GB2054556A - Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine - Google Patents
Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine Download PDFInfo
- Publication number
- GB2054556A GB2054556A GB8012349A GB8012349A GB2054556A GB 2054556 A GB2054556 A GB 2054556A GB 8012349 A GB8012349 A GB 8012349A GB 8012349 A GB8012349 A GB 8012349A GB 2054556 A GB2054556 A GB 2054556A
- Authority
- GB
- United Kingdom
- Prior art keywords
- isopropylamino
- pyrimidine
- preparation
- compounds
- general formula
- 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.)
- Granted
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
Abstract
Compounds of the general formula <IMAGE> A4 = H or OH A5 = H or OH A6 = H or OH A4 = A5 = A6 = H excluded are prepared by treating compounds of the general formula <IMAGE> A'4 = H or halogen A'5 = H or halogen A'6 = H or halogen A'4 = A'5 = A'6 = H excluded with a mineral base in water at from 100 DEG C to 150 DEG C in the presence of copper. The compounds I are of therapeutical interest.
Description
SPECIFICATION
Pyrimidine derivatives
The invention relates to a method for the preparation of hydroxy derivatives of 2-isopropylaminopyrimidine of the general formula I
wherein each of A4, A5 and A6 independently represents a hydrogen atom or a hydroxy group with the proviso that at least one of A4, A5 and A6 does not represent a hydrogen atom. These compounds are claimed per se in our copending Application No , and are of therapeutical interest.
The invention provides a method for the preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine of the general formula I as above defined, the method comprising treating halogeno derivatives of 2-isopropylamino-pyrimidine of the general formula II
wherein each of A'4, A'5 and A'6 independently represents a hydrogen or halogen atom with the proviso that at least one of A'4, A'5 and A'6 does not represent a hydrogen atom with a mineral base in water at from 1 00 C to 1 50 C in the presence of copper.
The invention is illustrated by the following Examples.
Example 1: 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 1 30 C to 1 35 C for 1 hour under stirring and then at 1 30 C to 1 40 C for about 1 2 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 6.5 to 7.0. 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 concentrated, causing reprecipitation of the product which was collected and recrystallied from water or from isopropyl acetate. The crystals were dried to give 2.45 g (yield 80%) of 2-isopropylamino-5-hydroxy-pyrimidine.Elemental analysis showed the expected empiricial formula C7H"N30. The 2-isopropylamino-5-bromo-pyrimidine starting material had been readily obtained by reacting, in stoichiometric proportions, 2isopropylamino-pyrimidine and N-bromo-succinimide in the presence of acetic acid (yield 84%).
Example 2: 2-isopropylamino-4-hydroxy-pyrimidine
The method described in Example 1 was repeated except that 2-isopropylamino-4-chloropyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. Yield was 77% of a white crystalline product melting at 1 40 C (Tottoli), elemental analysis of which showed a good correspondence with the formula C7H"N30. Structural analysis (U.V. Spectrum) confirmed the position of the hydroxy group.
Example 3: 2-isopropylamino-4, 6-dihydroxy-pyrimidine
The method described in Example 1 was repeated except that 2-isopropylamino-4,6-dichloropyrimidine was used instead of 2-isopropylamino-5-bromo-pyrimidine. Yield was 73% of a white crystalline product melting at 221-225"C (Tottoli) with decomposition, elemental analysis of which showed good correspondence with the formula C7H"02, HCI. Structrual analysis (U.V.
Spectrum) comfirmed the positions of the hydroxy groups.
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 Table 1:
TABLE 1
Compound
Ex. 1 Ex. 2 Ex.3
Route
1.p. 200 240 260 pesos 205 355 285
PHARMACOLOGY
The pharmacological activity of the compounds of the invention was studied by the following comparative experimentation undertaken on the regeneration of the sciatic nerve of the male adult rate (Wistar).
A lesion was made on the sciatic nerve of the rats by application of a thermosound at - 20"C for 20 minutes on the nerve. The rats were then treated i. p. by the reference product or by the compounds of the invention for a predetermined duration. At the end of the treatment, the rats were sacrificed, the sciatic nerves were 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 was researched on the platinum wires: the more distant wire where the signal can be collected gave the regenerated length.
Four compositions have been tested i.p.: the compounds of each of Examples 1, 2 and 3, each at the i.p. dose of 10 mg/kg and, as reference, a mixture of vitamins B1 (500 mg/kg), B6 (500 mg/kg) and B1 2 (5mg/kg) which mixture 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, 1 7 and 21 days) either for controls or for compounds 1, 2, 3 or reference mixture.
The results of this experimentation are summarized in the following Table 2 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.
TABLE 2
Duration (days)
7 11 14 17 21
Compound and dose i.p.
Controls 5.1 10.2 12.8 17.8 22.4
Example 1 6.6 14.1 26.3 - - 10 mg/kg
Example 2 6.8 14.4 26.1 - 1 Okg/mg Example 3 6.7 15.6 26.7 - 10 mg/kg
B1, B6, B12 8.8 13.4 15.8 20.4 23.7 500 mg/kg, 500 mg/kg and Smg/kg
Presentation - Posology
These derivatives may be presented in any therapeutically acceptable form including, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient; for an injectable form, the product may be dosed in phials containing at least 1 mg of active ingredient in the form of its hydrochloride dissolved in water. As to the posology for human use, oral adminstration requires from 20 mg to 1 g per diem whereas the injectable form may be administered at doses between 1 mg to 50 mg per diem.
An example of a suitable tablet formulation is:
Compounds of any of the Examples 5 mg
Lactose 70 mg
Talc 20 mg
Magnesium stearate 5 mg
100 mg.
Claims (2)
1. A method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I as herein defined, the method comprising treating a halogeno derivative of 2-isopropylamino-pyrimidine of the general formula II as herein defined with a mineral base in water at from 1 00 C to 1 50 C in the presence of copper.
2. A method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I as herein defined, the method being substantially as described herein with reference to any one of the Examples.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7914987 | 1979-04-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2054556A true GB2054556A (en) | 1981-02-18 |
GB2054556B GB2054556B (en) | 1983-01-26 |
Family
ID=10504858
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8012351A Expired GB2055801B (en) | 1979-04-30 | 1980-04-15 | Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine |
GB8012349A Expired GB2054556B (en) | 1979-04-30 | 1980-04-15 | Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8012351A Expired GB2055801B (en) | 1979-04-30 | 1980-04-15 | Preparation of hydroxy derivatives of 2-isopropylamino-pyrimidine |
Country Status (26)
Country | Link |
---|---|
JP (2) | JPS55145671A (en) |
AR (2) | AR222870A1 (en) |
AT (2) | AT380013B (en) |
BE (2) | BE882593A (en) |
CH (2) | CH645361A5 (en) |
DK (2) | DK183780A (en) |
EG (2) | EG14284A (en) |
ES (2) | ES491000A0 (en) |
FI (2) | FI66358C (en) |
FR (2) | FR2455588A1 (en) |
GB (2) | GB2055801B (en) |
HK (2) | HK55683A (en) |
IE (2) | IE49709B1 (en) |
IN (2) | IN154067B (en) |
IT (2) | IT1141296B (en) |
LU (2) | LU82332A1 (en) |
MA (1) | MA18824A1 (en) |
MX (2) | MX5878E (en) |
MY (2) | MY8400204A (en) |
NL (2) | NL8002271A (en) |
NO (2) | NO154055C (en) |
NZ (2) | NZ193421A (en) |
OA (2) | OA06527A (en) |
PT (2) | PT71154A (en) |
SG (2) | SG22583G (en) |
ZA (2) | ZA801958B (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 | ||
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 |
-
1980
- 1980-04-02 ZA ZA00801958A patent/ZA801958B/en unknown
- 1980-04-02 BE BE0/200083A patent/BE882593A/en not_active IP Right Cessation
- 1980-04-02 BE BE0/200084A patent/BE882594A/en not_active IP Right Cessation
- 1980-04-02 ZA ZA00801960A patent/ZA801960B/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 LU LU82333A patent/LU82333A1/en unknown
- 1980-04-03 FI FI801084A patent/FI66359C/en not_active IP Right Cessation
- 1980-04-07 IN IN254/DEL/80A patent/IN154067B/en unknown
- 1980-04-07 IN IN253/DEL/80A patent/IN154066B/en unknown
- 1980-04-08 CH CH269080A patent/CH645361A5/en not_active IP Right Cessation
- 1980-04-08 CH CH268980A patent/CH645633A5/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 GB8012351A patent/GB2055801B/en not_active Expired
- 1980-04-15 GB GB8012349A patent/GB2054556B/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 IT IT21542/80A patent/IT1141487B/en active
- 1980-04-22 MA MA19019A patent/MA18824A1/en unknown
- 1980-04-24 AT AT0221680A patent/AT380013B/en not_active IP Right Cessation
- 1980-04-24 AT AT0221580A patent/AT380012B/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 JP JP5557580A patent/JPS55145671A/en active Granted
- 1980-04-28 NO NO801234A patent/NO154055C/en unknown
- 1980-04-28 IE IE865/80A patent/IE49709B1/en unknown
- 1980-04-28 MX MX808786U patent/MX5878E/en unknown
- 1980-04-28 PT PT71154A patent/PT71154A/en unknown
- 1980-04-28 MX MX808783U patent/MX6514E/en unknown
- 1980-04-28 NO NO801235A patent/NO154056C/en unknown
- 1980-04-28 IE IE864/80A patent/IE49591B1/en unknown
- 1980-04-28 JP JP5557480A patent/JPS55145670A/en active Granted
- 1980-04-28 PT PT71155A patent/PT71155A/en unknown
- 1980-04-29 DK DK183780A patent/DK183780A/en unknown
- 1980-04-29 ES ES491000A patent/ES491000A0/en active Granted
- 1980-04-29 ES ES490999A patent/ES8103060A1/en not_active Expired
- 1980-04-29 DK DK183880A patent/DK183880A/en unknown
- 1980-04-29 EG EG257/80A patent/EG14284A/en active
- 1980-04-29 EG EG258/80A patent/EG14259A/en active
- 1980-04-30 FR FR8009732A patent/FR2455588A1/en active Granted
- 1980-04-30 FR FR8009733A patent/FR2455589A1/en active Granted
- 1980-04-30 OA OA57103A patent/OA06527A/en unknown
- 1980-04-30 OA OA57101A patent/OA06525A/en unknown
-
1983
- 1983-04-28 SG SG225/83A patent/SG22583G/en unknown
- 1983-04-28 SG SG222/83A patent/SG22283G/en unknown
- 1983-11-17 HK HK556/83A patent/HK55683A/en unknown
- 1983-11-17 HK HK555/83A patent/HK55583A/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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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |