IE47839B1 - Condensed pyrimidine derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

This invention relates to new nitrogen bridgehead condensed pyrimidine derivatives and process for their preparation. These new compounds can be used in therapy first of all as anti-allergic and anti-asthmatic agents.

Our invention also relates to pharmaceutical compositions containing these compounds.

It is known that pyrido(1,2-a)pyrimidine derivatives possess valuable analgesic and other effects on the central nervous system (U.K. Patent No.1,209,946). One of the most preferred representatives of these compounds used in clinical practice as analgesic is the 1,6-dimethyl-3ethoxycarbonyl-4-oxo-4H-pyrido(1,2-a)-pyrimidinium-methosulfate. (PROBON , Rimazolium) [ Ar-zneimi ttelforschung 22, 815/1972/]. Pyrido (1,2-a) pyrimidine derivatives may be prepared by cyclisation of the corresponding dialkyl-(2pyridyl-amino-methylene)-malonate. Other substituted pyrido(1,2-a)pyrimidine derivatives are described in U.K. Patent No.1,454,312.

This invention relates to new compounds of the general Formula I and pharmaceutically acceptable salts, hydrates, stereoisomers, optically active and geometrical isomers and tautomeric forms thereof (wherein R stands for hydrogen or lower alkyl; R^ is hydrogen, lower alkyl, styryl or a carboxylic 5 group or a derivative thereof; or R and together form a group of the Formula —(CH^CH^ and in this case the dotted line represents a further C—C bond, while in all other cases there is a single bond between positions 6 and 7; R is hydrogen, lower alkyl or hydroxy; R is hydrogen, lower alkyl, aryl, lower alkanoyl, a carboxylic group or a derivative thereof or a group of the Formula —(CH„) —COOH or a derivative thereof formed on the 2 TO. carboxylic group; m= is 1—3; R stands for hydrogen, lower alkyl which may be optionally substituted by hydroxy or carboxy; trifluoromethyl, optionally substituted aryl, phenyl-lower alkyl or an optionally substituted heterocyclic group; 478 39 R stands for hydrogen, lower alkanoyl, optionally substituted benzoyl or heteroaryl; or R4 and R5 together with the adjacent nitrogen atom form a piperidino, pyrrolidino or morpholino ring; or R and R together with the adjacent nitrogen atom form a group of the Formula —N=C 7 wherein R is hydrogen and R is optionally substituted phenyl; Z stands for an oxygen atom and n = 1).

The term “lower alkyl used throughout the specification - in itself or in combinations such as lower alkoxy — relates to straight or branched chain saturated aliphatic hydrocarbon groups having 1—6, preferably 1—4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, neopentyl, nhexyl group etc.).

The term derivative of the carboxylic group covers useful carboxylic acid derivatives e.g. lower alkoxycarbonyl, aryloxycarbonyl, araIkoxycarbonyl or other ester groups, a carbamoyl group optionally mono- or disubstituted by lower alkyl, aryl or aralkyl group(s); cyano, carboxylic acid hydrazido or hydroxamic acid (—CO—NHOH).

The term aryl group — used in itself or in comibina25 tions such as “aryloxy group — relates to optionally substituted aromatic groups having 6—10 carbon atoms (e.g. phenyl or naphthyl or substituted derivatives thereof).

The term aralkyl group — used in itself or in combinations, such as aralkoxy group — relates to alkyl groups having 1—3 carbon atoms substituted by phenyl or naphthyl group (e.g. benzyl, β-phenyl-ethyl, a,β-diphenylethyl, β,β-diphenyl-ethyl, etc.).

The term optionally substituted alkyl group relates to alkyl groups substituted by hydroxy group, halogen atom, carboxylic acid or a derivative thereof, amino, substituted amino, alkoxy or alkanoyloxy groups (e.g. trifluoromethyl, hydroxymethyl, aminoethyl, carboxymethyl, β-carboxyethyl etc.).

The term lower alkanoyl group relates to acid radicals of alkanoic acids having 1—6 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl etc.).

The term aroyl group relates to acid radicals of aromatic carboxylic acids (e.g. optionally substituted benzoic acid).

The term heteroaryl group relates to acid radicals of heterocyclic carboxylic acids (e.g. pyridine-2-, 3- or 4carboxylic acid, furane-carbox/lic acid etc.).

The term heterocyclic group relates to mono- or bicyclic, optionally substituted aromatic or partly or completely saturated rings containing 1—4 nitrogen, oxygen and/or sulfur hetero atoms (e.g. thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzofuranyl, benzoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, benzimidazolyl, indolyl, benzo30 thiazolyl, benzizothyazolyl, tetrazolyl, thiadiazolyl. 839 triazinyl, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, K-methyl-piperazinyl etc.).

The term heteroaryl group used throughout the specification relates to mono- or bicyclic optionally substituted aromatic rings containing 1—4 nitrogen, oxygen and/or sulfur heteroatoms (e.g. thienyl, furyl, pyrrolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, benzofuranyl, benzoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, benzimidazolyl, indolyl, benzothiazolyl, benzisothiazolyl,tetrazolyl, thiadiazolyl, triazinyl, etc.).

The aryl groups, the aryl ring of the aralkyl groups and the heterocyclic groups may optionally bear one or more suitable substituents e.g. one or more of the following groups and atoms; halogen (e.g. chlorine, bromine, iodine or fluorine), lower alkyl (e.g. methyl, ethyl), lower alkoxy (e.g. methoxy, ethoxy), lower alkylenedioxy (e.g. methylenedioxy, ethylenedioxy or propylenedioxy), mono-, di- or trihalogenoalkyl (e.g. trifluoromethyl), amino, alkanoylamino, substituted amino,carboxylic group or a derivative thereof, sulfonic acid group or a salt or ester thereof, hydroxy, alkanoyloxy, aroyloxy, heteroaroyloxy, nitro, mercapto, lower alkylthio group etc.

Preferred representatives of the compounds prepared by the process of the present invention are those derivatives in which R is hydrogen; R1 is hydrogen, lower alkyl (preferably methyl), styryl or lower alkoxycarbonyl (preferably methoxycarbonyl or ethoxycarbonyl); R is hydrogen, lower alkyl (e.g. methyl) or hydroxy; - 7 R^is a carboxylic group, lower alkoxycarbonyl (preferably methoxycarbonyl or ethoxycarbonyl), carbamoyl, cyano, formyl, lower alkyl (e.g. methyl) or phenyl group; or R is hydrogen, lower alkyl (preferably methyl), hydroxyethyl, carboxyalkyl, optionally substituted phenyl or naphthyl, trifluoromethyl, benzyl, 2-, 3- or 4-pyridyl, benzothiazol-2-yl, methoxycarbonyl or ethoxycarbonyl; r5 stands for hydrogen, lower alkanoyl (preferably formyl or acetyl), benzoyl or nicotinoyl; or the grouping 4 c of the formula —NR Rs is piperidinyl, pyrrolidinyl, 7 morpholiny1 or a group of the formula —N=CR R , wherein 6 7 R is hydrogen and R stands for optionally substituted 4 phenyl); R stands particularly preferably for a phenyl group which may optionally bear in the ortho-, meta- and/or para-position(s) one, two or three following substituents; hydroxy group, halogen atom, lower alkyl, sulfonic acid, carboxylic acid or a derivative thereof, alkoxy especially lower alkoxy, alkylenedioxy, especially methylenedioxy, amino substituted amino, nitro or trifluoromethyl group.

Compounds corresponding tothe following substituent definition constitute a class of compounds of the general Formula 1 having particularly preferable properties: R stands for hydrogen; R^ is methyl attached to position 6; 3 4 R is hydrogen, R is a carboxylic group; R is optionally substituted phenyl; R is hydrogen; Z is oxygen; n = 1 and pharmaceutically acceptable salts thereof.

The compounds of the general Formula 1 form salts with pharmaceutically acceptable organic or inorganic acids (e.g. hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, or maleates, succinates, acetates, 4-7 8 39 tartrates, lactates, fumarates, citrates etc.).

Compounds of the general Formula 1 containing a carboxylic group or a sulfonic acid group may form salts with pharmaceutically acceptable bases (e.g. alkali metal salts such as sodium or potassium salts? alkaline earth metal salts such as calcium or magnesium salts; ammonium salts, salts formed with organic amines e.g. triethylamine salts, ethanolamine salts etc.

The present invention encompasses the preparation 10 of optical and geometrical isomers and tautomeric forms of the compounds of the general Formula 1. The structure of the geometrical isomers is shown by the general Formulae (IA) and (IB).

R' IA.

IB The structure of the tautomers is illustrated by Reaction scheme A. „4 τ,5 R R I A REACTION SCHEME Compounds of the general Formula 1 in which R stands for a hydroxy group may show keto-enol tautomerism as illustrated by Reaction Scheme B. (In all these formulae the substituents have the same meaning as stated above). 4-7 8 39 - ίο R R R R' \ / \ / Ν N B REACTION SCHEME According to the process of the present invention compounds of the general Formula 1, pharmaceutically accept5 able salts, hydrates, optically active, geometrical and stereo isomers and tautomers thereof may be prepared by:10 a) for the preparation of compounds of the general 4 Formula 1, wherein R is an optionally substituted aryl or heteroaryl group and R5 is hydrogen, reacting a compound of the general Formula 11 with a R same meaning as general Formula stated above) 111 dotted line have the diazonium salt of the - 11 N„ Ar 111 or a reactive derivative thereof (wherein Ar stands for an optionally mono- or polysubstituted aryl or heteroaiyl group); or b) reacting compound of the general Formula 11 (wherein 12 3 R, R , R , R , Z, n and the dotted line have the same meaning as stated above) with a compound of the general Formula IV /' I \ IV (wherein R and R have the same meaning as stated above), or for the preparation of compounds of the general Formula 1, wherein R is hydrogen, with a reactive derivative thereof; or c) reacting a compound of the general Formula V 3 (wherein R, RA, R , R , Z, n and the dotted line have the same meaning as stated above and L stands for a leaving group) with a compound of the general Formula VI h2m VI - 12 4 5 (wherein R and R have the same meaning as stated above) and oxidizing the intermediate product thus formed after or without isolation? or d) reacting a compound of the general Formula Vll Vll 3 (wherein R, R , R , R , Z, n and the dotted line have the .1 sane meaning as stated above and L is a leaving group) or a tautomer thereof with a compound of the general Formula 4 5 VI (wherein R and R have the same meaning as stated above)? or e) reacting a compound of the general Formula VIII .1 the same meaning as stated above) with an amine of the general Formula IX - 13 HN / or a salt thereof as stated above); (wherein or and R have the same meaning f) for the preparation of compounds of the general 5 Formula 1, wherein R is hydrogen, reacting a compound of the general Formula X (wherein R, R , same meaning as Formula XI stated above) with a compound of the general (wherein R has the same meaning as stated above); or g) for the preparation of compounds of the general 4 Formula 1, wherein R is an optionally substituted aryl or 5 heteroaryl group and R is hydrogen, reacting a compound of the general Formula Xll 3 (wherein R, R , R , R , Z, n and the dotted line have the same meaning as stated above and K stands for a leaving group) with a diazonium salt of the general Formula 111 (wherein Ar has the same meaning as stated above) or a reactive derivative thereof and subjecting the intermediate product thus formed after or without isolation to removal of the K leaving group; and if desired subjecting a compound of the general Formula 1 thus obtained to one or more of the 1 2 following subsequent transformations; converting an R , R , 4 5 1 2 3 4 R , R , and/or R group into an other R , R , R , R , and/or R group by methods known per se; converting a compound of the general Formula 1 which contains an acidic group into a salt formed with a pharmaceutically acceptable base; conver15 ting a compound of the general Formula 1 of basical character into an addition salt formed with a pharmaceutically acceptable acid; setting free a compound of the general Formula 1 from its salt formed with an acid or a base; separating a racemic compound of the general Formula 1 into the optically active antipodes.

According to the variant a) of our process compounds 4 of the general Formula 1, wherein R is an optionally sub5 stituted aryl or heteroaryl group and R is hydrogen are prepared by reacting a compound of the general Formula 11 with a diazonium salt of the general Formula 111 or a reactive derivative thereof. As reactive diazonium salt derivative a compound of the general Formula Xlll Xlll AR (wherein Ar has the same meaning as stated above) or another derivative described in Org. Reactions Vol. 10, 147 (1959), (John Wilens and Sons Inc., London) may be used. The reaction may be carried out at a temperature below 50°C, preferably 0—20°C. The admixture of the components may be carried out in two ways; either the compound of the general Formula 11 is added to the acidic diazonium salt solution or vice versa. The components may be advantageously used in equimolar ratio but any component may alternatively be used in a small excess. The reaction may be optionally carried out in the presence of an acid binding agent (e.g. sodium acetate). The reaction may be preferably accomplished in an aqueous medium generally used in reactions carried out with diazonium salts.

According to variant b) of our process compounds of the general Formula 1, wherein R$ is hydrogen are prepared by reacting a compound of the general Formula 11 with a compound of the general Formula IV or a reactive derivative thereof. As reactive derivative a compound of the general 478 39 XIV - IS Formula XIV CH.

CH 2\ CH. ch2/ N-CH.-N 2 I N II 0 (wherein R has the same meaning as stated above) or any derivative described in Chem. Pharm. Bull. 25. 731—9 (1977) may be used. The reaction may be carried out in an inert organic solvent. As reaction medium preferably aromatic hydrocarbons (e.g. benzene, toluene, xylene), pyridine, alkanols (e.g. methanol, ethanol) may be used. The reaction may be accomplished at elevated temperature preferably at the boiling point of the reaction mixture. The water formed in the reaction may be removed by azeotropic distillation (benzene, toluene) or with the aid of a dehydrating agent (e.g. dicyclohexylcarbodiimide).

In the starting materials of the general Formula V used in variant c) of our process L represents a conventional leaving group, such as halogen, (e.g. chlorine or bromine), alkylsulfonyloxy (e.g. methanesulfonyloxy), optionally substituted arylsulphonyloxy (e.g. p-toluenesulphonyloxy or p-bromophenylsulfonyloxy group) or an alkanoyloxy group (e.g. acetoxy group). The reaction between the compounds of the general Formulae V and VI is carried out preferably in the presence of an acid binding agent. For this purpose preferably alkali metal carbonates (e.g. sodium or potassium carbonate), alkali metal hydrogen carbonates (e.g. sodium or potassium hydrogen carbonate), alkali metal salts of weak organic acids (e.g. sodium acetate) or the excess of the amine starting material of the general Formula VI may be used. - 17 The reaction may be accomplished in an inert solvent. As reaction medium preferably aromatic hydrocarbons) e.g. benzene, toluene, xylene), esters (e.g. ethyl acetate), alcohols (e.g. methanol, ethanol) or dimethylformamide may be used. The reaction may be carried out at 0—200°C, preferably at room temperature or under heating or at the boiling point of the reaction mixture, respectively.

In the above reaction presumably intermediate compounds of the general Formula XV are formed „4 „5 R R \ / N 2 3 4 5 (wherein R, R , R , R , R , R , Z, n and the dotted line have the same meaning as stated above) which are converted into the desired end-products of the general Formula 1 — after or without isolation — by means of oxidation. The intermediates of the general Formula XV are preferably not isolated but the reaction mixture containing the said intermediates is subjected to the effect of the oxygen-content of air at room temperature or under heating whereby oxidation takes place.

According to variant d) of our process a compound of the general Formula Vll or a tautomer thereof is reacted - 18 with a compound of the general Formula Vl. The symbol I? in the general Formula Vll represents a conventional leaving group, such as halogen (e.g. chlorine or bromine atom), alkylsulfonyloxy (e.g. methanesulfonyloxy), optionally substituted arylsulfonyloxy (e.g. p-toluenesulfonyloxy or pbromo-phenyl-sulfonyloxy group), alkanoyloxy (e.g. acetoxy) or hydroxy group. The reaction is preferably carried out in the presence of an acid binding agent. For this purpose advantageously alkali metal carbonates (e.g. sodium or potassium carbonate), alkali metal hydrogen carbonates (e.g. sodium or potassium hydrogen carbonate), alkali metal salts of weak organic acids (e.g. sodium acetate) or an excess of the amine starting material of the general Formula VI may be used. The reaction may be carried out in an inert solvent. As reaction medium preferably aromatic hydrocarbons (e.g. benzene, toluene, xylene), esters (e.g. ethyl acetate), alcohols (e.g. methanol, ethanol), or dimethylformamide may be used. The reaction may be carried out at 0—200°C, preferably at room temperature or under heating or at the boiling point of the reaction mixture, respectively.

When starting materials of the general Formula Vll are used, wherein L1 is a hydroxy group, the reaction may be carried out preferably in the presence of a dehydrating agent (e.g. dicyclohexylcarbodiimide).

According to variant e) of our process compounds of the general Formulae Vlll and IX are reacted under the conditions disclosed under reaction variant d). Ihe. amine of the general Formula IX may be used in the form of its salt (e.g. carbonate) too. - 19 According to variant f) of our process the compounds of the general Formulae X and XI are reacted preferably in an inert solvent. As reaction medium aromatic hydrocarbons (e.g. benzene, toluene, xylene), alkanols (e.g. methanol, ethanol), esters (e.g. ethyl acetate), ethers (e.g. dioxane) may be used. The reaction may be preferably carried out in the presence of a dehydrating agent (e.g. dicyclohexylcarbodiimide). The reaction temperature is 0—200°C, depending on the solvent used. One may preferably work under heating.

According to variant g) of our process a compound of the general Formula Xll is reacted with diazonium salt of the general Formula 111 or a reactive derivative thereof, whereafter the K leaving group is removed from the intermediate product formed after or without isolation. In the starting materials of the general Formula Xll K stands for any easily removable leaving group, such as formyl, lower alkanoyl (e.g. acetyl), optionally substituted aroyl (e.g. benzoyl), or heteroaryl or carboxylic group or a derivative thereof (e.g. a carboxylic acid ester, carbamoyl, substituted carbamoyl, acid azide or cyano). The reactive derivatives of the diazonium salts of the general Formula 111 may be those set forth in reaction variant a). The reaction may be carried out in water or a mixture of water and a watermiscible organic solvent (e.g. alkanols, pyridine). The reaction may be optionally accomplished in the presence of an acid binding agent. For this purpose e.g. sodium acetate or alkali metal hydroxides may be used. The reaction may be carried out at a temperature below 50°C, preferably at 0—20°C.

The intermediate compounds formed in the above reaction correspond presumably to the general Formula XVI. 4-78 39 - 20 N-Ar XVI 3 (wherein R, R , R , R , K, Z, n and the dotted line have the meaning as stated above). These compounds may be converted into the end-products of the general Formula 1 by acidic or alkaline treatment as described in Org. Reactions Vol. 10, 143—178 (1959) (John Wilnes and Sons, Iiic., London) in connection with the Japp-Klingemann reaction.

According to reaction variant g) compounds of the general 4 Formula 1 are obtained, wherein R is an optionally substitu5 ted aryl or heteroaryl group and R is hydrogen.

The compounds of the general Formula 1 obtained by the above reaction variants may be isolated from the reaction mixture by methods known per se. The compounds of the general Formula 1 often precipitate from the reaction mix15 ture in the form of their salt or hydrate and may be separated by means of filtration or centrifuging. If the reaction is carried out in aqueous medium the end product is extracted from the reaction mixture with suitable organic solvent (e.g. benzene, chlorine, ether) and isolated by evaporating the organic extract. If the reaction is carried out in an organic medium the compound of the general Formula 1 may be isolated by removing the organic solvent. The compounds of the general Formula 1 may be purified by recrystalliza•J 7 8 3 9 - 21 tion or by means of chromatography, if necessary.

The compounds of the general Formula 1 thus obtained may be converted into another compound of the general Formula 1 by one or more subsequent transformation(s) carried out by methods known per se. The said transformation may be carried out on the r\ R^, r\ r\ and/or R^ group. The said subsequent transformation may be accomplished by means of reactions and under conditions conveniently used in reactions of such types. 3 A carboxylic group standing for R , R , R or being 4 5 present in group R or R may be converted into an alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl group by esterification reactions known per se. Esterification may be carried out e.g. by reacting the carboxylic acid with the corresponding alcohol or phenol in the presence of an acidic catalyst (e.g. concentrated sulfuric acid) or with a diazoalkane (e.g. diazomethane, diazoethane).

Compounds containing a carboxylic group may be subjected to decarboxylation by heating whereby the corresponding compounds containing a hydrogen atom at the place of the carboxylic group are obtained? decarboxylation may be preferably carried out in the presence of an acid (e.g. phosphoric acid).

A derivative containing a carboxylic group may be converted into an optionally substituted acid amide by reacting with the corresponding amine. Substituted acid amides may be prepared in a manner known per se through an active ester (e.g. ethylchloroformate). 3 An ester group standing for R , R or R or being 4 5 present in the group R or R may be subjected to trans47839 - 22 esterification by heating with an excess of the corresponding alcohol. An ester of the general Formula 1 may be converted into the corresponding free carboxylic acid by acidic or alkaline treatment. Alkaline hydrolysis may be carried out by heating with an alkali metal hydroxide in aqueous or alkanoic medium and setting free the carboxylic acid from the alkali metal salt formed by acidification. Hydrolysis carried out with a mineral acid directly leads to the formation of the free carboxylic acid.

An ester of the general Formula 1 may be converted into the corresponding acid amide of the general Formula 1 hy reacting with ammonia in aqueous-alcoholic medium or into the corresponding hydrazide of the general Formula 1 by reacting with an optionally substituted hydrazine (e.g. hydrazine, methyl- or phenyl-hydrazine). 3 A cyano group standing for R , R or R or being pre4 5 sent in group R or R may be converted into a carboxylic group by heating with concentrated sulfuric acid, concentrated hydrochloric acid or a concentrated alkali metal hydr20 oxide, or may be transformed into an acid amide (carbamoyl) group by subjecting to acidic hydrolysis in the cold or to alkaline hydrolysis at a temperature of about 50°C. (Alkaline hydrolysis may be preferably carried out in the presence of hydrogen peroxide). 3 A carbamoyl group standing for R , R or R or being present in R or R may be converted into a carboxylic group by heating in alkaline or acidic medium. The hydrolysis of acid amides which do not readily hydrolyse may be carried out in the presence of nitric acid.

The carboxylic acid hydrazides of the general Formula 4-7839 - 23 1 may be hydrolised into the corresponding carboxylic acids of the general Formula 1 by warming in the presence of an acid or an alkali.

Compounds of the general Formula 1, wherein R is hydrogen, may be acylated into the corresponding compounds of the general Formula 1, wherein R is a formyl, alkanoyl, aroyl or heteroaroyl group. Acylation may be carried out by methods known per se by using the corresponding carboxylic acid or a reactive derivative therecf . As acylating agent IO preferably acid halides (e.g. acid chlorides), acid anhydrides or active esters (e.g. pentachlorophenyl esters) may be used. Acylation may be preferably accomplished in the presence of an acid binding agent (e.g. triethylamine). If acylation is carried out with a free carboxylic acid, the reaction may be advantageously accomplished in the presence of a dehydrating agent (e.g. dicyclohexylcarbodiimide). Acylation may be carried out by methods and acylating agents well-known in peptide chemistry.

Compounds of the general Formula 1, wherein R and R are hydrogen may be condensed with an aldehyde to yield the corresponding compound of the general Formula 1, wherein 4 5 the group —NR R stands for a group of the formula 6 7 —N=CR R . Condensation may be carried out in an inert solvent (e.g. benzene, toluene) at room temperature or under heating. The water formed in the reaction may be removed in the form of an azeotropic mixture or with the aid of a dehydrating agent. As aldehyde or ketone e.g. acetone, acetaldehyde or benzaldehyde may be used.

An aryl group standing for R and/or R may be subjec30 ted to one or more known transformations. Thus a compound - 24 4 5 of the general Formula 1, wherein R and/or R is an unsubstituted phenyl group may be nitrated with a mixture of nitric acid and sulfuric acid, the nitro derivative thus obtained may be optionally reduced (e.g. by catalytic hydrogenation) and the amino derivative thus obtained may be optionally alkylated or acylated.

The said subsequent transformation reactions form also part of the present invention.

A compound of the general Formula 1 may be set free from its salt formed with an acid or a base by methods known per se.

A compound of the general Formula 1 of basical character may be converted into an addition salt formed with an inorganic or organic acid. Salt formation may be carried out in a known manner by reacting the compound of the general Formula 1 with the corresponding acid — used in equimolar amount or in excess — in an ineirt organic solvent.

Compounds of the general Formula 1, which contain an acidic group (a carboxylic or sulfonic acid group) may be converted into their salts by reacting with the corresponding base (e.g. alkali metal hydroxides, alkaline earth metal hydroxides, organic amines) in a manner known per se.

Compounds of the general Formula 1, in which R and/or R1 are other than hydrogen contain a chiral (asymmetrical) centre and may be present in the form of an optically active antipode or a racemate. The optically active antipodes of the above compounds of the general Formula 1 may be prepared either by using in the reaction variants a-g) anoptically active starting material of the general Formulae 11, V, Vll, Vlll, X or Xll or subjecting a racemic compound - 25 of the general Formula 1 to resolution. The said resolution may be carried out by methods known per se. Compounds of the general Formula 1 containing a carboxylic acid may be separated into the optically active antipodes e.g. by reacting the racemate with a suitable optically active base [such as optically active threo-l-(p-nitro-phenyl)-2-aminopropane-1, 3-diol] , separating the members of the diastereomeric salt-pair thus formed on the basis of their different physical properties (e.g. by crystallization) and thereafter setting free the optically active antipode of the general Formula 1 from the salt by reacting with a strong base.

The nitrogen bridge-head starting materials used are partly known. The starting materials of the general Formulae 11, Vlll and X are known from prior art [Arzneimittelforschung 22, 815 (1972)] or can be prepared by analogous methods.

The starting materials of the general Formula V can be prepared from the compounds of the general Formula 11 by halogenation. The starting materials of the general Formula Vll can be prepared by reacting a compound of the general Formula V with a compound of the general Formula IX and subjecting the condensation product thus obtained to oxidation. The starting materials of the general Formula Xll may be prepared by reacting a compound of the general Formula 11 with a Vielsmeyer-Haack reactant or with phosgene immonium chloride and_ subjecting the compound thus obtained to further transformation.

The starting materials of the general Formulae 111, IV, vl, IX and XI are well known from literature and generally commercially available or can be readily prepared from commercially available compounds by methods known per se. - 26 The compounds of the general Formula 1 exhibit antiinflammatory, analgesic, thrombus-aggregation inhibiting, anti-atherogenic, heart function and circulation influencing, tranguillising, C N S - influencing, PG-antagonistic, anti5 ulcer, antibacterial and anti-fungal effects and can be used in human and veterinary therapy. Naturally not all compounds of the general Formula I exhibit all the above activities to a useful degree but useful compounds may readily be selected by simple tests, due regard being paid to the preferences expressed above. The anti-allergic and anti-asthmatic effects of the compounds of the general Formula 1 are particularly remarkable.

Allergic reactions induced by antigen-antibody interaction can vary variously manifest themselves in different organs and tissues. Asthma is the most common form of allergy. Disodium-chromoglycate [1,3-bis-(2-carboxy-chromon6-yl-oxy)-2-hydroxy-propane, Intal (Registered Trade Mark)---is generally used as anti-asthmatic agent but this compound_ _ is ineffective when administered orally and exhibits the desired effect only when administered by inhalation with the aid of a complicated therapeutic device (spinhaler). It has been found that the new compounds of the general Formula 1 cure allergic symptoms with excellent results when administered either orally or intravenously or by inhalation.

The activity of the compounds of the general Formula was proved by standard tests used for the determination of antiallergic effect. The PCA text [Ovary: J. Immun. 81. 355 (1958)] and the Curch test [British J. Pharm. 46, 56— (1972); Immunology 29, 527—534 (1975)] were used. The tests were carried out on rats. The results are summarized in Table 1. - 27 TABLE 1 Test PCA test Church test compound ou μΜ/kg ED5o μΜ/kg Example No. i.v. p.o. i.v. 14 0.60 1.2 0.31 37 0.29 1.0 0.14 Disodium- chromoglycate 1.00 ineffective 0.84 Test compound PCA test Released Hist. Example No. ED_„ i.v. μΜ/kg in vitro EC-ALty/L 50 50 18 0.53 100 23 0.53 120 41 1.0 50 0.42 45 0.61 43 0.57 Test compound PCA test; percentage of Released Hist. Example No. activity for a single in YifcCQ ECμπ/L dose of 320 μΜ/kg 26 89 90 35 100 17.6 16 100 2 41 100 100 48 100 100 50 100 73 45 10O 312 43 100 100 839 - 28 Pharmacological data The ED5q data of further compounds of the Formula 1 tested in the PCA test are summarized in the following Table: Compound EDso i.v. 9-[ (2-carboxy-phenyl)hydrazono]-6-methyl-4-oxo6,7,8,9-tetrahydro-4Hpyrido(1,2-a)pyrimidine-3carboxylic acid 0.48 9-[(4-ethoxy-phenyl)hydrazono]-6-methyl-4-oxo6,7,8,9-tetrahydro-4Hpyrido(1,2-a)pyrimidine-3carboxylic acid 1.0 It appears from the above data that the representatives of the compounds prepared according to the present invention are also active when administered orally, contrary to the disodium chromoglycate, which proved to be effective only when administered intraveneously. The compounds of the general Formula 1 are more active than the known reference compounds also when administered intravenously.

The toxicity of the compounds of the general Formula is low, the LD,__ value is generally above 500 mg./kg. p.o. 50 on rats and mice.

The compounds of the general Formula 1 can be used in therapy in the form of pharmaceutical compositions containing these active ingredients in admixture with solid or liquid, organic or inorganic carriers. The said compositions are prepared by methods of pharmaceutical industry known per se.

The compositions may be suitable for oral or parenteral administration or may be used for inhalation - 29 and may be finished in the form of tablets, dragees, capsules, lozenges, powder mixtures, aerosol spray, aqueous suspension or solution or injectable solution or syrups.

The compositions may contain suitable solid diluents or carriers, sterile aqueous solvent or non-toxic organic solvent. To the oral compositions sweetening or flavouring agents used for such purposes nay be added.

Tablets suitable for oral administration may contain carriers (e.g. lactose, sodium citrate, calcium carbonate), disintegrating agents (e.g. starch, alginic acid), lubricants (e.g. talc, sodium lauryl sulfate, magnesium stearate). The carrier of the capsules may generally be lactose or polyethyleneglycol. The aqueous suspensions may contain emulsifying or suspending agents. The diluent of suspensions formed with organic solvents may be ethanol, glycerol or chloroform etc.

