CH645361A5 - Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine - Google Patents

Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine Download PDF

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Publication number
CH645361A5
CH645361A5 CH269080A CH269080A CH645361A5 CH 645361 A5 CH645361 A5 CH 645361A5 CH 269080 A CH269080 A CH 269080A CH 269080 A CH269080 A CH 269080A CH 645361 A5 CH645361 A5 CH 645361A5
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CH
Switzerland
Prior art keywords
preparation
isopropylamino
hydrogen atom
isopropylaminopyrimidine
pyrimidine
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CH269080A
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French (fr)
Inventor
Andre Esanu
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Soc D Etudes Prod Chimique
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Publication of CH645361A5 publication Critical patent/CH645361A5/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)

Abstract

A process is described for the preparation of hydroxylated derivatives of isopropylaminopyrimidine corresponding to the formula: <IMAGE> in which A4, A5 and A6 each represent: - a hydrogen atom, - a hydroxyl radical, with the restriction that at least one of the substituents A4, A5 and A6 is not a hydrogen atom, consisting in reacting the corresponding 2-(isopropylamino)halopyrimidine with an inorganic base, in water at 100-150 DEG C, in the presence of copper. These compounds can be used in the preparation of medicaments for the treatment of nemopathies and of muscular dystrophies.

Description

La présente invention concerne un procédé de préparation de dérivés hydroxylés de l'isopropylaminopyrimidine intéressants dans le domaine thérapeutique, et plus particulièrement pour le traitement des différentes neuropathies et des dystrophies musculaires. The present invention relates to a process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine which are of interest 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: The general formula of these derivatives is as follows:

A, AT,

-CH -CH

CH. CH.

CH. CH.

Cu Cu

+ MOH y A, + MOH y A,

CH. CH.

\-NH-CH( \ -NH-CH (

CH. CH.

où A4, As et A6 représentent chacun un atome d'hydrogène ou un radical hydroxy, avec la restriction qu'au moins l'un des substituants A4, A5 et A6 n'est pas un atome d'hydrogène. where A4, As and A6 each represent a hydrogen atom or a hydroxy radical, with the restriction that at least one of the substituents A4, A5 and A6 is not a hydrogen atom.

Ces composés sont préparés en faisant réagir l'isopropylamino-2-halogénopyrimidine correspondante sur une base minérale, dans l'eau à 100-150°C, en présence de cuivre, selon le schéma suivant: These compounds are prepared by reacting the corresponding isopropylamino-2-halopyrimidine on a mineral base, in water at 100-150 ° C, in the presence of copper, according to the following scheme:

A4 A4

"N, "NOT,

io où A'4, A'5 et A'6 représentent chacun un atome d'hydrogène ou un atome d'halogène, avec la même restriction que ci-dessus, et où MOH représente une base minérale. where A'4, A'5 and A'6 each represent a hydrogen atom or a halogen atom, with the same restriction as above, and where MOH represents a mineral base.

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

15 15

Exemple 1: Example 1:

Isopropylamino-2-hydroxy-5-pyrimidine Isopropylamino-2-hydroxy-5-pyrimidine

Dans un réacteur de 11, on verse 80 ml d'eau, 3 g de soude, de la poudre de cuivre et 4,3 g (0.02 mol) d'isopropylamino-2-bromo-5-2o pyrimidine; le mélange réactionnel est maintenu à 130-135°C pendant 1 h, sous agitation, et ensuite à 130-140° C pendant environ 12 h, également sous agitation. 80 ml of water, 3 g of sodium hydroxide, copper powder and 4.3 g (0.02 mol) of isopropylamino-2-bromo-5-2o pyrimidine are poured into a reactor of 11; the reaction mixture is kept at 130-135 ° C for 1 h, with stirring, and then at 130-140 ° C for about 12 h, also with stirring.

Après filtration du cuivre, le mélange réactionnel est extrait deux fois avec du chloroforme. Les extraits combinés sont acidifiés avec 25 de l'acide acétique jusqu'à pH 6,5-7,0. La solution est ensuite saturée avec du chlorure de sodium, provoquant la précipitation du produit qui est récupéré et lavé à l'eau et, ensuite, avec du pêntane. Le produit est alors repris dans l'éther diéthylique et traité avec du noir de carbone. La solution est concentrée, provoquant de nouveau la pré-30 cipitation du produit qui est récupéré et recristallisé dans l'eau ou l'acétate d'isopropyle. After filtration of the copper, the reaction mixture is extracted twice with chloroform. The combined extracts are acidified with acetic acid to pH 6.5-7.0. The solution is then saturated with sodium chloride, causing the precipitation of the product which is recovered and washed with water and, then, with pntane. The product is then taken up in diethyl ether and treated with carbon black. The solution is concentrated, again causing the product to precipitate which is recovered and recrystallized from water or isopropyl acetate.

Les cristaux sont séchés pour donner 2,45 g (rendement 80%) d'isopropylamino-2-hydroxy-5-pyrimidine. L'analyse élémentaire montre une bonne correspondance avec la formule C7HuN30. 35 Le produit de départ isopropylamino-2-bromo-5-pyrimidine avait été facilement obtenu en faisant réagir, dans des proportions stœchiométriques, l'isopropylamino-2-pyrimidine et le N-bromosuc-cinimide en présence d'acide acétique (rendement 84%). The crystals are dried to give 2.45 g (80% yield) of isopropylamino-2-hydroxy-5-pyrimidine. Elementary analysis shows a good correspondence with the formula C7HuN30. The starting material isopropylamino-2-bromo-5-pyrimidine had been easily obtained by reacting, in stoichiometric proportions, isopropylamino-2-pyrimidine and N-bromosuc-cinimide in the presence of acetic acid (yield 84 %).

40 Exemple 2: 40 Example 2:

Isopropylamino-2-hydroxy-4-pyrimidine Isopropylamino-2-hydroxy-4-pyrimidine

On reprend la méthode de l'exemple 1, mais en utilisant de l'iso-propylamino-2-chloro-4-pyrimidine au lieu de l'isopropylamino-2-bromo-5-pyrimidine. Le rendement est de 77% d'un produit blanc 45 cristallin fondant à 140°C (Tottoli), dont l'analyse montre une correspondance parfaite avec la formule C7Hj !N30. L'analyse structurale (spectre UV) confirme la position du radical hydroxy. The method of Example 1 is repeated, but using isopropylamino-2-chloro-4-pyrimidine instead of isopropylamino-2-bromo-5-pyrimidine. The yield is 77% of a white crystalline product 45 melting at 140 ° C. (Tottoli), the analysis of which shows a perfect correspondence with the formula C7Hj! N30. Structural analysis (UV spectrum) confirms the position of the hydroxy radical.

Exemple 3: Example 3:

5o Isopropylamino-2-dihydroxy-4,6-pyrimidine 5o Isopropylamino-2-dihydroxy-4,6-pyrimidine

On reprend la méthode de l'exemple 1, mais en utilisant de l'iso-propylamino-2-dichloro-4,6-pyrimidine au lieu de l'isopropylamino-2-bromo-5-pyrimidine. Le rendement est de 73% d'un produit blanc cristallin fondant à 221-225°C (Tottoli), avec décomposition, dont 55 l'analyse montre une correspondance parfaite avec la formule C7Hlt02, HCl. L'analyse structurale (spectre UV) confirme la position du radical hydroxy. The method of Example 1 is repeated, but using isopropylamino-2-dichloro-4,6-pyrimidine instead of isopropylamino-2-bromo-5-pyrimidine. The yield is 73% of a white crystalline product melting at 221-225 ° C (Tottoli), with decomposition, 55 of which analysis shows a perfect correspondence with the formula C7Hlt02, HCl. Structural analysis (UV spectrum) confirms the position of the hydroxy radical.

Toxicité Toxicity

60 La toxicité aiguë (mg/kg) des composés de l'invention a été déterminée sur des souris par voie intrapéritonéale et per os; les valeurs sont reportées dans le tableau I. The acute toxicity (mg / kg) of the compounds of the invention was determined in mice intraperitoneally and per os; the values are given in table I.

( Tableau en tête de la colonne suivante) (Table at the top of the next column)

6J Pharmacologie 6J Pharmacology

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

3 3

645 361 645,361

On crée une lésion du nerf sciatique des rats, en appliquant sur le nerf, pendant 20 min, une thermosonde. Les rats sont alors traités par voie intrapéritonéale avec le produit de référence ou avec les composés de la présente invention, pour une durée 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 très fins en platine (intervalle 1 mm), et un signal électrique, appliqué en amont du point de lésion, est recherché sur les fils de platine: le fil le plus distant où le signal peut être capté donne la longueur régénérée. A lesion of the sciatic nerve of the rats is created by applying a thermoprobe to the nerve for 20 min. The rats are then treated intraperitoneally with the reference product or with the compounds of the present invention, for a predetermined duration. At the end of the treatment, the rats are killed, the sciatic nerves are separated and brought into contact with a series of 70 very fine parallel wires in platinum (interval 1 mm), and an electrical signal, applied upstream from the point of injury is sought on the platinum wires: the most distant wire where the signal can be received gives the regenerated length.

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

Quatre composés ont été testés par voie intrapéritonéale: le 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 Bj (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 intraperitoneally: 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 Bj (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 huit animaux ont été utilisés pour chaque période (7,11,14,17 et 21 d), soit pour des témoins, soit pour les composés 1, 2 et 3 ou pour le mélange de référence. Five batches of eight animals were used for each period (7, 11, 14, 17 and 21 d), either for controls, or for compounds 1, 2 and 3 or for the reference mixture.

Les résultats de cette expérimentation sont résumés dans le tableau II, 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. Lorsque aucun chiffre n'apparaît (17 et 21 d), cela signifie que la longueur régénérée excédait la longueur de l'échantillon prélevé. The results of this experiment are summarized in Table II, 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 d), this means that the regenerated length exceeded the length of the sample taken.

20 20

Présentation — Posologie Presentation - Dosage

Ces dérivés peuvent être présentés sous toute forme thérapeuti-quement acceptable, 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 dissous dans l'eau. Quant à la posologie en thérapeutique humaine, les doses vont de 20 mg à 1 g/d par voie orale, et de 1 à 50 mg/d par voie injectable. These derivatives can be presented in any therapeutically acceptable form, 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 / d orally, and from 1 to 50 mg / d by injection.

30 Un exemple de la forme comprimé est donné ci-dessous: An example of the compressed form is given below:

(mg) (mg)

Composé de l'un des exemples 5 Composed of one of examples 5

Lactose 70 Lactose 70

Talc 20 Talc 20

Stéarate de magnésium 5 Magnesium stearate 5

Total 100 Total 100

Tableau I Table I

R R

Claims (2)

645 361 645,361 2 2 REVENDICATIONS Procédé de préparation de dérivés hydroxylés de l'isopropylami-nopyrimidine répondant à la formule : Process for the preparation of hydroxylated derivatives of isopropylami-nopyrimidine corresponding to the formula: A, AT, NH CH< NH CH < , CH. , CH. CH. CH. dans laquelle A4, A5 et A6 représentent chacun un atome d'hydrogène ou un radical hydroxy, au moins l'un des substituants A4, As et A6 n'étant pas un atome d'hydrogène, caractérisé en ce qu'on fait réagir Fisopropylamino-2-halogènopyrimidine correspondante de formule: in which A4, A5 and A6 each represent a hydrogen atom or a hydroxy radical, at least one of the substituents A4, As and A6 not being a hydrogen atom, characterized in that the isopropylamino is reacted -2-halogenopyrimidine corresponding of formula: A ' AT ' A 4 At 4 où A'4, A's et A'6 représentent chacun un atome d'hydrogène ou un atome d'halogène, au moins un des substituants A 4, A's et A'6 n'étant pas un atome d'hydrogène, sur une base minérale, dans de l'eau à 100-150°C et en présence de cuivre. where A'4, A's and A'6 each represent a hydrogen atom or a halogen atom, at least one of the substituents A 4, A's and A'6 not being a hydrogen atom, on a base mineral, in water at 100-150 ° C and in the presence of copper.
CH269080A 1979-04-30 1980-04-08 Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine CH645361A5 (en)

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AR (2) AR222870A1 (en)
AT (2) AT380012B (en)
BE (2) BE882593A (en)
CH (2) CH645633A5 (en)
DK (2) DK183780A (en)
EG (2) EG14259A (en)
ES (2) ES8103061A1 (en)
FI (2) FI66358C (en)
FR (2) FR2455588A1 (en)
GB (2) GB2054556B (en)
HK (2) HK55583A (en)
IE (2) IE49709B1 (en)
IN (2) IN154066B (en)
IT (2) IT1141296B (en)
LU (2) LU82333A1 (en)
MA (1) MA18824A1 (en)
MX (2) MX5878E (en)
MY (2) MY8400204A (en)
NL (2) NL8002271A (en)
NO (2) NO154056C (en)
NZ (2) NZ193421A (en)
OA (2) OA06527A (en)
PT (2) PT71154A (en)
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ZA (2) ZA801960B (en)

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JPS63145595U (en) * 1987-03-13 1988-09-26
JPS645795U (en) * 1987-06-26 1989-01-13
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
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
LU82332A1 (en) 1980-07-02
LU82333A1 (en) 1980-07-02
FI66359B (en) 1984-06-29

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