CA1129410A - Amidino-benzylpyrimidines, processes for their manufacture and drugs containing the said compounds - Google Patents
Amidino-benzylpyrimidines, processes for their manufacture and drugs containing the said compoundsInfo
- Publication number
- CA1129410A CA1129410A CA307,427A CA307427A CA1129410A CA 1129410 A CA1129410 A CA 1129410A CA 307427 A CA307427 A CA 307427A CA 1129410 A CA1129410 A CA 1129410A
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- Prior art keywords
- pyrimidin
- amino
- trimethoxybenzyl
- acetamidine
- process according
- 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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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE: 5-Benzyl-4-amino-pyrimidine-2-amidines which may or may not be substituted in the phenyl ring, and their physiologically acceptable addition salts with acids, processes for their preparation, drugs containing these compounds, and their use in infectious diseases.
Description
94~1~
The present invention relates to novel amidino-benzyl-pyrimidines of the general formula I
R2 ~CH2 ~2~N=C - N ~I) where Rl, R2, and R3 are methoxy in the 3-, -4 and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl,benzyl,trLmethoxy-benzyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4-So2-NH-R7, where R is N,H Q
Il 11 or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hereto - atoms which may be identical or dif-ferent from one another and are nitrogen or oxygen, and which may be substituted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy, or R5 and R6 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 to their pharmacologically acceptable salts with acids conven-tionally used for this purpose.
.~
11294~(~
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.
Preferred compounds of the formule I
are those where R is lower alkyl of 1 to 4 carbon atoms or benzyl, and R5 and R6, which may be identical or dif-ferent, are hydrogen, lower alkyl of 1 to 4 carbon atoms, benzyl or phenyl, or together are polymethylene of 4 or 5 methylene groups, which may be interrupted by oxygen or ~ N-Y, where Y is methyl, benzyl or phenyl, or R5 is hydrogen and R6 is -C6H4-SO2NH-R , where R is NH O
~1 -C-NH2 ~ -C-NH2 or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl, 5-isopropyl-pyri.midin-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, and Rl, R2 and R3 have the same meaning as in formula I.
The compounds of the formula I are anti-microbially active in illnesses caused by bacteria and protozoa and, when comblned with sulLonamides, poten-tiate their antibacterial action. They may be used, for example, in ~actcrlal inrcc~lolls o~ ~IIC rcsplra~ory oryans, dk~cs-tive organs and urinary tract, in infections of the throat, nose and ears, in systemic infections in general, and in malaria.
294~0 Examples of suitable sulfonamides are
The present invention relates to novel amidino-benzyl-pyrimidines of the general formula I
R2 ~CH2 ~2~N=C - N ~I) where Rl, R2, and R3 are methoxy in the 3-, -4 and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl,benzyl,trLmethoxy-benzyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4-So2-NH-R7, where R is N,H Q
Il 11 or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hereto - atoms which may be identical or dif-ferent from one another and are nitrogen or oxygen, and which may be substituted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy, or R5 and R6 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 to their pharmacologically acceptable salts with acids conven-tionally used for this purpose.
.~
11294~(~
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.
Preferred compounds of the formule I
are those where R is lower alkyl of 1 to 4 carbon atoms or benzyl, and R5 and R6, which may be identical or dif-ferent, are hydrogen, lower alkyl of 1 to 4 carbon atoms, benzyl or phenyl, or together are polymethylene of 4 or 5 methylene groups, which may be interrupted by oxygen or ~ N-Y, where Y is methyl, benzyl or phenyl, or R5 is hydrogen and R6 is -C6H4-SO2NH-R , where R is NH O
~1 -C-NH2 ~ -C-NH2 or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl, 5-isopropyl-pyri.midin-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, and Rl, R2 and R3 have the same meaning as in formula I.
The compounds of the formula I are anti-microbially active in illnesses caused by bacteria and protozoa and, when comblned with sulLonamides, poten-tiate their antibacterial action. They may be used, for example, in ~actcrlal inrcc~lolls o~ ~IIC rcsplra~ory oryans, dk~cs-tive organs and urinary tract, in infections of the throat, nose and ears, in systemic infections in general, and in malaria.
294~0 Examples of suitable sulfonamides are
2-sulfanilamido-pyridine, 2-sulfanilamido-thiazole, 2-sulfanilamido-pyrimidine, 2-sulfanilamido-4-methyl-pyrimidine, 2-sulfanilamido-4,6-dimethyl-pyrimidine, 4-sulfanilamido-2,6-dimethyl-pyrimidine, 5-sulfanilamido-
3,4-dimethyl-isoxazole, 3-sulfanilamido-6-methoxy-pyri-dazine, 3-sulfanilamido-6-chloro-pyridazine, 4-sulfa-_ nilamido-2,6-dimethoxy-pyri~idine, 3-sulfanilamido-2-phenyl-pyrazole, 2-sulfanilamido-5-methyl-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimidine, 2-sulfanilamido-5-methyl-isoxazole, 2-sulfanilamido-4,5-dimethyloxazole, 2-sulfanilamido-3-methoxy-pyrazine, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 4-sulfanilamido-3-methoxy-1,2,5-thiadiazole and 4-aminobenzene-sulfonyl-guanidine.
The compounds of the formule I and . their salts can be combined with the sulfonamides, mentioned by way of example, '. , ' '' ~" '' .
.
., 1~94~0 O.Z. 0050/033064 in various ratios; the ratio Or the ~ormer to the latter may be from 1:10 to 5:1. However, preferred ratios are ~rom 1:1 to 1:5. As a rule, a ~uitable dosage is from 20 to 550 mg o~ an active ingredient of the formula I.
The compounds according to the invention, o. the ~or-mula I, are prepared by the conventional methods of preparing amidines, as de~cribed, inter alia, in Houben-Weyl, "Methoden der or~anischen Chemie", Volume 11~2, in which an imido-acid ester of the general formula II
~ NH2 4 (II) where Rl, R2, R3 and R4 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
H - N (III) \ 6 where R5 and R6 have the above meanings,to give the amidine of the general formula I
R2 ~ _ CN2 ~ \ ~ N-C-N~ (I) which then may or may not be converted to a pharmacologically acceptable addition salt with an acid conventionally used for this purpose.
~;29410 The imido-aci,d esters of the general formula II
and their preparatlon are described in our co-pending Canadian Patent application n 306,847 filed 5th of July 1978.
Examples of amlnes of the formula III are ammonia, methylamine, dlmethylamine, diethylamine, benzylamine, 3,4,5-trimethoxybenzylamine, N-phenyl-piperazine, furfurylamine, cyclo-hexylamine, pyrrolidine, piperidine, morpholine and aniline , and sulfonamides, eg. 2-sulfanilamido-pyrimidine, 2-sulfanilamido-4-methyl-pyrimidine, 2-sulfanilamido-5-methyl-pyrimidine,2-sulfa-nilamido-5-isopropyl-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimi-dine, 3-sulfanilamido-6-methoxy-pyridazine, 2-sulfanilamido-3-methoxy-pyrazine, 3-sulfanilamido-5-methyl-isoxazole and 2-sulfa-nilamido-pyridine.
These compounds may be prepared in the presence or absence of a solvent. Examples of suitable solvents are pyridine, ethanol, water and mixtures of these solvents. The reaction tem-peratures are from 0 to 150C, preferably from 20 to 120C, or up to the boiling point of the solvent used.
If, for example, N-~ 4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl~ -acetimido-acid ethyl ester and aniline are used as starting materials, the course of the reaction can be represented by the followlng equation~
` ~29~0 o, Z, 0o50/o3~o64 OCH~ NH2 X3C~-CHZ~>-N=C - oCz OCH NH CH
- \ 3 ~2 ~ 1 3 ~ ~ CzH50H
To demonstrate the action of the compounds accor-ding 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 Strepto-coccus agalactiae 7941 and 2 hours after infection were treated with a mixture of 300 mg of 2-sulfanilamido-4,5-dimethyloxazole + 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-4,5-dimethyloxazole ~ 60 mg of Trimethoprim. After 44 hours, the number of surviving animais was determined an'd divided by the number of survivors from the group treated with the reference substance The numerical value thus obtained tthe Trimethoprim factor) is a measure of the action of the compounds according to the invention compared to Trimetho-prim Accordingly, F = 2 means that the compound is twice as active as Trimethoprim. The Table whichfollo~s shows that the compounds according to the invention exhibit up to a 5.4-fold superiority over Trimethoprim.
1~2~ 0 O. Z. 0050/033064 .
TABLE
General formula CH30\ . N\2 N R4 CH 30 ~ C H 2-~ N~ -N = C-A
N~. R4- A .. .. F
CH ~- ~ CH3 1, 2 ~ CH3 2 CH3- _~ N~ . ; 1~7 3 CH 3- -NH~ . . 1 . 2
The compounds of the formule I and . their salts can be combined with the sulfonamides, mentioned by way of example, '. , ' '' ~" '' .
.
., 1~94~0 O.Z. 0050/033064 in various ratios; the ratio Or the ~ormer to the latter may be from 1:10 to 5:1. However, preferred ratios are ~rom 1:1 to 1:5. As a rule, a ~uitable dosage is from 20 to 550 mg o~ an active ingredient of the formula I.
The compounds according to the invention, o. the ~or-mula I, are prepared by the conventional methods of preparing amidines, as de~cribed, inter alia, in Houben-Weyl, "Methoden der or~anischen Chemie", Volume 11~2, in which an imido-acid ester of the general formula II
~ NH2 4 (II) where Rl, R2, R3 and R4 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
H - N (III) \ 6 where R5 and R6 have the above meanings,to give the amidine of the general formula I
R2 ~ _ CN2 ~ \ ~ N-C-N~ (I) which then may or may not be converted to a pharmacologically acceptable addition salt with an acid conventionally used for this purpose.
~;29410 The imido-aci,d esters of the general formula II
and their preparatlon are described in our co-pending Canadian Patent application n 306,847 filed 5th of July 1978.
Examples of amlnes of the formula III are ammonia, methylamine, dlmethylamine, diethylamine, benzylamine, 3,4,5-trimethoxybenzylamine, N-phenyl-piperazine, furfurylamine, cyclo-hexylamine, pyrrolidine, piperidine, morpholine and aniline , and sulfonamides, eg. 2-sulfanilamido-pyrimidine, 2-sulfanilamido-4-methyl-pyrimidine, 2-sulfanilamido-5-methyl-pyrimidine,2-sulfa-nilamido-5-isopropyl-pyrimidine, 2-sulfanilamido-5-methoxy-pyrimi-dine, 3-sulfanilamido-6-methoxy-pyridazine, 2-sulfanilamido-3-methoxy-pyrazine, 3-sulfanilamido-5-methyl-isoxazole and 2-sulfa-nilamido-pyridine.
These compounds may be prepared in the presence or absence of a solvent. Examples of suitable solvents are pyridine, ethanol, water and mixtures of these solvents. The reaction tem-peratures are from 0 to 150C, preferably from 20 to 120C, or up to the boiling point of the solvent used.
If, for example, N-~ 4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl~ -acetimido-acid ethyl ester and aniline are used as starting materials, the course of the reaction can be represented by the followlng equation~
` ~29~0 o, Z, 0o50/o3~o64 OCH~ NH2 X3C~-CHZ~>-N=C - oCz OCH NH CH
- \ 3 ~2 ~ 1 3 ~ ~ CzH50H
To demonstrate the action of the compounds accor-ding 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 Strepto-coccus agalactiae 7941 and 2 hours after infection were treated with a mixture of 300 mg of 2-sulfanilamido-4,5-dimethyloxazole + 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-4,5-dimethyloxazole ~ 60 mg of Trimethoprim. After 44 hours, the number of surviving animais was determined an'd divided by the number of survivors from the group treated with the reference substance The numerical value thus obtained tthe Trimethoprim factor) is a measure of the action of the compounds according to the invention compared to Trimetho-prim Accordingly, F = 2 means that the compound is twice as active as Trimethoprim. The Table whichfollo~s shows that the compounds according to the invention exhibit up to a 5.4-fold superiority over Trimethoprim.
1~2~ 0 O. Z. 0050/033064 .
TABLE
General formula CH30\ . N\2 N R4 CH 30 ~ C H 2-~ N~ -N = C-A
N~. R4- A .. .. F
CH ~- ~ CH3 1, 2 ~ CH3 2 CH3- _~ N~ . ; 1~7 3 CH 3- -NH~ . . 1 . 2
4 CH3- -NH-CH2~ 1. 3 S CH3~ H-CHz-(~OCH3 1,0 6 C H ~- - NH- ~3 ~ 50 2-NY'- (N--3 7 CH -NH-~-S02-N~ ~C~ 3 . 1,6 8 CH3- -N~_c3_so2-N~ y3-CH3 5 ~1 9 CH - -NH-~3~SO2-NH~N-~ 1,25 CH3- -NH-~ 3 S02 NH ~OCH3 1.0 O.Z. 0050/033064 Accordingly, the present invention also relates to 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 to 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 admini-stration, The preferred formulations are those suitable for oral administration. Examples are tablets, film tablets, dragees, capsules, pills, powders, solutions and suspensions.
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 at 70C. After concentration under reduced pressure, the residue is recrystallized from dioxane. 8.6 g (57.7% of theory) of N-C4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidine of melting point 207C 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-amino-5-(3,4,5-trimethoxy-`` ~Li294t1~
o.Z, 0050/033064 benzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine of melting point 189C are obtained.
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 50-60C. The crystalline precipitate is filtered off, washed with water and recrystallized from dioxane. 1.24 g (69% of theory) of N-~4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-dimethyl-acetamidine of melting point 220C are obtained.
Using the method described in Example 3, N-[4-amino-
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 admini-stration, The preferred formulations are those suitable for oral administration. Examples are tablets, film tablets, dragees, capsules, pills, powders, solutions and suspensions.
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 at 70C. After concentration under reduced pressure, the residue is recrystallized from dioxane. 8.6 g (57.7% of theory) of N-C4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamidine of melting point 207C 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-amino-5-(3,4,5-trimethoxy-`` ~Li294t1~
o.Z, 0050/033064 benzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine of melting point 189C are obtained.
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 50-60C. The crystalline precipitate is filtered off, washed with water and recrystallized from dioxane. 1.24 g (69% of theory) of N-~4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-dimethyl-acetamidine of melting point 220C are obtained.
Using the method described in Example 3, N-[4-amino-
5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-diethyl-acetamidine of melting point 154C was obtained from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamido-acid ethyl ester and diethylamine.
1.8 g of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester are suspended in 10 ml o~ N-phenylpiperazine and the mixture is heated at 65C
until all has dissolved and is then sti~red for 3 hours at 90-100C. After cooling, the mixture is treated with 100 ml o~ diethyl ether and the white crystalline precipitate is filtered off and recrystallized from butyl acetate. 1.6 g (67,b of theory) of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-aza-3-phenyl-pentamethylene)-acet-amidine of melting point 197C are obtained.
_ g _ o o. z . 0050/033064 Using the method described in Example 5, N-[4-amino-5-(3l4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-tetra-methylene-acetamidine of melting point 198C was prepared from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and pyrrolidine.
5.4 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 1,6 g o~
benzylamine are dissolved in 40 ml of pyridine and the mix-ture is stirred for 2 hours at 90C. After concentrating the mixture under reduced pressure, the residue is dissolved in 200 ml of warm ethyl acetate and the solution is clari-fied with active charcoal and cooled. 3.2 g (51% of theory) of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine of melting point 164C crystal-lize from the solution.
The follo~ing were prepared by the method described in Example 7:
8. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(3,4,5-trimethoxybenzyl)-acetamidine of melting point 143C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 3,4,5-trimethoxy-benzylamine.
9. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-o~a-pentamethylene)-acetamidine of melting point 205C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and morpholine.
10. N-[4-Amino-5-(3,4,5-trimethoxybenzyl~-pyrimidin-2-- 10 - `
1~29410 O.Z.0050/033064 yl]-N'-furfuryl-acetamidine of melting point 184C from N-[4-amino-5-t3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and furfurylamine.
11. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-cyclohexyl-acetamidine of melting point 183C from N-~4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imidc-acid ethyl ester and cyclohexylamine.
12. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-adamantyl-acetamidine of melting point 248C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and l-adamantylamine.
10,8 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 4.2 g of 2-sulfanilamido-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, 5.43 g (60.8~ of theory) of N-[4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-N'-[4-(5-methoxypyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 218C
crystallize out.
The following were prepared by the method described in ~xample 13:
14. N~[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 192C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester llZ~10 o.z. 0050/033064 and 2-sul~anilamido-5-methyl-pyrimidine (sulfaperine).
15. N-t4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 178C (with decomposition) fr~m N-[4-amino-5-(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-2-yl]-N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 162C from N-[4-amino-5-(3,4,5-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-2-yl]-N'-(4-sulfonylguanidino)-phenyl-acetamidine of melting point 246C 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-2-yl]-N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl-acetamidine of melting point 155C from N-[4-amino-5-(3,4,5-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-2-yl]-N'-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenyl-acetamidine of melting point 168C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 3-sulfanilamido-6-methoxy-pyridazine (sulfamethoxy-pyridazine) 20. N-[4-Amino-5-(3,4,5-trimethoxybenzyl~-pyrimidin-2-yl]-N'-[4-(pyridin-2-yl)-sulfonamido~-phenyl-acetamidine 1~2g~1~
o.z. 0050/033064 of melting point 237C from N-[4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-pyridine (sulfapyridine).
21. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-isopropyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 201C from ~-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-4-isopropyl-pyrimidine.
22. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl~-N'-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 148C (with decomposition) from N-[4-amino-5-(~,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and 2-sulfanilamido-3-methoxy~yrazine (sulfamethoxypyrazine, sulfalene).
Examples of pharmaceutical formulations.
23, 4 mg of 2-sulfanilamido-4,5-dimethyloxazole 80 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine (Example 7) 20 mg of corn starch 10 mg of gelatin 8 mg of talc 2 mg of magnesium stearate 20 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.
~1~129~10 o.z.0050/033064 24, 160 mg of 2-sulfanilamido-5-methoxy-pyrimidine 80 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine (Example 2) 5 mg of gelatin - 30 mg of corn starch 4 mg of talc 1 mg of magnesium stearate The active ingredients are granulated, using the aqueous gelatin solution, and the dried granules are mixed with corn starch,talc andmagnesium stearate, This mixture is tableted in the conventional manner.
25. 400 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine (Example 15) 20 mg of corn starch 10 mg of gelatin 8 mg of talc 2 mg of magnesium stearate 20 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-methoxy-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine llZ~410 o.z. 0050/03~064 (Example 13) 5 mg of gelatin 30 mg of corn starch 4 mg of talc 1 mg of magnesium stearate The active ingredient ~s granulated, using the aqueous gelatin solution, and the dried granules are mixed with corn starch, talc and magnesium stearate. This mix-ture is tableted in the conventional manner.
27. 4,00 g of 2-sulfanilamido-5-methoxy-pyrimidine ~10 2.00 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-dimethyl-acet-amidine (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 0.04g of Nipagin M
0.06gof Nipasol sodium ad 100.00 g demineralized water Thevery finelymilledactiveingredients aresuspended in the aqueous Tylose mucilage. All the other ingredi-ents 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-(~,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine 1129~1~
o. z . 0050~033064 (Example 14) 1.9 g of Tylose C 30 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 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.
1.8 g of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester are suspended in 10 ml o~ N-phenylpiperazine and the mixture is heated at 65C
until all has dissolved and is then sti~red for 3 hours at 90-100C. After cooling, the mixture is treated with 100 ml o~ diethyl ether and the white crystalline precipitate is filtered off and recrystallized from butyl acetate. 1.6 g (67,b of theory) of N-[(4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-aza-3-phenyl-pentamethylene)-acet-amidine of melting point 197C are obtained.
_ g _ o o. z . 0050/033064 Using the method described in Example 5, N-[4-amino-5-(3l4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-tetra-methylene-acetamidine of melting point 198C was prepared from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and pyrrolidine.
5.4 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 1,6 g o~
benzylamine are dissolved in 40 ml of pyridine and the mix-ture is stirred for 2 hours at 90C. After concentrating the mixture under reduced pressure, the residue is dissolved in 200 ml of warm ethyl acetate and the solution is clari-fied with active charcoal and cooled. 3.2 g (51% of theory) of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine of melting point 164C crystal-lize from the solution.
The follo~ing were prepared by the method described in Example 7:
8. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(3,4,5-trimethoxybenzyl)-acetamidine of melting point 143C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 3,4,5-trimethoxy-benzylamine.
9. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-o~a-pentamethylene)-acetamidine of melting point 205C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and morpholine.
10. N-[4-Amino-5-(3,4,5-trimethoxybenzyl~-pyrimidin-2-- 10 - `
1~29410 O.Z.0050/033064 yl]-N'-furfuryl-acetamidine of melting point 184C from N-[4-amino-5-t3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and furfurylamine.
11. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-cyclohexyl-acetamidine of melting point 183C from N-~4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imidc-acid ethyl ester and cyclohexylamine.
12. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-adamantyl-acetamidine of melting point 248C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and l-adamantylamine.
10,8 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 4.2 g of 2-sulfanilamido-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, 5.43 g (60.8~ of theory) of N-[4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-N'-[4-(5-methoxypyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 218C
crystallize out.
The following were prepared by the method described in ~xample 13:
14. N~[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 192C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester llZ~10 o.z. 0050/033064 and 2-sul~anilamido-5-methyl-pyrimidine (sulfaperine).
15. N-t4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 178C (with decomposition) fr~m N-[4-amino-5-(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-2-yl]-N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 162C from N-[4-amino-5-(3,4,5-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-2-yl]-N'-(4-sulfonylguanidino)-phenyl-acetamidine of melting point 246C 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-2-yl]-N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl-acetamidine of melting point 155C from N-[4-amino-5-(3,4,5-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-2-yl]-N'-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenyl-acetamidine of melting point 168C from N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 3-sulfanilamido-6-methoxy-pyridazine (sulfamethoxy-pyridazine) 20. N-[4-Amino-5-(3,4,5-trimethoxybenzyl~-pyrimidin-2-yl]-N'-[4-(pyridin-2-yl)-sulfonamido~-phenyl-acetamidine 1~2g~1~
o.z. 0050/033064 of melting point 237C from N-[4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-pyridine (sulfapyridine).
21. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-isopropyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 201C from ~-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester and 2-sulfanilamido-4-isopropyl-pyrimidine.
22. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl~-N'-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido]-phenyl-acetamidine of melting point 148C (with decomposition) from N-[4-amino-5-(~,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acet-imido-acid ethyl ester and 2-sulfanilamido-3-methoxy~yrazine (sulfamethoxypyrazine, sulfalene).
Examples of pharmaceutical formulations.
23, 4 mg of 2-sulfanilamido-4,5-dimethyloxazole 80 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine (Example 7) 20 mg of corn starch 10 mg of gelatin 8 mg of talc 2 mg of magnesium stearate 20 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.
~1~129~10 o.z.0050/033064 24, 160 mg of 2-sulfanilamido-5-methoxy-pyrimidine 80 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine (Example 2) 5 mg of gelatin - 30 mg of corn starch 4 mg of talc 1 mg of magnesium stearate The active ingredients are granulated, using the aqueous gelatin solution, and the dried granules are mixed with corn starch,talc andmagnesium stearate, This mixture is tableted in the conventional manner.
25. 400 mg of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine (Example 15) 20 mg of corn starch 10 mg of gelatin 8 mg of talc 2 mg of magnesium stearate 20 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-methoxy-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine llZ~410 o.z. 0050/03~064 (Example 13) 5 mg of gelatin 30 mg of corn starch 4 mg of talc 1 mg of magnesium stearate The active ingredient ~s granulated, using the aqueous gelatin solution, and the dried granules are mixed with corn starch, talc and magnesium stearate. This mix-ture is tableted in the conventional manner.
27. 4,00 g of 2-sulfanilamido-5-methoxy-pyrimidine ~10 2.00 g of N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-dimethyl-acet-amidine (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 0.04g of Nipagin M
0.06gof Nipasol sodium ad 100.00 g demineralized water Thevery finelymilledactiveingredients aresuspended in the aqueous Tylose mucilage. All the other ingredi-ents 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-(~,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine 1129~1~
o. z . 0050~033064 (Example 14) 1.9 g of Tylose C 30 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 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 (48)
1. A process for the preparation of an amidino-benzylpyrimidine of the general formula I
(I) where R1, R2 and R3 are methoxy in the 3-,4- and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, benzyl, trimethoxyben-zyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4-SO2-NH-R7, where R7 is , or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hetero-atoms which may be identical or different from one another and are nitrogen or oxygen, and which may be substi-tuted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy, or R5 and R6 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, said process which comprises reacting a com-pound of the general formula II
(II) where R1, R2, R3 and R4 have the above meaning and R8 is lower alkyl of 1 to 4 carbon atoms or benzyl, with an amine of the formula III
(III) where R5 and R6 have the above meanings, in the presence or absence of a solvent, and if desired converting the resulting compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
(I) where R1, R2 and R3 are methoxy in the 3-,4- and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, benzyl, trimethoxyben-zyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4-SO2-NH-R7, where R7 is , or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hetero-atoms which may be identical or different from one another and are nitrogen or oxygen, and which may be substi-tuted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy, or R5 and R6 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, said process which comprises reacting a com-pound of the general formula II
(II) where R1, R2, R3 and R4 have the above meaning and R8 is lower alkyl of 1 to 4 carbon atoms or benzyl, with an amine of the formula III
(III) where R5 and R6 have the above meanings, in the presence or absence of a solvent, and if desired converting the resulting compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
2. A process according to claim l, where R4 is lower alkyl of l to 4 carbon atoms or benzyl, and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, benzyl or phenyl, or together are polymethylene of 4 to 5 methylene groups, which may be interrupted by oxygen or >N-Y, where Y is methyl, benzyl or phenyl, or R5 is hydrogen and R6 is -C6H4-SO2NH-R7, where R7 is , 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.
3 A process according to claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimi-din-2-yl] -acetamido-acid ethyl ester with ammonia in the pres-ence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxyben-zyl)-pyrimidin-2-yl]-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
4. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamido-acid ethyl ester witn aniline in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
5. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-y]-acetimido-acid ethyl ester with dimethylamine in the absence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N', N'-dimethyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
6. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetamido-acid ethyl ester with diethylamine in the absence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N', N'-diethyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
7. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2- yl]-acetimido-acid ethyl ester with N-phenyl-piperazine in the absence of a solvent to obtain N-[(4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-N', N'-(3-aza-3-phenyl-pentamethylene)-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
8. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with pyrrolidine in the absence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N', N'-tetramethylene-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
9. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with benzylamine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
10. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 3,4,5-trimethoxybenzyl-amine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(3,4,5-trimethoxy-benzyl)-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conven-tionally used for this purpose.
11. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with morpholine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N', N'-(3-oxa-pentamethylene)-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
12. A process according to Claim 1, whi~ch comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with furfurylamine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-furfuryl-acetamidine and if desired convert-ing this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
13. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with cyclohexylamine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-cyclohexyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
14. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidun-2-yl]-acetimido-acid ethyl ester with l-adamantylamine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-adamantyl acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
15. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 2-sulfanilamido-5-methoxy-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]N'-[4-(5-meth pyrimidine-2-yl) sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
16. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]
acetimido-acid ethyl ester with 2-sulfanilamido-5-methyl-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
acetimido-acid ethyl ester with 2-sulfanilamido-5-methyl-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
17. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 2-sulfanilamido-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(pyrimidin-2-yl) sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
18. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 2-sulfanilamido-4-methyl-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
19. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 4-amino-benzenesulfonylguanidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(4-sulfonylguanidino)-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
20. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]
acetimido-acid ethyl ester with 3-sulfanilamido-5-methyl-isoxazole in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purposes.
acetimido-acid ethyl ester with 3-sulfanilamido-5-methyl-isoxazole in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purposes.
21. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 3-sulfanilamido-6-methoxy-pyridazine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-Nl-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
22. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-acetimido-acid ethyl ester with 2-sulfanilamido-pyridine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxy-benzyl)-pyrimidin-2-yl]-N'-[4-(pyridin-2-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid convention-ally used for this purpose.
23. A process according to Claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -acetimido-acid ethyl ester with 2-sulfanilamido-4-isopropyl-pyrimidine in the presence of a solvent to obtain N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-isopropyl-py-rimidin-2-yl)-sulfonamido]-phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
24. A process according to claim 1, which comprises reacting N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyri-midin-2-yl]-acetamido-acid ethyl ester with 2-sulfanilamido-3-methoxy-pyrazine in the presence of a solvent to obtain N-[4-a-mino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido] -phenyl-acetamidine and if desired converting this compound into a pharmacologically acceptable salt with an acid conventionally used for this purpose.
25. An amidino-benzylpyrimidine of the general formula I
(I) where R1, R2, and R3 are methoxy in the 3-,4-, and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, benzyl, trimethoxy-benzyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4 -SO2-NH-R7, where R7 is or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hetero-atoms which may be identical or different from one another and are nitrogen or oxygen, and which may be substituted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy or R5 and R6 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 to their pharmacologically acceptable salts with acids conventionally used for this purpose, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
(I) where R1, R2, and R3 are methoxy in the 3-,4-, and 5-position of the phenyl ring, R4 is alkyl of 1 to 6 carbon atoms or benzyl and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, phenyl, benzyl, trimethoxy-benzyl, cyclohexyl, adamantyl or furfuryl, or one of the radicals R5 and R6 is -C6H4 -SO2-NH-R7, where R7 is or a heterocyclic ring of 5-6 ring members, which contains from 1 to 3 hetero-atoms which may be identical or different from one another and are nitrogen or oxygen, and which may be substituted by chlorine, alkyl of 1 to 4 carbon atoms or methoxy or R5 and R6 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 to their pharmacologically acceptable salts with acids conventionally used for this purpose, whenever obtained by a process according to claim 1 or its obvious chemical equivalents.
26. A compound of the formula I according to claim 25, where R4 is lower alkyl of 1 to 4 carbon atoms or benzyl, and R5 and R6, which may be identical or different, are hydrogen, lower alkyl of 1 to 4 carbon atoms, benzyl or phenyl, or together are polymethylene of 4 or 5 methylene groups, which may be interrupted by oxygen or > N-Y, where Y is methyl, benzyl or phenyl, or R5 is hydrogen and R6 is -C6H4-So2NH-R7, where R7 is or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl, 5-isopropyl-pyrimidin-2yl, 5-methoxy-pyrimidin-2-yl, 6-methoxy-pyridazin-3-yl, 3-methoxy-pyrazin-2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl, whenever obtained by a process according to claim 2 or its obvious chemical equivalents.
27. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-y]-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 3 or its obvious chemical equivalents.
28. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-phenyl-acetamidine and its pharmacologically accept-able salts with acids, whenever obtained by a process according to claim 4 or its obvious chemical equivalents.
29. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-dimethyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 5 or its obvious chemical equivalents.
30. N-[4-Amino-5-(3,4,5,trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-diethyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 6 or its obvious chemical equivalents.
31. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-aza-3-phenyl-pentamethylene)-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 7 or its obvious chemical equivalents.
32. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-tetramethylene-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 8 or its obvious chemical equivalents.
33. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-benzyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 9 or its obvious chemical equivalents.
34. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-(3,4,5-trimethoxybenzyl)-acetamidine and its pharma-cologically acceptable salts with acids, whenever obtained by a process according to claim 10 or its obvious chemical equivalents.
35. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N',N'-(3-oxa-pentamethylene)-acetamidine and its pharmaco-logically acceptable salts with acids, whenever obtained by a process according to claim 11 or its obvious chemical equivalents.
36. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-furfuryl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 12 or its obvious chemical equivalents.
37. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-cyclohexyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 13 or its obvious chemical equivalents.
38. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-adamantyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 14 or its obvious chemical equivalents.
39. N-[4-Amino-5-t3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methoxypyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids whenever obtained by a process according to claim 15 or its obvious chemical equivalents.
40. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 16 or its obvious chemical equivalents.
41. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-p4-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 17 or its obvious chemical equivalents.
42. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(4-methyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 18 or its obvious chemical equivalents.
43. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl] -N'-(4-sulfonylguanidino)-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 19 or its obvious chemical equivalents.
44. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(5-methyl-isoxazol-3-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 20 or its obvious chemical equivalents.
45. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(6-methoxy-pyridazin-3-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 21 or its obvious chemical equivalents.
46. N-[4-[Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(pyridin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 22 or its obvious chemical equivalents.
47. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-Nl-[4-(4-isopropyl-pyrimidin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 23 or its obvious chemical equivalents.
48. N-[4-Amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl]-N'-[4-(3-methoxy-pyrazin-2-yl)-sulfonamido]-phenyl-acetamidine and its pharmacologically acceptable salts with acids, whenever obtained by a process according to claim 24 or its obvious chemical equivalents.
Applications Claiming Priority (2)
| 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 |
| DEP2732029.2 | 1977-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1129410A true CA1129410A (en) | 1982-08-10 |
Family
ID=6014014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA307,427A Expired CA1129410A (en) | 1977-07-15 | 1978-07-14 | 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 EP EP78100184A patent/EP0000336B1/en not_active Expired
- 1978-06-19 DE DE7878100184T patent/DE2860614D1/en not_active Expired
- 1978-07-03 IL IL55063A patent/IL55063A0/en unknown
- 1978-07-05 IT IT25382/78A patent/IT1096976B/en active
- 1978-07-05 IE IE1354/78A patent/IE47022B1/en unknown
- 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 AT AT513078A patent/AT360999B/en not_active IP Right Cessation
- 1978-07-14 DK DK315878A patent/DK143273C/en not_active IP Right Cessation
- 1978-07-14 ZA ZA00784012A patent/ZA784012B/en unknown
- 1978-07-14 NO NO782455A patent/NO782455L/en unknown
- 1978-07-14 CA CA307,427A patent/CA1129410A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| IE47022B1 (en) | 1983-11-30 |
| EP0000336B1 (en) | 1981-04-15 |
| HU179408B (en) | 1982-10-28 |
| DK143273B (en) | 1981-08-03 |
| IE781354L (en) | 1979-01-15 |
| EP0000336A1 (en) | 1979-01-24 |
| ATA513078A (en) | 1980-07-15 |
| NO782455L (en) | 1979-01-16 |
| ZA784012B (en) | 1979-08-29 |
| AU520820B2 (en) | 1982-03-04 |
| FI782221A (en) | 1979-01-16 |
| AU3790378A (en) | 1980-01-17 |
| DK315878A (en) | 1979-01-16 |
| JPS5419986A (en) | 1979-02-15 |
| IL55063A0 (en) | 1978-09-29 |
| DE2732029A1 (en) | 1979-02-01 |
| DE2860614D1 (en) | 1981-05-07 |
| AR227759A1 (en) | 1982-12-15 |
| IT7825382A0 (en) | 1978-07-05 |
| IT1096976B (en) | 1985-08-26 |
| AT360999B (en) | 1981-02-10 |
| DK143273C (en) | 1981-11-30 |
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