CA1132561A - Hydroxy pyrimidine derivatives - Google Patents
Hydroxy pyrimidine derivativesInfo
- Publication number
- CA1132561A CA1132561A CA346,981A CA346981A CA1132561A CA 1132561 A CA1132561 A CA 1132561A CA 346981 A CA346981 A CA 346981A CA 1132561 A CA1132561 A CA 1132561A
- Authority
- CA
- Canada
- Prior art keywords
- pyrimidine
- isopropylamino
- hydroxy
- preparing
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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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
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A B S T R A C T
Novel isopropylamino-pyrimidine derivatives of the general formula:
Novel isopropylamino-pyrimidine derivatives of the general formula:
Description
l~Z561 The present invention relates to novel iso-propylamino-pyrimidine derivatives having interesting therapeutic activities.
More particularly, the compounds of the present invention correspond to the following general formula:
~ /CH3 5 ~ />-- \
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen.
The novel compounds have been found to be useful in the field of nervous regeneration and for the treatment of muscular dystrophies.
The compounds of the present invention may be prepared by any of the following processes.
In one process, isopropylamine is reacted with a 2-thiomethyl-pyrimidine of the general formula:
~ N
5~ /~ 3 N
wherein A4, A5 and A6 are as defined previously, the reaction being carried out in a non-polar solvent at a 20 temperature of about 100 to about 120C.
In another process a 2-isopropylamino-halogeno-pyrimidine is treated with a mineral base in water at 100 to 150C in the presence of copper in accordance with the following reaction scheme:
~3'~
~ N /CH3 wherein A'4, A'5 and A'6 stand for hydrogen or halogen, with the proviso that at least one of A'4, A'5 and A'6 is other than hydrogen and A4, A5 and A6 are as defined previously while M is an alkali or alkaline earth metal.
As an example of suitable metals there may be mentioned sodium, potassium or calcium.
A further process comprises reducing a 2-isopropylamino aralkyloxy or alkyloxy pyrimidine with hydrogen under pressure and in the presence of a hydro-genation catalyst such as palladium in accordance with the following reaction scheme:
5 ~ /~ \ Pd 5 ~
A"6 A6 wherein A"4, A"5 and A"6 stand for hydrogen, aralkyloxy or alkyloxy with the proviso that at least one is other than hydrogen and A4, A5 and A6 are as defined previ-ously. The preferred aralkyloxy radical is benzyloxy while the preferred alkyloxy is methoxy, ethoxy, propyl-oxy and butoxy.
The present invention will be more readily understood by referring to the following Examples which are given to illustrate the invention.
4-hydroxy-2-isopropylamino-pyrimidine The starting methyl thiouracil is obtained by reacting methyl iodide with thiouracil in the presence of sodium methanolate. The methyl thiouracil thus obtained ~32561 20 g. (0.14 mol) is placed in a one litre pressurized reactor with 200 ml of dry toluene and 200 ml of iso-propylamine. The reaction is carried on for 24 hours under pressure, at 110-120C. The resulting mixture is evaporated to dryness, treated with acetone and diethyl ether (50/50), filtered, washed with water and recrystal-lized in isopropyl acetate. There is thus obtained 17 g (yield 84%) of a white crystalline product melting at 140C, the analysis of which shows a good correspondence with the formula C7HllN3O. There is also prepared the hydrochloride of this compound, melting point 233-234C
(Tottoli) which also is a white crystalline product; its U.V. Spectrum data are:
In water (for hydrochloride) In methanol (for base) : 266 nm El% = 210 ~ : 293 nm El% = 510 max lcm max lcm ~max : 217 nm lcm ~max : 222 nm lcm ~max 290 nm The base is a white crystalline product (molecular weight 153.18), insoluble in water but soluble in chloroform.
5-hydroxy-2-isopropylamino-pyrimidine The method of Example 1 was repeated but 5-hydroxy-2-thiomethyl-pyrimidine was used. Yield 83%.
The temperature of reaction was 105 C. Melting point 161 C (Tottoli). U.V. Spectrum in water 60/methanol 40 :
~max : 341 nm lcm max : 241 nm lcm ~3Z561 4,6-dihydroxy-2-isopropylamino-pyrimidine The method of Example l was repeated but 4,6-dihydroxy-2-thiomethyl-pyrimidine was used. Yield 67%.
Temperature of reaction 110C. Melting point 215-220 C, with decomposition (Tottoli) for the hydrochloride of formula C7HllN3O2, HCl. This is a white crystalllne product insoluble in water at room temperature.
More particularly, the compounds of the present invention correspond to the following general formula:
~ /CH3 5 ~ />-- \
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen.
The novel compounds have been found to be useful in the field of nervous regeneration and for the treatment of muscular dystrophies.
The compounds of the present invention may be prepared by any of the following processes.
In one process, isopropylamine is reacted with a 2-thiomethyl-pyrimidine of the general formula:
~ N
5~ /~ 3 N
wherein A4, A5 and A6 are as defined previously, the reaction being carried out in a non-polar solvent at a 20 temperature of about 100 to about 120C.
In another process a 2-isopropylamino-halogeno-pyrimidine is treated with a mineral base in water at 100 to 150C in the presence of copper in accordance with the following reaction scheme:
~3'~
~ N /CH3 wherein A'4, A'5 and A'6 stand for hydrogen or halogen, with the proviso that at least one of A'4, A'5 and A'6 is other than hydrogen and A4, A5 and A6 are as defined previously while M is an alkali or alkaline earth metal.
As an example of suitable metals there may be mentioned sodium, potassium or calcium.
A further process comprises reducing a 2-isopropylamino aralkyloxy or alkyloxy pyrimidine with hydrogen under pressure and in the presence of a hydro-genation catalyst such as palladium in accordance with the following reaction scheme:
5 ~ /~ \ Pd 5 ~
A"6 A6 wherein A"4, A"5 and A"6 stand for hydrogen, aralkyloxy or alkyloxy with the proviso that at least one is other than hydrogen and A4, A5 and A6 are as defined previ-ously. The preferred aralkyloxy radical is benzyloxy while the preferred alkyloxy is methoxy, ethoxy, propyl-oxy and butoxy.
The present invention will be more readily understood by referring to the following Examples which are given to illustrate the invention.
4-hydroxy-2-isopropylamino-pyrimidine The starting methyl thiouracil is obtained by reacting methyl iodide with thiouracil in the presence of sodium methanolate. The methyl thiouracil thus obtained ~32561 20 g. (0.14 mol) is placed in a one litre pressurized reactor with 200 ml of dry toluene and 200 ml of iso-propylamine. The reaction is carried on for 24 hours under pressure, at 110-120C. The resulting mixture is evaporated to dryness, treated with acetone and diethyl ether (50/50), filtered, washed with water and recrystal-lized in isopropyl acetate. There is thus obtained 17 g (yield 84%) of a white crystalline product melting at 140C, the analysis of which shows a good correspondence with the formula C7HllN3O. There is also prepared the hydrochloride of this compound, melting point 233-234C
(Tottoli) which also is a white crystalline product; its U.V. Spectrum data are:
In water (for hydrochloride) In methanol (for base) : 266 nm El% = 210 ~ : 293 nm El% = 510 max lcm max lcm ~max : 217 nm lcm ~max : 222 nm lcm ~max 290 nm The base is a white crystalline product (molecular weight 153.18), insoluble in water but soluble in chloroform.
5-hydroxy-2-isopropylamino-pyrimidine The method of Example 1 was repeated but 5-hydroxy-2-thiomethyl-pyrimidine was used. Yield 83%.
The temperature of reaction was 105 C. Melting point 161 C (Tottoli). U.V. Spectrum in water 60/methanol 40 :
~max : 341 nm lcm max : 241 nm lcm ~3Z561 4,6-dihydroxy-2-isopropylamino-pyrimidine The method of Example l was repeated but 4,6-dihydroxy-2-thiomethyl-pyrimidine was used. Yield 67%.
Temperature of reaction 110C. Melting point 215-220 C, with decomposition (Tottoli) for the hydrochloride of formula C7HllN3O2, HCl. This is a white crystalllne product insoluble in water at room temperature.
2-isopropylamino-5-hydroxy-pyrimidine Into a one litre reactor were poured 80 ml of - water, 3 g of sodium hydroxide, some copper powder and 4.3 g (0.02 mol) of 2-isopropylamino-5-bromo-pyrimidine;
the reaction mixture was maintained at 130 to 135C for 1 hour under stirring and then at 130 to 140C for about 12 hours, also under stirring.
After filtration off of the copper, the reaction mixture was extracted twice with chloroform.
The combined extracts were acidified with acetic acid to pH ~.5 to 7Ø The solution was then saturated with sodium chloride causing precipitation of the product, which was collected and washed with water and then with pentane. The product was then taken up in diethyl ether and treated with carbon black. The solution was concen-trated, causing reprecipitation of the product which was collected and recrystallized from water or from isopropyl acetate. The crystals were dried to give 2.45 g (yield 80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-mentary analysis showed the expected empirical formula The 2-isopropylamino-5-bromo-pyrimidine start-ing material had been readily obtained by reacting, in stoichiometric proportions, 2-isopropylamino-pyrimidine and N-bromo-succinimide in the presence of acetic acid (yield 84%).
1~3~56~
2-isopropylamino-4-hydroxy-pyrimidine The method of Example 1 was repeated except that 2-isopropylamino-4-chloro-pyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. Yield was 77% in a white crystalline product melting at 140C
(Tottoli), the analysis of which shows a perfect corre-spondence with the formula C7HllN3O. Structural analysis (U.V. Spectrum) confirms the position of the hydroxy group.
2-isopropylamino-4,6-dihydroxy-pyrimidine The method of Example 1 was repeated except that 2-isopropylamino-4,6-dichloro-pyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. ~ield was 73% in a white crystalline product melting at 221-225C (Tottoli) with decomposition, the analysis of which shows a perfect correspondence with the formula C7HllO2, HCl. Structural analysis (U.V. Spectrum) confirms the position of the hydroxy groups.
2-isopropylamino-5-hydroxy-pyrimidine In a pressurized reactor of 2 litre capacity, preferably cleared by a nitrogen flow, were placed 0.8 g of 2-isopropylamino-5-benzyloxy-pyrimidine, 40 ml of methanol and 80 mg of palladium catalyst; hydrogenation was performed for 2 hours at normal pressure. After filtration off of the catalyst and evaporation off of the methanol, the product was taken up in diethyl ether and the solution was filtered to eliminate insoluble matter.
The diethyl ether was evaporated off and the product was recrystallized first from water and then from ethyl acetate. After drying, there was obtained 0.4 g (yield 80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-mentary analysis showed the expected empirical formula C7Hl1N3O. Melting point 161 C (Tottoli). U.V. Spectrum ~.,13~5~i~
confirms the structure.
2-isopropylamino-4-hydroxy-pyrimidine The method as described in Example 1 was applied to 2-isopropylamino-4-ethoxy-pyrimidine instead of 2-isopropylamino-5-benzyloxy-pyrimidine. The yield was 83~ in a white crystalline product melting at 140C
(Tottoli), the analysis of which confirms the perfect correspondence with the formula C7HllN3O. U.V. Spectrum confirms the structure.
2-isopropylamino-4,6-dihydroxy-pyrimidine The method as described in Example 1 was applied to 2-isopropylamino-4,6-dibenzyloxy-pyrimidine instead of 2-isopropylamino-5-benzyloxy-pyrimidine. The yield was 78~ in a white crystalline product (hydro-chloride) melting at 218-221C (Tottoli), with decompo-sition, the analysis of which confirms the perfect corre-spondence with the formula C7HllN3O2, HCl. U.V.
Spectrum confirms the structure.
TOXICITY
The acute toxicity (mg/kg) of the compounds of the invention was determined on mice i.p. and per os and the values are reported in the following table:
Compound Route ~ Ex. 1 Ex. 2 Ex. 3 i.p. 200 240 260 per os 205 355 285 PHARMACOLOGY
The pharmacological activity of the compound of the invention has been researched by the following com-parative experimentation undertaken on the regeneration - 30 of the sciatic nerve of the male adult rat (Wistar).
1~L32561 A lesion is made on the sciatic nerve of the rats by application of a thermosound at -20C for 20 minutes on the nerve. The rats are then treated i.p. by the reference product or by the compounds of the in-vention for a predetermined duration. At the end of the treatment, the rats are killed, the sciatic nerves are separated and placed in contact with a sery of 70 thin parallel platinum wires (interval 1 mm) and an electric signal applied upstream the lesion point is researched on the platinum wires: the more distant wire where the signal can be collected gives the regenerated length.
For each tested composition and each duration of treatment, a batch of 8 rats is used.
Four compositions have been tested i.p.:
Example 1 compound, Example 2 compound, Example 3 compound, all at the i.p. dose of 10 mg/kg and, as a reference, a mixture of vitamins Bl (500 mg/kg), B6 (500 mg/kg) and B12 (5 mg/kg) which is known in the art to be the most effective composition in this field.
Controls received no treatment at all. Five batches of 8 animals were used for each duration (7, 11, 14, 17 and 21 days) either for controls or for compounds 1, 2, 3 or reference mixture.
The results of this experimentation are summa-rized in the following table together with the figures obtained for control animals. The lengths of regenerated nerves are indicated in mm. at the respective day columns as an average value of the lengths measured for all the animals of each batch. When no figure appears (17 and 21 days) this means that the regenerated length exceeded the length of the taken sample.
~ ~25~;~
Duration (days) Compound and ~ 7 11 14 17 21 Controls 5.110 2 12.817.8 22.4 Example 1 . 6 614.1 26.3 _ _ 10 mg/kg _ 6.814.4 26.1 _ _ Example 3 6 715.6 26.7 _ Bl, B6, B12 8 813 4 15 820 4 23 7 500 mg/kg, 500 mg/kg and 5mg/kg PRESENTATION - POSOLOGY
These derivatives may be presented in any thera-peutically acceptable form and, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient; for injectable form, the product may be dosed in phials containing at least 1 mg of active ingredient under the form of its hydrochloride dissolved in water. As to the posology for human use, oral administration requires from 20 mg to 1 g per diem whereas injectable form may be administered at doses between 1 mg to 50 mg per diem.
An example of the tablet form is given here-under:
- Compound of any of the examples 5 mg - Lactose 70 mg - Talc 20 mg - Magnesium stearate 5 mg 100 mg
the reaction mixture was maintained at 130 to 135C for 1 hour under stirring and then at 130 to 140C for about 12 hours, also under stirring.
After filtration off of the copper, the reaction mixture was extracted twice with chloroform.
The combined extracts were acidified with acetic acid to pH ~.5 to 7Ø The solution was then saturated with sodium chloride causing precipitation of the product, which was collected and washed with water and then with pentane. The product was then taken up in diethyl ether and treated with carbon black. The solution was concen-trated, causing reprecipitation of the product which was collected and recrystallized from water or from isopropyl acetate. The crystals were dried to give 2.45 g (yield 80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-mentary analysis showed the expected empirical formula The 2-isopropylamino-5-bromo-pyrimidine start-ing material had been readily obtained by reacting, in stoichiometric proportions, 2-isopropylamino-pyrimidine and N-bromo-succinimide in the presence of acetic acid (yield 84%).
1~3~56~
2-isopropylamino-4-hydroxy-pyrimidine The method of Example 1 was repeated except that 2-isopropylamino-4-chloro-pyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. Yield was 77% in a white crystalline product melting at 140C
(Tottoli), the analysis of which shows a perfect corre-spondence with the formula C7HllN3O. Structural analysis (U.V. Spectrum) confirms the position of the hydroxy group.
2-isopropylamino-4,6-dihydroxy-pyrimidine The method of Example 1 was repeated except that 2-isopropylamino-4,6-dichloro-pyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. ~ield was 73% in a white crystalline product melting at 221-225C (Tottoli) with decomposition, the analysis of which shows a perfect correspondence with the formula C7HllO2, HCl. Structural analysis (U.V. Spectrum) confirms the position of the hydroxy groups.
2-isopropylamino-5-hydroxy-pyrimidine In a pressurized reactor of 2 litre capacity, preferably cleared by a nitrogen flow, were placed 0.8 g of 2-isopropylamino-5-benzyloxy-pyrimidine, 40 ml of methanol and 80 mg of palladium catalyst; hydrogenation was performed for 2 hours at normal pressure. After filtration off of the catalyst and evaporation off of the methanol, the product was taken up in diethyl ether and the solution was filtered to eliminate insoluble matter.
The diethyl ether was evaporated off and the product was recrystallized first from water and then from ethyl acetate. After drying, there was obtained 0.4 g (yield 80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-mentary analysis showed the expected empirical formula C7Hl1N3O. Melting point 161 C (Tottoli). U.V. Spectrum ~.,13~5~i~
confirms the structure.
2-isopropylamino-4-hydroxy-pyrimidine The method as described in Example 1 was applied to 2-isopropylamino-4-ethoxy-pyrimidine instead of 2-isopropylamino-5-benzyloxy-pyrimidine. The yield was 83~ in a white crystalline product melting at 140C
(Tottoli), the analysis of which confirms the perfect correspondence with the formula C7HllN3O. U.V. Spectrum confirms the structure.
2-isopropylamino-4,6-dihydroxy-pyrimidine The method as described in Example 1 was applied to 2-isopropylamino-4,6-dibenzyloxy-pyrimidine instead of 2-isopropylamino-5-benzyloxy-pyrimidine. The yield was 78~ in a white crystalline product (hydro-chloride) melting at 218-221C (Tottoli), with decompo-sition, the analysis of which confirms the perfect corre-spondence with the formula C7HllN3O2, HCl. U.V.
Spectrum confirms the structure.
TOXICITY
The acute toxicity (mg/kg) of the compounds of the invention was determined on mice i.p. and per os and the values are reported in the following table:
Compound Route ~ Ex. 1 Ex. 2 Ex. 3 i.p. 200 240 260 per os 205 355 285 PHARMACOLOGY
The pharmacological activity of the compound of the invention has been researched by the following com-parative experimentation undertaken on the regeneration - 30 of the sciatic nerve of the male adult rat (Wistar).
1~L32561 A lesion is made on the sciatic nerve of the rats by application of a thermosound at -20C for 20 minutes on the nerve. The rats are then treated i.p. by the reference product or by the compounds of the in-vention for a predetermined duration. At the end of the treatment, the rats are killed, the sciatic nerves are separated and placed in contact with a sery of 70 thin parallel platinum wires (interval 1 mm) and an electric signal applied upstream the lesion point is researched on the platinum wires: the more distant wire where the signal can be collected gives the regenerated length.
For each tested composition and each duration of treatment, a batch of 8 rats is used.
Four compositions have been tested i.p.:
Example 1 compound, Example 2 compound, Example 3 compound, all at the i.p. dose of 10 mg/kg and, as a reference, a mixture of vitamins Bl (500 mg/kg), B6 (500 mg/kg) and B12 (5 mg/kg) which is known in the art to be the most effective composition in this field.
Controls received no treatment at all. Five batches of 8 animals were used for each duration (7, 11, 14, 17 and 21 days) either for controls or for compounds 1, 2, 3 or reference mixture.
