Fused pyrimidine derivatives and compositions for treating atherosclerosis containing them

The present invention relates to new optionally racemic or optically active fused pyrimidine derivatives of the formula ##STR2## or the salts thereof, wherein N = 0, 1, 2 OR 3; M = 0, 1 OR 2
R stands for a hydrogen atom, optionally substituted amino, optionally substituted alkyl, optionally substituted hydroxyl, optionally substituted aryl, optionally substituted aralkyl, carboxyl or a group derived from the carboxyl group;
R.sup.1 stands for a hydrogen atom, an optionally substituted alkyl group or
R and R.sup.1 together form a --(CH .dbd. CH).sub.2 --chain, wherein the dotted line represents an optional valency bond;
R.sup.2 stands for a hydrogen atom, a hydroxyl, alkoxy, mercapto, O-acyl or an optionally substituted amino group;
R.sup.3 stands for a hydrogen atom, or optionally together with R.sup.2 represents a valency bond,
R.sup.4 and R.sup.5 undependently represent a hydrogen atom or together form a valency bond;
R.sup.6 stands for a hydrogen atom, an optionally substituted aryl, optionally substituted heterocyclic, or carboxyl group, a group derived from a carboxyl group or a trihalomethyl group;
R.sup.7 and R.sup.8 independently represent a hydrogen atom or together form a valency bond;
R.sup.9 stands for a hydrogen atom, an optionally substituted hydroxyl, optionally substituted amino, alkylthio, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, carboxyl group, a group derived from the carboxyl group, a heterocyclic group containing nitrogen being attached to the pyrimidine ring through a nitrogen atom,
R.sup.10 stands for a hydrogen atom, an optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted amino, carboxyl group, cyano group, a group derived from the carboxyl group, an optionally substituted acyl group; and
R.sup.9 and R.sup.10 together may form a --(CH.sub.2).sub.p --chain, wherein p represents a number from 3 through 10,
R.sup.11 stands for an oxygen or sulfur atom or an R.sup.12 --N.dbd. -group, wherein R.sup.12 represents a hydrogen atom or an acyl group.
A preferred feature of the invention includes compounds of Formula I wherein m is 0, n is 1, R is hydrogen or alkyl, R.sup.1 and R.sup.9 are each hydrogen, R.sup.10 is carboxy or a carboxy derivative, R.sup.11 is oxygen, R.sup.2, R.sup.3, R.sup.7 and R.sup.8 are the same as above.
The new optionally racemic or optically active fused pyrimidine derivatives provided by the invention and the salts thereof may be prepared according to the invention
(a) by reacting an optionally racemic fused pyrimidine derivative of the formula ##STR3## wherein R, R.sup.1, R.sup.9, R.sup.10, R.sup.11, n and the dotted line have the same meaning as defined above, with an aldehyde of the formula
R.sup.6 -- (CH .dbd. CH).sub.m -- CHO (III)
wherein R.sup.6 and m have the same meaning as defined above, and optionally transforming the thus obtained fused pyrimidine derivative of the formula I, in which R.sup.4 and R.sup.5 as well as R.sup.7 and R.sup.8, respectively together form a chemical bond and R.sup.2 stands for a hydroxyl group, R.sup.3 stands for a hydrogen atom, by dehydration into a fused pyrimidine derivative of the formula I, in which R.sup.2 and R.sup.3 together form a valency bond; or
(b) by reacting an optionally optically active fused pyrimidine derivative of the formula II with an aldehyde derivative of the formula ##STR4## wherein R.sup.13 and R.sup.14 may be identical or different, thus may stand for a hydroxy, alkoxy, an optionally substituted amino, O-acyl or --SO.sub.3 Na group, or
R.sup.13 and R.sup.14 together may form a .dbd. S or .dbd. N--R.sup.15 group, wherein R.sup.15 represents a hydrogen atom, an alkyl or optionally substituted aryl group,
and optionally transforming the thus obtained optionally optically active fused pyrimidine derivative of the formula I, in which
R.sup.4 and R.sup.5 as well as R.sup.7 and R.sup.8, respectively together form a valency bond, and R.sup.2 represents a hydroxyl, alkoxy, optionally substituted amino, -O-acyl, mercapto group, R.sup.3 stands for a hydrogen atom, by splitting off a compound of the formula R.sup.2 H, wherein R.sup.2 stands for a hydroxyl, alkoxy, optionally substituted amino, -O-acyl, mercapto group, into an optionally optically active fused pyrimidine derivative of the formula I, in which R.sup.2 and R.sup.3 together form a valency bond, and if desired, by transforming groups R.sup.6, R.sup.9, R.sup.10 and R.sup.11 into other R.sup.6, R.sup.9, R.sup.10 and R.sup.11 groups, by per se known methods and/or by saturating the valency bonds formed by the attachment of R.sup.2 and R.sup.3, R.sup.4 and R.sup.5 as well as R.sup.7 and R.sup.8, respectively by hydrogenation in an optional order, gradually or simultaneously and optionally by transforming the thus obtained optionally optically active fused pyrimidine derivative of the formula I into its acid addition salts with a pharmaceutically acceptable inorganic or organic acid, or into its salts with a pharmaceutically acceptable inorganic or organic base and/or, if desired, setting it free from its salt or transforming it into an other salt of same, and if desired preparing optically active compounds of the formula I by resolution of the racemic compound of the formula I or by using optically active starting materials in step (a) or (b).
Process variants (a) and (b) can be performed in a suitable solvent or without any solvent, preferably at a temperature from -20.degree. C. to 250.degree. C.
As solvents there may be applied protic, apolar or dipolar aprotic solvents or the mixtures thereof.
Suitable protic solvents are for example the followings: alkanols having 1 to 6 carbon atoms, e.g. methanol, ethanol, iso-propanol, glycerin etc.; aliphatic carboxylic acids, e.g. formic acid, acetic acid; formamide etc.
As apolar solvents there may be used hydrocarbons, e.g. benzene, toluene, xylene etc.; chlorinated hydrocarbons, e.g. chloroform carbontetrachloride, chlorobenzene etc.; ethers, e.g. diethylether, tetrahydrofurane, dioxane etc.
As dipolar solvents there may be used dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, ketones, e.g. acetone, ethyl methyl ketone etc.; nitro benzene; aceto nitrile; hexamethyl phosphorous triamide etc.
The suitably chosen mixtures of the above-listed solvents can be also applied.
When accomplishing process variants (a) and (b) if desired, also basic or acidic catalysts can be used. Also the suitably chosen solvent itself may act as a catalyst. Thus solvents as acetic acid or formic acid may perform a double role, since they may act as acidic catalysts and as solvents at the same time.
Additionally acidic catalysts may be applied such as inorganic or organic acids, e.g. hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid etc.
As basic catalysts there may be used piperidine, diethyl amine and bifunctional catalysts such as piperidine acetate and pyridine, which are able to function as acidic and base catalysts as well.
If desired, the reaction of process variant (a) and (b) respectively can be conducted also in such a way that instead of the addition-products, i.e. the compounds of the formula I, in which R.sup.2 stands for a hydroxyl, mercapto, alkoxy, optionally substituted amino group and R.sup.3 stands for a hydrogen atom, the condensation-products, i.e. pyrimidine derivatives of the formula I in which R.sup.2 and R.sup.3 together form a valency bond, are obtained.
If required R.sup.6 can be transformed into a different R.sup.6 substituted by per se known methods. Thus, a carboxyl R.sup.6 may be transformed into the corresponding ester group with a suitable alcohol. The esterification may be carried out by the methods known in the art for this purpose. For example the reaction preferably can be accomplished by bubbling dry hydrogen chloride gas through the alcohol solution, when esterification takes place, or by heating the mixture of carboxylic acid and alcohol in the presence of concentrated sulphuric acid and eliminating the formed water by azeotropic distillation, with benzene or chloroform. A carboxyl R.sup.6 can be transformed, if desired, also to an acid amide through a suitable active ester, prepared by means of triethylamine or chloroformic acid, with ammonia or in N-substituted acid amide group with other amines.
If R.sup.6 stands for an ester group, it can be converted into another ester with a different kind of alcohol, preferably in the presence of hydrogen chloride, or can be transformed into an acid amide group with ammonia, for example in an alcohol solution, into a carbohydrazide group with hydrazine hydrate and into an N-substituted acid amide group with amines.
An optionally substituted acid amide group can be prepared also by transforming the carboxyl R.sup.6 into an acid halide group by means of thionyl chloride, phosphorous oxychloride, phosphorous pentachloride etc. and reacting the obtained compound with an optionally substituted amine or with ammonia.
If R.sup.6 stands for an acid amide group it can be transformed into a nitrile group by water. The water may be extracted for example using phosphorous oxychloride, phosphorous pentoxide, thionyl chloride etc.
If R.sup.6 represents a nitrile group, it can be transformed into an amidine group with ammonia, into an acid amide group with water and into a thioacid amide group with hydrogen sulphide.
If desired, an ester, acid amide or nitrile R.sup.6 may be transformed into a carboxy group by acidic or alkaline hydrolysis. The obtained carboxyl group, if desired, can be removed when a hydrogen atom remains. The decarboxylating reaction may be carried out under heating, preferably in quinoline, polyphosphoric acid etc.
The substituents represented by R.sup.9 can be transformed into different substituents by methods known in the art. For example the ester, acid amide and nitrile groups may be subjected to the above-described transformations.
If desired, also the substituents represented by R.sup.10 can be transformed into different substituents. For example if R.sup.10 stands for carboxyl, ester, acid amide or nitrile groups, it can be subjected to the transformations described in connection with R.sup.6.
If desired, the substituents represented by R.sup.11 can be transformed into a different substituent by methods known in the art. For example if R.sup.11 stands for an oxygen atom, it can be reacted with phosphorous pentasulphide in pyridine, when a sulphur atom is obtained; or if R.sup.11 represents an .dbd.NH group, it may be acylated with an acid halogenide or acid anhydride preparing an .dbd.N-acyl group; or an .dbd.N-R.sup.12 group represented by R.sup.11 can be transformed into an oxygen atom with alkaline hydrolysis.
The obtained compounds of the formula I, if desired, can be transformed into their salts with pharmaceutically acceptable acids. As acids there may be used for example hydrochloric acid, hydrogen bromide, sulphuric acid, phosphorous acid, lactic acid, tartaric acid, maleinic acid, nicotinic acid etc.
In the case that at least one of the substituents represented by R.sup.6, R.sup.9 or R.sup.10 is a carboxyl group or a group derived from a carboxyl acid also the salts of the compounds of the formula I prepared with bases can be prepared.
There can be advantageously prepared the salts of the compounds of the formula I formed with alkali metals, preferably with sodium, potassium; with alkali earth metals, preferably with calcium, magnesium, with aluminum, vanadium, ethylene diamine, 2-aminoethanol, 2-dimethylamino-ethanol, diidopropyl amine, etc.
The present invention includes also the geometric and optical isomers of the fused pyrimidine derivatives of the formula I.
The optically active compounds of the formula I can be prepared by subjecting a racemic compound of the formula I to resolution by methods known per se or by using an optically active starting material in reactions (a) or (b).
The term "optionally substituted hydroxyl group" as used herein and hereinbefore indicates a hydroxyl group, an alkoxy group having one to 6 carbon atoms, preferably a methoxy, ethoxy group, an aralkoxy group having 7 to 12 carbon atoms, preferably a benzyloxy group, an aryloxy group having 6 to 10 carbon atoms, preferably a phenoxy group.
The term "optionally substituted amino group" represents an amino group optionally bearing one or two identical or different substituents, such as an alkanoylamino group having one to 6 carbon atoms, preferably an acetylamino or propionylamino group, an aroylamino group having 6 to 10 carbon atoms, preferably a benzoylamino group, an alkylamino group having one to 6 carbon atoms, preferably a methylamino or ethylamino group, a dialkylamino group having 1 to 6 carbon atoms, in both alkyls, preferably a dimethylamino or diethylamino group, an aralkylamino group having 7 to 12 carbon atoms, preferably a benzylamino group, an arylamino group having 6 to 10 carbon atoms, preferably a phenylamino group, a piperidyl-pyrrolidinyl or a piperazinyl group.
The term "optionally substituted alkyl group" as used herein and hereinbelow means an alkyl group having one to 6 carbon atoms, preferably a methyl, ethyl, n-propyl group etc., which may bear one or more hydroxyl groups, preferably a 1-hydroxyl-ethyl group, carboxyl group or a group derived from a carboxyl acid e.g. alkoxycarbonyl, carboxamido, nitrile group etc.
The term "optionally substituted aryl group" as used herein represents a phenyl group optionally bearing one or more substituents selected from the following groups: alkyl having one to 6 carbon atoms, dialkylamino, nitro, alkoxy, methylendioxy, halogen, alkylthio having one to 6 carbon atoms, carboxyl group or a group derived from a carboxyl acid.
The term "optionally substituted aralkyl group" means an aralkyl group having 7 to 12 carbon atoms optionally substituted with one or more alkyl, alkoxy, halogen, amino, or nitro group.
The term "group derived from the carboxyl group" as used herein indicates an alkoxycarbonyl having one to 6 carbon atoms in the alkyl moiety, or aralkoxycarbonyl having 7 to 12 carbon atoms, optionally substituted aryloxycarbonyl having 6 to 10 carbon atoms, alkoxythiocarbonyl having one to 6 carbon atoms in the alkyl moiety, optionally substituted acid amide, acid hydrazide, optionally substituted amidine or nitrile.
The term "optionally substituted acid amide" as used herein means an acid amide, N-alkyl-, N,N-dialkyl-, N-phenylalkyl-, N-acyl-acid amide group.
The term "optionally substituted heterocyclic group" as used herein and herein below represents five-, six-or seven-membered monocyclic; nine-, ten- or eleven-membered bicyclic; or 14-membered tricyclic heterocyclic rings containing one or more oxygen, sulphur or nitrogen atom(s) optionally substituted with one or more of the following groups; alkyl having 1 to 6 carbon atoms, nitro, alkoxy, halogen, methylenedioxy, dialkylamino.
The heterocyclic ring is preferably a furane, pyrrol, pyridyl, quinolyl ring etc.
The optionally optically active compounds of the formula II used as starting materials may be prepared according to the procedures described in our Hungarian Pat. Nos. 156,119; 158,085; 162,384; 162,373; and 166,577 as well as in our Dutch Pat. No. 7,212,286 or with other similar methods.
The starting materials having the formulas III and IV are commercially available products.
As aldehydes of the formula III there may be used preferably benzaldehyde, isovanilline, vanilline, trimethoxy benzaldehyde, o-chloro-benzaldehyde, p-chloro-benzaldehyde, glyoxylic acid monohydrate, glyoxylic acid, methylenedioxy benzaldehyde, 5-nitro-2-furane-aldehyde, 2-thiophene-aldehyde, pyridine-3-aldehyde, pyridine-2-aldehyde, pyridine-4-aldehyde, cinnamon aldehyde, o-cinnamon-aldehyde, fluor-benzaldehyde, trifluoromethyl aldehyde, methyl benzaldehyde, furfurol, 2-pyrrol-aldehyde, 1-methyl-2-pyrrol-aldehyde, diethoxy benzaldehyde, bromo-benzaldehyde, hydroxy-benzaldehyde, veratrum aldehyde, anis aldehyde, salicyl aldehyde, dimethylamino benzaldehyde, nitro benzaldehyde, alkoxycarbonyl benzaldehyde, phthalic aldehyde, therephthalic aldehyde, formaldehyde, chloral, bromal etc.
As compounds of the formula IV there may be used for example a hemi-acetal, acetal, acylal, geminal diamine, geminal amino alcohol, Schiff-base, geminal glycol, aldehyde sodium bisulphite, aldehyde cyanohydrine.
The compounds of the formula I possess valuable pharmaceutical properties. They are especially effective against atherosclerosis, influencing not only the serum lipids, but decreasing the quantity of the lipids, deposited in vein walls, especially of cholesterin as well.
The compounds of the formula I have favorable toxical properties. The LD.sub.50 -value obtained on rabbits (p.o.) generally is over 2000 mg/kg.
The pharmaceutical activity of the compounds according to the invention was proved using various experimental set-ups. In the following Table I there are summarized the results obtained on cholesterin-fed rabbit atherosclerosis model (Beitr. path. Anat. 56, 379-403 (1913)).
It can be seen from the data of Table 1 that administration of compounds "C" and "D" result in a significant decrease of the serum lipid, aorta lipid and cholesterin lipid level as well.
Table 1______________________________________ Serum Aorta Dose total total mg/kg total choles- tri- total choles-Substance p.o. lipid terin glyceride lipid terin______________________________________Control-1 -- 658 326 75 1928 331Control-2 -- 2374 1504 103 2575 921Chlofibrate 250 1938 1137 115 2227 787A 50 2309 1419 121 2496 958B 50 2547 1531 190 2461 865C 50 1903 1176 119 1878 353D 50 1638 972 97 1355 186______________________________________
To make our table synoptical we have not listed in the mathematical-statistical data.
A = 6-methyl-9-(N-methyl-2-pyrrolyl)-methylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-carboxylic acid ethylester
B = 6-methyl-9-(4-chloro-phenyl)-methylene-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-carboxylic acid ethylester
C = 6-methyl-9-(ethoxycarbonyl-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-carboxylic acid ethylester
D = 6-methyl-3-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-yl-acetic acid.
In the group "Control-1" rabbits were fed with normal feeding stuff while to the rabbits in the "Control-2" group there were administered also 2 g of cholesterin. p Evaluating the experiments we found that the tested compound in contrast to the Chlorofibrate did not increase the weight of the liver in test animals.
The results obtained on normolyphaemic rats are listed in the following Table 2.
Table 2______________________________________ Dose mg/kg SerumSubstance p.o. triglyceride cholesterine______________________________________Control -- 185,1 103Chlofibrate 250 144,1 63.9E 50 127.9 86.5F 50 155.5 88.0G 50 127.5 88.0H 50 107.9 90.2______________________________________ E = 9-(ethoxycarbonyl-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyriidine-3-carboxylic acid ethylester F = 9-(carboxyl-methyl)-4-oxo-1,6,7,8,9,9-hexahydro-4H-pyrido(1,2a)pyrimidine3-carboxylic acid ethylester G = 9-(carboxyl-methyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-arboxylic acid ethylester H = 9-(methoxycarbonyl-methylene)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido1,2a)pyrimidine-3-carboxylic acid methylester
For the sake of simplicity the mathematical-statistical data have been omitted also in Table 2.
Other representatives of the compounds according to the present invention show a significant central neurotic system (CNS) activity. Thus some of the compounds exhibit significant degree of analgesic, antipyretic, anti-inflammatory activity, tranquillant narcotic potentiating activity, liverprotective, antidepressive, anti-bacterial or antituberculotic as well as anti-asthmatic activity.
The compounds prepared according to the invention find their application chiefly as pharmaceuticals but may be applied also as starting substances for the preparation of other, pharmaceutically active compounds.
The compounds of the formula I according to the invention may be applied in various application forms prepared by admixing them with inert, non-toxic solid or liquid diluents or carriers. The compositions may be finished as solid formulations, e.g. tablets, capsules, dragees, perl-capsules, or liquid formulations, e.g. solutions, suspension or emulsions.
