IE47022B1 - Novel amidino-benzylpyrimidines, processes for their manufacture and drugs containing the said compounds - Google Patents
Novel amidino-benzylpyrimidines, processes for their manufacture and drugs containing the said compoundsInfo
- Publication number
- IE47022B1 IE47022B1 IE1354/78A IE135478A IE47022B1 IE 47022 B1 IE47022 B1 IE 47022B1 IE 1354/78 A IE1354/78 A IE 1354/78A IE 135478 A IE135478 A IE 135478A IE 47022 B1 IE47022 B1 IE 47022B1
- Authority
- IE
- Ireland
- Prior art keywords
- pyrimidin
- trimethoxybenzyl
- amino
- methyl
- acetamidine
- Prior art date
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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
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
1. Amidino-benzylpyrimidines of the general formula I see diagramm : EP0000336,P9,F1 where R**1 , R**2 , and R**3 , which may be identical or different, are hydrogen, methyl, methoxy or chlorine, R**4 is alkyl of 1 to 6 carbon atoms or benzyl and R**5 and R**6 , which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, trimethoxybenzyl, benzyl or phenyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R**5 and R**6 is -C6 H4 -SO2 -NH-R**7 , where R**7 is see diagramm : EP0000336,P9,F2 see diagramm : EP0000336,P9,F3 or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl, 5-isopropyl-pyrimidin-2-yl, 5-methoxy-pyrimidin-2-yl, 6-methoxy-pyridazin-3-yl, 3-methoxy-pyrazin-2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl, or R**5 and R**6 together with the nitrogen to which they are bonded are a saturated heterocyclic ring of 5-7 members, which may contain an oxygen atom or the N-Y group, where Y is methyl, benzyl or phenyl, and their pharmacologically acceptable salts with acids conventionally used for this purpose.
Description
The present invention relates to novel amidino-benzylpyrimidines of the general formula I
where R1, R2 and r\ which may be identical or different, are hydrogen, methyl, methoxy or chlorine, R is alkyl of to 6 carbon atoms or benzyl and R^ and R , which may be identical or different, are hydrogen, lower alkyl of 1 to
4 carbon atoms, trimethoxybenzyl, benzyl, phenyl, cyclo5 hexyl, adamantyl or-furfuryl, or one ofthe radicals R and R6 is -CgH^-SOg-NH-R7, where R7 is
NH o
II
-C-NH2, C_NH2 or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methy115 pyrimidin-2-yl, 5-isopropyl-pyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 6-methoxy-pyridazin-2-yl, 3-methoxy-pyrazin· 2—yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl,
- la.47 0 22
R 6 » « or Fr and R together with the nitrogen to which they are bonded are a saturated hereocyclic ring of 5-7 members, which may contain an oxygen atom or the >N-Y gx’oup, where Y is methyl, benzyl or phenyl, and to their pharmacologically acceptable salts with acids conventionally used for this purpose.
Examples of conventional acids used to form pharmacologically acceptable salts are hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid and salicylic acid.
Preferably, the substituents R , R and R are in the 3-, 4- and 5-positions of the benzene ring.
Amongst the above compounds of the formula I, more 12 3 preferred compounds are those where R , R and R are hydrogen, methyl or methoxy, and amongst these, in turn, the com12 5 pounds where R , R and R are in the 3-, 4- and 5-positions of the benzyl radical and are each methoxy are especially preferred.
The compounds of the formula I are anti-microbially active in illnesses caused by bacteria and protozoa and, when combined with sulfonamides, potentiate their antibacterial
1° action. They may be used, for example, in bacterial infections of the respiratory organs, digestive organs and urinary tract, in infections of the throat, nose and ears, in systemic infections in general, and in malaria.
Examples of suitable sulfonamides are 2-sulfaniiamidopyridine, 2-sulfanilamido-thiazole, 2-sulfanilamido-pyrimidine, 2-sulfanilamido-4-methy1-pyrimidine, 2-sulfanilamido-4,6-dimethy 1-pyrimidine, 4-sulfanilamido-2·, 6-dimethy1-pyrimidine,
-sulfanilamido-3,4-dimethy1-isoxazole, 3-sulfanilamido-6methoxy-pyridazine, 3-sulfanilamido-6-ehloro-pyridazine,
4-sulfanilamido-2,6-dimethoxy-pyrimidine, 3-sulfanilamido2-pheny1-pyrazole, 2-sulfanilamido-5-methy1-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimidine, 2-sulfanilamido-5methy1-is oxazole, 2-sulfanilamido-4,5-dimethyloxazole, 2-sulfanilamido-3-methoxy-pyrazine, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 4-sulfanilamido-3-methoxy-l,2,5-thiadiazole and 4-aminobenzene-sulfonyl-guanidine.
The compounds of the formula I and their salts can be combined with the sulfonamides, mentioned by way of example,
- 3 47022 in various ratios; the ratio of the former to the latter may be from 1:10 to 5:1. However, preferred ratios are from 1:1 to 1:5. As a rule, a suitable dosage is from 20 to 550 mg of an active ingredient of the formula I.
The compounds according to the invention, of the formula I, are prepared by the conventional methods of preparing amidines, as described, inter alia, in Houben-Weyl, Methoden der organischen Chemie, Volume 11/2, in which an imido-acid ester of the general formula II
where R1, R2, R^ and R^ have the above meanings and R® is lower alkyl of 1 to 4 carbon atoms or benzyl, is reacted with an amine of the general formula III /r5
H-N (III)
Χ* where R^ and R^ have the above meanings, to give the amidine of the general formula I
which then may or may not be converted to a pharmacologically acceptable addition salt with an acid conventionally used for this purpose.
- ll 4 7 0 2 3
The imido-acid esters of the general formula II and their preparation are described in Patent Specification No. 47013. '
Examples of amines of the formula III are ammonia, methylamine, dimethylamine, diethylamine, benzylamine, 3»A,5 trimethoxybenzylamine, N-phenyl-piperazine, furfurylamine, cyclohexylamine, pyrrolidine, piperidine, morpholine and aniline, and sulfonamides, eg. 2-sulfanilamido-pyrimidine, 2-sulfanilamido-^pyrimidine, 2-sulfanilamido-5-methylio pyrimidine, 2-sulfanilamido-5-isoprppyl-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimidine, 3-sulfanilamido-6-methoxypyridazine r 2-sulfanilamido-3-methoxy-pyrazine, 3-sulfanilamido-5-methyl-isoxazole and 2-sulfanilamido-pyridine.
These compounds may he prepared in the presence or 15 absence of a solvent. Examples of suitable solvents are pyridine, ethanol, water and mixtures of these solvents.
The reaction temperatures are from 0 to 150°C, preferably from 20 to 120°C, or up to the boiling point of the solvent used.
f°r example, N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yr]-acetimido-acid ethyl ester and aniline are used as starting materials, the course.of the reaction can he represented by the following equation:
- 5 4 7 0 2 2
OCHj
To demonstrate the action of the compounds according to the' invention, the latter were tested in animal experiments, using'the Aronson sepsis model, infection being carried out with Streptococcus agalactiae, and were com• pared with the conventional drug Trimethoprim, Groups of 30 female mice were infected with a lethal dose of Streptococcus agalactiae 7941 and 2 hours after infection were treated with a mixture of 300 mg of 2-sulfanilamido-4,5dimethyloxazole +.60 mg of one of the compounds according to the invention. In addition to an untreated control group, a second group was treated with a mixture - serving as a reference substance - of 300 mg of 2-sulfanilamido-4,5dimethyloxazole + 60 mg of Trimethoprim. After 44 hours, the number of surviving animals was determined and divided by the number of survivors from the group treated with the reference substance. The numerical value thus obtained (the Trimethoprim factor) is a measure of the action of the compounds according to the invention compared to Trimethoprim, Accordingly, F = 2 means·that the compound is twice as active as Trimethoprim. The Table which follows shows that the compounds according to the invention exhibit up to a 5.4-fold superiority over Trimethoprim.
- 6 4 ί υ » —
General formula
8.
TABLE
No. R*· A
CHy -<C3 ^ch3 1,2 CHy w 1,7 CHy 1.2 CHy -nh-ch2-^J^ 1,3 CHy ' /^C0CH3 -NH-CH?-<_ >-OCH, '—^OCH3 1,0 CHy -ΝΗ-ξ^-εο,-ΝΚ-ξ) 5.4 CHy ' -nh-^>-so2-nh-<2>-och3 1,6 CHy -NH- -SO fNK-^ -ch3 5,1 CHy ^j_yCH3 -NH-^-SOyNH-^ -1.25 CHy -NH-<^^-s°2-NH- ^-och3 1.0 - 7 -
0 22
Accordingly, the present invention also provides chemotherapeutic agents which contain a compound of the formula I, in particular in combination with a sulfonamide, as the active ingredient, together with conventional carriers and excipients, and the use of the compounds of the formula I as sulfonamide potentiators.
The chemotherapeutic agents or formulations are prepared in the conventional manner, using the conventional 'carriers or excipients and conventional pharmacological assistants, in accordance with the desired route of administration.
The preferred formulations are those suitable for oral administration. Examples are tablets, film tablets, dragees, capsules, pills, powders, solutions and suspensions.
EXAMPLE 1
16.2 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester are dissolved in 120 ml of pyridine, 14 ml· of a saturated solution of ammonia in ethanol are added and the mixture is stirred for 12 hours
2o at 70°C. After concentration under reduced pressure, the residue is recrystallized from dioxane. 8.6 g (57.7% of theory) of N- [4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl]-acetamidine of melting point 207°C are obtained.
EXAMPLE 2
1.8 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester, 0.93 g of aniline and 20 ml of absolute ethanol are refluxed for 15 hours whilst stirring and are then cooled, and 80 ml of water are added.
1.1 g (53% of theory) of N-[4-araino-5-(3,4,5-trimethoxy- 8 4 7 0 2 2 benzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine of melting point 189°C are obtained.
EXAMPLE 3
1.8 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester are stirred with 20 ml of 40 per cent strength aqueous dimethylamine solution for 10 hours at 50-60°C. The crystalline precipitate is filtered off,, washed with water and recrystallized from dioxane. 1.24 g (69% of theory) of N-[4-amino-5-(3,4,5trimethoxybenzyl)-pyrimidin-2-yl]-N’,N'-dimethyl-acetamidine of melting point 220°C are obtained.
EXAMPLE 4
Using the method described in Example 3, N-[4-amino5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-Ν',N'-diethylanatamidine of melting point 154°C was obtained from N-[4amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidoacid ethyl ester and diethylamine..
EXAMPLE 5
1.8 g of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester are suspended in 10 ml of N-phenylpiperazine and the mixture is heated at 65°C until all has dissolved and is then stirred for 3 hours at
90-100°C. After cooling, the mixture is treated with 100 ml of diethyl ether and the white crystalline precipitate is filtered off and recrystallized from butyl acetate. 1.6 g (6750 of theory) of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-N',N’-(3-aza-3-phenyl-pentamethylene)-acetamidine of melting point 197°C are obtained.
- 9 4 7 0 2 2
EXAMPLE 6
Using the method, described in.Example 5, N-[4-amino5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N’,N1-tetramethylene-acetamidine of melting point 198°C was prepared from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]acetimido-acid ethyl ester and pyrrolidine.
EXAMPLE 7
.4 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester and 1.6 g of benzylamine are dissolved in 40 ml of pyridine and the mixture is stirred for 2 hours at 90°C. After concentrating the mixture under reduced pressure, the residue is dissolved in 200 ml of warm ethyl acetate and the solution is clarified with active charcoal and cooled. 3.2 g (51% of theory) of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl]-N'-benzyl-acetamidIne of melting point l64°C crystallize from the solution.
The following were prepared by the method described in Example 7:
8. N-[4-Amino-5-(3,4,5-trlmethoxybenzyl)-pyrimidin-2yl]-N'-(3,4,5-trimethoxybenzyl)-acetamidine of melting point 20 143°C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl]-acetimido-acid ethyl ester and 3,4,5-trimethoxybenzylamine.
9. N- [4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N',N’-(3-oxa-pentamethylene)-acetamidine of melting point 205°C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl]-acetimido-acid ethyl ester and morpholine.
. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidirt-2- 10 yl]-N’-furfuryl-acetamidine of melting point 184°C from N[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and furfurylamine.
11. N-[4-Amino-5- (3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N’-cyclohexyl-acetamidine of melting point 183°C from W-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and cyclohexylamine.
12. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N’-adamantyl-acetamidine of melting point 248°C from N10 [4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 1-adamantylamine,
EXAMPLE 13
.8 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester and 4.2 g of 2snlfaun ami dn-5-methoxy-pyrimidine (sulfamethoxydiazine) are dissolved in 80 ml of pyridine and the reaction mixture is stirred for 12 hours under reflux and then concentrated under reduced pressure. After dissolving the residue in warm acetone and treating the solution with active charcoal,
.43 g (60.8% of theory) of N-[4-amino-5-(3,4,5-trimethoxy20 b enzyl) -pyr imi din-2-yl ] -N' - [ 4- ( 5-methoxypyrimidin-2-yl) sulfonamido]-phenyl-acetamidine of melting point 218°C crystallize out.
The following were prepared by the method described in Example 13: ’
14. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl ]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenylacetamidine of melting point 192°C from ΓΓ-[4-amino-5-(3,4,5trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ‘ester
- 11 4702& and 2-sulfanilamido-5-methyl-pyrimidine (sulfaperine).
. N- [4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N’-[4-(pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 178°C (with decomposition) from N-[4-amino5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-pyrimidine (sulfadiazine).
16. N- [4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl] -N’-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenylacetamidine of melting point l62°C from N-[4-amino-5-(3,4,510 trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-4-methyl-pyrimidine (sulfamerazine).
17. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N'-(4-sulfonylguanidino)-phenyl-acetamidine of melting point 246°C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-acetimido-acid ethyl ester and 4-amino.benzenesulfonylguanidine (sulfaguanidine).
18. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N’-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenylacetamidine of melting point 155°C from N-[4-amino-5-(3,4,520 trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 3-sulfanilamido-5-methyl-isoxazole (sulfamethoxazole).
19. N-[4-Amino-5-(3 >4,5-trimethoxybenzyl)-pyrimidin-2yl]-N’-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenylacetamidine of melting point l68°C from N-[4-amino-5-(3,4,5trimethoxybenzyl)-pyrimidin-2-yl]-aoetimido-acid ethyl ester and 3-sulfanilamido-6-methoxy-pyridazine (sulfamethoxypyridazine).
. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N'-[4-(pyridin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 237°C from N-[4~amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid. ethyl ester and 2sulf anilamido-pyridine (sulf apyridine).
21. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2yl]-N'-[4-( 5-isopropyl-pyrimidin-2-yl)-sulfonamido]-phenylacetamidine of melting point 201°C from N-[4-amino-5-(3,4,5trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-4-isopropyl-pyrimidine.
22. N- [4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-210 yl] -N' - [ 4-(3-methoxy-pyrazin-2-yl)-sulfonamido]-phenylacetamidine of melting point l48°C (with decomposition) from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-3-methoxypyrazine (sulfamethoxypyrazine, sulfalen e ).
Examples of pharmaceutical formulations.
23. 400 mg of 2-sulfanilamido-4,5-dimethyloxazole mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-N*-benzyl-acetamidine (Example 7) mg of corn starch -° 10 mg of gelatin mg of talc mg of magnesium stearate mg of Primojel
The active ingredients are mixed with corn starch and granulated, using the aqueous gelatin solution. The dry granules are sieved and mixed with the additives. This mixture is tableted in'the conventional manner.
- 13 47022
24. 160 mg of 2-sulfanilamido-5-methoxy-pyrimidine mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-N’-phenyl-acetamidine (Example 2) mg of gelatin mg of com starch 4 mg of talc mg of magnesium stearate
The active ingredients are granulated, using the aqueous gelatin solution, and the dried granules are mixed 10 with com starch, talc and magnesium stearate. This mixture is tableted in the conventional manner.
. 400 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-N'-[4-pyrimidin-2-yl)sulfonamidoJ-phenyl-acetamidine (Example 15) mg of com starch 10 mg of gelatin mg of talc mg of magnesium stearate mg of Primojel
The active ingredient is mixed with corn starch and granulated, using the aqueous gelatin solution. The dry granules are sieved and mixed with the additives.
This mixture is tableted in the conventional manner.
26. 250 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-N'-[4-(5-methoxypyrimidin-2-yl)-sulfonamido]-phenylacetamidine
- 14 (Example 13) mg of gelatin 30 mg of com starch.
mg of talc mg of magnesium stearate The active ingredient is granulated, using the aqueous gelatin solution, and the dried granules are mixed with com starch, talc and magnesium stearate. This mixture is tableted in the conventional manner,
27. 4.00 g of 2-sulfanilamido-5-methoxy-pyrimidine
2.00 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)pyrimidin-2-yl]-II ’,N’-dimethyl-acetamidine (Example 3)
1.9 g of Tylose C 30 30.0 g of sugar 10.0 g of glycerol 2.5 g of bentonite 0.06gof flavoring 0.04gof Nipagin M O.OGgof Nipasol sodium ad 100.00 g demineralized water The very finely milled active ingredients are suspended in the aqueous Tylose mucilage. All the other ingredients are then added successively, whilst stirring.
Finally, the mixture is made up to 100.0 g with water.
28. 0.300 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)· pyrimidin-2-yl]-N’4-(5-methylpyrimidin-2-yl)-sulfonamido]-phenylacetamidine
- 15 . 47022 (Example 14)
1.9 g of Tylose C 30
.0 g of sugar 10.0 g of glycerol
2.5 g of bentonite'
0.06 g of flavoring 0.04 g of Nipagin M 0.06 g of Nipasol sodium ad 100.00 g demineralized water
The very finely milled active ingredient is suspended 10 in the aqueous Tylose mucilage. All the other ingredients are then added successively, whilst stirring. Finally, the mixture is made up to 100.0 g with water.
Claims (10)
1. An amidino-benzylpyrimidine of the general formula I •fg ch 2 in N=C \R 6 (I) where R 1 , R 2 and R^, which may be identical or different, 4 are hydrogen, methyl, methoxy or chlorine, R is alkyl of 5 6 1 to 6 carbon atoms or benzyl and R and R , which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, trimethoxybenzyl, benzyl, phenyl, cyclo. 5 hexyl, adamantyl or furfuryl, or one of the radicals R and R^ is -CgHjj-SO-j-NH-R?, where R? is NH 0 -c-nh 2 , -c-nh 2 or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methylpyrimidin-2-yl, 5-isopropyl-pyrimidin-2-yl, 5-methoxypyrimidin-2-yl, 6-methoxy-pyridazin-2-yl, 3-methoxypyrazin-2-yl, 5 - methyl-isoxazol-3~yl or 2-pyridinyl, or 5 6 . . R and R together with the nitrogen to which they are bonded are a saturated heterocyclic ring of 5~7 members, which may contain an oxygen atom or the >N-Y group, where Y is methyl, benzyl or phenyl, and their pharmacologically acceptable salts with acids conventionally used for this purpose.
2. An- amidino-benzylpyrimidine as claimed in claim 1 12 3 wherein the substituents R , R and R J are in the 3-4- and 5-positions on the relevant benzene ring. - 17 47028
3. N-Q4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl3-acetamidine and its pharmacologically acceptable salts with acids.
4. N-£4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin5 2-yiJ -Ν'-pheny1-acetamidine and its pharmacologically acceptable salts with acids.
5. N-£4-Amino-5-(3 > 4,5-trimethoxybenzyl)-pyrimidin2-yl]-N'jN'-dimethyl-acetamidine and its pharmacologically acceptable salts with acids. 10
6. N-£4“Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-yl]-N',Ν'-diethy1-acetamidine and its pharmacologically acceptable salts with acids.
7. N-£4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin2-ylJ-N',N'-(3-aza-3-phenyl-pentamethylene)-acetamidine 15 and its - 18
8. A process for the preparation of a compound as P-ι aimed in any of claims 1-7 , wherein^a compound of the general formula II R J where R 1 , R 2 , R 3 and have the same meaning as in formula I and R 8 is lower alkyl of 1 to 4 carbon atoms or benzyl, is reacted with an amine of the formula III n (III) X R 6 where R 3 and R 8 have the same meaningsas in formula I, in the presence or absence of a solvent, after which the resulting compound may or may not be converted into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
9. · A drug containing a compound as claimed in any of claims 1 to 7 , and non-toxic, therapeutically acceptable solid or liquid carriers and galenical assistants.
10. A drug as claimed in claim 9 also containing an antibacterially active sulfonamide.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19772732029 DE2732029A1 (en) | 1977-07-15 | 1977-07-15 | NEW AMIDINO-BENZYLPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE781354L IE781354L (en) | 1979-01-15 |
| IE47022B1 true IE47022B1 (en) | 1983-11-30 |
Family
ID=6014014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1354/78A IE47022B1 (en) | 1977-07-15 | 1978-07-05 | Novel amidino-benzylpyrimidines, processes for their manufacture and drugs containing the said compounds |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP0000336B1 (en) |
| JP (1) | JPS5419986A (en) |
| AR (1) | AR227759A1 (en) |
| AT (1) | AT360999B (en) |
| AU (1) | AU520820B2 (en) |
| CA (1) | CA1129410A (en) |
| DE (2) | DE2732029A1 (en) |
| DK (1) | DK143273C (en) |
| FI (1) | FI782221A (en) |
| HU (1) | HU179408B (en) |
| IE (1) | IE47022B1 (en) |
| IL (1) | IL55063A0 (en) |
| IT (1) | IT1096976B (en) |
| NO (1) | NO782455L (en) |
| ZA (1) | ZA784012B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2730468A1 (en) * | 1977-07-06 | 1979-01-18 | Basf Ag | NEW N-PYRIMIDINYL IMIDIC ACID ESTERS, PROCESS FOR THEIR PRODUCTION AND MEDICINAL PRODUCTS CONTAINING THEM |
| US4333936A (en) * | 1978-07-03 | 1982-06-08 | Basf Aktiengesellschaft | Novel amidino-benzylpyrimidines, processes for their manufacture and antibacterial and antiprotozoal use thereof |
| DE3045720A1 (en) * | 1980-12-04 | 1982-07-08 | Basf Ag, 6700 Ludwigshafen | N-PYRIMIDINYL-CARBAMINE ACID ESTER, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME |
| JPS5915110U (en) * | 1982-07-22 | 1984-01-30 | クラリオン株式会社 | constant voltage circuit |
| JPH0618012B2 (en) * | 1983-01-25 | 1994-03-09 | セイコーエプソン株式会社 | Constant voltage circuit |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4849791A (en) * | 1971-10-26 | 1973-07-13 |
-
1977
- 1977-07-15 DE DE19772732029 patent/DE2732029A1/en not_active Withdrawn
-
1978
- 1978-06-19 DE DE7878100184T patent/DE2860614D1/en not_active Expired
- 1978-06-19 EP EP78100184A patent/EP0000336B1/en not_active Expired
- 1978-07-03 IL IL55063A patent/IL55063A0/en unknown
- 1978-07-05 IE IE1354/78A patent/IE47022B1/en unknown
- 1978-07-05 IT IT25382/78A patent/IT1096976B/en active
- 1978-07-10 AU AU37903/78A patent/AU520820B2/en not_active Expired
- 1978-07-11 AR AR272912A patent/AR227759A1/en active
- 1978-07-11 FI FI782221A patent/FI782221A/en not_active Application Discontinuation
- 1978-07-13 JP JP8462878A patent/JPS5419986A/en active Pending
- 1978-07-13 HU HU78BA3676A patent/HU179408B/en unknown
- 1978-07-14 ZA ZA00784012A patent/ZA784012B/en unknown
- 1978-07-14 DK DK315878A patent/DK143273C/en not_active IP Right Cessation
- 1978-07-14 NO NO782455A patent/NO782455L/en unknown
- 1978-07-14 AT AT513078A patent/AT360999B/en not_active IP Right Cessation
- 1978-07-14 CA CA307,427A patent/CA1129410A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ZA784012B (en) | 1979-08-29 |
| EP0000336B1 (en) | 1981-04-15 |
| IL55063A0 (en) | 1978-09-29 |
| AU520820B2 (en) | 1982-03-04 |
| CA1129410A (en) | 1982-08-10 |
| HU179408B (en) | 1982-10-28 |
| DK143273C (en) | 1981-11-30 |
| EP0000336A1 (en) | 1979-01-24 |
| IE781354L (en) | 1979-01-15 |
| FI782221A (en) | 1979-01-16 |
| IT7825382A0 (en) | 1978-07-05 |
| NO782455L (en) | 1979-01-16 |
| ATA513078A (en) | 1980-07-15 |
| AU3790378A (en) | 1980-01-17 |
| IT1096976B (en) | 1985-08-26 |
| JPS5419986A (en) | 1979-02-15 |
| DE2860614D1 (en) | 1981-05-07 |
| DK315878A (en) | 1979-01-16 |
| AR227759A1 (en) | 1982-12-15 |
| DK143273B (en) | 1981-08-03 |
| DE2732029A1 (en) | 1979-02-01 |
| AT360999B (en) | 1981-02-10 |
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