The results of this experimentation are summa-rized in the following table together with the figures obtained for control animals. The lengths of regenerated nerves are indicated in mm. at the respective day columns as an average value of the lengths measured for all the animals of each batch. When no figure appears (17 and 21 days) this means that the regenerated length exceeded the length of the taken sample.
~ ~25~;~
Duration (days) Compound and ~ 7 11 14 17 21 Controls 5.110 2 12.817.8 22.4 Example 1 . 6 614.1 26.3 _ _ 10 mg/kg _ 6.814.4 26.1 _ _ Example 3 6 715.6 26.7 _ Bl, B6, B12 8 813 4 15 820 4 23 7 500 mg/kg, 500 mg/kg and 5mg/kg PRESENTATION - POSOLOGY
These derivatives may be presented in any thera-peutically acceptable form and, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient; for injectable form, the product may be dosed in phials containing at least 1 mg of active ingredient under the form of its hydrochloride dissolved in water. As to the posology for human use, oral administration requires from 20 mg to 1 g per diem whereas injectable form may be administered at doses between 1 mg to 50 mg per diem.
An example of the tablet form is given here-under:
- Compound of any of the examples 5 mg - Lactose 70 mg - Talc 20 mg - Magnesium stearate 5 mg 100 mg
Claims (14)
1. The process for preparing a 2-isopropyl-amino-pyrimidine derivative of the general formula:
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen, which comprises A. reacting isopropylamine with a 2-thiomethyl-pyrimidine of the formula:
wherein A4, A5 and A6 are as previously defined, the reaction being carried out in a non-polar solvent at a temperature of from about 100° to about 120°C; or B. reacting a 2-isopropylamino-halogeno-pyrimidine of the formula:
wherein A'4, A'5 and A'6 stand for hydrogen or halo-gen, with the proviso that at least one of A'4, A'5 and A'6 is other than hydrogen, with a mineral base in water at a temperature of from 100° to 150°C; or C. hydrogenating a compound of the formula:
in the presence of a hydrogenation catalyst, A"4, A"5 and A"6 stand for hydrogen, aralkyloxy or alkyloxy with the proviso that at least one of A"4, A"5 and A"6 is other than hydrogen.
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen, which comprises A. reacting isopropylamine with a 2-thiomethyl-pyrimidine of the formula:
wherein A4, A5 and A6 are as previously defined, the reaction being carried out in a non-polar solvent at a temperature of from about 100° to about 120°C; or B. reacting a 2-isopropylamino-halogeno-pyrimidine of the formula:
wherein A'4, A'5 and A'6 stand for hydrogen or halo-gen, with the proviso that at least one of A'4, A'5 and A'6 is other than hydrogen, with a mineral base in water at a temperature of from 100° to 150°C; or C. hydrogenating a compound of the formula:
in the presence of a hydrogenation catalyst, A"4, A"5 and A"6 stand for hydrogen, aralkyloxy or alkyloxy with the proviso that at least one of A"4, A"5 and A"6 is other than hydrogen.
2. Process for preparing 4-hydroxy-2-isopropylamino-pyrimidine, which comprises reacting methyl thiouracil with isopropylamine in a non-polar solvent at a temperature of from 110-120°C.
3. Process for preparing 5-hydroxy-2-thiomethyl-pyrimidine, which comprises reacting 5-hydroxy-2-thiomethyl-pyrimidine with isopropylamine in a non-polar solvent at a temperature of about 105°C.
4. Process for preparing 4,6-dihydroxy-2-isopropylamino-pyrimidine, which comprises reacting 4,6-dihydroxy-2-thiomethyl-pyrimidine with isopropylamine in a non-polar solvent at a temperature of about 110°C.
5. Process for preparing 5-hydroxy-2-isopropylamino-pyrimidine, which comprises reacting 2-isopropylamino-5-bromo-pyrimidine with sodium hydroxide in the presence of copper powder at a temperature of from 130 to 135°C.
6. Process for preparing 4-hydroxy-2-isopropylamino-pyrimidine, which comprises reacting 2-isopropylamino-4-chloro-pyrimidine with sodium hydroxide in the presence of copper powder at a temperature of from 130 to 135°C.
7. Process for preparing 4,6-dihydroxy-2-isopropylamino-pyrimidine, which comprises reacting 2-isopropylamino-4,6-dichloro-pyrimidine with sodium hydroxide in the presence of copper powder at a tempera-ture of from 130 to 135°C.
8. Process for preparing 5-hydroxy-2-isopropylamino-pyrimidine, which comprises hydrogenating 2-isopropylamino-5-benzyloxy-pyrimidine in the presence of palladium catalyst.
9. Process for preparing 4-hydroxy-2-isopropylamino-pyrimidine, which comprises hydrogenating 2-isopropylamino-4-ethoxy-pyrimidine in the presence of palladium catalyst.
10. Process for preparing 4,6-dihydroxy-2-isopropylamino-pyrimidine, which comprises hydrogenating 2-isopropylamino-4,6-dibenzyloxy-pyrimidine in the presence of palladium catalyst.
11. A 2-isopropylamino-pyrimidine derivative of the general formula:
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
wherein A4, A5 and A6 each stand for hydrogen or hydroxy with the proviso that at least one of A4, A5 and A6 is other than hydrogen, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
12. The 4-hydroxy-2-isopropylamino-pyrimidine, when prepared by the process defined in Claims 2, 6 or 9 or by an obvious chemical equivalent.
13. The 5-hydroxy-2-isopropylamino-pyrimidine, when prepared by the process defined in Claims 3, 5 or 8 or by an obvious chemical equivalent.
14. The 4,6-dihydroxy-2-isopropylamino-pyrimidine, when prepared by the process defined in Claims 4, 7 or 10 or by an obvious chemical equivalent.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7908494 | 1979-03-10 | ||
| GB79.08494 | 1979-03-10 | ||
| GB7914987 | 1979-04-30 | ||
| GB79.14987 | 1979-04-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1132561A true CA1132561A (en) | 1982-09-28 |
Family
ID=26270867
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA346,981A Expired CA1132561A (en) | 1979-03-10 | 1980-03-04 | Hydroxy pyrimidine derivatives |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JPS55122768A (en) |
| AR (1) | AR222691A1 (en) |
| AU (1) | AU533547B2 (en) |
| BE (1) | BE881752A (en) |
| CA (1) | CA1132561A (en) |
| CH (1) | CH644368A5 (en) |
| DE (3) | DE3009071C2 (en) |
| EG (1) | EG14282A (en) |
| FI (1) | FI66357C (en) |
| FR (2) | FR2451191A1 (en) |
| GB (1) | GB2045756B (en) |
| HK (1) | HK55383A (en) |
| IE (1) | IE49547B1 (en) |
| IN (1) | IN153791B (en) |
| LU (1) | LU82185A1 (en) |
| MX (1) | MX6218E (en) |
| MY (1) | MY8400200A (en) |
| NL (1) | NL184833C (en) |
| NO (1) | NO154054C (en) |
| NZ (1) | NZ192927A (en) |
| OA (1) | OA06484A (en) |
| PT (1) | PT70882A (en) |
| SE (1) | SE435180B (en) |
| SG (1) | SG22683G (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE894517A (en) * | 1981-10-16 | 1983-01-17 | Sod Conseils Rech Applic | NEW ISOPROPYLAMINO PYRIMIDINE DERIVATIVE, ITS PREPARATION AND THERAPEUTIC COMPOSITION BASED ON ITS COMPOUNDS |
| US4673677A (en) * | 1983-10-03 | 1987-06-16 | Pfizer Inc. | Method for treatment of gastrointestinal disorders |
| US4554276A (en) * | 1983-10-03 | 1985-11-19 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
| US4711888A (en) | 1985-07-24 | 1987-12-08 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
| WO1989000423A1 (en) * | 1987-07-09 | 1989-01-26 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| US4910204A (en) * | 1988-06-28 | 1990-03-20 | Pfizer Inc. | 2-amino-5-hydroxy-4-pyrimidones |
| HU206337B (en) * | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
| US5264435A (en) * | 1988-12-29 | 1993-11-23 | Mitsui Petrochemical Industries, Ltd. | Pyrimidines and their pharmaceutical acceptable salts, and their use as medicines |
| US4940712A (en) * | 1989-05-26 | 1990-07-10 | Pfizer Inc. | Derivatives of hydroxyprimidines as leukotriene synthesis inhibitors |
| US5270319A (en) * | 1991-09-09 | 1993-12-14 | Warner-Lambert Company | 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents |
| US5220025A (en) * | 1992-02-24 | 1993-06-15 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-butyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US5196431A (en) * | 1992-02-24 | 1993-03-23 | Warner-Lambert Company | 2-substituted amino-4, 6-di-tertiary-buthyl-5-hydroxy-1, 3-pyrimidines as antiinflammatory agents |
| US9133212B1 (en) * | 2005-06-15 | 2015-09-15 | Vanderbilt University | Inhibitors of hemeprotein-catalyzed lipid peroxidation |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB741667A (en) * | 1952-12-05 | 1955-12-07 | Ici Ltd | New pyrimidine derivatives |
| GB756189A (en) * | 1954-02-01 | 1956-08-29 | Ici Ltd | New pyrimidine derivatives |
| ZA711152B (en) * | 1970-03-02 | 1971-11-24 | Ici Ltd | Manufacture of pyrimidines |
| GB1525995A (en) * | 1976-02-18 | 1978-09-27 | Soc D Etudes Prod Chimique | Aminopyrimidine salt |
-
1980
- 1980-02-12 IN IN103/DEL/80A patent/IN153791B/en unknown
- 1980-02-15 BE BE0/199421A patent/BE881752A/en not_active IP Right Cessation
- 1980-02-20 NZ NZ192927A patent/NZ192927A/en unknown
- 1980-02-20 LU LU82185A patent/LU82185A1/en unknown
- 1980-02-26 FI FI800566A patent/FI66357C/en not_active IP Right Cessation
- 1980-02-27 AR AR280106A patent/AR222691A1/en active
- 1980-02-29 PT PT70882A patent/PT70882A/en unknown
- 1980-03-03 CH CH165080A patent/CH644368A5/en not_active IP Right Cessation
- 1980-03-04 CA CA346,981A patent/CA1132561A/en not_active Expired
- 1980-03-04 NL NLAANVRAGE8001289,A patent/NL184833C/en not_active IP Right Cessation
- 1980-03-07 GB GB8007908A patent/GB2045756B/en not_active Expired
- 1980-03-07 NO NO800664A patent/NO154054C/en unknown
- 1980-03-07 IE IE477/80A patent/IE49547B1/en unknown
- 1980-03-07 AU AU56248/80A patent/AU533547B2/en not_active Ceased
- 1980-03-07 SE SE8001812A patent/SE435180B/en not_active IP Right Cessation
- 1980-03-09 EG EG131/80A patent/EG14282A/en active
- 1980-03-10 FR FR8005277A patent/FR2451191A1/en active Granted
- 1980-03-10 MX MX808702U patent/MX6218E/en unknown
- 1980-03-10 OA OA57049A patent/OA06484A/en unknown
- 1980-03-10 FR FR8005278A patent/FR2451370A1/en active Granted
- 1980-03-10 DE DE3009071A patent/DE3009071C2/en not_active Expired
- 1980-03-10 DE DE3050999A patent/DE3050999C2/en not_active Expired
- 1980-03-10 JP JP2931280A patent/JPS55122768A/en active Granted
- 1980-04-30 DE DE19803016752 patent/DE3016752A1/en active Granted
-
1983
- 1983-04-28 SG SG226/83A patent/SG22683G/en unknown
- 1983-11-17 HK HK553/83A patent/HK55383A/en unknown
-
1984
- 1984-12-30 MY MY200/84A patent/MY8400200A/en unknown
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |