CA1088063A - Derivatives of thiazolo-[3,2-a]pyrimidin-7-one and thiadiazolo-[3,2-a]pyrimidin-7-one - Google Patents
Derivatives of thiazolo-[3,2-a]pyrimidin-7-one and thiadiazolo-[3,2-a]pyrimidin-7-oneInfo
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- CA1088063A CA1088063A CA278,986A CA278986A CA1088063A CA 1088063 A CA1088063 A CA 1088063A CA 278986 A CA278986 A CA 278986A CA 1088063 A CA1088063 A CA 1088063A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
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Abstract
ABSTRACT OF THE DISCLOSURE
Compounds, and procedure for their preparation, of general formula wherein: R represents hydrogen, a pharmaceutically acceptable cation, or an alkyl group of 1 to 5 carbon atoms; X represents nitrogen or the group R2?;
and R1 and R2, subject to certain restrictions, represent hydrogen, alkyl radicals of 1 to 5 carbon atoms; aralkyl, phenyl, thienyl or pyridyl group optionally substituted by halogen, alkyl or alkoxy radicals of up to 4 carbon atoms, or cycloalkyl radicals of 5 to 7 carbon atoms, and pharmaceutically acceptable salts thereof. These compounds have been found to stimulate the immune system, and are thus of use in treating a number of situations, typical of which is a virus infection.
Compounds, and procedure for their preparation, of general formula wherein: R represents hydrogen, a pharmaceutically acceptable cation, or an alkyl group of 1 to 5 carbon atoms; X represents nitrogen or the group R2?;
and R1 and R2, subject to certain restrictions, represent hydrogen, alkyl radicals of 1 to 5 carbon atoms; aralkyl, phenyl, thienyl or pyridyl group optionally substituted by halogen, alkyl or alkoxy radicals of up to 4 carbon atoms, or cycloalkyl radicals of 5 to 7 carbon atoms, and pharmaceutically acceptable salts thereof. These compounds have been found to stimulate the immune system, and are thus of use in treating a number of situations, typical of which is a virus infection.
Description
1~138~63 This invention relates to a process for the manufacture of new heterocyclic compounds corresponding to the formula COOR
~ S / ~ N ~ O I
in which X represents a nitrogen atom or the group R2-C, R represents hydrogen, a pharmaceutically acceptable cation or an aIkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different and, (with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and that X cannot represent a nitrogen atom when R1 is a methyl group), represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or araIkyl, phenyl, thienyl or pyridyl 10 radicals optionally substituted by halogen atoms~ aIkyl or alkoxy radicals with up to 4 carbon atoms in the aIkyl radical, or cycloaIkyl radicals con-taining 5 to 7 carbon atoms, and pharmaceutically acceptable salts of these compounds.
When it represents an alkyl radical, R preferably contains 1 or 2 atoms.
The aralkyl radicals in question are, in particular, the benzyl and phenyl ethyl radicals.
In cases where at least one of the substituents Rl and R2 contain halogen atoms, the halogen atoms in question are preferably fluorine, chlorine, or bromine atoms.
It has surprisingly been found that the compounds of formula I show pronounced activity in stimulating the immune system and, by virtue of this property, are valuable therapeutic agents for diseases where an increase in the body's defences is required, especially when the immunity of the diseased organism is disturbed or inadequately developed. ~xamples of diseases such as 10~8063 these which can be treated with the medicaments according to the invention are virus infections, bacterial infections, systemic Lupus erythematodes, tumours, also for preventing metastasis, etc.
The immunity-stimulating effect was experimentally determined as follows:
a) Study of phagocytosis performances _ vitro:
Doses of 1, 5, lO and 15 mg of 3-phenyl-7H-thiazolo{~2a]-pyrimidin-7-one-5-carboxylic acid ethyl ester (hereinafter referred to as "substance A") per kg of body weight are orally administered to groups of 20 mice. The mice thus treated together with 20 untreated control animals are then killed and the peritoneal macrophages and polymorphonuclear leucocytes are flushed out from the abdominal cavity with tissue culture media. The cells are washed, adjusted to the same number per volume in the individual samples and incubated for 1~ 2 and 3 hours either with latex particles or with pathogenic staphyl-ococcii. The cells are then washed again, applied to specimen holders and coloured. The phagocytosis index is determined by counting out the cells laden with latex particles or with staphylococcii in relation to the free cells.
It is also possible to inject the test animals intraperitoneally with the test substance in the various doses 1 hour before the beginning of the test and then to proceed in the manner described above.
In either way, an impressive increase in phagocytosis is obtained by administering substance A, values of up to about 150% of the phagocytosis indexes determined on cells of untreated control animals being observed.
b) Study of the phagocytosis performance in vivo:
Groups of 20 mice are pretreated with substance A in the same way as described in a). 3 days after the substance has been administered, the test animals are injected intraperitoneally with latex particles or staphyl-ococcii. The animals are then killed in corresponding sub-groups 1, 2 and 3 hours after the injection of these particles to be phagocytosed. The peritone-al cells are removed, washed, applied to specimen holders by means of a cytocentrifuge and subsequently coloured. By determining the phagocytosis indexes, the phagocytosis~stimulating influence of substance A was confirmed by this method, too.
; Corresponding results were also obtained when the substance mention-ed above was replaced by other compounds corresponding to formula I such as, for example, 2-methyl-3-phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester, 3-(~-tolyl)-7H-thiazolo-[3,2-a~-pyrimidin-7-one-5-carboxylic acid ethyl ester, 2-methyl-3-(~-bromophenyl~-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester, etc.
c) Stimulation of immunoglobulin~G-receptor activity on the macrophage surface:
Single doses of 0.1, 1 or 10 mg of the substance to be tested per kg of body weight are administered subcutaneously to groups of female mice weigh-ing between 18 and 20 g. After 24 hours, the animals are killed and the peritoneal macrophages are flushed out from the abdominal cavity with a cell culture medium containing 10~ of calf's serum, adjusted to a density of 10 cells/ml, placed in Petri dishes (5 cm in diameter) in volumes of 3 ml and incubated in an incubation cabinet for 4 hours at 37 C. The cells which do not adhere to the glass are carefully washed off with cell culture medium. There-after 3 ml of a 0.1% suspension of human erythrocytes of blood group Al are introduced into each Petri dish. [These erythrocytes had been previously incubated for 30 minutes at room temperature with the serum (diluted with cell culture medium in a ratio of 1 : 50) of 80-day-old female C 57 BL/10-mice, whereby they were charged with the specific "natural" antibody formed by the female C 57 BL/10-mouse]. The macrophages adhering to the Petri dish bind the human erythrocytes thus pretreated to different extents, depending upon the immunoglobulin-&-receptor activity at their surface.
~0t~63 -It was found that the macrophages of animals pretreated with the substances of formula I bind significantly more (antibody-laden) erythrocytes than the macrophages of untreated animals, the differencesoften amounting to several hundred percent.
In order to demonstrate the effec+s against virus infections, mice were infected with hepatitis viruses (murine) and, 24 hours laterg were treated with test substances in the single (oral) doses shown in the following Table. The survival rates quoted in the Table were obtained for the treated animals, whilst from 80 to 100 % of untreated, infected control animals died:
. . .
R Rl X R2 Dose % surviving (mg/kg) animals C2H5 H R2~C,- ~ O.5 60 - 70 2H5 CH3 R2-,C,- ~ 0.5 60 2H5 H R2-Cn- CH3 ~ 1.0 50 2H5 H R2-C- C2H ~ 1.0 60 2H5 CH3 R2-,C,- Br ~ 0.1 50 H3 H N 0.1 60 ~2~5 ~ ~ ~ 50 - 60 These test results demonstrate the surprising therapeutic value of the compounds corresponding to formula I, especially for the treatment of virus infections as well. The compounds of formula I may be incorporated into medicaments contain-ing one or more active principles of formula I in such a quantity that the daily dose amounts so up to approximately 1500 mg and preferably to between 25 and 500 mg. The treatment is best carried out with 2 to 3 single doses per day. Suitable formulations for oral administration are standard tablets, ~0~1063 dragees, syrups, drops and other pharmaceutical formulations commonly used for oral therapy, including for example those from which the active principles are released with delay.
However, the compounds of formula I may also be applied as ingredi-ents of suppositories produced in the usual way.
Since the compounds of formula I, particularly when R represents a pharmaceutically acceptable cation, are readily soluble in water and represent adequately stable sterile, injectable solutions of these active principles can be prepared and administered.
Other pharmaceutical formulations of the compounds of formula I
include sprays, especially for intranasal application.
The compounds corresponding to formula I are obtained by reacting a 2-aminothiazole or 2-amino-1,3,4-thiadiazole corresponding to the formula Rl S NH2 in which R1 and X have the same meaning as above, with an acetylene dicarboxy-lic acid dialkyl ester derived from an aIkanol containing from 1 to 5 carbon atoms.
In cases where the group ~COOR in a compound of formula I is intend-ed to represent a carboxyl group or a salt derived therefrom, whilst R
represents an aIkyl radical containing from 1 to 5 carbon atoms, it is readily possible to saponify the ester group then present and optionally to convert the resulting compound of formula I containing a free carboxyl group into pharmaceutically useable salts by reaction with suitable bases. Salts such as these are, in particular, aIkali, alkaline earth and ammonium salts of the compounds of formula I.
The compounds of formula I are capable for forming salts with acids, ~0~38063 particularly when R represents an alkyl radical containing from 1 to 5 carbon atoms. Pharmaceutically acceptable salts such as these are, for example the formates, acetates, propionates, hydrochlorides, hydrobromides, sulphates, phospha~es, etc. The reaction of the compound of formula II with the acety-lene dicarboxylic acid dialkyl ester is carried out in the presence of a solvent or suspending agent, optionally at elevated temperature. Suitable solvents or suspending agents, are for example, lower aliphatic alcohols, especially methanol, ethanol and propanols, acetic acid ethyl or propyl ester, acetonitrile, tetrahydrofuran, dioxane, chlorobenzene or dimethyl formamide, etc. If at least one of the radicals R1 and R2 represents a pyridyl radical, the condensation reaction is best carried out in the presence of at least 1 mole of an acid, preferably acetic acid. It is also possible with advantage initially to react the reactants in ethanol for example and then to complete the ring-closing reaction by heating in a solvent of higher boiling point, for example chlorobenzene.
The formation of resin-like, dark coloured by-products can be largely avoided by working in the absence of light and air.
The production of the compounds is illustrated by the following non-limiting Examples in which no importance was attached to the production of optimum yields. All the temperatures quoted are uncorrected.
, 17.6 g of 2-amino-4-phenylthiazole are dissolved in 100 ml of tetra-hydrofuran, the resulting solution is cooled to approximately 15 C and 17.5 g of acetylene dicarboxylic acid diethyl ester are slowly added to it with stirring at that temperature. The mixture is left standing for 3 days, after which the crystals formed are filtered off the quantity of which was increased by concentrating the mother liquor to approximately half its original volume and recrystallized from ethanol. 3-Phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester is thus obtained inayield of 16.9 g, corresponding to 56.3% of the theoretical. Melting point: 173 - 17S C.
C H N S
calculated: 60.0~ 4.03% 9.34% 10.6%
observed: 59~7% 4.30% 9.60~ 10.5%
3-Phenyl-?H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester, which melts at 195 - 199C with decomposition, is similarly obtained from acetylene dicarboxylic acid dimethyl ester.
.
The procedure is as in Example 1, except that 19 g of 2-amino-4-phenyl-5-methylthiazole are used. 2-Methyl-3-phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 161 to 163 C after recrystallization from ethyl acetate is obtained in this way.
C H N
calculated: 61.1% 4.49% 8.92%
observed: 60.7% 4.46% 8.61%
. . _ .
The procedure is as in Example 1, except that ethanol is used as i 20 solvent in place of tetrahydrofuran, the air is displaced from the reaction vessel by nitrogen and the reaction mixture is stored in darkness. In this way, the product is obtained in substantially pure form in a yield of 86.4%
of the theoretical.
9O5 g of 2-amino-4-(~-tolyl)-thiazole are reacted with 8.7 g of acetylene dicarboxylic acid diethyl ester in 100 ml of tetrahydrofuran in the same way as described in Example lo The reaction mixture is concentrated, the residue is dissolved in ethylacetate and ligroin is added to the resulting solution. 3-(p-Tolyl)-7H-thiazolo-[3,2-a-]pyrimidin-7-one-5-carboxylic acid ~0~t3063 ethyl ester melting at 122 - 125 C (decomposition) is obtained.
C16H14N23S (314-37) C H N S
calculated: 61.1% 4.49% 8.92% 10.18%
observed: 60.7% 4.60% 8.67% 9.87%
The procedure is as in Example 1, except that 9.4 g of 2-amino-4-(~-bromophenyl)-5-methyl thiazole and 5.95 g of acetylene dicarboxylic acid diethyl ester are used. 3-(~-Bromophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 217 to 220C (decomposition) is obtained.
C16H13BrN203S (393.27) C H N S ~ --^
calculated: 48.75% 3.33% 7.12% 8.13%
observed: 48.75% 3.30% 6.85~ 8.02%
The reaction of 12.2 g of 2-amino-4-(21,4l-dichlorophenyl)-thiazole with 8.5 g of acetylene dicarboxylic acid diethyl ester in the presence of 150 ml of ethanol in accordance with Example 3 gives 3-(2',4'-dichlorophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester which melts at 189 - 192 C with decomposition.
C H N S
calculated: 48.78% 2.72% 7.57% 8.67~
observed: 48O82% 2.75% 7.56% 8.53%
10 g of 2-amino-4-(41-ethylphenyl)-thiazole are dissolved in 50 ml of ethanol and 8.4 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. After standing overnight, the mixture is concentrated by evaporation in vacuo to dryness at a bath temperature of 40 to 50 CO 50 ml 108~063 of chlorobenzene are added to the residue, followed by heating under reflux for 1 hour. After concentration by evaporation in vacuo, the residue is dissolved in ether, treated with carbon, filtered and petroleum ether subse-quently added. The product precipitating is washed with a little ether and dried. 3-(4~-Ethylphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 142 - 144 G is thus obtained.
C H N S
calculated: 62.17% 4.91% 8.53% 9.75%
observed: 62.04% 4.83% 8.26% 9.46 8.5 g of 2-amino-4-(3',4'-dimethoxyphenyl)-thiazole and 6.1 g of acetylene dicarboxylic acid diethyl ester are introduced into 100 ml of ethanol. After the air in the reaction vessel has been displaced by nitrogen, the mixture is heated to approximately 50 C until aclear solution is obtained.
After standing for 2 days at room temperature, the solution thus obtained is concentrated in vacuo to dryness. The residue is washed with ethylacetate and then with ether and subsequently dried. The 3-(3~,4~-dimethoxyphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester thus obtained melts at 172 to 174 C with decomposition.
12 16 2 5 ( ) C H N S
calculated: 56.65% 4.47% 7.78% 8.88~
observed: 55.93% 4.84% 7.51% 8.80%
,,~IE 9 A mixture of 12.8 g of 2-amino-4,5~-dimethylthiazole, 150 ml of ethanol and 17 g of acetylene dicarboxylic acid diethyl ester is heated to approximately 30 C, producing a weakly exothermic reactionO The mixture is left standing overnight, subsequently concentrated in vacuo to dryness and the residue is boiled for 1 hour with 100 ml of chlorobenzene. After concentration _ g _ )63 by evaporation in vacuo, the residue is treated with ethylacetate, crystalliz-ation occurring. The product is filtered off under suction, washed with ether and dried. The 2,3-dimethyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained melts at 140 to 142 C.
CllH12N23S (252.3) C H N S
calculated: 52.35% 4.79~0 11.09% 12.69%
observed: 52.43% 4.72% 10.97% 12.93%
100 ml of tetrahydrofuran are added to 10.1 g of 2-amino-1,3~4-thiadiazole, followed by the gradual introduction of 14.2 g of acetylene dicarboxylic acid dimethyl ester. The reaction mixture is left standing for 3 days, resulting in the formation of a clear, yellow coloured solution~ The solution thus formed is concentrated by evaporation in vacuo to dryness.
Recrystallization of the residue from ethylacetate gives 7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5- carboxylic acid methyl ester melting at 134C with decomposition.
C H N S
calculated: 39.80% 2.39% 19.90% 15.18%
observed: 39.70% 2.44% 19.65% 15.11%
E~A~LE 11 A mixture of 10 g of 2-amino-5-phenyl_1,3,4-thiadiazole, 100 ml of ethanol and 9.6 g of acetylene dicarboxylic acid diethyl ester is heated in a water bath until a clear solution has formed. 2-Phenyl-7H-1,3,4-thiadiazolo-[3,2-a]- pyrimidin-7-one-5-carboxylic acid ethyl ester crystallizes out on standing overnight, being filtered off under suction and washed with a little ethanol Melting point 169 - 172 C.
_ 10 --101~3063 C H N S
calculated: 55.80% 3.68% 13.95% 10O64%
observed: 55.65% 3.80% 14.00% 10.87%
11.5 g of 2-amino-5-(~-methoxyphenyl)-1,3,4-thiadiazole are reacted with 9.5 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol in the same way as described in Example 11. 7 g of the crude 2-(~-methoxy-phenyl~-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained, melting at 216 - 218 C, are introduced into a solution of 1.3 g of potassium hydroxide in 200 ml of ethanol. The reaction mixture is briefly boiled and then left standing overnight. The crystals precipitated are dissolved by the addition of water. After acidification with hydrochloric acid to approximately pH 2, the crystals are filtered off under suction, washed with water and dried. 2-(~-Methoxyphenyl)-7H-1,3,4-thiadiazolo-[3~2-a]-pyrimidin-7-one-5-carboxylic acid melting with decomposition at 227 - 230 C
is thus obtained.
C H N S
calculated: 51.53% 2.99% 13.87% 10.58%
observed: 51.16% 3.04% 13.61% 10.57%
The procedure is as in Example 12, except that 13.2 g of 2-amino-5-(3',4'-dimethoxyphenyl)-1,3,4-thiadiazole are used instead of 2-amino-5-(~-methoxyphenyl)-1,3,4-thiadiazole, 2-(3',4'-dimethoxyphenyl)-7H-1,3,4-thiadia-zolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ultimately being obtained.
Melting point: 150 C with decomposition.
C H N S
calculated: 50.40% 3.33% 12.62% 9.62%
observed: 49.95% 3.40% 12.74% 9~43%
_............................................................. !
The reaction of 9.7 g of 2-amino-5(3',4',5'-trimethoxyphenyl)-1,3,4-thiadiazole with 6.2 g of acetylene dicarboxylic acid dimethyl ester in 200 ml of ethanol in accordance with Example 12 gives 2-(3~,4',5'-trimethoxyphenyl) -7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester which, as a crude product, melts at 205 - 207C with decomposition and which is converted as described in Example 12 into the corresponding free acid melting at 220 - 223 C with decomposition.
C H N S
calculated: 49.57% 3.61% 11.57% 8.83%
observed: 49.36% 4.00~ 11.21% 9.09%
A mixture of 4.5 g of 2-amino-5-(thienyl-2')-],3,4-thiadiazole, 100 ml of 95% ethanol and 4.2 g of acetylene dicarboxylic acid diethyl ester is left standing overnight, subsequently boiled for 30 minutes and then left to cool. The product is filtered off under suction~ recrystallized from ethanol and finally washed with ether and dried. 2-(Thienyl-2~)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is obtained in the form of its monohydrate. Melting point: 184 - 186 C with decomposition.
C H N S
calculated: 44.30% 3.39% 12.92% 19.72%
observed: 43.87% 3.71% 12.87% 19.13%
A mixture of 6.5 g of 2-amino-5-(pyridyl-4~)-1,3,4-thiadiazole, 100 ml of glacial acetic acid and 6.3 g of acetylene dicarboxylic acid diethyl ester is briefly heated to 60 C and then left standing for 1 day. After con~
centration by evaporation to dryness, the residue is treated with a little ethylacetate, filtered under suction and recrystallized from a little ethanol.
~ S / ~ N ~ O I
in which X represents a nitrogen atom or the group R2-C, R represents hydrogen, a pharmaceutically acceptable cation or an aIkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different and, (with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and that X cannot represent a nitrogen atom when R1 is a methyl group), represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or araIkyl, phenyl, thienyl or pyridyl 10 radicals optionally substituted by halogen atoms~ aIkyl or alkoxy radicals with up to 4 carbon atoms in the aIkyl radical, or cycloaIkyl radicals con-taining 5 to 7 carbon atoms, and pharmaceutically acceptable salts of these compounds.
When it represents an alkyl radical, R preferably contains 1 or 2 atoms.
The aralkyl radicals in question are, in particular, the benzyl and phenyl ethyl radicals.
In cases where at least one of the substituents Rl and R2 contain halogen atoms, the halogen atoms in question are preferably fluorine, chlorine, or bromine atoms.
It has surprisingly been found that the compounds of formula I show pronounced activity in stimulating the immune system and, by virtue of this property, are valuable therapeutic agents for diseases where an increase in the body's defences is required, especially when the immunity of the diseased organism is disturbed or inadequately developed. ~xamples of diseases such as 10~8063 these which can be treated with the medicaments according to the invention are virus infections, bacterial infections, systemic Lupus erythematodes, tumours, also for preventing metastasis, etc.
The immunity-stimulating effect was experimentally determined as follows:
a) Study of phagocytosis performances _ vitro:
Doses of 1, 5, lO and 15 mg of 3-phenyl-7H-thiazolo{~2a]-pyrimidin-7-one-5-carboxylic acid ethyl ester (hereinafter referred to as "substance A") per kg of body weight are orally administered to groups of 20 mice. The mice thus treated together with 20 untreated control animals are then killed and the peritoneal macrophages and polymorphonuclear leucocytes are flushed out from the abdominal cavity with tissue culture media. The cells are washed, adjusted to the same number per volume in the individual samples and incubated for 1~ 2 and 3 hours either with latex particles or with pathogenic staphyl-ococcii. The cells are then washed again, applied to specimen holders and coloured. The phagocytosis index is determined by counting out the cells laden with latex particles or with staphylococcii in relation to the free cells.
It is also possible to inject the test animals intraperitoneally with the test substance in the various doses 1 hour before the beginning of the test and then to proceed in the manner described above.
In either way, an impressive increase in phagocytosis is obtained by administering substance A, values of up to about 150% of the phagocytosis indexes determined on cells of untreated control animals being observed.
b) Study of the phagocytosis performance in vivo:
Groups of 20 mice are pretreated with substance A in the same way as described in a). 3 days after the substance has been administered, the test animals are injected intraperitoneally with latex particles or staphyl-ococcii. The animals are then killed in corresponding sub-groups 1, 2 and 3 hours after the injection of these particles to be phagocytosed. The peritone-al cells are removed, washed, applied to specimen holders by means of a cytocentrifuge and subsequently coloured. By determining the phagocytosis indexes, the phagocytosis~stimulating influence of substance A was confirmed by this method, too.
; Corresponding results were also obtained when the substance mention-ed above was replaced by other compounds corresponding to formula I such as, for example, 2-methyl-3-phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester, 3-(~-tolyl)-7H-thiazolo-[3,2-a~-pyrimidin-7-one-5-carboxylic acid ethyl ester, 2-methyl-3-(~-bromophenyl~-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester, etc.
c) Stimulation of immunoglobulin~G-receptor activity on the macrophage surface:
Single doses of 0.1, 1 or 10 mg of the substance to be tested per kg of body weight are administered subcutaneously to groups of female mice weigh-ing between 18 and 20 g. After 24 hours, the animals are killed and the peritoneal macrophages are flushed out from the abdominal cavity with a cell culture medium containing 10~ of calf's serum, adjusted to a density of 10 cells/ml, placed in Petri dishes (5 cm in diameter) in volumes of 3 ml and incubated in an incubation cabinet for 4 hours at 37 C. The cells which do not adhere to the glass are carefully washed off with cell culture medium. There-after 3 ml of a 0.1% suspension of human erythrocytes of blood group Al are introduced into each Petri dish. [These erythrocytes had been previously incubated for 30 minutes at room temperature with the serum (diluted with cell culture medium in a ratio of 1 : 50) of 80-day-old female C 57 BL/10-mice, whereby they were charged with the specific "natural" antibody formed by the female C 57 BL/10-mouse]. The macrophages adhering to the Petri dish bind the human erythrocytes thus pretreated to different extents, depending upon the immunoglobulin-&-receptor activity at their surface.
~0t~63 -It was found that the macrophages of animals pretreated with the substances of formula I bind significantly more (antibody-laden) erythrocytes than the macrophages of untreated animals, the differencesoften amounting to several hundred percent.
In order to demonstrate the effec+s against virus infections, mice were infected with hepatitis viruses (murine) and, 24 hours laterg were treated with test substances in the single (oral) doses shown in the following Table. The survival rates quoted in the Table were obtained for the treated animals, whilst from 80 to 100 % of untreated, infected control animals died:
. . .
R Rl X R2 Dose % surviving (mg/kg) animals C2H5 H R2~C,- ~ O.5 60 - 70 2H5 CH3 R2-,C,- ~ 0.5 60 2H5 H R2-Cn- CH3 ~ 1.0 50 2H5 H R2-C- C2H ~ 1.0 60 2H5 CH3 R2-,C,- Br ~ 0.1 50 H3 H N 0.1 60 ~2~5 ~ ~ ~ 50 - 60 These test results demonstrate the surprising therapeutic value of the compounds corresponding to formula I, especially for the treatment of virus infections as well. The compounds of formula I may be incorporated into medicaments contain-ing one or more active principles of formula I in such a quantity that the daily dose amounts so up to approximately 1500 mg and preferably to between 25 and 500 mg. The treatment is best carried out with 2 to 3 single doses per day. Suitable formulations for oral administration are standard tablets, ~0~1063 dragees, syrups, drops and other pharmaceutical formulations commonly used for oral therapy, including for example those from which the active principles are released with delay.
However, the compounds of formula I may also be applied as ingredi-ents of suppositories produced in the usual way.
Since the compounds of formula I, particularly when R represents a pharmaceutically acceptable cation, are readily soluble in water and represent adequately stable sterile, injectable solutions of these active principles can be prepared and administered.
Other pharmaceutical formulations of the compounds of formula I
include sprays, especially for intranasal application.
The compounds corresponding to formula I are obtained by reacting a 2-aminothiazole or 2-amino-1,3,4-thiadiazole corresponding to the formula Rl S NH2 in which R1 and X have the same meaning as above, with an acetylene dicarboxy-lic acid dialkyl ester derived from an aIkanol containing from 1 to 5 carbon atoms.
In cases where the group ~COOR in a compound of formula I is intend-ed to represent a carboxyl group or a salt derived therefrom, whilst R
represents an aIkyl radical containing from 1 to 5 carbon atoms, it is readily possible to saponify the ester group then present and optionally to convert the resulting compound of formula I containing a free carboxyl group into pharmaceutically useable salts by reaction with suitable bases. Salts such as these are, in particular, aIkali, alkaline earth and ammonium salts of the compounds of formula I.
The compounds of formula I are capable for forming salts with acids, ~0~38063 particularly when R represents an alkyl radical containing from 1 to 5 carbon atoms. Pharmaceutically acceptable salts such as these are, for example the formates, acetates, propionates, hydrochlorides, hydrobromides, sulphates, phospha~es, etc. The reaction of the compound of formula II with the acety-lene dicarboxylic acid dialkyl ester is carried out in the presence of a solvent or suspending agent, optionally at elevated temperature. Suitable solvents or suspending agents, are for example, lower aliphatic alcohols, especially methanol, ethanol and propanols, acetic acid ethyl or propyl ester, acetonitrile, tetrahydrofuran, dioxane, chlorobenzene or dimethyl formamide, etc. If at least one of the radicals R1 and R2 represents a pyridyl radical, the condensation reaction is best carried out in the presence of at least 1 mole of an acid, preferably acetic acid. It is also possible with advantage initially to react the reactants in ethanol for example and then to complete the ring-closing reaction by heating in a solvent of higher boiling point, for example chlorobenzene.
The formation of resin-like, dark coloured by-products can be largely avoided by working in the absence of light and air.
The production of the compounds is illustrated by the following non-limiting Examples in which no importance was attached to the production of optimum yields. All the temperatures quoted are uncorrected.
, 17.6 g of 2-amino-4-phenylthiazole are dissolved in 100 ml of tetra-hydrofuran, the resulting solution is cooled to approximately 15 C and 17.5 g of acetylene dicarboxylic acid diethyl ester are slowly added to it with stirring at that temperature. The mixture is left standing for 3 days, after which the crystals formed are filtered off the quantity of which was increased by concentrating the mother liquor to approximately half its original volume and recrystallized from ethanol. 3-Phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester is thus obtained inayield of 16.9 g, corresponding to 56.3% of the theoretical. Melting point: 173 - 17S C.
C H N S
calculated: 60.0~ 4.03% 9.34% 10.6%
observed: 59~7% 4.30% 9.60~ 10.5%
3-Phenyl-?H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester, which melts at 195 - 199C with decomposition, is similarly obtained from acetylene dicarboxylic acid dimethyl ester.
.
The procedure is as in Example 1, except that 19 g of 2-amino-4-phenyl-5-methylthiazole are used. 2-Methyl-3-phenyl-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 161 to 163 C after recrystallization from ethyl acetate is obtained in this way.
C H N
calculated: 61.1% 4.49% 8.92%
observed: 60.7% 4.46% 8.61%
. . _ .
The procedure is as in Example 1, except that ethanol is used as i 20 solvent in place of tetrahydrofuran, the air is displaced from the reaction vessel by nitrogen and the reaction mixture is stored in darkness. In this way, the product is obtained in substantially pure form in a yield of 86.4%
of the theoretical.
9O5 g of 2-amino-4-(~-tolyl)-thiazole are reacted with 8.7 g of acetylene dicarboxylic acid diethyl ester in 100 ml of tetrahydrofuran in the same way as described in Example lo The reaction mixture is concentrated, the residue is dissolved in ethylacetate and ligroin is added to the resulting solution. 3-(p-Tolyl)-7H-thiazolo-[3,2-a-]pyrimidin-7-one-5-carboxylic acid ~0~t3063 ethyl ester melting at 122 - 125 C (decomposition) is obtained.
C16H14N23S (314-37) C H N S
calculated: 61.1% 4.49% 8.92% 10.18%
observed: 60.7% 4.60% 8.67% 9.87%
The procedure is as in Example 1, except that 9.4 g of 2-amino-4-(~-bromophenyl)-5-methyl thiazole and 5.95 g of acetylene dicarboxylic acid diethyl ester are used. 3-(~-Bromophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 217 to 220C (decomposition) is obtained.
C16H13BrN203S (393.27) C H N S ~ --^
calculated: 48.75% 3.33% 7.12% 8.13%
observed: 48.75% 3.30% 6.85~ 8.02%
The reaction of 12.2 g of 2-amino-4-(21,4l-dichlorophenyl)-thiazole with 8.5 g of acetylene dicarboxylic acid diethyl ester in the presence of 150 ml of ethanol in accordance with Example 3 gives 3-(2',4'-dichlorophenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester which melts at 189 - 192 C with decomposition.
C H N S
calculated: 48.78% 2.72% 7.57% 8.67~
observed: 48O82% 2.75% 7.56% 8.53%
10 g of 2-amino-4-(41-ethylphenyl)-thiazole are dissolved in 50 ml of ethanol and 8.4 g of acetylene dicarboxylic acid diethyl ester are added to the resulting solution. After standing overnight, the mixture is concentrated by evaporation in vacuo to dryness at a bath temperature of 40 to 50 CO 50 ml 108~063 of chlorobenzene are added to the residue, followed by heating under reflux for 1 hour. After concentration by evaporation in vacuo, the residue is dissolved in ether, treated with carbon, filtered and petroleum ether subse-quently added. The product precipitating is washed with a little ether and dried. 3-(4~-Ethylphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 142 - 144 G is thus obtained.
C H N S
calculated: 62.17% 4.91% 8.53% 9.75%
observed: 62.04% 4.83% 8.26% 9.46 8.5 g of 2-amino-4-(3',4'-dimethoxyphenyl)-thiazole and 6.1 g of acetylene dicarboxylic acid diethyl ester are introduced into 100 ml of ethanol. After the air in the reaction vessel has been displaced by nitrogen, the mixture is heated to approximately 50 C until aclear solution is obtained.
After standing for 2 days at room temperature, the solution thus obtained is concentrated in vacuo to dryness. The residue is washed with ethylacetate and then with ether and subsequently dried. The 3-(3~,4~-dimethoxyphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester thus obtained melts at 172 to 174 C with decomposition.
12 16 2 5 ( ) C H N S
calculated: 56.65% 4.47% 7.78% 8.88~
observed: 55.93% 4.84% 7.51% 8.80%
,,~IE 9 A mixture of 12.8 g of 2-amino-4,5~-dimethylthiazole, 150 ml of ethanol and 17 g of acetylene dicarboxylic acid diethyl ester is heated to approximately 30 C, producing a weakly exothermic reactionO The mixture is left standing overnight, subsequently concentrated in vacuo to dryness and the residue is boiled for 1 hour with 100 ml of chlorobenzene. After concentration _ g _ )63 by evaporation in vacuo, the residue is treated with ethylacetate, crystalliz-ation occurring. The product is filtered off under suction, washed with ether and dried. The 2,3-dimethyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained melts at 140 to 142 C.
CllH12N23S (252.3) C H N S
calculated: 52.35% 4.79~0 11.09% 12.69%
observed: 52.43% 4.72% 10.97% 12.93%
100 ml of tetrahydrofuran are added to 10.1 g of 2-amino-1,3~4-thiadiazole, followed by the gradual introduction of 14.2 g of acetylene dicarboxylic acid dimethyl ester. The reaction mixture is left standing for 3 days, resulting in the formation of a clear, yellow coloured solution~ The solution thus formed is concentrated by evaporation in vacuo to dryness.
Recrystallization of the residue from ethylacetate gives 7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5- carboxylic acid methyl ester melting at 134C with decomposition.
C H N S
calculated: 39.80% 2.39% 19.90% 15.18%
observed: 39.70% 2.44% 19.65% 15.11%
E~A~LE 11 A mixture of 10 g of 2-amino-5-phenyl_1,3,4-thiadiazole, 100 ml of ethanol and 9.6 g of acetylene dicarboxylic acid diethyl ester is heated in a water bath until a clear solution has formed. 2-Phenyl-7H-1,3,4-thiadiazolo-[3,2-a]- pyrimidin-7-one-5-carboxylic acid ethyl ester crystallizes out on standing overnight, being filtered off under suction and washed with a little ethanol Melting point 169 - 172 C.
_ 10 --101~3063 C H N S
calculated: 55.80% 3.68% 13.95% 10O64%
observed: 55.65% 3.80% 14.00% 10.87%
11.5 g of 2-amino-5-(~-methoxyphenyl)-1,3,4-thiadiazole are reacted with 9.5 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol in the same way as described in Example 11. 7 g of the crude 2-(~-methoxy-phenyl~-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained, melting at 216 - 218 C, are introduced into a solution of 1.3 g of potassium hydroxide in 200 ml of ethanol. The reaction mixture is briefly boiled and then left standing overnight. The crystals precipitated are dissolved by the addition of water. After acidification with hydrochloric acid to approximately pH 2, the crystals are filtered off under suction, washed with water and dried. 2-(~-Methoxyphenyl)-7H-1,3,4-thiadiazolo-[3~2-a]-pyrimidin-7-one-5-carboxylic acid melting with decomposition at 227 - 230 C
is thus obtained.
C H N S
calculated: 51.53% 2.99% 13.87% 10.58%
observed: 51.16% 3.04% 13.61% 10.57%
The procedure is as in Example 12, except that 13.2 g of 2-amino-5-(3',4'-dimethoxyphenyl)-1,3,4-thiadiazole are used instead of 2-amino-5-(~-methoxyphenyl)-1,3,4-thiadiazole, 2-(3',4'-dimethoxyphenyl)-7H-1,3,4-thiadia-zolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ultimately being obtained.
Melting point: 150 C with decomposition.
C H N S
calculated: 50.40% 3.33% 12.62% 9.62%
observed: 49.95% 3.40% 12.74% 9~43%
_............................................................. !
The reaction of 9.7 g of 2-amino-5(3',4',5'-trimethoxyphenyl)-1,3,4-thiadiazole with 6.2 g of acetylene dicarboxylic acid dimethyl ester in 200 ml of ethanol in accordance with Example 12 gives 2-(3~,4',5'-trimethoxyphenyl) -7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester which, as a crude product, melts at 205 - 207C with decomposition and which is converted as described in Example 12 into the corresponding free acid melting at 220 - 223 C with decomposition.
C H N S
calculated: 49.57% 3.61% 11.57% 8.83%
observed: 49.36% 4.00~ 11.21% 9.09%
A mixture of 4.5 g of 2-amino-5-(thienyl-2')-],3,4-thiadiazole, 100 ml of 95% ethanol and 4.2 g of acetylene dicarboxylic acid diethyl ester is left standing overnight, subsequently boiled for 30 minutes and then left to cool. The product is filtered off under suction~ recrystallized from ethanol and finally washed with ether and dried. 2-(Thienyl-2~)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is obtained in the form of its monohydrate. Melting point: 184 - 186 C with decomposition.
C H N S
calculated: 44.30% 3.39% 12.92% 19.72%
observed: 43.87% 3.71% 12.87% 19.13%
A mixture of 6.5 g of 2-amino-5-(pyridyl-4~)-1,3,4-thiadiazole, 100 ml of glacial acetic acid and 6.3 g of acetylene dicarboxylic acid diethyl ester is briefly heated to 60 C and then left standing for 1 day. After con~
centration by evaporation to dryness, the residue is treated with a little ethylacetate, filtered under suction and recrystallized from a little ethanol.
2-(Pyridyl-4~)-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ~.o~ )63 ethyl ester melting at 185 - 187 C with decomposition is thus obtained.
C H N S
calculated: 51.65% 3~31~o 18.53% 10.60%
observed: 51.74% 3.27% 18~20~o 10.64%
8.9 g of 2-amino-5-(pyridyl-3')-1,3,4-thiadiazole, 50 ml of glacial acetic acid and 8.5 g of acetylene dicarboxylic acid dimethyl ester are heated in a boiling water bath until a clear solution has formed. The solution thus obtained is then filtered over carbon. It is then left standing overnight, boiled for 10 to 15 minutes and subsequently concentrated to dryness. The residue is treated with ethylacetate, as a result of which it crystallizes.
After recrystallization from a mixture of ethylacetate and ethanol (2:1), the 2-(pyridyl-3')-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained melts at 185 - 187C with decomposition.
C H N S
calculated: 51.65% 3.31% 18.53% 10~60~o observed: 51.79% 3.64% 18.38% 10.83%
2 g of 2-amino-5-benzyl-1,3,4-thiadiazole are introduced into 50 ml of ethanol, followed by the addition of 1.6 g of acetylene dicarboxylic acid diethyl ester. After standing overnight, the product is concentrated to dryness, 50 ml of chlorobenzene are added and the product is boiled for 1 hour. After concentration by evaporation, the residue is dissolved in ethyl-acetate, filtered and 2-benzyl-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is precipitated by the addition of ether and petroleum ether. Melting point: 116 - 118 CO
C H N S
calculated: 57.11% 4.16% 13~32% 10.15 observed: 56.99~ 4.13% 13.08% 9.98 _ 13 -:
.... . .. .
8.1 g of 2-amino-5-(~-phenylethyl)-1,3,4-thiadiazole are heated with 6.8 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol until a clear solution has formed. After standing overnight, the solution is con-centrated by evaporation to drynessO The residue crystallizes on triturating with ether. 2-(~-Phenylethyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 95 to 98 C is thus obtained.
C H N S
calculated: 58.33% 4.59~ 12.75% 9.73%
observed: 57.76~ 4.58% 12.61% 9.67%
It is also possible to obtain inter alia the following compounds of general formula I by the process described above, particularly in the Examples:
2-phenyl-3-methyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester
C H N S
calculated: 51.65% 3~31~o 18.53% 10.60%
observed: 51.74% 3.27% 18~20~o 10.64%
8.9 g of 2-amino-5-(pyridyl-3')-1,3,4-thiadiazole, 50 ml of glacial acetic acid and 8.5 g of acetylene dicarboxylic acid dimethyl ester are heated in a boiling water bath until a clear solution has formed. The solution thus obtained is then filtered over carbon. It is then left standing overnight, boiled for 10 to 15 minutes and subsequently concentrated to dryness. The residue is treated with ethylacetate, as a result of which it crystallizes.
After recrystallization from a mixture of ethylacetate and ethanol (2:1), the 2-(pyridyl-3')-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester thus obtained melts at 185 - 187C with decomposition.
C H N S
calculated: 51.65% 3.31% 18.53% 10~60~o observed: 51.79% 3.64% 18.38% 10.83%
2 g of 2-amino-5-benzyl-1,3,4-thiadiazole are introduced into 50 ml of ethanol, followed by the addition of 1.6 g of acetylene dicarboxylic acid diethyl ester. After standing overnight, the product is concentrated to dryness, 50 ml of chlorobenzene are added and the product is boiled for 1 hour. After concentration by evaporation, the residue is dissolved in ethyl-acetate, filtered and 2-benzyl-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester is precipitated by the addition of ether and petroleum ether. Melting point: 116 - 118 CO
C H N S
calculated: 57.11% 4.16% 13~32% 10.15 observed: 56.99~ 4.13% 13.08% 9.98 _ 13 -:
.... . .. .
8.1 g of 2-amino-5-(~-phenylethyl)-1,3,4-thiadiazole are heated with 6.8 g of acetylene dicarboxylic acid diethyl ester in 100 ml of ethanol until a clear solution has formed. After standing overnight, the solution is con-centrated by evaporation to drynessO The residue crystallizes on triturating with ether. 2-(~-Phenylethyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester melting at 95 to 98 C is thus obtained.
C H N S
calculated: 58.33% 4.59~ 12.75% 9.73%
observed: 57.76~ 4.58% 12.61% 9.67%
It is also possible to obtain inter alia the following compounds of general formula I by the process described above, particularly in the Examples:
2-phenyl-3-methyl-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester
3-(~-fluorophenyl)-7H-thiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester 7H-thiazolo-[3,2-a]- and 7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid propyl ester 3~4l-isobutyloxyphenyl)-7H-thiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester 2-(~-fluorophenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester 2-~-tolyl-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester 2-(4l-ethylphenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester 2-(4'-butoxyphenyl)-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester 2-(2',4'-dichlorophenyl)-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid methyl ester 2-cyclopentyl- and 2-cyclohexyl-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester 2-(~-chlorobenzyll-7H-1~3,4-thiadiazolo-[3,2-~1-pyrimidin-7-one-5-carboxylic acid ethyl ester 2-ethyl-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5_carboxy1ic acid ethyl ester 2-C~-butyl)-7H-1~3,4-thiadiazolo-[3~2-~ -pyrimidin-7-one-5-carboxylic acid methyl ester 2-(tert.-butyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid methyl ester 2-isopropyl-7H-1,3,4-thiadiazolo-[3,2-~ -pyrimidin-7-one-5-carboxylic acid ethyl ester and, from these esters, the corresponding acids.
_ 15 -
_ 15 -
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of new heterocyclic compounds corresponding to the general formula I
in which X represents a nitrogen atom or the group R2-?,R represents hydro-gen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different and, with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and X cannot be a nitrogen atom when R1 is a methyl group - represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or aralkyl, phenyl, thienyl or pyridyl radicals optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, or cycloalkyl radicals with 5 to 7 carbon atoms, and pharmaceutically acceptable salts of these compounds, wherein a compound corresponding to the formula II
in which R1 and X have the same meaning as above, is condensed with an acety-lene dicarboxylic acid dialkyl ester derived from an alkanol containing 1 to 5 carbon atoms, in the presence of a solvent or suspending agent, and the radical R is then replaced by hydrolysis by a hydrogen atom, and/or the com-pounds obtained are optionally converted into pharmaceutically acceptable salts.
in which X represents a nitrogen atom or the group R2-?,R represents hydro-gen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different and, with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and X cannot be a nitrogen atom when R1 is a methyl group - represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or aralkyl, phenyl, thienyl or pyridyl radicals optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, or cycloalkyl radicals with 5 to 7 carbon atoms, and pharmaceutically acceptable salts of these compounds, wherein a compound corresponding to the formula II
in which R1 and X have the same meaning as above, is condensed with an acety-lene dicarboxylic acid dialkyl ester derived from an alkanol containing 1 to 5 carbon atoms, in the presence of a solvent or suspending agent, and the radical R is then replaced by hydrolysis by a hydrogen atom, and/or the com-pounds obtained are optionally converted into pharmaceutically acceptable salts.
2. A process as claimed in Claim 1, wherein to produce compounds of formula I in which R1 and/or R2 represent a pyridine radical, reaction of the compound of formula II with the acetylene dicarboxylic acid ester is carried out in the presence of at least 1 mole of acid preferably acetic acid, per mole of the compound of formula II.
3. A process as claimed in Claim 1 for producing compounds corresponding to the formula Ia in which R represents hydrogen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms, R'1 and R'2 are the same or different and, with the proviso that R'1 cannot be hydrogen when R'2 is hydrogen or methyl, represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or phenyl or thienyl radicals optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, and pharmaceutically acceptable salts of these compounds, wherein a 2-aminothiazole corresponding to the formula IIa in which R'1 and R'2 have the same meaning as above, is condensed with an acetylene dicarboxylic acid dialkyl ester derived from an alkanol containing 1 to 5 carbon atoms in the presence of a solvent or suspending agent, the radical R is then optionally converted by hydrolysis by a hydrogen atom and/or the compounds obtained are optionally converted into pharmaceutically compat-ible salts.
4. A process as claimed in Claims 1 and 2 for producing compounds corresponding to the formula Ib in which R represents hydrogen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms and R?' represents hydrogen, an alkyl radical with 2 to 5 carbon atoms or an aralkyl, phenyl, thienyl or pyridyl radical optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, or a cycloalkyl radical with 5 to 7 carbon atoms, and pharmaceutically useable salts of these compounds, wherein a 2-amino-1,3,4-thiadiazole corresponding to the formula ]
in which R?' has the same meaning as above, is condensed with an acetylene dicarboxylic acid dialkyl ester derived from an alkanol containing 1 to 5 carbon atoms in the presence of a solvent or suspending agent, the radical R is then optionally converted by hydrolysis by a hydrogen atom and/or the compounds obtained are optionally converted into pharmaceutically compatible salts.
in which R?' has the same meaning as above, is condensed with an acetylene dicarboxylic acid dialkyl ester derived from an alkanol containing 1 to 5 carbon atoms in the presence of a solvent or suspending agent, the radical R is then optionally converted by hydrolysis by a hydrogen atom and/or the compounds obtained are optionally converted into pharmaceutically compatible salts.
5. Heterocyclic compounds of the formula I
in which X represents a nitrogen atom or the group R2-?, R represents hydro-gen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different, and with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and X can-not be a nitrogen atom when R1 is a methyl group - represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or aralkyl, phenyl, thienyl or pyridyl radicals optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, or cycloalkyl radicals with 5 to 7 carbon atoms, and/or pharmaceutically acceptable salts of these compounds, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
in which X represents a nitrogen atom or the group R2-?, R represents hydro-gen, a pharmaceutically acceptable cation or an alkyl radical with 1 to 5 carbon atoms, R1 and R2 are the same or different, and with the proviso that R1 cannot represent hydrogen when R2 is hydrogen or methyl and X can-not be a nitrogen atom when R1 is a methyl group - represent hydrogen, alkyl radicals with 1 to 5 carbon atoms or aralkyl, phenyl, thienyl or pyridyl radicals optionally substituted by halogen atoms, alkyl or alkoxy radicals with up to 4 carbon atoms in the alkyl radical, or cycloalkyl radicals with 5 to 7 carbon atoms, and/or pharmaceutically acceptable salts of these compounds, whenever prepared by the process of claim 1 or by an obvious chemical equivalent thereof.
6. Process as claimed in claim 1 when carried out at an elevated temperature.
7. Process as claimed in claim 1, when carried out under an inert atmosphere.
8. Process as claimed in claim 1, when carried out in the absence of light.
9. A process as claimed in claim 1 wherein R represents an acetylene dicarboxylic acid dialkyl ester derived from an alkanol having 1 to 2 carbon atoms is used.
10. Heterocyclic compounds of the formula I
in which X1, R1 and R2 have the same meaning as in claim 1, wherein R represents an alkyl radical with 1 or 2 carbon atoms, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
in which X1, R1 and R2 have the same meaning as in claim 1, wherein R represents an alkyl radical with 1 or 2 carbon atoms, whenever prepared by the process of claim 9 or by an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 in which X represents the group R2-C1" and R has the same meaning as in claim 1 and wherein R1 and R2 are the same or different and are benzyl or phenyl.
12. Heterocyclic compounds of the formula I
in which X represents the group R2-C1" and R has the same meaning as in claim 1, wherein R1 and R2 are the same or different and are benzyl or phenyl whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
in which X represents the group R2-C1" and R has the same meaning as in claim 1, wherein R1 and R2 are the same or different and are benzyl or phenyl whenever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.
13. A process as claimed in claim 1 in which X represents the group R2-C1" and R has the same meaning as in claim 1, wherein at least one of the substituents R1 and R2 is an aralkyl, phenyl, thienyl or pyridyl radical substituted by one or more fluorine, chlorine, or bromine atoms.
14. Heterocyclic compounds of the formula I
in which X represents the group R2-C1" and R has the same meaning as in claim 1, wherein at least one of the substituents R1 and R2 is an aralkyl, phenyl, thienyl or pyridyl radical substituted by one or more fluorine, chlorine or bromine atoms, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
in which X represents the group R2-C1" and R has the same meaning as in claim 1, wherein at least one of the substituents R1 and R2 is an aralkyl, phenyl, thienyl or pyridyl radical substituted by one or more fluorine, chlorine or bromine atoms, whenever prepared by the process of claim 13 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP2625117.2 | 1976-06-04 | ||
| DE19762625117 DE2625117A1 (en) | 1976-06-04 | 1976-06-04 | Thia(dia)zolo-(3,2-a)-pyrimidinone carboxylic acids - which stimulate the immunologic system, useful e.g. for treating virus infections |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088063A true CA1088063A (en) | 1980-10-21 |
Family
ID=5979809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA278,986A Expired CA1088063A (en) | 1976-06-04 | 1977-05-24 | Derivatives of thiazolo-[3,2-a]pyrimidin-7-one and thiadiazolo-[3,2-a]pyrimidin-7-one |
Country Status (7)
| Country | Link |
|---|---|
| AT (1) | AT351038B (en) |
| BE (1) | BE855334A (en) |
| CA (1) | CA1088063A (en) |
| DE (1) | DE2625117A1 (en) |
| DK (1) | DK142175C (en) |
| SE (1) | SE7706349L (en) |
| ZA (1) | ZA772502B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2755615A1 (en) * | 1977-12-14 | 1979-06-21 | Gruenenthal Gmbh | NEW HETEROCYCLIC COMPOUNDS, MEDICINAL PRODUCTS CONTAINING THESE PRODUCTS AND METHODS OF MANUFACTURING THEM |
-
1976
- 1976-06-04 DE DE19762625117 patent/DE2625117A1/en not_active Withdrawn
-
1977
- 1977-03-30 AT AT221377A patent/AT351038B/en not_active IP Right Cessation
- 1977-04-26 ZA ZA00772502A patent/ZA772502B/en unknown
- 1977-05-24 CA CA278,986A patent/CA1088063A/en not_active Expired
- 1977-05-31 SE SE7706349A patent/SE7706349L/en unknown
- 1977-06-02 BE BE178149A patent/BE855334A/en unknown
- 1977-06-03 DK DK247577A patent/DK142175C/en active
Also Published As
| Publication number | Publication date |
|---|---|
| DE2625117A1 (en) | 1977-12-15 |
| SE7706349L (en) | 1977-12-05 |
| DK142175B (en) | 1980-09-15 |
| DK247577A (en) | 1977-12-05 |
| ZA772502B (en) | 1978-04-26 |
| DK142175C (en) | 1981-02-09 |
| ATA221377A (en) | 1978-12-15 |
| AT351038B (en) | 1979-07-10 |
| BE855334A (en) | 1977-10-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |