CH645633A5 - Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine - Google Patents
Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine Download PDFInfo
- Publication number
- CH645633A5 CH645633A5 CH268980A CH268980A CH645633A5 CH 645633 A5 CH645633 A5 CH 645633A5 CH 268980 A CH268980 A CH 268980A CH 268980 A CH268980 A CH 268980A CH 645633 A5 CH645633 A5 CH 645633A5
- Authority
- CH
- Switzerland
- Prior art keywords
- isopropylamino
- hydrogen atom
- preparation
- isopropylaminopyrimidine
- hydrogen
- Prior art date
Links
Classifications
-
- 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
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 de différentes neuropathies et des dystrophies musculaires. The present invention relates to a process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine, which are 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: The general formula of these derivatives is as follows:
A. AT.
NH- NH-
■CH ■ CH
CH. CH.
CH- CH-
dans laquelle A4, A5 et A6 représentent chacun: in which A4, A5 and A6 each represent:
— un atome d'hydrogène, - a hydrogen atom,
— un radical hydroxy, - a hydroxy radical,
avec la restriction qu'au moins l'un des substituants A4, As et A6 n'est pas un atome d'hydrogène. with the restriction that at least one of the substituents A4, As and A6 is not a hydrogen atom.
Ces composés sont préparés en réduisant l'isopropylamino-2 aralcoyloxy- ou alcoyloxypyrimidine correspondante par l'hydrogène, sous pression normale, et en présence d'un catalyseur d'hydrogénation tel que, par exemple, le palladium, selon le schéma suivant: These compounds are prepared by reducing the 2-isopropylamino-aralkoyloxy- or corresponding alkyloxypyrimidine with hydrogen, under normal pressure, and in the presence of a hydrogenation catalyst such as, for example, palladium, according to the following scheme:
A" AT"
io dans lequel A"4, A"5 et A"6 représentent chacun un atome d'hydrogène ou un radical aralcoyloxy ou alcoyloxy, avec la même restriction que ci-dessus. io in which A "4, A" 5 and A "6 each represent a hydrogen atom or an aralkyloxy or alkyloxy radical, with the same restriction as above.
La présente invention sera mieux comprise grâce aux exemples suivants: The present invention will be better understood from the following examples:
is is
Exemple 1 Example 1
Isopropylamino-2 hydroxy-5 pyrimidine Isopropylamino-2-hydroxy-5 pyrimidine
Dans un réacteur pressurisé, d'une capacité de 2 1, de préférence 20 soumis à un courant d'azote, on place 0,8 g d'isopropylamino-2 ben-zyloxy-5 pyrimidine, 40 ml de méthanol et 80 mg d'un catalyseur à base de palladium; l'hydrogénation est effectuée pendant 2 h, sous pression normale. Après filtration du catalyseur et évaporation du méthanol, le produit est repris dans de l'éther diéthylique et la solu-25 tion est filtrée afin d'éliminer les matières insolubles. L'éther diéthylique est évaporé et le produit est recristallisé d'abord dans l'eau, puis dans l'acétate d'isopropyle. Après séchage, on obtient 0,4 g (rendement 80%) d'isopropylamino-2 hydroxy-5 pyrimidine. L'analyse élémentaire montre une excellente correspondance avec la 30 formule C7H! jN30. Point de fusion 161° C (Tottoli). Le spectre UV confirme la structure. 0.8 g of isopropylamino-2 ben-zyloxy-5 pyrimidine, 40 ml of methanol and 80 mg of liquid are placed in a pressurized reactor, with a capacity of 2 l, preferably 20 subjected to a stream of nitrogen. 'a palladium-based catalyst; the hydrogenation is carried out for 2 h, 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 matters. 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. Elemental analysis shows excellent correspondence with formula C7H! jN30. Melting point 161 ° C (Tottoli). The UV spectrum confirms the structure.
Exemple 2 Example 2
Isopropylamino-2 hydroxy-4 pyrimidine Isopropylamino-2-hydroxy-4 pyrimidine
35 35
La méthode décrite dans l'exemple 1 est appliquée à l'isopropylamino-2 éthoxy-4 pyrimidine au lieu d'être appliquée à l'isopropyl-amino-2 benzyloxy-5 pyrimidine. Le rendement est de 83% d'un produit blanc cristallin fondant à 140° C (Tottoli), dont l'analyse 40 confirme la correspondance parfaite avec la formule C7Hj !N30. Le spectre UV confirme la structure. The method described in example 1 is applied to isopropylamino-2-ethoxy-4 pyrimidine instead of being applied to isopropyl-amino-2-benzyloxy-5 pyrimidine. The yield is 83% of a crystalline white product melting at 140 ° C. (Tottoli), the analysis of which confirms the perfect correspondence with the formula C7Hj! N30. The UV spectrum confirms the structure.
Exemple 3 Example 3
4S Isopropylamino-2 dihydroxy-4,6 pyrimidine 4S Isopropylamino-2 dihydroxy-4,6 pyrimidine
La méthode décrite dans l'exemple 1 est appliquée à l'isopropyl-amino-2 dibenzyloxy-4,6 pyrimidine au lieu d'être appliquée à l'iso-propylamino-2 benzyloxy-5 pyrimidine. Le rendement est de 78% d'un produit blanc cristallin (chlorhydrate) fondant à 218-221° C 50 (Tottoli), avec décomposition, dont l'analyse montre une correspondance parfaite avec la formule CvHj ,N302,HC1. Le spectre UV confirme la structure. The method described in Example 1 is applied to isopropyl-amino-2-dibenzyloxy-4,6 pyrimidine instead of being applied to iso-propylamino-2 benzyloxy-5 pyrimidine. The yield is 78% of a crystalline white product (hydrochloride) melting at 218-221 ° C 50 (Tottoli), with decomposition, the analysis of which shows a perfect correspondence with the formula CvHj, N302, HC1. The UV spectrum confirms the structure.
5S Toxicité 5S Toxicity
La toxicité aiguë (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: 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:
60 60
65 65
Composé Compound
Voie Way
Ex. 1 Ex. 1
Ex. 2 Ex. 2
Ex. 3 Ex. 3
i.p. i.p.
200 200
240 240
260 260
per os per os
205 205
355 355
285 285
3 3
645 633 645,633
Pharmacologie 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).
On crée une lésion du nerf sciatique des rats, en appliquant sur le nerf, pendant 20 min, une thermosonde. Les rats sont alors traités i.p. avec le produit en référence ou les composés de la présente invention pendant 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 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 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 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 platinum wires: the most distant wire, where the signal can be picked up, gives the regenerated length.
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., ceux de l'exemple 1, de l'exemple 2, 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), mélange connu pour être la composition la plus efficace dans ce domaine. Les animaux témoins n'ont reçu aucun traitement. Four compounds were tested ip, those of Example 1, of Example 2, 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), a mixture known to be the most effective composition in this field. Control animals received no treatment.
Cinq lots de 8 animaux ont été utilisés pour chaque période (7, 11,14,17 et 21 d) 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 d) 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. Lorsque aucun chiffre n'apparaît (17 et 21 d), cela signifie que que la longueur régénérée excédait la longueur de l'échantillon prélevé. 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 number appears (17 and 21 d), this means that the regenerated length exceeded the length of the sample taken.
5 5
10 10
15 15
Présentation - Posologie Presentation - Dosage
Ces dérivés peuvent être présentés sous toute forme thérapeuti-quement 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 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, 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 / d orally and from 1 to 50 mg / d, by injection.
Un exemple de comprimé est donné ci-dessous: An example of a tablet is given below:
Composé de l'un des exemples 5 mg Composed of one of the examples 5 mg
Lactose 70 mg Lactose 70 mg
Talc 20 mg Talc 20 mg
Stéarate de magnésium 5 mg Magnesium stearate 5 mg
100 mg 100 mg
Durée (d) Duration (d)
Composé et dose i.pi^^^^ Compound and dose i.pi ^^^^
7 7
11 11
14 14
17 17
21 21
Références References
5,1 5.1
10,2 10.2
12,8 12.8
17,8 17.8
22,4 22.4
Exemple 1 (10 mg/kg) Example 1 (10 mg / kg)
6,6 6.6
14,1 14.1
26,3 26.3
— -
— -
Exemple 2 (10 mg/kg) Example 2 (10 mg / kg)
6,8 6.8
14,4 14.4
26,1 26.1
— -
— -
Exemple 3 (10 mg/kg) Example 3 (10 mg / kg)
6,7 6.7
15,6 15.6
26,7 26.7
— -
— -
B1 (500 mg/kg), B6 (500 mg/kg, B12 (5 mg/kg) B1 (500 mg / kg), B6 (500 mg / kg, B12 (5 mg / kg)
8,8 8.8
13,4 13.4
15,8 15.8
20,4 20.4
23,7 23.7
25 25
R R
Claims (2)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7914987 | 1979-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH645633A5 true CH645633A5 (en) | 1984-10-15 |
Family
ID=10504858
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH268980A CH645633A5 (en) | 1979-04-30 | 1980-04-08 | Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine |
| CH269080A CH645361A5 (en) | 1979-04-30 | 1980-04-08 | Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH269080A CH645361A5 (en) | 1979-04-30 | 1980-04-08 | Process for the preparation of hydroxylated derivatives of isopropylaminopyrimidine |
Country Status (26)
| Country | Link |
|---|---|
| JP (2) | JPS55145670A (en) |
| 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) |
| SG (2) | SG22283G (en) |
| ZA (2) | ZA801960B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1980
- 1980-04-02 BE BE0/200083A patent/BE882593A/en not_active IP Right Cessation
- 1980-04-02 ZA ZA00801960A patent/ZA801960B/en unknown
- 1980-04-02 BE BE0/200084A patent/BE882594A/en not_active IP Right Cessation
- 1980-04-02 ZA ZA00801958A patent/ZA801958B/en unknown
- 1980-04-03 LU LU82333A patent/LU82333A1/en unknown
- 1980-04-03 LU LU82332A patent/LU82332A1/en unknown
- 1980-04-03 FI FI801083A patent/FI66358C/en not_active IP Right Cessation
- 1980-04-03 FI FI801084A patent/FI66359C/en not_active IP Right Cessation
- 1980-04-07 IN IN253/DEL/80A patent/IN154066B/en unknown
- 1980-04-07 IN IN254/DEL/80A patent/IN154067B/en unknown
- 1980-04-08 CH CH268980A patent/CH645633A5/en not_active IP Right Cessation
- 1980-04-08 CH CH269080A patent/CH645361A5/en not_active IP Right Cessation
- 1980-04-11 NZ NZ193421A patent/NZ193421A/en unknown
- 1980-04-11 NZ NZ193422A patent/NZ193422A/en unknown
- 1980-04-15 GB GB8012349A patent/GB2054556B/en not_active Expired
- 1980-04-15 GB GB8012351A patent/GB2055801B/en not_active Expired
- 1980-04-18 NL NL8002271A patent/NL8002271A/en unknown
- 1980-04-18 NL NL8002272A patent/NL8002272A/en not_active Application Discontinuation
- 1980-04-22 IT IT21543/80A patent/IT1141296B/en active
- 1980-04-22 MA MA19019A patent/MA18824A1/en unknown
- 1980-04-22 IT IT21542/80A patent/IT1141487B/en active
- 1980-04-24 AT AT0221580A patent/AT380012B/en not_active IP Right Cessation
- 1980-04-24 AT AT0221680A patent/AT380013B/en not_active IP Right Cessation
- 1980-04-25 AR AR280811A patent/AR222870A1/en active
- 1980-04-25 AR AR280810A patent/AR222869A1/en active
- 1980-04-28 MX MX808786U patent/MX5878E/en unknown
- 1980-04-28 MX MX808783U patent/MX6514E/en unknown
- 1980-04-28 JP JP5557480A patent/JPS55145670A/en active Granted
- 1980-04-28 PT PT71154A patent/PT71154A/en unknown
- 1980-04-28 IE IE865/80A patent/IE49709B1/en unknown
- 1980-04-28 IE IE864/80A patent/IE49591B1/en unknown
- 1980-04-28 JP JP5557580A patent/JPS55145671A/en active Granted
- 1980-04-28 PT PT71155A patent/PT71155A/en unknown
- 1980-04-28 NO NO801235A patent/NO154056C/en unknown
- 1980-04-28 NO NO801234A patent/NO154055C/en unknown
- 1980-04-29 ES ES491000A patent/ES8103061A1/en not_active Expired
- 1980-04-29 ES ES490999A patent/ES490999A0/en active Granted
- 1980-04-29 EG EG258/80A patent/EG14259A/en active
- 1980-04-29 EG EG257/80A patent/EG14284A/en active
- 1980-04-29 DK DK183780A patent/DK183780A/en unknown
- 1980-04-29 DK DK183880A patent/DK183880A/en unknown
- 1980-04-30 FR FR8009732A patent/FR2455588A1/en active Granted
- 1980-04-30 OA OA57103A patent/OA06527A/en unknown
- 1980-04-30 FR FR8009733A patent/FR2455589A1/en active Granted
- 1980-04-30 OA OA57101A patent/OA06525A/en unknown
-
1983
- 1983-04-28 SG SG222/83A patent/SG22283G/en unknown
- 1983-04-28 SG SG225/83A patent/SG22583G/en unknown
- 1983-11-17 HK HK555/83A patent/HK55583A/en unknown
- 1983-11-17 HK HK556/83A patent/HK55683A/en unknown
-
1984
- 1984-12-30 MY MY204/84A patent/MY8400204A/en unknown
- 1984-12-30 MY MY203/84A patent/MY8400203A/en unknown
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