GB2045756A - Hydroxy derivatives of 2- isopropylamino-pyrimidine - Google Patents
Hydroxy derivatives of 2- isopropylamino-pyrimidine Download PDFInfo
- Publication number
- GB2045756A GB2045756A GB8007908A GB8007908A GB2045756A GB 2045756 A GB2045756 A GB 2045756A GB 8007908 A GB8007908 A GB 8007908A GB 8007908 A GB8007908 A GB 8007908A GB 2045756 A GB2045756 A GB 2045756A
- Authority
- GB
- United Kingdom
- Prior art keywords
- pyrimidine
- isopropylamino
- hydroxy
- general formula
- hydrochloride
- 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
- 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
There are provided compounds of the general formula <IMAGE> A4=H or OH A5=H or OH A6=H or OH A4=A5=A6=H excluded These compounds are prepared by reacting compounds of the general formula <IMAGE> A4=H or OH A5=H or OH A6=H or OH A4=A5=A6=H excluded with isopropylamino under pressure in a non-polar solvent at from 100 DEG C to 120 DEG C. There are of interest in the field of nervous regeneration and in the treatment of muscular distrophy. Therapeutic compositions containing them are disclosed.
Description
SPECIFICATION
Pyrimidine Derivatives
The invention relates to pyrimidine derivatives, to a method for their preparation, and to compositions containing them.
The invention provides hydroxy derivatives of 2-isopropyl-amino-pyrimidine of the general formula I
wherein each of A5 and As 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, and their acid addition salts.
These compounds are of special interest for their action in the field of nervous regeneration and for the treatment of muscular dystrophy. The invention thus also provides a therapeutical composition comprising -a therapeutically effective amount of a hydroxy derivative of 2-isopropyl-amino-pyrimidine of the general formula I as herein defined or a therapeutically acceptable salt thereof in admixture with a therapeutically acceptable diluent or carrier.
The invention further provides a method for the preparation of hydroxy derivatives of the general formula I as above defined, the method comprising reacting hydroxy derivatives of 2-methylthio-pyrimidine of the general formula II
wherein A4, A5 and A6 are as above defined (including the proviso with isopropylamine under pressure in a non-polar solvent at from 10000 to 120 C.
The invention is illustrated by the following Examples.
EXAMPLE 1: 4-hydroxy-2-isopropylamino-pyrimidine
4-Hydroxy-2-methylthio-pyrimidine was obtained by reacting methyl iodide with 4-hydroxy-2-mercaptopyrimidine (thiouracil) in the presence of sodium methanolate. The S-methyl-thioracil thus obtained (20 g, 0.14 mol) was placed in a one litre pressurized reactor with 200 ml of dry toluene and 200 ml of isopropylamine. The reaction was carried on for 24 hours under pressure at 110"C to 120 C. The resulting mixture was evaporated to dryness, treated with acetone and diethyl ether (50/50), filtered, washed with water and recrystallized from isopropyl acetate.There were thus obtained 17 g (yield 84%) of a white crystalline product, insoluble in water but soluble in chloroform, melting at 140"C, elemental analysis of which showed a good correspondence with the formula C7H11N30 (molecular weight 153.18). The hydrochloride of this compound was also prepared; it was also a white crystalline product and had a melting point of 233"C to 234"C (Tottoli).
U.V. Spectral data for the base and hydrochloride were:
In water (for hydrochloride) In Methanol (for base) Amax:266nmEX C M = 210 Amax:293nmE/ m = 510 max:217nmEi1c = 740 Xmax: 222 nm E1 / m = 730 Xmas: 290 nm
EXAMPLE 2: 5-hydroxy-2-isopropylamino-p yrimidine The method described in Example 1 was repeated but 5-hydroxy-2-methylthio-pyrimidine was used instead of 4-hydroxy-2-methylthio-pyrimidine. Yield 83%. The temperature of reaction was 105"C. Melting point 161 C (Tottoli). U.V.Spectrum in water:methanol (60:40): AmaX :341 nm E1 hm = 205 AmaX :241 nm E1 / m = 1210
EXAMPLE 3: 4,6-dihydroxy-2-isopropylamino pyrimidine
The method described in Example 1 was repeated but4,6-dihydroxy-2-thiomethyl-pyrimidinewas used instead of 4-hydroxy-2-methylthio-pyrimidine. Yield 67%. Temperature of reaction 1 100C. Melting point 21 50C to 2200C with decomposition (Tottoli), for the hydrochloride of formula C7H11N302,HCI. This was a white crystalline product insoluble in water at room temperature.
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 i.p. 200 240 260
peros 205 355 285
Pharmacology
The pharmacological activites of the compounds of the invention have been researched by the following comparative experimentation undertaken on the regeneration of the sciatic nerve of the male adult rat (Wistar).
A lesion is made on the sciatic nerve of the rats by application of a thermosound at -20 C for 20 minutes on the nerve. The rats are 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 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 B1 (500 mg/kg), B6 (500 mg/kg) and B1 2 (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 summarized in Table 2 together with the figures obtained for control animals. The lengths of regenerated nerves are indicated in mm at 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)
Compound and
dosei.p. 7 11 14 17 21
Controls 5.1 10.2 12.8 17.8 22.4
Example 1
10 mg/kg 6.6 14.1 26.3 -
Example 2
10 mg/kg 6.8 14.4 26.1 -
Example 3
10 mg/kg 6.7 15.6 26.7 -
B1, B6, B12 8.8 13.4 15.8 20.4 23.7
500 mg/kg, 500 mg/kg 500 mg/kg
Presentation - Posology
These derivatives may be presented in any therapeutically acceptable form, for instance, in tablets or in gelatine capsules containing 5 mg per dosage unit together with an excipient or in injectable form 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 administration requires from 20 mg to 1 g diem whereas the injectable form may be administered at does between 1 mg to 50 mg per diem.
An example of a suitable tablet formulation is given hereunder:
Compound of any of the Examples 5 mg
Lactose 70 mg
Talc 20 mg
Magnesium stearate 5 mg
100 mg
Claims (7)
1. A hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I as herein defined or an acid addition salt thereof.
2. 4-Hydroxy-2-isopropylamino-pyrimidine or its hydrochloride.
3. 5-Hydroxy-2-isopropylamino-pyrimidine or its hydrochloride.
4. 4,6-Dihydroxy-2-isopropylamino-pyrimidine or its hydrochloride.
5. A method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine of the general formula I as herein defined, the method comprising reacting a hydroxy derivative of 2-methylthio-pyrimidine of the general formula Il as herein defined with isopropylamine under pressure in a non-polar solvent at from 100 C to 1 200C.
6. A method for the preparation of a hydroxy derivative of 2-isopropylamino-pyrimidine according to claim 1, the method being substantially as described herein with reference to any of the Examples.
