LU82332A1 - PREPARATION OF HYDROXYL DERIVATIVES OF ISOPROPYLAMINO-PYRIMIDINE - Google Patents

PREPARATION OF HYDROXYL DERIVATIVES OF ISOPROPYLAMINO-PYRIMIDINE Download PDF

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Publication number
LU82332A1
LU82332A1 LU82332A LU82332A LU82332A1 LU 82332 A1 LU82332 A1 LU 82332A1 LU 82332 A LU82332 A LU 82332A LU 82332 A LU82332 A LU 82332A LU 82332 A1 LU82332 A1 LU 82332A1
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Prior art keywords
isopropylamino
pyrimidine
preparation
hydrogen atom
hydroxyl derivatives
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LU82332A
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French (fr)
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A Esanu
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Soc D Etudes Prod Chimique
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Publication of LU82332A1 publication Critical patent/LU82332A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Catalysts (AREA)

Description

♦ -1-♦ -1-

La présente invention concerne un procédé de préparation des dérivés hydroxylés de 11isopropylamino-pyrimidine, intéressant dans le domaine thérapeutique, et plus particulièrement pour le traitement de différentes neuropathies et des 5 dystrophies musculaires.The present invention relates to a process for the preparation of hydroxylated derivatives of isopropylamino-pyrimidine, useful in the therapeutic field, and more particularly for the treatment of various neuropathies and muscular dystrophies.

La formule générale de ces dérivés est la suivante : v /V Z*3 *5—4 /—nh —ch/ \_n/ CH3 A6 dans laquelle A^, Ag et Ag représentent chacun : - un atome d'hydrogène, - un radical hydroxy, 10 avec la restriction qu'au moins l'un des substituants ’A^, A^ et A6 n'est pas un atome d'hydrogène.The general formula of these derivatives is as follows: v / VZ * 3 * 5—4 / —nh —ch / \ _n / CH3 A6 in which A ^, Ag and Ag each represent: - a hydrogen atom, - a hydroxy radical, with the restriction that at least one of the substituents' A ^, A ^ and A6 is not a hydrogen atom.

Ces composés peuvent être préparés, par exemple, en réduisant 1'isopropylamino-2 aralcoyloxy ou alcoyloxy pyri-midine correspondante par l'hydrogène, sous pression normale, 15 et en présence d'un catalyseur d'hydrogénation tel que, par exemple, le palladium, selon le schéma suivant : / \ /CH3 H2 'S/Z=^N\ /CH3 H r-\ A"6 A6 dans lequel A''^, A"^ et A”g représentent chacun un atome d'hydrogène ou un radical aralcoyloxy ou alcoyloxy avec la même restriction que ci-dessus.These compounds can be prepared, for example, by reducing the corresponding 2-isopropylaminoalkyloxy or alkoxy pyri-midine with hydrogen, under normal pressure, and in the presence of a hydrogenation catalyst such as, for example, palladium, according to the following diagram: / \ / CH3 H2 'S / Z = ^ N \ / CH3 H r- \ A "6 A6 in which A' '^, A" ^ and A ”g each represent an atom of hydrogen or an aralkoyloxy or alkoxy radical with the same restriction as above.

-2- »-2- ”

La présente invention sera mieux comprise, grâce aux exemples suivants :The present invention will be better understood from the following examples:

Exemple 1 : isopropylamino-2 hydroxy-5 pyrimidine.Example 1: 2-isopropylamino-5-hydroxypyrimidine.

Dans un réacteur pressurisé, d'une capacité de 2 litres, 5 de préférence soumis a un courant d'azote, on place 0,8 g d'isopropylamino-2 benzyloxy-5 pyrimidine, 40 ml de méthanol . et 80mg d'un catalyseur à base de palladium ; l'hydrogénation est effectuée pendant 2 heures, sous pression normale. Après filtration du catalyseur et évaporation du méthanol, 10 le produit est repris dans de l'éther diéthylique et la solution est filtrée afin d'éliminer les matières insolu-0.8 g of 2-isopropylamino-5-benzyloxy-pyrimidine, 40 ml of methanol are placed in a pressurized reactor with a capacity of 2 liters, preferably subjected to a stream of nitrogen. and 80 mg of a palladium-based catalyst; the hydrogenation is carried out for 2 hours, under normal pressure. After filtration of the catalyst and evaporation of methanol, the product is taken up in diethyl ether and the solution is filtered in order to remove the insoluble matter.

'V'V

blés. L'éther diéthylique est évaporé et le produit est recristallisé d'abord dans l'eau, puis dans l'acétate d'iso-propyle. Après séchage, on obtient 0,4 g (rendement 80%) 15 d'isopropylamino-2 hydroxy-5 pyrimidine. L'analyse élémentaire montre une excellente correspondance avec la formule C^H^N^O. Point de fusion 161°C (Tottoli) . Le Spectre ÜV confirme la structure.wheat. The diethyl ether is evaporated and the product is recrystallized first from water, then from isopropyl acetate. After drying, 0.4 g (80% yield) of 2-isopropylamino-5 hydroxy-pyrimidine is obtained. Elementary analysis shows an excellent correspondence with the formula C ^ H ^ N ^ O. Melting point 161 ° C (Tottoli). The ÜV Specter confirms the structure.

Exemple 2 : isopropylamino-2 hydroxy-4 pyrimidine.Example 2: isopropylamino-2 hydroxy-4 pyrimidine.

20 La méthode décrite dans l'exemple 1 est appliquée à 1'isopropylamino-2 éthoxy-4 pyrimidine au lieu d'être appliquée à 1'isopropylamino-2 benzyloxy-5 pyrimidine. Le rendement est de 83% d'un produit blanc cristallin fondant à 140°C (Tottoli), dont l'analyse confirme la correspondance 25 parfaite avec la formule C^H^N^O. Le Spectre UV confirme la structure.The method described in Example 1 is applied to 2-isopropylamino-4-ethoxy-pyrimidine instead of being applied to 2-isopropylamino-5-benzyloxy-pyrimidine. The yield is 83% of a white crystalline product melting at 140 ° C. (Tottoli), the analysis of which confirms the perfect correspondence with the formula C ^ H ^ N ^ O. The UV spectrum confirms the structure.

Exemple 3 : isopropylamino-2 dihvdroxy-4,6 pyrimidine.Example 3: isopropylamino-2 dihvdroxy-4,6 pyrimidine.

La méthode décrite dans l'exemple 1 est appliquée à 1'isopropylamino-2 dibenzyloxy-4,6 pyrimidine au lieu d'être 30 appliquée à 1'isopropylamino-2 benzyloxy-5 pyrimidine. Le " rendement est de 78% d'un produit blanc cristallin (chlor hydrate) fondant à 218-221°C (Tottoli), avec décomposition, ß -3- dont l'analyse montre une correspondance parfaite avec la formule ,HC£.The method described in Example 1 is applied to isopropylamino-2-dibenzyloxy-4,6 pyrimidine instead of being applied to isopropylamino-2 benzyloxy-5 pyrimidine. The "yield is 78% of a white crystalline product (hydrochloride) melting at 218-221 ° C (Tottoli), with decomposition, ß -3- whose analysis shows a perfect correspondence with the formula, HC £.

v Le Spectre UV confirme la structure.v The UV spectrum confirms the structure.

TOXICITETOXICITY

5 La toxicité aigue (mg/kg) des composés de l'invention a été déterminée sur des souris i.p. et per os et les valeurs sont reportées dans le tableau suivant : ♦ composé "The acute toxicity (mg / kg) of the compounds of the invention was determined in i.p. and per os and the values are given in the following table: ♦ compound "

Ex. I Ex. 2 Ex. 3 _voie —^___ i.p. 200 240 260 per os 205 355 285Ex. I Ex. 2 Ex. 3 _voi - ^ ___ i.p. 200 240 260 per os 205 355 285

PHARMACOLOGIEPHARMACOLOGY

On a recherché l'activité pharmacologique des composés selon l'invention en effectuant une expérimentation compd-rative sur la régénération du nerf sciatique du rat mâle 15 adulte (Wistar) .The pharmacological activity of the compounds according to the invention was sought by carrying out a computational experiment on the regeneration of the sciatic nerve of the adult male rat (Wistar).

On crée une lésion du nerf sciatique des rats, en .We create a lesion of the sciatic nerve of rats, in.

.. appliquant sur le nerf, pendant 20 minutes, une thermosonde... applying a thermoprobe to the nerve for 20 minutes.

Les rats sont alors traités i.p. avec le produit en référence ou les composés de la présente invention pour une durée 20 prédéterminée. A la fin du traitement, les rats sont tués, les nerfs sciatiques sont séparés et mis en contact avec une série de 70 fils parallèles en platine (intervalle 1 mm) très fins et un signal électrique, appliqué en amont du point de lésion, est recherché sur les fils de platine : le fil 25 le plus distant, où le signal peut être capté, donne la longueur régénérée.The rats are then treated i.p. with the reference product or the compounds of the present invention for a predetermined period. At the end of the treatment, the rats are killed, the sciatic nerves are separated and brought into contact with a series of 70 parallel platinum wires (interval 1 mm) very fine and an electrical signal, applied upstream of the point of injury, is sought on the platinum wires: the most distant wire 25, where the signal can be received, gives the regenerated length.

-4--4-

AAT

Pour chaque composé testé et chaque durée de traitement, on utilise un lot de 8 rats.For each compound tested and each treatment duration, a batch of 8 rats is used.

Quatre composés ont été testés par voie i.p. : le v composé de l'exemple 1, le composé de l'exemple 2, le composé de l'exemple 3, tous à la dose de 10 mg/kg et, comme référence, un mélange de vitamines B1 (500 mg/kg), B6 (500 mg/kg) et B12 (5 mg/kg), ce qui est connu pour être la composition la plus efficace dans ce domaine. Les animaux-témoins n'ont reçu aucun traitement.Four compounds were tested i.p. : the compound of Example 1, the compound of Example 2, the compound of Example 3, all at a dose of 10 mg / kg and, as reference, a mixture of vitamins B1 (500 mg / kg ), B6 (500 mg / kg) and B12 (5 mg / kg), which is known to be the most effective composition in this area. Control animals received no treatment.

Cinq lots de 8 animaux ont été utilisés pour chaque » période (7, 11, 14, 17 et 21 jours) soit pour des témoins, soit pour les composés 1, 2, 3 ou pour le mélange de référence .Five batches of 8 animals were used for each period (7, 11, 14, 17 and 21 days) either for controls, or for compounds 1, 2, 3 or for the reference mixture.

Les résultats de cette expérimentation sont résumés dans le tableau suivant, avec les chiffres obtenus pour les animaux-témoins ; les longueurs des nerfs régénérés sont indiquées dans les colonnes respectives des jours comme valeur moyenne des longueurs mesurées pour tous les animaux de chaque lot. Lorsqu'aucun chiffre n'apparaît (17 et 21 jours), cela signifie que la longueur régénérée excédait la longueur de l'échantillon prélevé. { —---- Durée (jours)The results of this experiment are summarized in the following table, with the figures obtained for the control animals; the lengths of the regenerated nerves are indicated in the respective columns of the days as the average value of the lengths measured for all the animals in each batch. When no figure appears (17 and 21 days), this means that the regenerated length exceeded the length of the sample taken. {—---- Duration (days)

Composé et dosè~T7pT--—-_ 7 il 14 17 21 Références 5,1 10,2 12,8 17,8 22,4 __ ioemgAg2__6'8 14-4 Z1'1 - fHg/kg3__6'7 15'6 26>7 -Compound and dosed ~ T7pT --—-_ 7 il 14 17 21 References 5,1 10,2 12,8 17,8 22,4 __ ioemgAg2__6'8 14-4 Z1'1 - fHg / kg3__6'7 15'6 26> 7 -

Im mg/kg/sOO mg/kg et 5 mg/kg 8·8 13'4 15-8 20'4 23'7 # -5-Im mg / kg / sOO mg / kg and 5 mg / kg 8 · 8 13'4 15-8 20'4 23'7 # -5-

PRESENTATION - POSOLOGIEPRESENTATION - DOSAGE

Ces dérivés peuvent être présentés sous toute forme , thérapeutiquement acceptable, et, par exemple, en comprimés ou en gélules contenant 5 mg par unité de dosage avec un excipient ; en ce qui concerne la forme injectable, le produit peut être présenté dans des ampoules contenant au moins 1 mg de produit actif sous la forme de son chlorhydrate dissout dans l'eau. Quant à la posologie en thérapeutique humaine, les doses vont de 20 mg à 1 g par jour par voie orale et de 1 mg à 50 mg par jour, par voie injectable.These derivatives can be presented in any therapeutically acceptable form and, for example, in tablets or capsules containing 5 mg per dosage unit with an excipient; as regards the injectable form, the product can be presented in ampoules containing at least 1 mg of active product in the form of its hydrochloride dissolved in water. As for the dosage in human therapy, the doses range from 20 mg to 1 g per day by the oral route and from 1 mg to 50 mg per day by the injectable route.

♦ ’ Un exemple de la forme comprimé est donné ci-dessous : - Composé de l'un des exemples 5 mg - Lactose 70 mg - Talc 20 mg - Stéarate de magnésium 5 mg 100 mg \‘ ·» 1 s»;♦ ’An example of the tablet form is given below: - Composed of one of the examples 5 mg - Lactose 70 mg - Talc 20 mg - Magnesium stearate 5 mg 100 mg \" 1 s ";

Claims (1)

»JF“ -6- REVENDICATION Procédé de préparation des dérivés hydroxylés de l'iso-propylamino-pyrimidine répondant à la formule : A4 )=% Z”3 As“\ /~NH—CH< V—/ CH3 A6 ** dans laquelle A4, A5 et Ag représentent chacun : - un atome d’hydrogène, 5. un radical hydroxy, avec la restriction qu'au moins l'un des substituants et Ag n'est pas un atome d'hydrogène, consistant à réduire 1 'isopropylamino-2 aralcoyloxy ou alcoyloxy pyrimidine.. correspondante par l'hydrogène, sous pression normale et en présence 10 d'un catalyseur d'hydrogénation tel que, par exemple, le palladium., selon le schéma suivant : A"4 A4 -N\ CH /=·Ν. CH / \ / n3 H / \ / n3 A"c—\\ /)—NH— CH/ -1-»A.-h(. VnH-CH< Y_f \h3 m 5 \_/ \h, )-N 3 >-N 3 A", A/ p 6 6 ·/ dans lequel A"4, A"5 et A"g représentent chacun un atome d'hydrogène ou un radical aralcoyloxy ou alcoyloxy avec la même restriction que ci-dessus.»JF“ -6- CLAIM Process for the preparation of hydroxylated derivatives of isopropylamino-pyrimidine corresponding to the formula: A4) =% Z ”3 As“ \ / ~ NH — CH <V— / CH3 A6 ** in which A4, A5 and Ag each represent: - a hydrogen atom, 5. a hydroxy radical, with the restriction that at least one of the substituents and Ag is not a hydrogen atom, consisting in reducing 1 isopropylamino-2 aralkoyloxy or alkyloxy pyrimidine .. corresponding by hydrogen, under normal pressure and in the presence of a hydrogenation catalyst such as, for example, palladium., according to the following scheme: A "4 A4 - N \ CH / = · Ν. CH / \ / n3 H / \ / n3 A "c - \\ /) - NH— CH / -1-" A.-h (. VnH-CH <Y_f \ h3 m 5 \ _ / \ h,) -N 3> -N 3 A ", A / p 6 6 · / in which A" 4, A "5 and A" g each represent a hydrogen atom or an aralkoyloxy or alkyloxy radical with the same restriction as above.
LU82332A 1979-04-30 1980-04-03 PREPARATION OF HYDROXYL DERIVATIVES OF ISOPROPYLAMINO-PYRIMIDINE LU82332A1 (en)

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GB7914987 1979-04-30
GB7914987 1979-04-30

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JPS63145595U (en) * 1987-03-13 1988-09-26
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JPH01100695U (en) * 1987-12-21 1989-07-06
US5264435A (en) * 1988-12-29 1993-11-23 Mitsui Petrochemical Industries, Ltd. Pyrimidines and their pharmaceutical acceptable salts, and their use as medicines
HU206337B (en) * 1988-12-29 1992-10-28 Mitsui Petrochemical Ind Process for producing pyrimidine derivatives and pharmaceutical compositions

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IT1141487B (en) 1986-10-01
SG22583G (en) 1983-12-16
AR222869A1 (en) 1981-06-30
IT1141296B (en) 1986-10-01
ZA801960B (en) 1981-04-29
JPS6116272B2 (en) 1986-04-28
IT8021542A0 (en) 1980-04-22
BE882593A (en) 1980-07-31
FR2455588A1 (en) 1980-11-28
SG22283G (en) 1983-12-16
FI801084A (en) 1980-10-31
IT8021543A0 (en) 1980-04-22
NO154056B (en) 1986-04-01
HK55683A (en) 1983-11-25
CH645361A5 (en) 1984-09-28
GB2054556B (en) 1983-01-26
ES8103060A1 (en) 1981-02-16
FI66358B (en) 1984-06-29
MY8400204A (en) 1984-12-31
ES491000A0 (en) 1981-02-16
NO154055C (en) 1986-07-09
ES490999A0 (en) 1981-02-16
EG14284A (en) 1983-09-30
CH645633A5 (en) 1984-10-15
DK183880A (en) 1980-10-31
FI66358C (en) 1984-10-10
JPS55145671A (en) 1980-11-13
IN154067B (en) 1984-09-15
GB2055801A (en) 1981-03-11
ATA221580A (en) 1985-08-15
NO154055B (en) 1986-04-01
NO801235L (en) 1980-10-31
FI801083A (en) 1980-10-31
NZ193422A (en) 1981-12-15
OA06525A (en) 1981-07-31
IN154066B (en) 1984-09-15
FR2455589A1 (en) 1980-11-28
NL8002271A (en) 1980-11-03
ZA801958B (en) 1981-04-29
ATA221680A (en) 1985-08-15
FR2455588B1 (en) 1983-04-15
AT380012B (en) 1986-03-25
GB2055801B (en) 1983-02-09
JPS55145670A (en) 1980-11-13
NO154056C (en) 1986-07-09
NO801234L (en) 1980-10-31
GB2054556A (en) 1981-02-18
PT71155A (en) 1980-05-01
AR222870A1 (en) 1981-06-30
JPS6116273B2 (en) 1986-04-28
OA06527A (en) 1981-07-31
BE882594A (en) 1980-07-31
IE800864L (en) 1980-10-30
MX5878E (en) 1984-08-16
EG14259A (en) 1983-09-30
IE800865L (en) 1980-10-30
NL8002272A (en) 1980-11-03
MY8400203A (en) 1984-12-31
PT71154A (en) 1980-05-01
FI66359C (en) 1984-10-10
FR2455589B1 (en) 1981-07-10
DK183780A (en) 1980-10-31
ES8103061A1 (en) 1981-02-16
MX6514E (en) 1985-06-26
NZ193421A (en) 1981-11-19
AT380013B (en) 1986-03-25
MA18824A1 (en) 1980-12-31
IE49709B1 (en) 1985-11-27
IE49591B1 (en) 1985-10-30
HK55583A (en) 1983-11-25
LU82333A1 (en) 1980-07-02
FI66359B (en) 1984-06-29

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