The dose depends on the field of the application and of the pharmaceutical form used. Thus generally compositions containing 1 mg to 100 mg of active ingredient may be prepared.
As carriers the generally used substances, such as talcum, calcium carbonate, magnesium stearate, water, polyethylene glycolate may be employed.
The compositions contain, if desired, also some other conventionally used excipients, such as emulsifiers, decomposing agents etc.
The compositions, if desired, may be finished also in forms showing retarded activity.
This invention also comprehends the compounds 3-ethoxycarbonyl-7-methyl-9-(ethoxycarbonyl-methylene)4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)-pyrimidine and 3-ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido (1,2a) pyrimidine-9-acetic acid.
Further details of our invention are to be found in the following non-limiting Examples.

EXAMPLE 1
The mixture of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine and 10.6 g of benzaldehyde is stirred at 40.degree. C. whereupon 10 ml of ethanol are added and the reaction mixture is allowed to stand overnight. The precipitated crystals are filtered off. White 3-ethoxy-carbonyl-9-(1'-hydroxy-benzyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained melting after recrystallization from ethanol at 186.degree. to 187.degree. C.
Analysis: Calculated: C, 66.65%; H, 6.48%; N, 8.18%. Found: C, 66.72%; H, 6.50%; N, 8.19%.
EXAMPLE 2
According to the method described in Example 1 but using chloral or chloral hydrate as the aldehyde component 3-ethoxycarbonyl-9-(1-hydroxyl-2,2,2-trichloroethyl)-6-methyl-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained. Melting point after recrystallisation from ethanol: 165.degree. to 166.degree. C. Yield: 61%.
Analysis: Calculated: C, 43.83%; H, 4.47%; N, 7.30%; Cl, 27.70%. Found: C, 43.70%; H, 4.51%; N, 73.9%; Cl, 27.37%.
EXAMPLE 3
The mixture of 118.0 g of 3-ethoxy-carbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine and 30 g of paraformaldehyde in 1200 ml of ethanol is heated for 2 hours, whereupon 15 g of paraformaldehyde are added to the reaction mixture which is then stirred for an additional one hour. Thereafter there is added an additional 15 g portion of paraformaldehyde and the mixture is boiled for a further one hour. The reaction mixture is evaporated, the residue is dissolved in 1200 ml of water and shaken out subsequently with benzene and chloroform. After drying the chloroform solution is evaporated, and the residue is recrystallized from ethanol twice to yield 3-ethoxycarbonyl-9,9-di-(hydroxymethyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)-pyrimidine melting at 119.degree. to 120.degree. C.
Analysis: Calculated: C, 56.75%; H, 6.80%; N, 9.45%. Found: C, 56.89%; H, 6.80%; N, 9.40%.
EXAMPLE 4
34.2 g of 3-ethoxycarbonyl-9-(1'-hydroxyl-benzyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine are boiled in the mixture of 100 ml of ethanol and 10 ml of 15 percent by weight solution of hydrochloric acid in ethanol. Upon cooling the precipitated yellow crystals are filtered off, and recrystallized from ethanol to yield 3-ethoxycarbonyl-9-benzylidene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine. The product does not decrease the melting point of the product prepared according to Example 5, when admixed with that.
EXAMPLE 5
23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine and 10.6 g of benzaldehyde are reacted in the mixture of 10 ml ethanol and 5 ml of 15 percent by weight solution of hydrochloric acid in ethanol. The resulted 3-ethoxycarbonyl-9-(1'-hydroxyl-benzyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is transformed without separation, under further heating and stirring into the yellow 3-ethoxycarbonyl-9-benzylidene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a) pyrimidine. The melting point of the above compound after recrystallization from ethanol is 140.degree. to 141.degree. C. Yield: 70%.
Analysis: Calculated: C, 70.35%; H, 6.22%; N, 8.64%. Found: C, 70.24%; H, 5.99%; N, 8.60%.
According to the method described in Example 5 using the appropriate starting materials the following compounds listed in Table 3 are prepared.
Table 3__________________________________________________________________________ ##STR5## M.p. .degree. C Analysis solvent used Calculated for crystal- Yield FoundNo. R.sub.16 R.sub.17 R.sub.18 R.sub.19 Solvent Catalyst lisation % C H N__________________________________________________________________________ %6. 5-nitro-2-furyl CH.sub.3 H COOC.sub.2 H.sub.5 pyridine -- 194-195 85 56.82 4.77 11.69 56.75 4.79 11.807. 2-furyl CH.sub.3 H COOC.sub.2 H.sub.5 n-propanol -- 152-154 78 64.96 5.77 8.91 DMF 64.99 5.68 9.078. 2-pyrryl CH.sub.3 H COOC.sub.2 H.sub.5 ethylene HCl 246 76 65.16 6.11 13.41 glycol ethanol 65.03 6.04 13.659. N-methyl-2- CH.sub.3 H COOC.sub. 2 H.sub.5 ethanol HCl 165-166 61 66.04 6.47 12.84 pyrryl ethanol 65.94 6.43 12.7810. 3,4,5-tri- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 138-141 80 63.76 6.32 6.76 methoxy-phenyl ethanol 63.49 6.30 6.9011. 3-hydroxy-4- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 190-192 82 64.85 5.99 7.56 methoxy-phenyl 65.00 5.90 7.4512. 3,4-methylene- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 140-142 65.21 5.47 7.60 dioxy-phenyl dimethyl- 65.40 5.40 7.86 formamide13. 3,4-dimethoxy- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 134-135 65 65.61 6.29 7.29 phenyl ethanol 65.86 6.18 7.3714. 4-hydroxy- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 240-242 88 67.05 5.92 8.22 phenyl DMF 67.11 5.78 8.4015. 4-chloro-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 carbontetra- -- 183-185 85 63.60 5.34 7.81 chloride n-propanol 63.42 5.12 8.00 Cl 9.88 Cl 9.7816. 2-phenyl-vinyl CH.sub.3 H COOC.sub.2 H.sub.5 carbontetra- -- 167-169 75 71.98 6.33 7.99 chloride n-propanol 71.60 6.32 8.1517. 4-methoxy- CH.sub.3 H COOC.sub.2 H.sub.5 carbontetra- -- 114-116 61 67.78 6.26 7.90 phenyl chloride ethanol 67.58 6.28 8.0218. 2-hydroxy- CH.sub.3 H COOC.sub.2 H.sub.5 carbontetra- -- 200-201 81 67.05 5.92 8.23 phenyl chloride dioxane 66.82 6.01 8.3419. 4-dimethyl- CH.sub.3 H COOC.sub.2 H.sub.5 carbontetra- -- 161-162 81 68.64 6.86 11.44 amino-phenyl chloride ethanol 68.32 6.74 11.5920. 2-(2-nitro- CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 166-168 77 63.79 5.35 10.63 phenyl)-vinyl propanol 63.60 5.41 10.5421. 2-chloro-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 ethanol -- 138-140 50 63.60 5.34 7.81 ethanol 63.81 5.29 7.88 Cl 9.88 Cl 10.0222. 2-nitro-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 ethanol HCl 158-159 50 61.78 5.19 11.38 ethanol 61.63 5.15 11.5823. 4-nitro-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 218-220 46 61.78 5.19 11.38 sulfonic- ethyl- 61.49 5.15 11.35 acid acetate24. 2-ethoxy-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 149-151 44 68.46 6.57 7.60 sulfonic ethanol 68.34 6.46 7.56 acid25. 3-nitro-phenyl CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 151-153 46 61.78 5.19 11.38 sulfonic- ethanol 61.88 5.13 11.26 acid26. 3,4-dichloro- CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 148-150 51 58.03 4.61 7.12 phenyl sulfonic ethanol 58.03 4.51 7.08 acid27. 3-cyano-phenyl CH.sub.3 H COOC.sub. 2 H.sub.5 benzene p-toluene- 148- 20 68.76 5.48 12.03 sulfonic ethanol 69.08 5.36 12.07 acid28. 3-pyridyl CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 108-110 37 66.86 5.30 13.00 sulfonic ethanol 66.65 5.40 12.98 acid29. 4-acetylamino- CH.sub.3 H COOC.sub.2 H.sub.5 benzene p-toluene- 212-214 86 64.62 6.84 9.83 phenyl sulfonic ethanol 64.60 6.80 9.89 acid30.*** carboxy CH.sub.3 H COOC.sub.2 H.sub.5 ethanol -- 167-168 73 57.53 5.52 9.58 ethanol 57.65 5.48 9.7031.* carboxy CH.sub.3 H COOC.sub.2 H.sub.5 ethanol -- 168-170 72 57.53 5.52 9.58 ethanol 57.45 5.70 9.5732.** carboxy CH.sub.3 H COOC.sub.2 H.sub.5 ethanol -- 169-171 74 57.53 5.52 9.58 ethanol 57.62 5.46 9.7233. phenyl CH.sub.3 H COOH xylene sulfuric 204-205 71 68.91 5.44 9.45 acid DMF 68.68 5.46 9.5634. 5-nitro-2-furyl CH.sub.3 H COOH benzene -- 253-254 50 54.23 3.96 12.68 DMF 54.55 3.85 12.5835. 2-hydroxy- CH.sub.3 H COOH benzene -- 235-236 67 65.38 5.16 8.97 phenyl DMF 65.17 5.10 8.9236. 2-chloro- CH.sub.3 H COOH xylene sulfuric 205 61.73 4.57 8.47 phenyl acid DMF 61.64 4.68 8.56 Cl 10.72 Cl 10.4037. 4-chloro- CH.sub.3 H COOH benzene -- 222-223 61.73 4.57 8.47 phenyl DMF 61.59 4.51 8.32 Cl 10.72 Cl 10.4838. N-methyl-2- CH.sub.3 H COOH benzene -- 210-211 33 64.20 5.72 14.04 pyrryl DMF 64.08 5.57 14.1039. 2-nitro-phenyl CH.sub.3 H COOH benzene -- 199-200 73 59.82 4.43 12.31 DMF 59.72 4.47 12.2140. 4-hydroxy- CH.sub.3 H COOH benzene -- 279-280 98 65.38 5.16 8.97 phenyl DMF 65.42 5.11 8.9041. 2-pyrryl CH.sub.3 H COOH benzene -- 287-288 87 63.15 5.30 14.73 DMF 63.47 5.27 14.8142. 3,4-methylene- CH.sub.3 H COOH benzene -- 247-248 85 63.53 4.74 8.23 dioxy-phenyl DMF 62.98 4.75 8.2343. carboxy CH.sub.3 H COOH benzene -- 202-203 95 54.60 4.58 10.62 ethanol 54.74 4.55 10.5644. 2-(2-nitro- CH.sub.3 H COOH benzene -- 234-235 62 62.13 4.66 11.44 phenyl)-vinyl DMF 62.01 4.59 11.4145. 3-hydroxy-4- CH.sub.3 H COOH benzene -- 256-257 79 63.14 5.30 8.18 methoxy-phenyl DMF 63.14 5.38 8.2746. 3,4,5-tri- CH.sub.3 H COOH benzene -- 184-185 90 62.17 5.74 7.25 methoxy-phenyl DMF 62.03 5.53 7.2047. 4-methoxy- CH.sub.3 H COOH benzene -- 195-196 64 66.25 5.56 8.58 phenyl DMF 66.42 5.56 8.4948. 2-furyl CH.sub.3 H COOH benzene -- 225-227 90 62.93 4.93 9.79 DMF 62.84 4.88 9.7749. 2-phenyl-vinyl CH.sub.3 H COOH benzene -- 223-224 78 70.80 5.63 8.69 DMF 70.86 5.50 8.7550. 3,4-dimethoxy- CH.sub.3 H COOH benzene -- 222 64.04 5.66 7.86 phenyl DMF 64.30 5.61 7.7351. 4-dimethyl- CH.sub.3 H COOH benzene -- 228-229 97 67.24 6.24 12.38 amino-phenyl DMF 67.48 6.18 12.2652. 4-hydroxy-3- CH.sub.3 H COOH benzene -- 254-255 67 63.14 5.30 8.18 methoxy-phenyl DMF 62.98 5.32 8.1153. 5-nitro-2-furyl CH.sub.3 H CH.sub.3 benzene acetic 183-184 46 59.80 5.02 13.95 acid ethanol 60.07 5.06 14.0654. 5-nitro-2-furyl CH.sub.3 H CONHN dimethyl -- 288-290 53 51.28 3.44 17.94 ##STR6## formamide DMF 50.86 3.47 17.7655. 5-nitro-2-furyl CH.sub.3 H CONH.sub.2 methanol -- 278-280 68 54.54 4.27 16.96 DMF 54.50 4.15 16.9156. 5-nitro-furyl H H C.sub.6 H.sub.5 acetone HCl 245-246 61 65.32 4.33 12.03 DMF 65.25 4.02 11.9757. 5-nitro-2-furyl CH.sub.3 H H formamide -- 196 80 58.23 4.57 14.63 dioxane 58.15 4.49 14.6058. 5-nitro-2-furyl H H COOC.sub.2 H.sub.5 chloroform -- 240 82 55.65 4.38 12.17 DMF 55.45 4.28 12.1259. 5-nitro-2-furyl CH.sub.3 CH.sub.3 H ethanol HCl 235 63 59.80 5.02 13.95 n-propanol 60.07 5.15 14.0160. 5-nitro-2-furyl H CH.sub.3 H ethanol HCl 217 66 58.25 4.56 14.63 ethanol 58.03 4.50 14.4061. carboxy CH.sub.3 H CONH.sub.2 ethanol -- 242 85 54.75 4.98 15.96 DMF 54.60 5.09 15.8362. carboxy H H COOC.sub.2 H.sub.5 ethanol -- 170-171 81 56.11 5.07 10.07 ethanol 56.18 5.10 9.8563. carboxy CH.sub.3 H COOCH.sub.3 ethanol -- 160-162 90 56.11 5.07 10.07 ethanol 55.99 5.01 9.8264. carboxy CH.sub.3 H ##STR7## ethanol -- 205-206 ethanol 85 58.82 58.91 5.92 6.02 9.16 9.0965. carboxy CH.sub.3 H COO(CH.sub.2).sub.2 CH.sub.3 ethanol -- 167-168 80 58.82 5.92 9.16 ethanol 58.42 5.87 9.1966. carboxy CH.sub.3 H COO(CH.sub.2).sub.3 CH.sub.3 ethanol -- 140-141 59.99 6.29 8.75 ethanol 60.02 6.15 8.7367. carboxy CH.sub.3 H CH.sub.2 COOC.sub.2 H.sub.5 benzene -- 123-124 59.40 4.99 9.24 ethyl- 59.56 5.07 9.20 acetate68. carboxy CH.sub.3 H H benzene -- 213-214 60 59.99 5.49 12.72 ethanol 59.94 5.52 12.5369. carboxy CH.sub.3 H CH.sub.3 benzene -- 239-240 40 61.53 6.03 11.96 ethanol 61.58 5.81 12.0170. carboxy CH.sub.3 H C.sub.6 H.sub.5 benzene -- 210-211 54 68.44 6.08 9.39 methanol 68.56 6.12 9.3871. carboxy CH.sub.3 H CN ethanol -- 242-243 45 58.77 4.52 17.13 DMF- 59.00 4.47 17.18 ethanol72. carboxy CH.sub.3 CH.sub.3 H ethanol HCl 227 65 61.53 6.02 11.96 61.84 6.22 11.8273. carboxy H CH.sub.3 H ethanol HCl 254 45 59.99 5.49 12.72 59.83 5.49 12.61__________________________________________________________________________ *[.alpha.].sub.D.sup.20 = -217.degree. (c = 2,methanol) **[.alpha.].sub.D.sup.20 = +216.degree. (c = 2,methanol) ***by the preparation of compounds wherein R.sup.16 is carboxy, as aldehyde component glyoxilic acid or glyoxilic acid monohydrate may be used.
EXAMPLE 74
23.6 g of 3-ethoxycarbonyl-7-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine and 10.0 g of glyoxylic acid monohydrate are reacted and the obtained 3-ethoxycarbonyl-7-methyl-9-(carboxy-(hydroxymethyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is heated in 150 ml ethanol under stirring for 3 hours. After cooling the crystals are filtered off and recrystallized from ethanol. Thus 3-ethoxycarbonyl-7-methyl-9-(carboxy-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine melting at 110.degree. to 112.degree. C. is obtained. Yield: 51%.
Analysis: Calculated: C, 57.53%; H, 5.52%; N, 9.58%. Found: C, 57.32%; H, 5.60%; N, 9.56%.
EXAMPLE 75
The benzene mother liquor obtained by example 17 is evaporated in vacuo. The residue is dissolved in 10 ml of ethanol whereupon 15 ml of ethanol containing 16% hydrochloric acid are added. The 3,6-dimethyl-9-(5-nitro-2-furfurylidene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidinium-hydrochloride melts at 215.degree.-216.degree. C. after recrystallization from ethanol.
Analysis: Calculated: C, 53.34%; H, 4.78%; N, 12.44%; Cl, 10.50%. Found: C, 53.22%; H, 4.83%; N, 12.55%; Cl, 10.55%.
EXAMPLE 76
3-ethoxycarbonyl-9-(1'-phenylamino-benzyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine obtained by reacting 47.2 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine and 36.2 g of benzalaniline is stirred on water bath for 8 hours, whereupon 3-ethoxycarbonyl-9-benzylidene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained accompanied by the formation of aniline. The reaction mixture is dissolved in 300 ml of benzene and shaken out with 5 percent by weight solution of hydrochloric acid in water. The benzene phase is dried, evaporated and the residue is recrystallized from ethanol twice. Yellow 3-ethoxycarbonyl-9-benzylidene-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine melting at 138.degree. to 139.degree. C. is obtained. The product does not give any decrease in the melting point of the product prepared according to Example 5 when admixed therewith.
EXAMPLE 77
55.6 g of 3-ethoxycarbonyl-9-(carboxy-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine are hydrogenated in 500 ml of ethanol in the presence of 20 g of 9 percent by weight Pd/C catalyst containing metal. When 1 mole of hydrogen has been used up, the catalyst is removed from the reaction mixture by filtration and the solution is evaporated under reduced pressure. The residue is recrystallized from ethanol. 3-ethoxycarbonyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-9-acetic acid melting at 156.degree. to 157.degree. C. is obtained. Yield: 57%.
Analysis: Calculated: C, 55.71%; H, 5.75%; N, 10.00%. Found: C, 55.51%; H, 5.62%; N, 10.07%.
According to the method described in Example 77 using the appropriate starting material the following compounds listed in Table 4 are obtained.
Table 4__________________________________________________________________________ ##STR8## Analysis M.p. .degree. C Calculated solvent used FoundNo. R.sub.18 R.sub.19 for cryst. Yield C% H% N%__________________________________________________________________________78. H COOC.sub.2 H.sub.5 153-154 68 57.14 6.17 9.52 ethanol 57.02 6.22 9.5479.* H COOC.sub.2 H.sub.5 130-132 75 57.14 6.17 9.52 ethanol 57.23 6.20 9.5180.** H COOC.sub.2 H.sub.5 133-134 68 57.14 6.17 9.52 ethanol 57.10 6.30 9.6081. H C.sub.6 H.sub.5 162-164 89 68.44 6.08 9.39 ethanol 68.06 6.00 9.2882. H COOCH.sub.3 215 80 55.71 5.75 9.99 55.65 5.72 10.0383. H COOCH(CH.sub.3).sub.2 148 60 58.43 6.54 9.09 ethanol 58.05 6.57 8.9884. H COO(CH.sub.2).sub.2 CH.sub.3 137 57 58.43 6.54 9.09 ethanol 58.20 6.34 8.9485. H H 178 65 59.45 6.35 12.60 ethanol 59.36 6.43 12.7186. CH.sub.3 H 175-176 68 61.00 6.83 11.86 ethanol 60.96 6.86 11.90__________________________________________________________________________ *[.alpha.].sub.D.sup.20 = -164.degree. (c = 1, methanol) **[.alpha.].sub.D.sup.20 = +165.degree. (c = 1, methanol)
EXAMPLE 87
34.0 g of 3-ethoxycarbonyl-9-(carboxy-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine are hydrogenated in 600 ml of ethanol in the presence of 20 g of 9 percent by weight Pd/C catalyst containing metal. When 2 moles of hydrogen have been used up, the catalyst is filtered off from the reaction mixture and the mixture is evaporated under reduced pressure. The residue is recrystallized from ethanol. 3-ethoxycarbonyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid melting at 205.degree. C. is obtained.
Analysis: Calculated: C, 55.31%; H, 6.43%; N, 9.92%. Found: C, 55.25%; H, 6.32%; N, 10.03%.
EXAMPLE 88
29.4 g of 3-methoxycarbonyl-6-methyl-4-oxo,6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid methylester are dissolved in methanol at 10.degree. C. The aqueous solution of 5 g of sodiumborohydride is added to the solution dropwise. The precipitated crystals are filtered off, and washed with water and then with methanol. 3-methoxycarbonyl-6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid methylester is obtained. Yield: 89%.
The melting point after recrystallization from dimethylformamide is 225.degree. to 226.degree. C. (decomp.)
Analysis: Calculated: C, 56.75%; H, 6.80%; N, 9.45%. Found: C, 56.74%; H, 6.89%; N, 9.63%.
EXAMPLE 89
According to the method described in Example 88 but starting from 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid ethyl ester. 3-ethoxycarbonyl-6-methyl-4-oxo-1,6,7,8,9,9a-hexahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid ethyl ester is obtained. Melting point after recrystallization from dimethylformamide 206.degree. C. Yield: 56%.
Analysis: Calculated: C, 59.25%; H, 7.46%; N, 8.64%. Found: C, 59.03%; H, 7.56%; N, 8.63%.
EXAMPLE 90
55.6 g of 3-ethoxycarbonyl-9-(carboxy-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine are suspended in 400 ml of ethanol. The reaction mixture is saturated with hydrogen chloride gas under stirring and external cooling, then allowed to stand at room temperature overnight. Ethanol is distilled off under reduced pressure and the obtained residue is recrystallized from ethanol. 3-ethoxycarbonyl-9-(ethoxycarbonylmethylene)-4-oxo-6,7,8,9,-tetrahydro-4H-pyrido(1,2a)-pyrimidine melting at 120.degree. to 121.degree. C. is obtained. Yield: 90%.
Analysis: Calculated: C, 58.82%; H, 5.92%; N, 9.15%. Found: C, 58.72%; H, 5.70%; N, 9.29%.
According to the method described in Example 90 using the appropriate starting material the following compounds listed in Table 5 are prepared.
Table 5__________________________________________________________________________ ##STR9## Analysis M.p. .degree. C Calculated solvent used Found YieldNo. R.sub.18 R.sub.19 X Y for cryst. C% H% N% %__________________________________________________________________________91. H COOC.sub.2 H.sub.5 valency bond 133-135 59.99 6.29 8.75 82 isopropanol 59.48 6.22 9.0192.* H COOC.sub.2 H.sub.5 valency bond 121-123 59.99 6.29 8.75 69 isopropanol 59.78 6.32 8.7493.** H COOC.sub.2 H.sub.5 valency bond 122-123 59.99 6.29 8.75 65 isopropanol 60.12 6.20 8.7994. H H valency bond 120 62.89 6.50 11.28 68 ethanol 62.95 6.51 11.1995. H C.sub.6 H.sub.5 valency bond 129-131 70.35 6.22 8.64 85 isopropanol 70.62 6.30 8.7696. CH.sub.3 H valency bond 124-126 64.11 6.92 10.68 74 ethanol 64.23 6.94 10.8097. H COOC.sub.2 H.sub.5 H H oil 59.63 6.88 8.69 65 59.90 6.80 8.6198. H H H H 78-79 62.89 6.50 11.28 84 petrol- 62.38 6.42 11.12 ether99. CH.sub.3 H H H 71-73 63.62 7.63 10.60 60 petrol- 63.76 7.72 10.61 ether__________________________________________________________________________ *[.alpha.].sub.D.sup.20 = -215.degree. (c = 2, methanol) **[.alpha.].sub.D.sup.20 = +215.5.degree. (c = 2, methanol)
EXAMPLE 100
14.7 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid are heated in the mixture of 23 g of ethanol and 5 ml of sulphuric acid for 5 hours, whereupon the ethanol is distilled off under reduced pressure and the residue is poured on ice and shaken out with chloroform. The chloroform solution is dried and evaporated under reduced pressure. Ethylacetate is distilled through the residue. 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid ethylester is obtained in the form of non-crystallizing yellow oil. Yield: 50%.
Analysis: Calculated: C, 59.62%; H, 6.88%; N, 8.69%. Found: C, 60.02%; H, 6.90%; N, 8.65%.
EXAMPLE 101
According to the process described in Example 100 but starting from 3-ethoxycarbonyl-6-methyl-9-(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine 3-ethoxycarbonyl-6-methyl-9-(ethoxycarbonylmethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is obtained. The product does not give any decrease in melting point when admixed with the product of the Example 91.
EXAMPLE 102
14.7 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid are heated in the mixture of 4.6 g of ethanol, 0.25 g of sulphuric acid and 25 ml of chloroform and the water deliberating during the esterification is continuously collected in a water separator.
The reaction mixture is shaken out with 2-fold 30 ml of 5 percent by weight sodium carbonate solution, dried and the chloroform is distilled off under reduced pressure. Thus 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-3-acetic acid ethyl ester is obtained in the form of non-crystallizing oil.
Analysis: Calculated: C, 59.62%; H, 6.88%; N, 8.69%. Found: C, 59.70%; H, 6.98%; N, 8.54%.
EXAMPLE 103
According to the process adescribed in Example 102 but starting from 3-ethoxycarbonyl-6-methyl-9-(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)-pyrimidine-3-ethoxycarbonyl-6-methyl-9-(ethoxycarbonylmethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine melting at 134.degree. to 135.degree. C. is obtained. The product does not give any decrease in the melting point when admixed with the product of the Example 91 and 100, respectively.
EXAMPLE 104
43.84 g of 3-ethoxycarbonyl-6-methyl-9-(carboxymethylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)-pyrimidine are suspended in 400 ml of methanol. The mixture is saturated with hydrogen chloride gas under stirring, at 0.degree. to 5.degree. C. and the reaction mixture is allowed to stand in a refrigerator overnight. The reaction mixture is evaporated under reduced pressure and the residue is admixed with 200 ml of water. The precipitated crystals are filtered off, washed with water and recrystallized from n-propanol. 3-methoxy-carbonyl-6-methyl-9-(methoxycarbonyl-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2a)pyrimidine is obtained. Melting point: 135.degree. to 137.degree. C. Yield: 80%.
Analysis: Calculated: C, 57.53; H, 5.52%; N, 9.58%. Found: C, 57.66%; H, 5.34%; N, 9.60%.
EXAMPLE 105
50 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-yl-acetic acid are dissolved in methanol and gaseous hydrogene chloride is introduced for 5 hours at -10.degree. C. The reaction mixture is allowed to stand at room temperature over night and evaporated in vacuo. The residue is dissolved in water and the pH of the solution is adjusted to 7 with aqueous sodium hydrogen carbonate solution. After extraction with benzene and drying and evaporation of the extract 3-methoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid methyl ester are obtained. Mp.: 101.degree.-103.degree. C. after recrystallization from ethyl acetate. Yield: 67%.
Analysis: Calculated: C, 57.14%; H, 6.17%; N, 9.52%. Found: C, 57.57%; H, 6.34%; N, 9.50%.
EXAMPLE 106
58.8 g of 3-methoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid methyl ester are stirred with aqueous sodium hydroxide solution. The reaction mixture is neutralized with hydrochloric acid. The precipitated crystals are filtered off. Thus 3-carboxy-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2a)pyrimidine-9-acetic acid are obtained. Yield: 75%. Mp.: 190.degree. C., decomposition, after recrystallization from n-propanol.
Analysis: Calculated: C, 54.13%; H, 5.30%; N, 10.52%. Found: C, 54.17%; H, 5.32%; N, 10.31%.
EXAMPLE 107
0.65 of magnesium is reacted with 20 ml of ethanol in the presence of 0.1 g of iodine as catalyst. To the magnesiumethylate solution thus obtained 14.7 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetic acid and 300 ml of ethanol are added. The reaction mixture is heated to boiling, filtered off and the filtrate is evaporated in vacuo. Thus 13.0 g of crude magnesium-3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine-9-acetate are obtained. M.p: above 360.degree. C. decomposition, after recrystallization from a mixture of ethanol and ethyl acetate.
Analysis: Calculated: C, 55.05%; H, 5.60%; N, 9.17%. Found: C, 54.18%; H, 5.68%; N, 8.93%.
EXAMPLE 108
50 g of 3-(ethoxycarbonyl-methyl)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine are reacted with 28.2 g of 5-nitro-8-furfurol and the obtained 3-(ethoxycarbonyl-methyl)-6-methyl-9-[(5-nitro-2-furyl)-hydroxymethyl]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidine is boiled without separation in the mixture of 600 ml of benzene and 2 ml of 16 percent weight solution of hydrochloric acid in ethanol in a flask equipped with a water separator, and then the reaction mixture is evaporated under reduced pressure. The obtained residue is recrystallized from ethanol containing hydrochloric acid twice. Thus 3-(ethoxycarbonyl-methyl)-6-methyl-9-(5-nitro-2-furfurylidene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2a)pyrimidinium hydrochloride is obtained. Yield: 72%.
Analysis: Calculated: C, 52.76%; H, 4.92%; N, 10.43%; Cl, 8.65%. Found: C, 52.98%; H, 4.86%; N, 10.26%; Cl, 8.63%.
EXAMPLE 109
750 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(1,2a)pyrimidine-9-yl-acetic acid are homogenized with 1050 g of crystalline cellulose and 140 g of amylopectine. Granules are formed with 155 g of Eudragite lacquer solution, whereupon it is dried at 40.degree. C., regranulated and homogenized with a powder mixture of 20 g of talc and 20 g of magnesium stearate. Tablets weighing 200 mg and containing 75 mg of active ingredient are pressed in a known manner.
EXAMPLE 110
1500 g of 3-ethoxycarbonyl-6-methyl-4-oxo--6,7,8,9-tetrahydro-4H-pyrido-(1,2a)pyrimidine-9-yl-acetic acid, 1500 g of crystalline cellulose, 250 g of polyvinyl pyrrolidone are admixed in powdered form in a homogenisator. The powder mixture is granulated with a propanolic solution of 45 g of Eudragit. The granules are dried at 50.degree. C., regranulated and homogenized with a powder mixture of 65 g of talk and 45 g of magnesium stearate. Thus tablets weighing 345 mg and containing 150 mg of the active ingredient are pressed in a known manner. The dragee core thus obtained can be equipped with a film or sugar layer in a known manner.
EXAMPLE 111
100 g of 3-ethoxycarbonyl-6-methyl-4-oxo--6,7,8,9-tetra-hydro-4H-pyrido(1,2a)pyrimidine-9-yl-acetic acid are powdered (120 mesh) and homogenized with 5 g of colloidal silicic acid. The powder mixture is uniformly dispersed in 2895 g of molten Witepsol-H at 42.degree. C. From the mass suppositories weighing 3 g and containing 100 mg of active ingredient are prepared in a known manner.
The process of Examples 109-111 may also be carried out by using as active ingredient any compound of the formula I in the place of 3-ethoxycarbonyl-6-methyl-4-oxo-4H-pyrido(1,2a)pyrimidine-9-yl-acetic acid.

Number	Name	Date	Kind
3696197	Meszaros et al.	Oct 1972
3898224	Yale et al.	Aug 1975

Fused pyrimidine derivatives and compositions for treating atherosclerosis containing them

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Yale, J. Heterocycl. Chem., vol. 12, No. 2, pp. 427-431, Apr. 1975.
Gupta et al., Indian J. Chem., vol. 9, pp. 201-206, 3/71.