FR2475549A1 - Anti:anoxia des:ethylated vincamine derivs. - prepd. from indolo-quinolizine and bromo:pyruvate:phenyl-hydrazone - Google Patents
Anti:anoxia des:ethylated vincamine derivs. - prepd. from indolo-quinolizine and bromo:pyruvate:phenyl-hydrazone Download PDFInfo
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- FR2475549A1 FR2475549A1 FR8003010A FR8003010A FR2475549A1 FR 2475549 A1 FR2475549 A1 FR 2475549A1 FR 8003010 A FR8003010 A FR 8003010A FR 8003010 A FR8003010 A FR 8003010A FR 2475549 A1 FR2475549 A1 FR 2475549A1
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- 206010021143 Hypoxia Diseases 0.000 title description 4
- CMLQXZNMSSZRCH-UHFFFAOYSA-N indoloquinolizine Natural products C1=CC=CC2=C3N=C(C=CC=C4)C4=C3C=CN21 CMLQXZNMSSZRCH-UHFFFAOYSA-N 0.000 title description 3
- 206010002660 Anoxia Diseases 0.000 title 1
- 241000976983 Anoxia Species 0.000 title 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 title 1
- 230000007953 anoxia Effects 0.000 title 1
- 125000001246 bromo group Chemical group Br* 0.000 title 1
- DBVVQINTNHWWGH-UHFFFAOYSA-N indolo[3,2-a]quinolizine Chemical compound C1=CC=CC2=C3C4=CC=CC=C4N=C3C=CN21 DBVVQINTNHWWGH-UHFFFAOYSA-N 0.000 title 1
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical class C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 title 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 238000007127 saponification reaction Methods 0.000 claims description 3
- PRRZDZJYSJLDBS-UHFFFAOYSA-N 3-bromo-2-oxopropanoic acid Chemical compound OC(=O)C(=O)CBr PRRZDZJYSJLDBS-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- 230000000496 anti-anoxic effect Effects 0.000 abstract description 2
- 230000002490 cerebral effect Effects 0.000 abstract description 2
- 208000009999 tuberous sclerosis Diseases 0.000 abstract description 2
- 125000003545 alkoxy group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 208000014674 injury Diseases 0.000 abstract 1
- 230000003340 mental effect Effects 0.000 abstract 1
- 230000008733 trauma Effects 0.000 abstract 1
- 208000019553 vascular disease Diseases 0.000 abstract 1
- 150000002081 enamines Chemical class 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- -1 alkoxy radical Chemical class 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- 239000000155 melt Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000006229 carbon black Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000007954 hypoxia Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 101100295738 Gallus gallus COR3 gene Proteins 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- JGZKIGWXPPFMRG-QCKBJSBLSA-N Paynantheine Natural products O=C(OC)/C(=C\OC)/[C@@H]1[C@@H](C=C)CN2[C@H](c3[nH]c4c(c(OC)ccc4)c3CC2)C1 JGZKIGWXPPFMRG-QCKBJSBLSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UXMCFEBDJVHVNH-HOJAQTOUSA-N ac1l52id Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(O)=O)N5C2=C1 UXMCFEBDJVHVNH-HOJAQTOUSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical group 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000006213 oxygenation reaction Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YHQSXWOXIHDVHQ-UHFFFAOYSA-N quinoline;hydrobromide Chemical compound [Br-].[NH+]1=CC=CC2=CC=CC=C21 YHQSXWOXIHDVHQ-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000287 tissue oxygenation Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
La présente invention concerne des dérivés vincaminiques, désoxyvincaminiques et apovincaminiques déséthyles, leur pre- paration et leur application en thérapeutique.The present invention relates to vincaminic, deoxyvincaminic and apovincaminic deethyl derivatives, their preparation and their therapeutic application.
Les composés de la présente demande répondent â la formule (I)
dans laquelle, soit
R1 et R2 représentent chacun un atome d'hydrogène, soit R1 est un atome d'hydrogène et R2 est le groupe hydroxy, soit
R1 et R2 représentent ensemble une double liaison,
R3 est, soit le radical hydroxy, soit un radical alcoxy de 2 à 4 atomes de carbone, soit un radical NR5R6 dans lequel
R5et R6 représentent chacun indépendamment l'un de l'autre un atome d'hydrogène, un radical alkyle de 1 a 4 atomes de carbone ou un radical cycloalkyle de 3 à 6 atomes de carbone,
R4 représente un atome d'hydrogène ou d'halogène, le radical méthyle ou méthoxy ou le groupe nitro.The compounds of the present application have the formula (I)
in which either
R1 and R2 each represent a hydrogen atom, or R1 is a hydrogen atom and R2 is the hydroxy group, or
R1 and R2 together represent a double bond,
R3 is either the hydroxy radical or an alkoxy radical of 2 to 4 carbon atoms, ie a radical NR5R6 in which
R5 and R6 are each independently of one another a hydrogen atom, an alkyl radical of 1 to 4 carbon atoms or a cycloalkyl radical of 3 to 6 carbon atoms,
R4 represents a hydrogen or halogen atom, the methyl or methoxy radical or the nitro group.
Les composés de l'invention (I) peuvent exister sous les dif férentes formes stéréoisomères - les deux atomes d'hydrogène en ?positions 3 et 16 peuvent
avoir la strocimie relative cis ou trans, - les radicaux R2 et COR3 peuvent être en position ou ,cl
De plus, les composés de l'invention peuvent exister sous la forme de racémates oud'enantiomères. The compounds of the invention (I) can exist in the various stereoisomeric forms - the two hydrogen atoms in the 3 and 16 positions can
have the relative cis or trans strocimies, - the radicals R2 and COR3 can be in position or,
In addition, the compounds of the invention may exist as racemates or enantiomers.
Les sels d'addition des composés (I) aux acides pharmaceutiquement acceptables font partie de l'invention. The addition salts of compounds (I) with pharmaceutically acceptable acids form part of the invention.
Selon l'invention, on peut préparer les composés (I) à partir d'une énamine de formule (II) selon le schéma réactionnel représenté a la page suivante.
L'énamine dans laquelle R4 est H est décrite par R.N.SHUT et T.J.LEIPZIG (Journal of Heterocyc}ic Chemistry 1966,3-101).The enamine in which R4 is H is described by R.N.SHUT and T.J.LEIPZIG (Journal of Heterocycic Chem Chemistry 1966, 3-101).
Les énarnines dans lesquelles R4 est différent de H sont prépa- rées selon le schéma de synthèse suivant
Four préparer les composés (I), on fait réagir le composé (II) avec la (dinitro-2,4 phenyl)-hydrazone du bromopyruvate d'éthyle le (III). On réduit alors le composé intermédiaire (IV) à l'aide de Ticl3 - soit dans de l'acide acétique pour obtenir les composés (I) dans lesquels R1 est H, R2 est OH et R3 est 2:5 - soit dans de l'acide formique pour obtenir les composés (I)
dans lesquels R1 et R2 forment une double liaison et R3 est 5. To prepare the compounds (I), the compound (II) is reacted with ethyl dinitrophenyl (2,4-dinitro-phenyl) -hydrazone (III). Intermediate compound (IV) is then reduced with Ticl3 - either in acetic acid to give compounds (I) wherein R1 is H, R2 is OH and R3 is 2: 5 - either in formic acid to obtain the compounds (I)
in which R1 and R2 form a double bond and R3 is 5.
A partir de ces composés (I) on prépare par diverses réactions classiques d'autres composés (I)
- hydrogénation conduisant aux composés dans lesquels
R1 et R2 sont des atomes d'hydrogène et R3 est Oalkyle,
- saponification conduisant aux composés dans lesquels
R3 est OH,
- amidification conduisant aux composés (I) dans lesquels R3 est NR5R67
- estérification conduisant aux composés (I) dans lesquels P.3 est @ alie. From these compounds (I) are prepared by various other conventional reactions other compounds (I)
hydrogenation leading to the compounds in which
R1 and R2 are hydrogen atoms and R3 is Oalkyl,
saponification leading to the compounds in which
R3 is OH,
amidification leading to the compounds (I) in which R3 is NR5R67
- esterification leading to the compounds (I) in which P.3 is @ alie.
SCHEMA REACTIONNEL
SCHEMA REACTIONNEL (suite)
Les exemples suivants illustreront les différentes étapes du procédé de l'invention.The following examples will illustrate the different steps of the process of the invention.
Les exemples ci-après conduisent aux composés (I) sous la forme de racémates et dans lesquels les atomes d'hydrogène en positions 3 et 16 sont de stréochimie cis.The following examples give compounds (I) in the form of racemates and in which the hydrogen atoms in positions 3 and 16 are cis-stoichiometry.
Les analyses , les snectres IR et RMN sont en accord avec la structure des composés. The analyzes, the IR and NMR snectres are in agreement with the structure of the compounds.
Exemple 1 (+) Déséthyl-vincaminate d'éthyle (R1=H R2 OH
R3 = OC2H5 R4 = H)
1. Bromure de((dinitro-2,4 phényl)-hydrazono-2 éthoxycarbonyl -2 éthyl3-l hexahydro-1,2,3,4,6,7 (12H) indolo- [2,3a]quino-
lizine-5-ium (composé IV)
On introduit dans un ballon, tout en agitant 66,5g d'énamine
(II) dans laquelle R4 est H, 665 ml d'éthanol et 665 ml d'ace-- tonitrile puis on ajoute en une seule fois. 112 g de (dinitro2,4 phényl)-hydrazone du bromopyruvate d'éthyle (III).Example 1 (+) ethyl desethyl vincaminate (R 1 = H 2 OH)
R3 = OC2H5 R4 = H)
1. (2,4-Dibenzylphenyl) -2-hydrazonoethoxycarbonyl-2-ethyl-1H-hexahydro-1,2,3,4,6,7 (12H) indolo- [2,3a] quinoline bromide
lizine-5-ium (compound IV)
66.5 g of enamine are introduced into a flask while stirring.
(II) wherein R 4 is H, 665 ml of ethanol and 665 ml of acetonitrile and then added all at once. 112 g of ethyl dinitro (2,4-phenyl) -hydrazone of bromopyruvate (III).
Après 16h d'agitation à la température du laboratoire, il se forme un précipité que l'on essore. Après séchage on obtient le composé intermédiaire (IV) dans lequel R4 est H que l'on utilise tel quel dans l1étape suivante.After 16 hours of stirring at laboratory temperature, a precipitate is formed which is filtered off. After drying, the intermediate compound (IV) is obtained in which R 4 is H which is used as it is in the next step.
2. t(Dinitro-2,4 phényl)-hydrazono-2 éthoxycarbonyl-2 éthyle
-1 octahydro-1,2,3,4,6,7,12,12b indolo [2,3a] - quinoli
zine. (composé V)
Tout en agitant, on ajoute 134,5 g (2,14 moles) de NaBH3CN à une suspension de 87,4 g (0,146 mole) du composé intermé- diaire (IV) obtenu précédemment dans 1500 ml de méthanol et 1500 mi d'acétonitrile.2. t (2,4-Dinitrophenyl) -hydrazono-2-ethoxycarbonyl-2-ethyl
-1 octahydro-1,2,3,4,6,7,12,12b indolo [2,3a] - quinoli
Zine. (compound V)
While stirring, 134.5 g (2.14 mol) of NaBH3CN was added to a suspension of 87.4 g (0.146 mol) of the intermediate compound (IV) obtained previously in 1500 ml of methanol and 1500 ml of acetonitrile.
Après 16 h d'agitation à la température ambiante, on essore
le précipité formé. On le rince à l'éther éthylique et on le
sèche. On obtient le composé intermédiaire (V) dans lequel
R4 est H. On l'utilise tel quel dans l'étape suivante.After stirring for 16 hours at room temperature,
the precipitate formed. It is rinsed with ethyl ether and is
dried. The intermediate compound (V) in which
R4 is H. It is used as it is in the next step.
3. Déséthyl-vincaminate d'éthyle
A une solution chauffée à 600C et agitée, de 400 ml d'acétone,
100 ml de formol à 37% et-300 ml de TiCl3 à 15%, on ajoute une suspension de 10g du composé intermédiaire (V) obtenu précédemment dans 250 ml d'acide acétique à 50% et 600 ml d'acétone.3. ethyl desethyl vincaminate
To a solution heated to 600C and stirred, 400 ml of acetone,
100 ml of 37% formalin and 300 ml of 15% TiCl 3 are added, a suspension of 10 g of the intermediate compound (V) obtained above is added in 250 ml of 50% acetic acid and 600 ml of acetone.
On continue à agiter le mélange réactionnel à 600C pendant 20 minutes. On ajoute alors 1 litre d'eau glacée et on extrait 3 fois avec 500 ml de CH2C12.The reaction mixture is stirred at 600 ° C. for 20 minutes. 1 liter of ice water is then added and the mixture is extracted 3 times with 500 ml of CH 2 Cl 2.
On réunit et concentre les phases organiques On obtient une résine que l'on reprend par 300 ml d'eau et alcalinise avec de l'ammoniaque jusqu'à pH 8*
Le précipité formé est essoré puis traité au noir de carbone.The organic phases are combined and concentrated. A resin is obtained which is taken up in 300 ml of water and basified with ammonia to pH 8 *.
The precipitate formed is drained and then treated with carbon black.
Après recristallisation dans du toluène, le composé fond à -2300C. After recrystallization from toluene, the compound melts at -2300C.
Exemple 2 Déséthyl-apovincaminate d'éthyle
(R1 et R2= double liaison R3 = OC2H5 R4 = H)
On introduit une suspension de 20g du composé intermédiaire (V) obtenu dans l'exemple 1, paragraphe 2, dans 200 ml d'acide formique à 99%, dans 600 ml de TiC13 à 15% portés à la tempé- rature de reflux, sous agitation.Example 2 ethyl desethyl-apovincaminate
(R1 and R2 = double bond R3 = OC2H5 R4 = H)
A suspension of 20 g of the intermediate compound (V) obtained in Example 1, paragraph 2, in 200 ml of 99% formic acid, is introduced into 600 ml of 15% TiCl 3 brought to reflux temperature. with stirring.
On maintient le reflux pendant 20 mn. I1 se forme un précipité oue l'on élimine après refroidissement par filtration sur terre d'infusoires. On extrait le filtrat avec 5 fois 300 ml de CH2C12 et concentre les phases organia;ues réunies.The reflux is maintained for 20 minutes. A precipitate is formed which is removed after cooling by filtration on the infusorial soil. The filtrate is extracted with 5 times 300 ml of CH 2 Cl 2 and the combined organics are concentrated.
On re?rend la résine obtenue par 60 ml d'acide formique à 99%.The resulting resin is returned with 60 ml of 99% formic acid.
On porte le mélange réactionnel à la température de reflux pen- dant 15 heures. On refroidit, verse la solution dans 600 nl d'eau et alcalinise avec de l'ammoniaque jusqu'à pH 8. On ob tient une comme que l'on extrait avec CH2Cl2 et que l'on fait cristalliser dans de l'éther isopropylique. Après recristallisation dans un minimum d'éther isooronylique avec passage au noir de carbone, le désthyl-a:?ovincaninate d'éthyle fond à 104-106,5 C.The reaction mixture is brought to reflux temperature for 15 hours. The solution is cooled, poured into 600 ml of water and made alkaline with ammonia to pH 8. It is obtained as it is extracted with CH 2 Cl 2 and crystallized from isopropyl ether. . After recrystallization from a minimum of isooronyl ether with a change to carbon black, ethyl-ethylhexaninate melts at 104.degree.-106.degree.
Exemple 3 ( t ) Déséthyl-désoxyvincaminate d'éthyle
(R1= R2 = H R3 = OC2H5 R4 = H)
On réduit le (t) déséthyl-apovincaminate d'éthyle de la manière suivante
A une solution de 5 g de ce composé dans 160 ml de méthanol et 40 ml d'acide acétique, on ajoute 500 mg de palladium à 10% sur carbone. On hydrogène pendant 6 heures sous une pression de 50 psi (3,5 kg/cm2) d'hydrogène, dans un aareil de Parr.Example 3 (t) ethyl Desethyl-deoxyvincaminate
(R1 = R2 = H R3 = OC2H5 R4 = H)
Ethyl desethyl-apovincaminate (t) is reduced in the following manner
To a solution of 5 g of this compound in 160 ml of methanol and 40 ml of acetic acid is added 500 mg of 10% palladium on carbon. Hydrogen is hydrogenated for 6 hours under a pressure of 50 psi (3.5 kg / cm 2) in a Parr apparatus.
La réaction terminée, on filtre le catalyseur, chasse le m6- thanol et dilue à 500 ml avec de l'eau. On neutralise le milieu réactionnel avec de l'ammoniaque jusqu'à pH 8. I1 se forme un précipité que l'on-essore.When the reaction is complete, the catalyst is filtered, the methanol removed and diluted to 500 ml with water. The reaction medium is neutralized with ammonia to pH 8. A precipitate is formed which is spun.
Après recristallisation dans de l'éther isopropylique, le (*) déséthyl-désoxyvincaminate d'éthyle fond à 960 C. After recrystallization from isopropyl ether, the (*) ethyl deethyl-deoxyvincaminate melts at 960 C.
Exemple 4 (+) Déséthyl-désoxyvincaminamide
(R1 = R2 = E R3 = NH2 R4 H) 1. On prépare l'acide déséthyl-désoxyvincaminique en agitant pendant 16 heures, à la température du laboratoire, une solution de 5,5 g de déséthyl-désoxyvincaminate d'éthyle dans 75 ml de méthanol avec 4,4 g de potasse en pastilles. L'agitation terminée, on amène à siccité, reprend par 35 ml d'eau et acidifie à pH 6 avec de l'acide chlorhydrique afin d'obtenir un volume final de 55 ml. Le composé cristallise. Après 2 heures d'agitation, on essore le composé qui, après recristallisation dans le minimum d'eau fond à 230-2350c. Example 4 (+) Desethyldeoxyvincaminamide
(R 1 = R 2 = E R 3 = NH 2 R 4 H) 1. The deethyl-deoxy vincaminic acid is prepared by stirring for 16 hours, at laboratory temperature, a solution of 5.5 g of ethyl desethyl-deoxyvincaminate in 75 hours. ml of methanol with 4.4 g of potassium hydroxide pellets. The stirring is complete, brought to dryness, taken up in 35 ml of water and acidified to pH 6 with hydrochloric acid in order to obtain a final volume of 55 ml. The compound crystallizes. After stirring for 2 hours, the compound which after recrystallization in the minimum amount of water melts at 230-2350c is filtered off with suction.
2. On porte une solution de 1,18 g de l'acide ainsi obtenu dans 885 ml d'acétonitrile et 2,5 ml de chlorure d'oalyle, à la température de reflux, pendant 10 heures. 2. A solution of 1.18 g of the acid thus obtained is brought into 885 ml of acetonitrile and 2.5 ml of oalyl chloride at reflux temperature for 10 hours.
On laisse reposer le mélange réactionnel une nuit à la température ambiante. On refroidit à OOC puis fait barboter du gaz ammoniac pendant 30 mn à OOC. On filtre le précipité, amène le filtrat à sec et reprend le résidu par 75 ml de CHCl On lave la phase organique à l'eau, sèche sur :ta2SO4, filtre et élimine le solvant. On reprend le résidu obtenu par de ltéther isopropylique.The reaction mixture is allowed to stand overnight at room temperature. Cooled to OOC then bubbled ammonia gas for 30 minutes at OOC. The precipitate is filtered off, the filtrate is taken to dryness and the residue is taken up in 75 ml of CHCl. The organic phase is washed with water, dried over: ta 2 SO 4, filtered and the solvent is removed. The residue obtained is taken up with isopropyl ether.
Après recristallisation dans le minimum d'acétonitrile avec passage au noir de carbone, le déséthyl-désoxyvincaminamide fond à 2280C.After recrystallization from acetonitrile to carbon black, deethyldeoxyvincaminamide melts at 2280C.
EXEMPLE 5 Déséthyl chmoro-l0 vincaminate d'éthyle.EXAMPLE 5 Ethyl ethyl 10-chloroacrylate
1 = H, R2 OH, R3= OC2H5, R4= C1-10 1.Enamine (II)
On dissout, tout en agitant, 30 g (129,7mmoles) de chlorhydrate de chlorotryptamine dans 650 ml de méthoxy-éthanol puis on ajoute 13,9 g (131mmoles) de Na2CO3. On porte à la température de reflux et on ajoute par petites portions en 30 heures 27,3 g (130,6mmoles) de 5-bromo-valérianate d'éthyle.1 = H, R2 OH, R3 = OC2H5, R4 = C1-10 1.Enamine (II)
30 g (129.7 mmol) of chlorotryptamine hydrochloride are dissolved in 650 ml of methoxyethanol while stirring and then 13.9 g (131 mmol) of Na 2 CO 3 are added. The reflux temperature is raised and 27.3 g (130.6 mmol) of ethyl 5-bromo valerianate are added in small portions over 30 hours.
L'introduction terminée, on maintient le reflux pendant encore 9 heures. On filtre énsuite les sels minéraux et concentre le filtrat à sec. On reprend la résine par environ 500 ml d'eau, puis extrait avec 3 fois 300 ml de CH2C12. On lave les phases organiques réunies avec de l'acide chlorhydrique N puis avec de l'eau jusqu'a neutralité. On sèche sur Na2SO4, filtre et amene à siccité. On reprend le produit par 100 ml d'acétate d'éthyle. On essore, lave à l'éther isopropylique et isole le composé intermédiaire
On dissout 20 g de ce composé dans 1 litre de benzène, tout en agitant, et sous azote. Puis on ajoute goutte à goutte 20 ml de POC13. On porte le mélange réactionnel à la température de reflux pendant 2 heures.On refroidit et ajoute 500 ml d'eau et porte de nouveau à la tempérarure de reflux pendant 30 mn-.20 g of this compound are dissolved in 1 liter of benzene, with stirring, and under nitrogen. Then 20 ml of POCl3 are added dropwise. The reaction mixture is heated at reflux temperature for 2 hours. Cool and add 500 ml of water and return to reflux temperature for 30 minutes.
On élimine la phase aqueuse puis lave la phase organique avec 200 ml d'eau On verse alors une solution chaude de 20 g de perchlorate de sodium dans 400 ml d'eau dans le mélange réactionnel. Il se forme un précipité que l'on essore après 1 heure d' agitation. The aqueous phase is removed and then the organic phase is washed with 200 ml of water. A hot solution of 20 g of sodium perchlorate in 400 ml of water is then poured into the reaction mixture. A precipitate forms which is filtered off after stirring for 1 hour.
On obtient le compose
On dissout 22,5 g de ce composé dans 500 ml de NaOH N. On agite à la température du laboratoire pendant une nuit. Puis on essore et lave le composé formé. On obtient l'énamine (II) qui fond à 1340C. 22.5 g of this compound are dissolved in 500 ml of N NaOH. The mixture is stirred at laboratory temperature overnight. Then, the compound formed is drained and washed. Enamine (II) is obtained which melts at 1340C.
2. On fait réagir cette énamine (Il) dans les mêmes conditions que dans l'exemple 1 paragraphes 1, 2 et 3 et on obtient le déséthyl chloro-10 vincaminate d'éthyle qui fond à 212-2140C. 2. This enamine (II) is reacted under the same conditions as in Example 1, paragraphs 1, 2 and 3, and ethyl desethyl chloro-10-vincaminate, which melts at 212 ° -240 ° C., is obtained.
Les composés préparés à titre d'exemples et sous forme de base sont représentés dans le tableau suivant
<tb> Compose <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> F(OC)
<tb> <SEP> 1 <SEP> H <SEP> OH <SEP> OC2H5 <SEP> 1 <SEP> H <SEP> 230
<tb> <SEP> 2 <SEP> H <SEP> OH <SEP> OC2H5 <SEP> C1-10 <SEP> 212-214
<tb> <SEP> 3 <SEP> liaison <SEP> OC <SEP> H <SEP> H <SEP> 104-106,5
<tb> <SEP> 4 <SEP> " <SEP> C2H5 <SEP> C1-10 <SEP> 134-135
<tb> <SEP> 5 <SEP> " <SEP> OH <SEP> Cl-10 <SEP> Y <SEP> 230
<tb> <SEP> 6 <SEP> H <SEP> H <SEP> C2H5 <SEP> H <SEP> 96
<tb> <SEP> 7 <SEP> H <SEP> H <SEP> OH <SEP> H <SEP> 230-235
<tb> <SEP> 8 <SEP> H <SEP> H <SEP> NH2 <SEP> H <SEP> 228
<tb> <SEP> 9 <SEP> H <SEP> H <SEP> N,- <SEP> H <SEP> 238
<tb> <SEP> 10 <SEP> H <SEP> H <SEP> OC2Hg <SEP> C1-10 <SEP> résine
<tb>
Les composés de l'invention ont été soumis à des essais pharmacologiques ; en particunier ils ont été étudiés dans le test de l'hypoxie hvpobare. <tb> Compose <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> F (OC)
<tb><SEP> 1 <SEP> H <SEP> OH <SEP> OC2H5 <SEP> 1 <SEP> H <SEP> 230
<tb><SEP> 2 <SEP> H <SEP> OH <SEP> OC2H5 <SEP> C1-10 <SEP> 212-214
<tb><SEP> 3 <SEP> binding <SEP> OC <SEP> H <SEP> H <SEP> 104-106.5
<tb><SEP> 4 <SEP>"<SEP> C2H5 <SEP> C1-10 <SEP> 134-135
<tb><SEP> 5 <SEP>"<SEP> OH <SEP> Cl-10 <SEP> Y <SEP> 230
<tb><SEP> 6 <SEP> H <SEP> H <SEP> C2H5 <SEP> H <SEP> 96
<tb><SEP> 7 <SEP> H <SEP> H <SEP> OH <SEP> H <SEP> 230-235
<tb><SEP> 8 <SEP> H <SEP> H <SEP> NH2 <SEP> H <SEP> 228
<tb><SEP> 9 <SEP> H <SEP> H <SEP> N, - <SEP> H <SEP> 238
<tb><SEP> 10 <SEP> H <SEP> H <SEP> OC2Hg <SEP> C1-10 <SEP> Resin
<Tb>
The compounds of the invention have been subjected to pharmacological tests; in particular they have been studied in the test of hypoxia hvpobare.
HYPOXIE HYPOBARE
Des souris de souche CD1 sont maintenues dans une atmosphère appauvrie en oxygène, par réalisation d'un vide partiel
(190 mm de mercure correspondant à 5,25% d'oxygène).HYPOBIC HYPOXIA
CD1 strain mice are maintained in an oxygen-depleted atmosphere, by carrying out a partial vacuum
(190 mm of mercury corresponding to 5.25% of oxygen).
Le temps de survie des animaux est noté. Ce temps est augmenté par les agents capables de favoriser l'oxygénation tissulaire et en particulier cérébrale. Les composés étudiés sont administrés à plusieurs doses, par voie intrapéritonéale, 10 minutes avant l'essai. Les pourcentages d'augmentation du temps de survie par rapport aux valeurs obtenues chez les animaux témoins sont calculés. La dose moyenne (DAM), dose qui augmente le temps de survie de 100% est déterminée graphiquement.The survival time of the animals is noted. This time is increased by the agents capable of promoting tissue oxygenation and in particular cerebral oxygenation. The compounds studied are administered at several doses, intraperitoneally, 10 minutes before the test. The percentages of increase of the survival time compared to the values obtained in the control animals are calculated. The mean dose (AMD), which increases the survival time by 100%, is determined graphically.
La DAM des composés de l'invention varie de Z à 1C mg/kg par voie i.p. The DAM of the compounds of the invention ranges from Z to 1C mg / kg i.p.
L'étude pharmacologique des composés de l'invention montre qu'ils sont actifs dans l'épreuve d'hypoxie hypobare chez la souris tout en n'étant que peu toxiques.The pharmacological study of the compounds of the invention shows that they are active in the hypobaric hypoxia test in the mouse while being only slightly toxic.
Les composés de l'invention possédant une activité antianoxique, peuvent être utilisés en thérapeutique pour le traitement des troubles de la vigilance, en particulier pour lutter contre les troubles du comportement imputables à des dommages vasculaires cérébraux et,à la sclérose cérébrale en gériatrie, ainsi que pour le traitement des absences dues à des traumatismes crâniens.The compounds of the invention possessing an anti-anoxic activity can be used therapeutically for the treatment of vigilance disorders, in particular for combating behavioral disorders attributable to cerebrovascular damage and, in cerebral sclerosis in geriatrics, and only for the treatment of absences due to head trauma.
L'invention comprend par conséquent, toutes compositions pharmaceutiques renfermant les composés et/ou leurs sels comme principes actifs, en association avec tous excipients appropriés à leur administration, en particulier par voie orale ou parentérale.The invention therefore includes any pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their administration, in particular orally or parenterally.
Les voie d'administration peuvent être. les voies orale et paren térale. The routes of administration can be. the oral and parenteral routes.
La posologie quotidienne peut aller de 10 à 100 mg. The daily dosage can range from 10 to 100 mg.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8003010A FR2475549A1 (en) | 1980-02-12 | 1980-02-12 | Anti:anoxia des:ethylated vincamine derivs. - prepd. from indolo-quinolizine and bromo:pyruvate:phenyl-hydrazone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8003010A FR2475549A1 (en) | 1980-02-12 | 1980-02-12 | Anti:anoxia des:ethylated vincamine derivs. - prepd. from indolo-quinolizine and bromo:pyruvate:phenyl-hydrazone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2475549A1 true FR2475549A1 (en) | 1981-08-14 |
| FR2475549B1 FR2475549B1 (en) | 1983-01-14 |
Family
ID=9238470
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR8003010A Granted FR2475549A1 (en) | 1980-02-12 | 1980-02-12 | Anti:anoxia des:ethylated vincamine derivs. - prepd. from indolo-quinolizine and bromo:pyruvate:phenyl-hydrazone |
Country Status (1)
| Country | Link |
|---|---|
| FR (1) | FR2475549A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2514357A1 (en) * | 1981-10-08 | 1983-04-15 | Roussel Uclaf | NOVEL 20,21-DINOREBURNAMENINE DERIVATIVES POSSIBLY SUBSTITUTED ON CYCLE E, PREPARATION METHOD AND APPLICATION AS MEDICAMENTS |
| US4686225A (en) * | 1986-04-29 | 1987-08-11 | American Home Products Corporation (Del.) | Vinpocetine for pulmonary hemorrhage and edema |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2190113A5 (en) * | 1972-06-19 | 1974-01-25 | Anvar |
-
1980
- 1980-02-12 FR FR8003010A patent/FR2475549A1/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2190113A5 (en) * | 1972-06-19 | 1974-01-25 | Anvar |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2514357A1 (en) * | 1981-10-08 | 1983-04-15 | Roussel Uclaf | NOVEL 20,21-DINOREBURNAMENINE DERIVATIVES POSSIBLY SUBSTITUTED ON CYCLE E, PREPARATION METHOD AND APPLICATION AS MEDICAMENTS |
| US4501740A (en) * | 1981-10-08 | 1985-02-26 | Roussel Uclaf | Blood oxygenating and cerebral vasoregulating 20,21-dinoreburnamenines |
| US4686225A (en) * | 1986-04-29 | 1987-08-11 | American Home Products Corporation (Del.) | Vinpocetine for pulmonary hemorrhage and edema |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2475549B1 (en) | 1983-01-14 |
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