7. A therapeutical composition comprising a therapeutically effective amount of a hydroxy derivative of 2-isopropylamino-pyrimidine according to claim 1 or a therapeutically acceptable salt thereof in admixture with a therapeutically acceptable diluent or carrier.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT2036180A IT1151082B (en) | 1979-03-10 | 1980-03-05 | 2-Isopropyl:amino-hydroxy:pyrimidine cpds. - useful in neural regeneration and in treatment of muscular dystrophy |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB7908494 | 1979-03-10 | ||
GB7914987 | 1979-04-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB2045756A true GB2045756A (en) | 1980-11-05 |
GB2045756B GB2045756B (en) | 1983-01-26 |
Family
ID=26270867
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8007908A Expired GB2045756B (en) | 1979-03-10 | 1980-03-07 | Hydroxy derivatives of 2-isopropylamino-prorimidine |
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) | DE3050999C2 (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) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0138464A2 (en) * | 1983-10-03 | 1985-04-24 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
EP0210044A2 (en) | 1985-07-24 | 1987-01-28 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
US4673677A (en) * | 1983-10-03 | 1987-06-16 | Pfizer Inc. | Method for treatment of gastrointestinal disorders |
US4940712A (en) * | 1989-05-26 | 1990-07-10 | Pfizer Inc. | Derivatives of hydroxyprimidines as leukotriene synthesis inhibitors |
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 |
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 |
US20160067256A1 (en) * | 2005-06-15 | 2016-03-10 | Vanderbilt University | Inhibitors of Hemeprotein-Catalyzed Lipid Peroxidation |
Families Citing this family (6)
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 |
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 |
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 |
US5270319A (en) * | 1991-09-09 | 1993-12-14 | Warner-Lambert Company | 5-hydroxy-2-pyrimidinylmethylene derivatives useful as antiinflammatory agents |
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 NL NLAANVRAGE8001289,A patent/NL184833C/en not_active IP Right Cessation
- 1980-03-04 CA CA346,981A patent/CA1132561A/en not_active Expired
- 1980-03-07 AU AU56248/80A patent/AU533547B2/en not_active Ceased
- 1980-03-07 IE IE477/80A patent/IE49547B1/en unknown
- 1980-03-07 NO NO800664A patent/NO154054C/en unknown
- 1980-03-07 SE SE8001812A patent/SE435180B/en not_active IP Right Cessation
- 1980-03-07 GB GB8007908A patent/GB2045756B/en not_active Expired
- 1980-03-09 EG EG131/80A patent/EG14282A/en active
- 1980-03-10 MX MX808702U patent/MX6218E/en unknown
- 1980-03-10 DE DE3050999A patent/DE3050999C2/en not_active Expired
- 1980-03-10 FR FR8005277A patent/FR2451191A1/en active Granted
- 1980-03-10 OA OA57049A patent/OA06484A/en unknown
- 1980-03-10 DE DE3009071A patent/DE3009071C2/en not_active Expired
- 1980-03-10 JP JP2931280A patent/JPS55122768A/en active Granted
- 1980-03-10 FR FR8005278A patent/FR2451370A1/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
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0138464A2 (en) * | 1983-10-03 | 1985-04-24 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
US4554276A (en) * | 1983-10-03 | 1985-11-19 | Pfizer Inc. | 2-Amino-5-hydroxy-4-methylpyrimidine derivatives |
EP0138464A3 (en) * | 1983-10-03 | 1986-08-20 | Pfizer Inc. | 2-amino-5-hydroxy-4-methylpyrimidine derivatives |
US4673677A (en) * | 1983-10-03 | 1987-06-16 | Pfizer Inc. | Method for treatment of gastrointestinal disorders |
EP0210044A2 (en) | 1985-07-24 | 1987-01-28 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
EP0210044A3 (en) * | 1985-07-24 | 1987-10-21 | Pfizer Inc. | Hydroxy and alkoxy pyrimidines |
US4940712A (en) * | 1989-05-26 | 1990-07-10 | Pfizer Inc. | Derivatives of hydroxyprimidines as leukotriene synthesis inhibitors |
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 |
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 |
US5284949A (en) * | 1992-02-24 | 1994-02-08 | Warner-Lambert Company | 2-substituted amino-4,6-di-tertiary-butyl-5-hydroxy-1,3-pyrimidines as antiinflammatory agents |
US20160067256A1 (en) * | 2005-06-15 | 2016-03-10 | Vanderbilt University | Inhibitors of Hemeprotein-Catalyzed Lipid Peroxidation |
US10675285B2 (en) * | 2005-06-15 | 2020-06-09 | Vanderbilt University | Inhibitors of hemeprotein-catalyzed lipid peroxidation |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PCNP | Patent ceased through non-payment of renewal fee |