893 mg of (N-benzyloxycarbonyl) -D-alanine (4 mmol) - 0.6 ml of triethylamine (4.3 mmol)
The resulting solution was cooled to -50 ° C. and 0.4 ml of ethyl chloroformate (4.2 mmol) was added.
Après 90 minutes d'agitation, on additionne 964 mg d'amino-5'-didéoxy-2',5'-méthyl-5-uridine et laisse 60 minutes à -50C puis une nuit à température ambiante. After stirring for 90 minutes, 964 mg of amino-5'-dideoxy-2 ', 5'-methyl-5-uridine are added and the mixture is left for 60 minutes at -50 ° C. and then overnight at room temperature.
On filtre le précipité formé.et le lave par 15 ml d'eau permutée. Après séchage à l'étuve sous vide à 600C, on obtient 1,33 g de N-[(N-benzyloxycarbonyl)-D-alanyl]-amino-5'-didéoxy- 2',5'-méthyl-5-uridine. Une cristallisation dans 50 ml de méthanol conduit à 1,2 g d'un composé de pureté satisfaisante (Rdt : 67 ). The precipitate formed is filtered off and washed with 15 ml of deionized water. After drying in a vacuum oven at 600 ° C., 1.33 g of N - [(N-benzyloxycarbonyl) -D-alanyl] -amino-5'-dideoxy-2 ', 5'-methyl-5-uridine are obtained. . Crystallization from 50 ml of methanol gives 1.2 g of a compound of satisfactory purity (yield: 67).
L'hydrogénolyse et une purification analogues à celles décrites dans l'exemple 1, conduisent au N- < D-alanyl)-amino 5'-didéoxy-2',5'-méthyl-5-uridine (B 1272) optiquement pur [m = 715 mg ; 2,3 mmoles ; Rdt 57 %] F = 180-1840C (Thermovar)
IR (KBr) : 1670 cm 1 (C = 0) ; 1275 cm 1, 1580 cm 1, 3250 cm 1 (N - H) ; C.C.M. : (MeOH, H20 : 80/20) rf = 0,21 Silice 60 F254.Hydrogenolysis and purification analogous to those described in Example 1, lead to optically pure N- (D-alanyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine (B 1272) [ m = 715 mg; 2.3 mmoles; Yield 57%] F = 180-1840C (Thermovar)
IR (KBr): 1670 cm -1 (C = O); 1275 cm -1, 1580 cm -1, 3250 cm 1 (N-H); TLC: (MeOH, H2O: 80/20) rf = 0.21 Silica 60 F254.
En utilisant des processus expérimentaux analogues à ceux décrits dans les exemples 1 et 2 et que l'homme de métier retrouvera facilement, on a préparé les composés suivants
N-(L-alanyl)-amino 5'-didéoxy-2',5'-éthyl-5-uridine
N-(L-alanyl)-amino 5'-didéoxy-2',5'-butyl-5-uridine
N-(L-alanyl)-amino 5'-didéoxy-2',5'-propyl-5-uridine
N-(L-valyl)-amino 5'-didéoxy-2',5'-méthyl-5-uridine N- (L-leucyl) -amino 5'-didéoxy-2',5'-méthyl-5-uridine
N-(sarcosyl)-amino 5'-didéoxy-2' ,5'-méthyl-5-uridine N-( -alanyl)-amino 5'-didéoxy-2' ,5'-méthyl-5-uridine
N-(L-alanyl)-L-alanyl)-amino 5'-didéoxy-2' ,5'-méthyl-5-uridine
N-(L-alanyl-L-alanyl-L-alanyl)-amino 5'-didéoxy-2',5'méthyl-5-uridine
N-(L-glycyl)-amino 5'-didéoxy-2',5'-méthyl-5-uridine N-L(L-alanyl)j6-amino 5'-didéoxy-2' ,5'-méthyl-5-uridine
N-(L-alanyl)-amino 5'-didéoxy-2',5'-bromo-5-uridine
N-(L-alanyl)-amino 5'-didéoxy-2' ,5'-chlorométhyl-5-uridine
N-(L-alanyl)-amino 5'-didéoxy-2',5'-chloro-4-phényl-5-uridine
L'activité des composés selon l'invention, comme inhibiteurs de la synthèse de l'ADN des cellules cancéreuses en voie de prolifération a été mise en oeuvre selon le mode opératoire suivant
Des cellules du cancer du sein hormonodépendantes (MCF7) qui contiennent 95-96 ,0 de thymidine kinase foetale, sont traitées par les ultrasons et centrifugées à 105.000 g.Using experimental procedures analogous to those described in Examples 1 and 2 and which is readily apparent to those skilled in the art, the following compounds were prepared:
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-ethyl-5-uridine
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-butyl-5-uridine
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-propyl-5-uridine
N- (L-valyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine N- (L-leucyl) -amino 5'-dideoxy-2', 5'-methyl-5-uridine
N- (sarcosyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine N- (-alanyl) -amino 5'-dideoxy-2', 5'-methyl-5-uridine
N- (L-alanyl) -L-alanyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine
N- (L-alanyl-L-alanyl-L-alanyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine
N- (L-glycyl) -amino 5'-dideoxy-2 ', 5'-methyl-5-uridine N- (L-alanyl) 6-amino-5'-dideoxy-2', 5'-methyl-5-uridine
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-bromo-5-uridine
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-chloromethyl-5-uridine
N- (L-alanyl) -amino 5'-dideoxy-2 ', 5'-chloro-4-phenyl-5-uridine
The activity of the compounds according to the invention as inhibitors of DNA synthesis of proliferating cancer cells was carried out according to the following procedure
Hormone-dependent breast cancer cells (MCF7) that contain 95-96% fetal thymidine kinase are sonicated and centrifuged at 105,000 g.
La concentration des protéines du cytosol obtenu est mesurée et ajustée par dilution à 1,5 mg de protéines par ml de cytosol. The protein concentration of the cytosol obtained is measured and adjusted by dilution to 1.5 mg of proteins per ml of cytosol.
Celui-ci est incubé, à 370C pendant 10 minutes, dans un tampon Tris (pH : 7,6) en présence de thymidine [C14-2] (40 - umolaire), d'ATP -(8 mMolaire) et de chlorure de magnésium. La réacton enzymatique est stoppée par l'addition d'acide perchlorique. This is incubated at 370 ° C. for 10 minutes in Tris buffer (pH 7.6) in the presence of [C14-2] thymidine (40 μmolar), ATP (8 mMolar) and sodium chloride. magnesium. The enzymatic reaction is stopped by the addition of perchloric acid.
Les nucléotides formés sont séparés par électrophorèse haute tension, les taches sont découpées et comptées. The nucleotides formed are separated by high voltage electrophoresis, the spots are cut and counted.
On a donné au Tableau I les résultats des essais réalisés avec les composés des exemples 1 et 2 ainsi qu'avec des témoins sans inhibiteur, à titre de comparaison. Table I gives the results of the tests carried out with the compounds of Examples 1 and 2 as well as with controls without inhibitor, for comparison.
Les valeurs données sont exprimées en picomoles par millilitre de cytosol par minute. The values given are expressed in picomoles per milliliter of cytosol per minute.
TABLEAU 1
<tb> <SEP> Composé <SEP> Concentration <SEP> TMP <SEP> + <SEP> TTP <SEP> TTP
<tb> (Témoin) <SEP> sans <SEP> inhibiteur <SEP> 1993 <SEP> 1573
<tb> <SEP> Ex. <SEP> 1 <SEP> 1 <SEP> mMolaire <SEP> 1329 <SEP> 38
<tb> (Témoin) <SEP> sans <SEP> inhibiteur <SEP> 486 <SEP> i <SEP> 368
<tb> <SEP> Ex. <SEP> 2 <SEP> 1 <SEP> mMolaire <SEP> 388 <SEP> 46
<tb>
Ce test biochimique est basé sur la connaissance du fait que la thymidine kinase occupe une position stratégique dans.les processus biochimiques aboutissant à la synthèse de l'ADN, qui utilise le thymidine triphosphate (TTP) qui peut être considéré comme le produit final d'une réaction complexe initiée par la thymidine kinase.<tb><SEP> Compound <SEP> Concentration <SEP> TMP <SEP> + <SEP> TTP <SEP> TTP
<tb> (Control) <SEP> without <SEP> Inhibitor <SEP> 1993 <SEP> 1573
<tb><SEP> Ex. <SEP> 1 <SEP> 1 <SEP> mMolar <SEP> 1329 <SEP> 38
<tb> (Control) <SEP> Without <SEP> Inhibitor <SEP> 486 <SEP> i <SEP> 368
<tb><SEP> Ex. <SEP> 2 <SEP> 1 <SEP> mMolar <SEP> 388 <SEP> 46
<Tb>
This biochemical test is based on the knowledge that thymidine kinase occupies a strategic position in the biochemical processes leading to the synthesis of DNA, which uses thymidine triphosphate (TTP) which can be considered as the final product of a complex reaction initiated by thymidine kinase.
Comme le montre le tableau 1, les composés selon l'invention agissent comme inhibiteurs de la synthèse du TTP, et donc vraisemblablement de la synthèse de l'ADN des cellules cancéreuses en voie de prolifération. As shown in Table 1, the compounds according to the invention act as inhibitors of TTP synthesis, and thus presumably DNA synthesis of proliferating cancer cells.
Claims (7)
Priority Applications (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8802255A FR2627492B1 (en) | 1988-02-24 | 1988-02-24 | NOVEL AMINO-5 (PRIME) -DIDEOXY-2 (PRIME) -5 (PRIME) -URIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
| DE68917479T DE68917479D1 (en) | 1988-02-24 | 1989-02-23 | DERIVATIVES OF DEOXY-2'-URIDINE SUBSTITUTED IN THE 5, 3 'OR 5' POSITION BY ACYLATED ALPHA-AMINO GROUPS, METHOD FOR THE PRODUCTION AND MEDICINAL PRODUCTS THEREOF. |
| AT89903177T ATE109789T1 (en) | 1988-02-24 | 1989-02-23 | DERIVATIVES OF DEOXY-2'-URIDINE SUBSTITUTED IN THE 5, 3' OR 5' POSITION BY ACYLATED ALPHA-AMINO GROUPS, PROCESSES FOR THE PREPARATION AND PHARMACEUTICALS THEREOF. |
| PCT/FR1989/000072 WO1989008115A1 (en) | 1988-02-24 | 1989-02-23 | NEW DERIVATIVES OF DEOXY-2'-URIDINE SUBSTITUTED IN THE 5, 3' OR 5' POSITION BY ACYLATED alpha-AMINO GROUPS, PROCESS FOR OBTAINING THEM AND DRUGS CONTAINING THEM |
| AU32137/89A AU631119B2 (en) | 1988-02-24 | 1989-02-23 | New derivatives of deoxy-2'-uridine substituted in the 5,3' or 5' position by acylated alpha-amino groups, process for obtaining them and drugs containing them |
| JP1502971A JPH03504492A (en) | 1988-02-24 | 1989-02-23 | New derivatives of 2'-deoxyuridine substituted in the 5-, 3'-, or 5'-position by an α-aminoacyl group and methods for their production and drugs in which they exist. |
| US07/566,344 US5212161A (en) | 1988-02-24 | 1989-02-23 | Derivatives of 2'-deoxyuridine substituted in the 5-,3'-or 5'-position by α-aminacyl groups, process for their preparation and drugs in which they are present |
| EP89903177A EP0448550B1 (en) | 1988-02-24 | 1989-02-23 | New derivatives of deoxy-2'-uridine substituted in the 5, 3' or 5' position by acylated alpha-amino groups, process for obtaining them and drugs containing them |
| DK200290A DK200290A (en) | 1988-02-24 | 1990-08-21 | DERIVATIVES OF 2'-DESOXYURIDINE SUBSTITUTED IN 5, 3 'OR 5' POSITION WITH ALFA AMINOACYL GROUPS, PROCEDURES FOR THEIR PREPARATION AND MEDICINES CONTAINING THEM |
| FI904171A FI92324C (en) | 1988-02-24 | 1990-08-23 | Process for the preparation of 2'-deoxyuridine derivatives useful as medicaments |
| NO903704A NO173507C (en) | 1988-02-24 | 1990-08-23 | Analogous Procedure for Preparation of Therapeutically Active Derivatives of Deoxy-2'.uridine |
| OA59844A OA09306A (en) | 1988-02-24 | 1990-08-24 | "New derivatives of deoxy-2'-uridine substituted in position 5, 3 'or 5' by acylated x-amino groups, process for their production and medicaments containing them". |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8802255A FR2627492B1 (en) | 1988-02-24 | 1988-02-24 | NOVEL AMINO-5 (PRIME) -DIDEOXY-2 (PRIME) -5 (PRIME) -URIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2627492A1 true FR2627492A1 (en) | 1989-08-25 |
| FR2627492B1 FR2627492B1 (en) | 1990-08-10 |
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| FR8802255A Expired - Lifetime FR2627492B1 (en) | 1988-02-24 | 1988-02-24 | NOVEL AMINO-5 (PRIME) -DIDEOXY-2 (PRIME) -5 (PRIME) -URIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS |
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| FR (1) | FR2627492B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992008727A1 (en) * | 1990-11-13 | 1992-05-29 | Consiglio Nazionale Delle Ricerche | L-2'-desoxyuridines and pharmaceutical compositions containing them |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4128639A (en) * | 1977-12-14 | 1978-12-05 | Research Corporation | Nitrosourea analogs of thymidine |
-
1988
- 1988-02-24 FR FR8802255A patent/FR2627492B1/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4128639A (en) * | 1977-12-14 | 1978-12-05 | Research Corporation | Nitrosourea analogs of thymidine |
Non-Patent Citations (4)
| Title |
|---|
| JOURNAL OF MEDICINAL CHEMISTRY, vol. 22, no. 6, 1979, pages 621-631, American Chemical Society, Columbus, Ohio, US; A.HAMPTON et al.: "Design of species- or isozyme-specific enzyme inhibitors. I. Effect of thymidine substituents on affinity for the thymidine site of hamster cytoplasmic thymidine kinase" * |
| JOURNAL OF MEDICINAL CHEMISTRY, vol. 29, no. 6, 1986, pages 1052-1056, American Chemical Society, Columbus, Ohio, US; R.D.ELLIOTT et al.: "Reactive 5'-substituted thymidine derivatives as potential inhibitors of nucleotide biosynthesis" * |
| JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 5, 1987, pages 927-930, American Chemical Society, Columbus, Ohio, US; R.D.ELLIOTT et al.: "Reactive 5'-substituted 2',5'-dideoxyuridine derivatives as potential inhibitors of nucleotide biosynthesis" * |
| JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 93, no. 6, 24 mars 1971, pages 1474-1480, Columbus, Ohio, US; M.J.ROBINS et al.: "Nucleoside peptides. I. The synthesis of 5'-deoxy-5'-amino-5'-N-aminoacyl peptide. Derivatives of guanosine, adenosine, and 2'-deoxyadenosine and their effect on cell-free protein synthesis" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992008727A1 (en) * | 1990-11-13 | 1992-05-29 | Consiglio Nazionale Delle Ricerche | L-2'-desoxyuridines and pharmaceutical compositions containing them |
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| FR2627492B1 (en) | 1990-08-10 |
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