Compositions for parenteral administration or inhalation comprise the solution or suspension of the active ingredient in a suitable medium (e.g. coconut oil, sesame oil, polypropyleneglycol or water). The injectable compositions may be administered intramuscularly, intravenously or subcutaneously. The injectable solutions are preferably prepared in aqueous media and the pH is adjusted to a suitable value. The solutions may be prepared in an isotonic salt or glucose solution, if necessary.

The compositions may be applied into the organism for the treatment of asthma also by inhalation by means of conventional inhaling and atomising apparatus.

The active ingredient content of the pharmaceutical compositions may vary between wide ranges and may be from - 30 0.005% to 90%.

The daily active ingredient dosage may also vary between wide ranges and depends on the condition, age and weight of the patient, the mode of formulation and the efficiency of the given active ingredient. In the case of oral administration the daily active ingredient dosage is generally 0.05—15 mg./kg., while when administered by inhalation or intravenously it amounts to 0.001—5 mg./kg.; the said dosage may be administered at once or in divided doses. The above ranges are but of informative character and the actual dose used may be lower or higher, depending on the prescriptions of the physical and the circumstances of the given case.

Further details of the present invention are to be found in the examples. It is, however, by no means intended to limit our invention to the examples.

EXAMPLE 1 To a mixture of 18.6 g. (0.2 mole) of aniline and 100 ml. of a 1:1 diluted aqueous hydrochloric acid a solution of 13.8 g. (0.02 mole) of sodium nitrite and 100 ml. of water is slowly added at 0—5°C under stirring dropwise.

Thereafter to the reaction mixture a solution of 47,2 g (0.2 mole) of ethyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H~ pyrido(l,2-a)pyrimidine-3-carboxylate in 10O ml. of water is slowly added dropwise under vigorous stirring. The reaco tion mixture is stirred at 0—5 C for 2—3 hours whereupon it is allowed to stand in a refrigerator overnight. The precipitated crystals are filtered off and washed with some water. The substance thus obtained is treated with 500 ml. of water and 500 ml. of chloroform, whereupon the pH of the - 31 aqueous phase is adjusted to 7 with a 5 weight/volume aqueous sodium carbonate solution. The organic layer is separated and the aqueous phase is extracted twice with 500 ml. of chloroform each. The united organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo. The residual red oil is crystallised from a 2—3 fold amount of ethanol. Yield: 48.7 g. (63.0%). Mp.: 86-~€7°C.

The product crystallizes with 1 mole of etiianol and the ethanol content may be removed by drying in vacuo at 90—100°C over phosphorous pentoxide. The melting point of the dried ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate amounts to 138—139°C.

Analysis for the formula c1gH2oN4°3 Calculated: C: 63.51%; H: 5.92%; N: 16.45%; Found: C, 63.53%; H: 6.03%; N: 16.60%.

EXAMPLE 2 6.3 g. (0.02 mole) of ethyl-9-bromo-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are dissolved in 30 ml. of anhydrous ethanol and 4.3 ml. (0.044 mole) of phenyl-hydrazine are added to the solution. The reaction mixture is heated to boiling for 4 hours whereupon the solvent is distilled off in vacuo. To the residue 30 ml. of water and 15 ml. of chloroform are added and the pH of the aqueous layer is adjusted to 2—3 with a 10 weight/ volume % aqueous hydrochloric acid solution under stirring. The organic layer is separated and the aqueous phase is extracted twice with 15 ml. of chloroform each. The united organic layer is dried over anhydrous sodium sulfate and - 32 the solvent is removed in vacuo. The residual red oil crystallizes from a 2—3 fold amount of ethanol. Yield: .3 g. (68.6%). Mp.: 86—87°C.

The product obtained crystallizes with 1 mole of o ethanol which can be removed by drying in vacuo at 90—100 C over phosphorous pentoxide. The melting point of the dried ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido(l,2-a)pyrimidine-3-carboxylate amounts to 138—139°C, The product does not give a melting point depression when admixed with the compound prepared according to Example 1.

EXAMPLE 3 2.5 g. (0.01 mole) of ethyl-9-hydroxy-6-methyl-4-oxo6,7-dihydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are dissolved in 7.5 ml. of anhydrous ethanol. To the solution 1.2 ml. (0.012 mole) of phenyl-hydrazine are added. The reaction mixture is heated to boiling for half an hour, whereupon it is allowed to cool. Orange coloured crystals precipitate. Yield: 3.5 g. (90.6%), Mp.: 8&—87°C.

The product crystallizes with 1 mole of ethanol which can be removed by drying at 90—1OO°C over phosphorous pentoxide in vacuo. The melting point of the dried ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate amounts to 138—139°C. The product does not show a melting point depression when admixed with the compound prepared according to Example 1 or 2.

EXAMPLES 4—5) The process described in Example 1 is carried out except that aniline is replaced by p-bromo-aniline and m30 toluidine, respectively. The following compounds are 4-7 8 39 - 33 prepared: 4) Ethyl-9-(p-bromo-phenyl-hydrazono)-6-methyl-4oxo-6,7,8,9-tetrahyflro-4H-pyrido(1,2-a)pyrimidine-3carboxylate, mp.: 188—189°C.

Analysis for the formula C£gHigN4°3Br Calculated: C: 51.69%; H: 4.34%; N: 13.39%; Br: 19.10%; Found: C: 51.84%; H: 4.54%; N: 13.26%; Br: 19.13%.

) Ethyl-9-(m-methyl-phenyl-hydrazono)-6-methyl-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate, mp.: 159—-160°C.

Analysis for the formula C^9H22N4°3 Calculated: C: 63.39%; H: 6.25%; N: 15.80%; Found: C: 64.30%; H: 6.22%; N: 15.85%.

EXAMPLE 6 To a mixture of 2.5 g. (0.02 mole) of p-chloroaniline and 10 ml. of a 1:1 diluted aqueous hydrochloric acid a solution of 1.4 g. (0.01 mole) of sodium nitrite and 10 ml. of water is slowly added dropwise at 0—5°C under stirring. To the reaction mixture 12.0 g. of solid sodium acetate are added in portions, whereupon a solution of 4.7 g. (0.02 mole) of ethyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 10 ml. of water is slowly added dropwise under vigorous stirring. The reaction mixture is stirred at 0—5°C for 2—3 hours, whereupon it is allowed to stand in a refrigerator overnight. The precipitated crystals are filtered off and washed with a small amount of water. After recrystallization from ethanol 4.2 g. (56.0%) of ethyl-9-(p-chloro-phenylhydrazono)-6-methyl4-oxo-6,7,8,9-tetrahydro-4H-pyrido-(l,2-a)pyrimidine-3carboxylate are obtained. Mp.: 177—178°C. - 34 Analysis for the formula C1OH N 0 Cl io xy 4 □ Calculated: C: 57.67%; H: 4.30%; N: 14.90%; Cl: 9.45%; Found: C: 57.35%; H: 4.40%; Ns 15.04%; Cl: 9.57%.

EXAMPLE 7 To a mixture of 2.9 g. (0.02 mole) of p-toluidinemonohydrochloride and 6 ml. of a 1:1 dilute aqueous hydrochloric acid solution at 0—5°C under stirring a solution of 1.4 g. (0.02 mole) of sodium nitrite and 10 ml. of water is slowly added dropwise.

Thereafter one proceeds exactly as described in Example . Yield: 4.0 g. (56.4%) of ethyl-6-methyl-9-(p-methylphenyl-hydrazono)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate. Mp.: 147—149°C.

Analysis for the formula ClnH_.N.0. xy όώ 4 J Calculated: C: 64.39%; H: 6.35%; Ns 15.80%; Found: C: 64.05%; H: 6.34%; N: 15.71%.

EXAMPLES 8—13 The process described in Example 6 is carried out except that p-chloro-aniline is replaced by 2,6-dichloro20 aniline, o-toluidine, 3,4-methylenedioxy-aniline, o-nitroaniline, p-nitro-aniline and sulfanilamide, respectively.

The following compounds are prepared. 8) Ethyl-9-(2,6-dichloro-phenyl-hydrazono)-6-methyl4-OXO-6,7,8,9-tetrahydro-4H-pyrido-(1,2-a)pyrimidine-3- carboxylate, mp. : 153—154°C. Analysis for the formula Calculated: C: 52.82%; H: 4.43%; N: 13.68%; Cl: 17.32%; Found: C: 52.52%; H: 4.47%; N: 13.75%; Cl: 17.26%. 9) Ethyl-6-methyl-9-(o-methyl-phenyl-hydrazono)-4>47839 - 35 oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate, mp.: 185°C.

Analysis for the formula C19H22N4°3 Calculated: C: 64.39 %; H: 6.25 %; N: 15.80 %; Found: C; 64.45 H: 6.01 %; N: 15.75 %; ) Ethyl-6-methyl-9-(3,4-methylenedioxy-phenylhydrazono)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3- carboxylate, mp.: 172-173°C.

Analysis for the formula cj_9H20N4°5 Calculated: C: 58.02 %; H: 5.38 %; N: 14.23 %; Found: C: 58.22 %; H: 5.39 %; N: 14.35 %; 11) Ethyl-6-methyl-9-(o-nitro-phenyl-hydrazono)4- OXO-6,7,8,9-tetrahydro-4H-pyrido(1,2, a) pyrimidine-3carboxylate, mp.: 19O-192°C.

Analysis for the formula cx8Hi9N5°5 Calculated: C: 56.10 %; H: 4.96 %; N: 18.17 %; Found: C: 56.12 %; H. 5.04 %; N: 18.12 %; 12) Ethyl-6-methyl-9-(£-nitro-phenyl-hydrazono)4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2,a)pyrimidine-3carboxylate, mp.: 218-219°C.

Analysis for the formula cigHi9N5°5 Calculated: C: 56.10 %; H: 4.96 %; N: 18.17 %; Found: C: 55.98 %; Hi 4.80 S; N: 18.03 %; 13) Ethyl-9-/g-(aminosulphonyl)-phenylhydrazono/- 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate-monohydrate, mp.: 21O-213°C.

Analysis for the formula ci8H21N5°5S'H2° Calculated: C: 49.42%; H: 5.30 %; N: 16.01 if S: 7.33 %; Found: C: 49.01 %; II: 5.11 %; N: 15.74 %; S: 7.52 %; - 36 EXAMPLE 14 To a mixture of 93.1 g. (1.0 mole) of aniline and 480 ml. of a 1:1 diluted aqueous hydrochloric acid solution at 0—5°C under stirring a solution of 68.9 g. (1.0 mole) of sodium nitrite and 500 ml. of water is slowly added dropwise. Thereafter to the reaction mixture 65.0 g. of solid sodium acetate are added in portions.

To 208.2 g. (1.0 mole) of 6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid 500 ml. of water are added and the pH is adjusted to 7 with a 10 weight/volume % aqueous sodium carbonate solution; hereby a solution is formed. The said solution is slowly added dropwise under vigorous stirring to the previously prepared diazonium salt.

The reaction mixture is stirred at O—5°C for 2—3 hours whereupon it is allowed to stand in a refrigerator overnight. The precipitated crystals are filtered off and washed with a small amount of water.

The crude product is dissolved in an aqueous sodium hydroxide solution and clarified with activated charcoal.

The solution is then acidified and the precipitated crystals are filtered off. Yield: 293.0 g. (93.8%) of 9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid. Mp.: 255—256°C. (After re25 crystallization from dimethylformamide the melting point rises to 267—268°C.) Analysis for the formula C H N.O. lo lo 4 J Calculated: C: 61.53%; H: 5.16%; N: 17.94%; Found: C: 61.62%; H: 5.26%; N: 18.10%. - 37 EXAMPLE 15 To a solution of 0.6 g. (0.015 mole) of sodium hydroxide and 25 ml. of water 3.4 g. (0.01 mole) of ethyl9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido(l,2-a)pyrimidine-3-carboxylate are added. The suspension formed is stirred at 50—60°C for 4—5 hours whereby a solution is obtained. The pH is adjusted to 2 by adding a 1:1 diluted aqueous hydrochloric acid solution. The precipitated crystals are filtered off and washed with a small amount of water. Yield: 2.7 g. (86.4%) of 9-(phenyl-hydrazono) -6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid. Mp.: 267—268°C. The product does not give a melting point depression when admixed with the compound prepared according to Example 14.

EXAMPLE 16—23 The process according to Example 14 is carried out except that aniline is replaced by p-bromo-aniline, anthranilie acid, ja-chloro-aniline, o-toluidine, 2,6-dimethylaniline, 2,4,5-trimethyl-aniline, 2,4,6-trimethyl-aniline and 3-amino-pyridine, respectively. The following compounds are prepared. 16) 9-(p-bromo-phenyl-hydrazono)-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid, mp. : 250—252°C.

Analysis for the Formula C27Hi6N4°5 Calculated: C: 49.12%: H: 3.86%; Ns 14.32%; Br: 20.43%; Found: C: 48.90%; H: 3.86%; N: 14.36%; Br: 20.66%. 17) 9- (o_-carboxy-phenyl-hydrazono) -6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid, mp.: 266—268°C. - 38 Analysis for the formula ^7^5^4^5 Calculated: C: 57.30%; H: 4.53%; N: 15.72%; Found: C: 57.87%; H: 4.40%; Ns 15.62%. 18) 9- (p-chloro-phenyl-hydrazono)-6-methyl-4-oxo5 6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid, mp.: 262—264°C.

Analysis for the formula C^gH^gN^OjCl Calculated: C: 55.42%; H: 4.36%; N: 16.16%; Cl: 10.22%; Found: C: 55.40%; H: 4.21%; N: 16.02%; Cl: 10.21%. 19) 6-methy1-9-(o-methyl-phenyl-hydrazono)-4-oxo6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid, mp.: 221—223°C.

Analysis for the formula C]_7H]_gH4°3 Calculated: C: 62.57%; H: 5.56%; N: 17.17%; Found: C: 62.83%; H: 5.55%; N: 16.83%. ) 6-methyl-9-(2,6-dimethyl-phenyl-hydrazono)-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3carboxylic acid, mp.: 192—193°C.

Analysis for the formula N.0„ 4 3 Calculated: C: 63.14%; H: 5.88%; N: 16.36%; Found. C: 63.14%; H: 5.93%; N: 16.15%. 21) 6-methyl-9-(2,4,5-trimethyl-phenyl-hydrazono)-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate acid, mp.: 224—226°C.

Analysis for the formula C Η -N 0, iy 4 j Calculated: C: 62.78%; H: 6.28%; N: 15.81%; Found: C: 62.43%; H: 6.07%; N: 15.32%. 22) 6-methyl-9-(2,4,6-trimethyl-phenyl-hydrazono)-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-347839 - 39 carboxylic acid, mp.: 195 —197°C.

Analysis for the formula c^gH22N4°3 Calculated! C: 62.78%; H; 6.26%; N: 15.81%; Found; C: 63.29%; H: 6.17%; N: 15.68%. 23) 6-methyl-9-(3-pyridyl-hydrazono)-4~oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid, mp.: 236—237°C.

Analysis for the formula C£5Hi5Ng°3 Calculated: C: 57.50%; H: 4.83%; N: 22.35%; Found: C: 57.81%; H: 4.85%; N: 22.27%.

EXAMPLE 24 1.8 g. (0.01 mole) of 2,4-dinitro-aniline are dissolved in a mixture of 15 ml. of glacial acetic acid and 1.1 ml. of concentrated sulfuric acid. The solution is cooled to 10— °C whereupon 0.7 g. (0.01 mole) of sodium nitrite are added under stirring in portions. The diazonium salt is precipitated by addition of ether, separated by decanting and dissolved in 10—15 ml. of ice-cold water.

Thereafter one proceeds as described in Example 14 except that no sodium acetate is added to the reaction mixture.

On recrystallizing the crude product from acetonitrile 0.8 g (20.0%) of 6-methyl-9-(2,4-dinitrophenyl-hydrazono)-4oxo-6,7,8,9-tetrahydro-4H-pyrido{l,2-a)pyrimidine-3-carboxylic acid are obtained. Mp.: 257—258°c.

Analysis for the formula Calculated: N: 47.88%; H: 3.26%; N: 20.94%; Found: N: 47.74%; H: 3.39%; N: 20.66%. - 40 EXAMPLE 25 A solution of 1.9 g (0,01 mole)of sulfanilic acid {0.8 g. (0.01 mole) of sodium hydrogen carbonate and 0.7 g. (0.01 mole) of sodium nitrite in 10 ml. of water is added dropwise at 0—5°C under stirring to 5 ml. of a 1:1 diluted aqueous hydrochloric acid solution. Thereafter one proceeds in the same manner as described in Example 14. The crude product is recrystallized from a 75% aqueous methanol.

Yield: 0.3 g. (7.6%) of 6-methyl-4-oxo-9-(p-sulfo-phenyl)10 hydrazono-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3carboxylic acid. Mp.: above 290°C.

Analys is for the formula C Η N 0 S 16 16 4 6 Calculated: C: 48.98%; H: 4.11%; N: 14.28%; S: 8.17%; Found: C: 49.11%; H: 4.10%; N: 14.21%; S: 8.25%; EXAMPLE 26 To 780 ml. of methanol, 80.0 g. (0.28 mole) of 9bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid are added whereafter to the suspension 155 ml. of a 50 weight/volume % aqueous hydrazine hydrate solution are rapidly poured at once under stirring.

The reaction mixture warms up and a solution is formed. The reaction mixture is stirred at room temperature for 2—=3 hours, whereupon the precipitated crystals are filtered off.

The filtered hydrazinium salt is dissolved in 400 ml. of water and the acid is set free by adding an equivalent amount of solid potassium hydrogen sulfate. The precipitated crystals are filtered off, washed with a small amount of water and dried. After recrystallization from 50% aqueous ethanol 40.2 g. (60.8%) of 9-hydrazono-6-methyl-4-oxo30 6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid are obtained. Mp.: 202-—2O3°C. - 41 Analysis for the formula ci0Hi2N4°3 Calculated: C: 50.84%; Hs 5.12%; N: 23.72%; Found: C: 50.46%; H: 5.30%; N: 23.68%.

EXAMPLE 27 Into a suspension of 34.0 g. (0.14 mole) of 9-hydrazono6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine3-carboxylie acid and 700 ml. of anhydrous ethanol dry gaseous hydrogen chloride is introduced at 10—15°C under stirring. After saturation took place the solution is allowed to stand in a refrigerator overnight.

Next day the solvent is distilled off in vacuo. The residue is dissolved in 50 ml of water, the solution obtained is neutralized with a 5 weight/volume % aqueous sodium carbonate solution and extracted four times with 100 ml. of chloroform each. The united organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo.

After crystallization of the residue from methanol 18.0 g. (48.6%) of ethyl-9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylate are obtained, mp.: 199—200°C.

Analysis for the formula ci2H16N4°3 Calculated: C: 54.54%; Hs 6.10%; N: 21.20%; Found: C: 53.88%; H: 6.20%; N: 21.10%.

EXAMPLE 28 To a solution of 2.0 g. (7.57 millimoles) of ethyl 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylate and 20 ml. of anhydrous chloroform 1.6 ml. (11.35 millimoles) of triethylamine and 1.3 ml. (11.35 millimoles) of benzoyl chloride are added.

The mixture is heated to boiling for 2 hours, whereupon it - 42 is cooled to room temperature and thoroughly admixed with 20 ml. of water. The organic phase is separated and the aqueous layer is extracted with 10 ml. of chloroform. The united organic phase is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from methanol. Thus 1.5 g. (53.6%) of ethyl-9-(benzoylhydrazono)-6-me thyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are obtained. Mp.: 209— 210°C.

Analysis for the formula C ,„H„ Ν O 19 20 4 4 Calculated: C: 61.96%; H : 5.47%; N: 15.20%; Found: C: 62.02%; H : 5.58%; N: 15.61%.

EXAMPLE 29 A suspension of 2.0 g. (7.57 millimoles) of ethyl-9hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 20 ml. of ethanol is heated to boiling whereupon 4.0 ml. of a 50 weight/volume % aqueous hydrazine hydrate solution is added dropwise. The reaction mixture is heated to boiling for 15 minutes, whereby a solution is formed. On cooling crystallization takes place.

On recrystallization of the crude product from methanol 1.0 g. (52.8%) of 9-hydrazono-6-methyl-4-oxo5,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carbohydr- azide are obtained. Mp. : 219—-22O°C. Analysis for the formulaC10H14N6°2 Calculated: C: 47.99%; H: 5.64%; N: 33.58%; Found: C: 48.43%; H: 5.67%; N: 23.59%. EXAMPLE 30 To a solution of 4.0 g. (12.73 millimoles) of ethyl9-bromo-6-methy1-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)47839 - 43 pyrimidine-3-carboxylate and 20 ml. of ethanol 8.0 ml. of a 50 weight/volume % aqueous hydrazine-hydrate solution are added dropwise under stirring. The solution is stirred at room temperature for 2 hours. The precipitated crystals are filtered off, washed with a small amount of ethanol and dried. On recrystallization from ethanol 1.6 g. (50.2%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carbohydrazide are obtained. Mp.: 219— 220°C. The product does not show a melting point depression when admixed with the compound prepared according to Example 29.

EXAMPLE 31 .0 g. (0.03 mole) of ethyl-9-(phenyl-hydrazono)-6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylate are dissolved in 30 ml. of ethanol under warming. To the solution 40 ml. of a concentrated aqueous ammonium hydroxide solution are added under stirring. The reaction mixture is allowed to stand for a day, then the precipitated crystals are filtered off.

On recrystallizing the crude product from nitromethane 5.0 g. (53.5%) of 9-(phenyl-hydrazono)-6-methyl-4oxo-6.7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are obtained. Mp.: 246—247°C.

Analysis for the formula cxgHi7N5°2 Calculated: C: 61.73%; H: 5.50%; N: 22.49%; Found: C: 61.51%; H: 5.58%; N: 23.17%.

EXAMPLE 32 One proceeds as described in Example 6 except that instead of an aqueous solution of ethyl-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate - 44 an acetonous solution of 6-methyl-4-oxo-6,7,8,9-!tetrahydro4H-pyrido(l,2-a)pyrimidine-3-carbonitrile is added dropwise to the reaction mixture. The melting point of the 9(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H5 pyrido(l,2-a)pyrimidine-3-carbonitrile-monohydrate thus obtained amounts to 223—224°C.

Analysis for the formula Calculated: C: 61.73%? H: 5.50%; N: 22.49%; Found: C: 61.40%; H: 5.32%; N: 22.76%.

EXAMPLE 33 To a mixture of 0.9 g. (0.01 mole) of aniline and 5 ml. of a 1:1 dilute aqueous hydrochloric acid solution at 0—5°C tinder stirring a solution of 0.7 g. (0.01 mole) of sodium nitrite and 5 ml. of water is slowly added dropwise.

To the reaction mixture 6.0 g. of solid sodium acetate are added in portions, whereupon a solution of 2.5 g. (0.01 mole) of ethyl-9-formyl-6-methyl-4-oxo-l,6,7,8-tetrahydro4H-pyrido(1,2-a)pyrimidine-3-carboxylate and 20 ml. of acetone is added under vigorous stirring.

The reaction mixture is stirred at 0—-5°C for 3—4 hours, whereupon the acetone is distilled off in vacuo.

The residual aqueous solution is extracted three times with 10 ml. of chloroform each. The united organic phases are thoroughly admixed with 30 ml. of water, the layers are separated, the chloroform solution is dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is recrystallized from ethanol, the crystals are dried at 90— 100°C over phosphorous pentoxide in a vacuum-drier. Thus 0.7 g. (20.6%) of ethyl-9-(phenyl-hydrazono)-6-methyl-430 oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxy47839 - 45 late is obtained, which melts at 138—139°C and does not give any melting point depression when admixed with the compound prepared according to Example 1, 2 or 3, EXAMPLE 34 To 12 ml. of dimethylsulfoxide 2.0 g. (7.57 millimoles) of ethyl-9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are added.

To the suspension 1.2 ml. (11.88 millimoles) of benzaldehyde are added. The reaction mixture is allowed to stand at room temperature for 4--6 days, whereby a solution is obtained. The solution is diluted with 20 ml. of water and extracted three times with 30 ml. of benzene each. The united organic layer is dried over anhydrous sodium sulfate and evaporated in vacuo. To the residual dark oil 25 ml. of diethyl ether are added, whereby crystals precipitate.

The crystals are filtered off and washed with a small amount of ether. Yield: 2.0 g. (75.0%). The end-product is a mixture of isomers. The isomers are separated on a preparative plate prepared with a Kieselgel 60 PF254+366 absorbent (20 x 20 cm., thickness 1.5 mm.) by thin layer chromatography. Developing agent: 7:1 mixture of benzene and methanol. Eluent: 1:10 mixture of methanol and dichloromethane. The product having a higher value is the ethyl-9-(benzylidene-hydrazino)-6-methyl-4-oxo-6,7dihydro-4H-pyrido(l,2-a}pyrimidine-3-carboxylate, mp.: 142—144°C.

Analysis for the formula Cjg^2o^4^3 Calculated: C: 64.77%; H: 5.72%; N: 15.89%; Found: C: 64.70%; H: 5.85%; N: 15.73%.

The product having a lower R_ value is the ethyl-94 7 8 3 9 - 46 (benzylidene-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido(l,2-a)pyrimidine-3-carboxylate, mp.: 133—134°C. yield: 0.75 g.

Analysis for the formula cxg^2OH4°3 Calculated: C: 64.77%; H: 5.72%; N: 15.89%; Found: C: 64.43%; H: 5.53%; N: 15.82%.

EXAMPLE 35 One proceeds as described in Example 14 except that aniline is replaced by p-phenetidine. Thus 9-(p-ethoxy10 phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido(1,2-a)pyrimidine-3-carboxylie acid are obtained. Yield: 7.6 g. (53.3%). Mp.: 218—219°C.

Analysis for the formula C,„H__N0 J 18 20 4 4 Calculated: C: 60.67%; H: 5.66%; N: 15.72%; 15 Found: C: 60.52%; H: 5.73%; N: 15.74%.

EXAMPLE 36 One proceeds as described in Example 14 except that 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylic acid is replaced by (-)-6-methyl-4-oxo-6,7,8,920 tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid [ 91.0%.

Analysis for the formula C,.H,-N 0_ J 16 16 4 3 Calculated: C: 61.53%; H: 5.16%; N: 17.94%; Found: C: 61.48%; H: 5.04%; KF: 17.82%. 7 8 3 9 - 47 EXAMPLE 37 One proceeds as described in Example 14 except that 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylic acid is replaced by (+)-6-methyl-4-oxo-6,7,8,8tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid [α]2°=+1ΐ0Ο (C = 2, methanol) . Thus (+)-9-(phenylhydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid is obtained [a]^°= +407.5° (C = 2, dimethylformamide) . mp.: 255—256°C.

Yield: 92.5%.

Analysis for the formula c^gH^5N4°3 Calculated: C: 61.53%? H: 5.16%; N: 17.94%; Pound: C: 61.72%; H: 5.22%; N: 18.01%.

EXAMPLE 38 One proceeds as described in Example 1 except that 6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylic acid is replaced by 7-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid.

Thus 9-(phenyl-hydrazono)-7-methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid is obtained.

Mp.: 255—256°C.

Analysis for the formula <-]_θΗ]_5Ν4θ3 Calculated: C: 61.53%; H: 5.16%; N: 17.94%; Found: C: 61.27%; H: 5.17%; N: 17.78%.

EXAMPLE5 39—62 0.03 mole of an aniline derivative disclosed in Table 1 is dissolved in 14.4 ml. of 18 weight/volume % hydrochloric acid, the solution is cooled to 0—5°C and at this temperature a solution of 2.1 g. of sodium nitrite and 15 ml. of water is added dropwise. To the reaction mixture 18 g. of sodium acetate are added and the diazonium salt 839 - 48 solution thus formed a mixture of 0.03 mole of 6-methyl-4oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3carboxylic acid in an aqueous solution of 30 ml. of water and 7 ml. of 10 weight/volume % sodium hydroxide is added dropwise at a temperature below 5°C. The addition having been completed the reaction mixture is stirred at 0—5°C and the precipitated crystals are filtered off and washed with water. The product is crystallized from the solvent disclosed in Table 1.

EXAMPLE 63 7.8 g. (0.02 mole) of ethyl-9-phenyl-hydrazono)-6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine3-carboxylate are dissolved in 100ml. of ethanol. To the solution 6.0 ml. of 98% hydrazine-hydrate are added and the reaction mixture is refluxed for 2 hours. On cooling the precipitation of crystals begins. The crystals are filtered off and washed with ethanol. Thus 5.4 g. (82.7%) of 9(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido(l,2-a)pyrimidine-3-carbhydrazide are obtained.

Analysis for the formula C Η N 0 Ιο 18 b 2 Calculated: C: 58.89%; H: 5.56%; Ns 25.75%; Pound:. C: 59.06%; H: 5.47%; Ns 25.52%.

EXAMPLE 64 In 150 ml. of methanol 10.0 g. (34.95 millimoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidxne-3-carboxamide are dissolved under heating. To the solution 20 ml. hydrazine hydrate are added dropwise under stirring carefully within 10 minutes. The reaction mixture is heated to boiling for 40 minutes whereupon the methanol is distilled off in vacuo. The crystals are 7 8 3 9 - 49 filtered off, washed with water and crystallized from water. Thus 3.8 g. (46.5%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are obtained. Mp.: 248—25O°C.

Analysis for the formula Clr>H. _N 0_ XU □ 2 Calculated! C: 51.06%; H; 5.57%; N: 29.77%; Found: C: 50.59%; H: 5.46%; N: 29.85%, EXAMPLES 65—67 2.9 g. of (0.01 mole) of 9-bromo-6-methyl-4-oxo-6,7,8, 9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are dissolved in 20 ml. of methanol and 0.025 mole of a hydrazine derivative enumerated in Table 11 is added. The reaction mixture is stirred for 1—3 hours at the boiling point.

The product is filtered off or isolated by evaporation.

The product may be recrystallized from water.

EXAMPLES 68—69 2.9 g. (0.01 mole) of 9-bromo-6-methyl-4-oxo-6,7,8,9tetrahydro-4H~pyrido(l,2-a)pyrimidine-3-carboxylic acid are dissolved in 20 ml. of methanol and 0.025 mole of a hydrazine derivative enumerated in Table 111 are added. The reaction mixture is heated to boiling for 1—3 hours. The product is either filtered off or isolated by evaporation and may be recrystallized from water.

EXAMPIE 70 The compound of 9-(phenyl-hydrazono)-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid is prepared by the process disclosed in Example 14 except that sodium acetate is added to the reaction mixture. Yield: 75%, Mp.: 256—57°C. The product does not show a melting point depression when admixed with the compounds 8 39 - 50 prepared according to Example 14.

Analysis for the formulaC16 ,H16N4°3 Calculated: C: 61.53%; H: 5.16%; H: 17.94%; Found: C: 61.48%; H: 5.01%; N: 17.80%.

EXAMPLE 71 The process according to Example 6 is carried out except that ρ-ehloro-aniline is replaced by aniline and ethyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylate is replaced by ethyl-7-methyl-410 oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxy· late, respectively. Thus ethyl-9-(phenyl-hydrazono)-7methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylate is obtained with a yield of 60.2%. Mp.: 165— 167°C.

Analysis for the formulaC18H20N4°3 Calculated: C: 63.51%; H: 5.92%; KT: 16.45%; Found: C: 63.24%; H: 5.80%; N: 16.35%.

EXAMPLE 72 The process according to Example 6 is carried out 20 with the difference that aniline and ethyl-8-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are used as starting material. Thus ethyl-9-(phenyl-hydrazo no)-8-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimi dine-3-carboxylate is obtained with a yield of 61.5%. Mp.: 108—11O°C.

Analysis for the formula c^gH2oN4°3 Calculated: C: 63.51%; H: 5.92%; N: 16.45%; Found: C: 63.30%; H: 6.01%; N: 16.52%.

EXAMPLE 73 The process according to Example 6 is carried out - 51 with the difference that aniline and dimethylformamide solution of 2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido(l,2-a)pyrimidine-3-carboxamide is used. The crude 9-(phenyl-hydrazono)-2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro5 4H-pyrido(1,2-a)pyrimidine-3-carboxamide melts at 235— 237°C, yield: 49.2%.

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H· I 3* m; S H> ~ I o i i I £» E _ I π·*ϋ I H· 00 ω ex * §<« σ\ 81 o vo I J I H· Ω Qi 3 O K w 0 * N to 3 I 3 DJ H> *-* * 3 tf -J O 0 2 --—'Pi CD I N (X » σ» S h· VO I H 3 1 3 H· 3 ft ro CX rt 3 ft 3 34 <+ 3* 3 S H S 0 t~> 3 Η I I I I A in O tn to to to tO to co CD 00 1 O I 1 bJ 1 w to o o to Ω o Ω Ω £ Qi & sr H' Pi X —. H· £ Ω h3 th a g § 0 P M W 3 O to o to o to cn σι in in σν <5V Ω 00 00 co w co CO n 3 • • « • • H* K i—4 in O H CO Ω to σ> Ό o to 00 • σν σν cn 0> • • • • • a cn -j O δ o o -J K ω ch o in to to co co CO CO cn in CD co to to 0 • • • • • • a 3 4^ 4^ o O co VO 3 b-* ω o VO -4 ω 0» - 59 σ' oo 3* ρΡΐ >< 8* Φ I η ω <+ φ Φ Φ »3 Ν a κ Ο Φ ο 3 Φ 1 I 81? Φ Ν Ρ Ρ· I 3 Φ g (Β h Ρ· Φ Ρ S3 8* et- η» Ρ· Ν 3 Ρ· κβ ϊ ρ 3 Ρ· *-* ng ω κ ο Ρ· ρ 3 Οι ΡΙ a £ ? φ »ϋ 0 34 κο η — rt 3 KD X Μ ί 0J r—> Φ IS I 0 a Η * <+ ft ζ—. π to Ο* Μ Η 3- 3 σ' φ | Ο 1 81 Φ « Ν Φ X Ρ 3· ft •ο Ο Ν —1< 1 3* «· 3 Φ Η>Ο & Α»< 00 Ο »3 η·>3 μ 1 Ρ * Ρ Ο Η Ο Ο I κο 1 3 Η· 1 X 3* 1 σ' ►< 8· 3 £ Ο ft | Ρ η η· ta 1 & φ 3 Ρ· Η· Οι 1 σ> π ft rt ΕΤ S3 8-1 Ο I ι Q, μ. 3 Φ I ω Ό * 3 SON π * Ο Ρ· 00 3 a * jL Ο KO Τ ι ι σ' ι Ρ to σ' ρ σ' I σ' | 1 Ό Ρ Ο 00 Ω Ω Ρ Ρ σ» Ρ_ Β Β to ρ ρ A Β Β ιη A Ο Ο ω ω υι U1 Ό -ο • 00 κο ΙΟ κθ Όκο σ' σ» to ω κο 00 to to Ρ Ρ « • Ρ Ρ ο ω KOtO tOtO to GJ 0000 a & ►s Η* Φ Ρ a (?$ Ρ · φ ο > • 3 Φ Ρ k* ω ρω *1 & - 60 EXAMPLE 74 .7 g. (0.02 mole) of 9-bromo-6-methyI-4-oxo-6,7,8,9 tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-earboxylic acid are dissolved in 30 ml. of anhydrous ethanol, whereupon 4.3 ml. (0.044 mole) of phenyl-hydrazine are added. The reaction mixture is refluxed for 4 hours under stirring, whereupon the precipitated crystals are filtered off and washed with ethanol. Thus 4.7 g. (75.2%) of 9-(phenyl-hydrazono)-6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine10 3-carboxylic acid are obtained. Mp.: 258—260°C. After recrystallization from dimethylformamide the melting point rises to 267—268°C. The product does not give a melting point depression when admixed with the product prepared according to Example 14.

EXAMPLE 75 2.2 g. (0.01 mole) of 9-hydroxy-6-methyl-4-oxo-6,7dihydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid are dissolved in 15 ml of anhydrous ethanol. To the solution 1.2 ml (0.012 mole) of phenylhydrazine are added. The reaction mixture is refluxed for half an hour under stirring. The precipitated crystals are filtered off and washed with ethanol. Thus 2,4 g. (76%) of 9-(phenyl-hydrazono)-6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-carboxylic acid are obtained. Mp.: 267—8°C. (from di25 methylformamide). No melting point depression with the product according to Example 14.

EXAMPLE 76 One proceeds according to Example 74 except that (-) 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)30 pyrimidine-3-carboxylic acid [(α)^θ= -450 (c = 1, methanol)] - 61 is used. Thus (+)-9-(phenyl-hydrazono)-6-methyl~4-oxo6.7.8.9- tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid is obtained. The product is identical with the compound prepared according to Example 37 and gives with the same no melting point depression. Yield: 76.0%. Mp.: 256—7°C; (α)^θ= +407.5° (c = 2, dimethylformamide).

EXAMPLE 77 To a mixture of 0.45 ml. (0.005 mole) of aniline and 2.5 ml. of a 1:1 mixture of aqueous hydrochloric acid a solution of 0.3 g. (0.005 mole) of sodium nitrite and 2.5 ml. of water is slowly added at 0—5°C. To the reaction mixture 3.0 g. of solid sodium acetate are added whereupon a solution of 1.2 g. (0.005 mole) of ethyl-(6-methyl-4-oxo6.7.8.9- tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-yl)-acetate and 2.5 ml. of water is slowly added under vigorous stirring. The reaction mixture is stirred at 0—5°C. for 2—3 hours whereupon it is allowed to stand in a refrigerator overnight. The aqueous phase is decanted and the residual yellowish gum is recrystallized from methanol. Thus 0.5 g. (25.9%) of ethyl-[9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyriraidine-3-yl] -acetate are obtained. The product contains 1 molequivalent of crystal methanol. ¢¢).: 100—102°C.

Analysis for the formula C^gH^N^O^.CH^OH Calculated: C: 62.16%; H: 6.78%; N: 14.50% Pound: C: 62.34%; H: 6.69%; N: 14.73%.

EXAMPLE 78 One proceeds according to Example 77 except that (6methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine3-yl)-acetic acid is used as starting material. The crude - 62 product obtained is diluted with a tenfold amount of water, the pH is adjusted to the value of 8 with sodium hydroxide solution, whereupon the solution formed is acidified to pH = 3 with hydrochloric acid. The precipita5 ted crystals are filtered off and washed with water. Thus [9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido(l,2-a)pyrimidine-3-yl]-acetic acid is obtained. Yield: 59.5%. Mp.: 160—2°C.

Analysis for the formula Ο^Η^θΝ^Ο^ Calculated: C: 62.57%; H: 5.56%; N: 17.17%; Found: C: 63.11%; H: 5.49%; N: 16.98%.

EXAMPLE 79 One proceeds according to Example 77 except that 6methyl-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyximidine-4-one is used as starting material. Thus 9-(phenyl-hydrazono)-6methy1-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-4-one is obtained. Yield: 52.2%. Mp. : 163—165°C.

Analysis for the formula 0,_Η,^ΝΛ0 15 16 4 Calculated: C: 67.15%; H: 6.01%; N: 20.88%; Found: C: 66.92%; H: 5.98%; N: 21.00%.

EXAMPLES 80—87 The following compounds of the general Formula 1 enumerated in Table IV are prepared according to the process described in Example 39—62. - 63 oo to Φ rt to 3 3 ι η·Μ 3 μ» W Ρ 31 I ” Ω to Qi Φ I H K Φ 0 I Ο tt 4* a I Η· K Oi H· H« P, 3 O Φ I 1 σι ro 3* ko * rtKJ I 8-fe CD Η Φ I * 1 N 3 Φ I I 3 tt ft 0 iO 3* Φ XN £ rt 0 P H I oikj Φ I I 1 H to I H *J 4* 8?. ft ft £3 I Φ to CO σι σι σι σι μ* to A <0 4* Ul 10 Ο 4* μι μι μ* Ul υι • • μι 4^ σι ί 01 ο 3 I ro to Ο_ ςη σι υι υι • * σι ω 00 4* A 4*> • • 00 10 10 00 μ* μι ω ω • a 00 4* Ul Ο1 ί> Η· I >0 Φ δ 3 Φ Η· 3 3 Κ! 0 I-· I 05 Φ ft ft Φ ω Ο 3 ι « >< ο u a Οι ι π Μ Φ Ο 0“^ I Ρ Ό & a ι Ο. Η· κ· a a ο φ σι g 3* ω » Φ >< I 00^ Φ I μ· Ν Οι I Ο Η· 4* 3 tt ό^Φ Ο < μ< σ» to φ φ Ω Ω Η· Φ 0« ft Η· Ω to <0 σι σι 00 00 a • to ο 4* ω UI υι a • to μ» ω ω μι μ* 4*ι 4* • a to 4* 00 to i_itq Η Oj tt Η & Ω ft Η« * © ο a Ott ω » ο φ <Γ Η φ (ο ft rt Hi O w H · Φ Ω > • 3 Φ μ» Η· 0) tt Q 839 σι A heated to boiling in methanol. β (B ? 3 Ό Φ M 3* 0 I Φ Φ Φ 3 ft 3 OOH' 3 I 3 Φ A 3 I Ρ Ω Ρ M3 Η* Φ 3 3 Φ Ο I Φ A 3 I Ρ· Φ ρ £ 3 »< Φ ρ ι Φ ω 3 ω ο ι Φ ι ρ ο >ϋ Φ a φ 3* 3 κ (+ ρο4 3 3 ο φ ο χ η ι Φ Μ ρ 3 I Ρ· Φ Ω I I Ρ φ CQ φ (+ (+ φ Φ κ 3 ft Ρ· ΡΦ 3 Ρ ΐΩ Iq, .

H to ID O' I I 0 BI Οχ K 2 J 1“* H· rt DI 3? £81 P 0 3 I Φ A I X ω ι l *0 N ID 0 I 3 K. ^ubI I Φ σι Ω ι Φ 3 rt φ m; rt· P 3- I u p y I if A 3 I >< X V1 ? £ Φ p< A 0 S' KO PW XS J . ι j μ: σ» φ i ω Η * ν Φ I ρ -J Ο Ω η a * 3 Φ Φ Ο 00 ίο (+ π O' Ρ ΚΟ I ιΟ * ι σ' ι X Μ (+ I Ό ^ΙΦ33w Φ (+ Φ Φ H (+3 Ω *0 Φ 3* ρ s-^ Ρ Φ Α »< Ρ I Ω Ρ Ο» I Ρ 3 Κ A Ω» Ρ Ο ί I I Pl a Ρ X 3 I Φ Ό iS I ΡΩ a φ ο κ Z-S ' tf Ρ κο ο * I X w <+ Μι I Φ Ο 3* κο X μ; ι ? σι φ ι * Ν Ω •4 Ο S * 3 Φ 03.0 3 ^4 Ο I I σ' +j I - 3 3 Φ Φ 3 ft μ; 3* Ρ I Η ω ·ϋ φ . MJ tfS φ 3 μ; ρ Ω Ρ· Οι I ρ· 3 π A a ρο ι I I Ω Φ ρ Ρ * σ μ ο ι )- Τ) Ρφ 3 Ω Ρ ρ a &Η· Φ I σ' φ ι * Ν Φ -4 0(+ οο κο ι ι ι σ»>ϋ α ι 3 W 3 (D J Φ 3 Ό r+»< < 3 P A Mi I P· P a L O A ) ) ΦΌ κο A3 ; Φ ρ* Φ ρ a γ+ tr ο π X ρ 3 μ; - μρ ΙΌ Ωι Ρ» ί Π Ω Φ Ο I Φ Ό Α Ω MJ Β ρ· κ ι a ρ· σ' 3 κο ί Φ j ft (+ I 3* 3* Ω μ; Μ- φ Ρ Ρ Η ί I ο1 Α 3* Ο sH Ο Φ ω I Ν I σ' ο > 3 I Η a »π H Ο % Ω (+ Mi Ρφ Ο Ω H* fl) a ft P· KO ω § 2. iff Φ ο 3 I Φ σι σ' ρ Ρ οο ρ Κ) Μ ω ι ΙΌ ΙΌ σι § 3 φ ρ· rt rt 3* Η Φ Ο 3 I Φ σ' σ' ο Ο ΙΌ tO ρ ρ Α -4 Ο G' P tO C> σι w -j σ' σ' Ρ ΙΌ οο Ο Ο *4 Α ω α *4 θ' in sj ρ κο ο s ω »σ « # Ο Φ ρ Ω < Η φ μ; 3 φ ft <+ Ρ ~ Κ 3 3 ο 3 Ρ Ρ · Ω Ω Φ Ρ > Ω 3 • Φ ω ρ*3 ΒΙ & TABLE IV (Continued)

Claims (62)

1. Compounds of the general Formula 1 and their pharmaceutically acceptable salts, hydrates, stereoisomers, optically active isomer: , geometrical isomers and tautomers where such exist R 4 R 5 \ z (wherein R stands for hydrogen or lower alkyl; R^ is hydrogen, lower alkyl, styryl or a carboxylic 10 group or a derivative thereof; R and R 1 together form a group of the Formula — (CH=CH)2— and in this case the dotted line represents a further C—c bond, while in all other cases there is a single bond between positions 6 and 7; 15 R is hydrogen, lower alkyl or hydroxy; R is hydrogen, lower alkyl, aryl, lower alkanoyl, a carboxylic group or a derivative thereof or a group of the Formula —(CH.) —COOH or a derivative thereof formed on 2 m the carboxylic group; m = 1—3; - 66 4 R stands for hydrogen, lower alkyl which may be optionally substituted by hydroxy or carboxy; trifluoromethyl, optionally substituted aryl, phenyl-lower alkyl or an optionally substituted heterocyclic group; r5 stands for hydrogen, lower alkanoyl, optionally substituted benzoyl or heteroaryl; or 4 5 R and R together with the adjacent nitrogen atom form a piperidino, pyrrolidino or morpholino ring; or 4 5 . R and R together with the adjacent nitrogen atom form a group of the Formula R 6 z —N=C 6 7 wherein R is hydrogen and R is optionally substituted phenyl; Z stands for an oxygen atom and n=l) .

2. Compounds according to claim 1 wherein R is hydrogen and R 1 is hydrogen or lower alkyl.

3. Compounds according to claim 2 wherein R^ is methyl.

4. Compounds according to claim 2 or 3 wherein R is hydrogen.

5. Compounds according to any of claims 2—4 wherein R is a carboxylic group.

6. Compounds according to any of claims 2—4 wherein R is lower alkoxycarbonyl, carbamoyl, cyano, phenyl, lower alkyl or formyl.

7. Compounds according to any of claims 2—6 wherein R - 67 is a phenyl group optionally substituted by one, two or three identical or different substituent(s) selected from hydroxy, lower alkoxy, nitro, carboxylic group, lower alkyl, trifluoromethyl, methylenedioxy, amino and halogen; or a naphthyl group or a pyridyl group and R is hydrogen, formyl, acetyl, benzoyl or nicotinoyl.

8. Compounds according to Claim 1 wherein R is hydrogen, 1 2 3 R is methyl attached to position 6, R is hydrogen, R is a carboxylic group, R is optionally substituted phenyl and r5 is hydrogen.

9. 9-Phenylhydrazono-6~methyl-4-oxo-6,7,8,9-tetrahydro4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

10. (+)-9-Phenylhydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

11. Compounds according to claim 1 substantially as illustrated herein with reference to the Examples,

12. The compounds for which pharmacological data is given herein excepting the compounds of claims 9 and 10.

13. A process for the preparation of compounds of the general Formula 1 as defined in claim 1, wherein R is an 5 optionally substituted aryl or heteroaryl group and R is hydrogen, which comprises reacting a compound of the general Formula 11 68 1 2 (wherein R, R , R , Ζ, n and the dotted line are as defined in claim 1) with a diazonium salt of the general Formula III N„ Ar III or a reactive derivative thereof (wherein Ar stands for an optionally mono- or polysubstituted aryl or heteroaryl group).

14. A process according to claim 13 wherein said reactive derivative of a diazonium salt of the general Formula 111 is a compound of the general Formula Xlll XIII AS (wherein Ar has the meaning defined in claim 1).

15. A process according to claim 13 or 14, wherein the o reaction is performed at a temperature below 50 C.

16. A process according to claim 15 wherein said temperature 15 is in the range of 0—20 C.

17. A process for the preparation of compounds of the general Formula 1 as defined in claim 1 which comprises reacting a compound of the general Formula 11 as defined in claim 13 with a compound of the general Formula IV /' I \ IV 4783 - 69 4 5 (wherein R and R are as defined in claim 1) or for the preparation of compounds of the general Formula 1, wherein 5 R is hydrogen, with a reactive derivative thereof.

18. A process according to claim 17, wherein said reactive derivative of the compound of the general Formula IV is a compound of the general Formula XlV ,4 CH„ CH. X R 2 \ I N-CH -N } XIV CH„ (wherein R* has the meaning defined in claim 1).

19. A process according to claim 17 or 18 wherein water 10 formed during the reaction is removed by azeotropic distilla tion or with a dehydrating agent.

20. A process for the preparation of compounds of the general formula 1 as defined in claim 1 which comprises reacting a compound of the general Formula V 12 3 (wherein R, R , R , R , Z, n and the dotted line have the meanings defined in claim 1 and L stands for a leaving group) with a compound of the general Formula VI H-N—-N _ 2 \ 5 x R VI - 70 (wherein R 4 and Z have the meanings defined in claim 1) and oxidizing the intermediate product thus formed after or without isolation.

21. A process according to claim 20 wherein L in the com5 pound of general Formula V, stands for a halogen atom or a methanesulphonyloxy, p-toluene-sulphonyloxy, p-bromophenylsulphonyloxy or acetoxy group.

22. A process according to claim 20 or 21 wherein the intermediate product of the general Formula XV R 4 R 5 \ Z N 1 2 3 4 5 (wherein R, R , R , R , R , R , Z, n and the dotted line have the meanings defined in claim 1) is oxidized without isolation with the oxycen of air.

23. A process for the preparation of a compound of general Formula 1 as defined in claim 1 which comprises reacting a compound of the general formula Vll (wherein R, R meaning defined in claim 1 and L is a leaving group) or a tautomer thereof with a compound of the general Formula Vl as defined in claim 20.

24. A process according to claim 23, wherein L 1 in said starting material of the general Formula Vll stands for a halogen atom or a methanesulphonyloxy, p-toluene~sulphonyloxy, p-bromo-phenylsulphonyloxy, acetoxy or hydroxy group. 10

25. A process for the preparation of a compound of general Formula 1 as defined in claim 1 which comprises reacting a compound of the general Formula Vlll (wherein R, the meaning defined in claim 1 and L is a leaving group with an amine of the general Formula IX 4 7 8 3 9 - 72 IX HN i / I \ 4 5 or a salt thereof (wherein R and R have the meanings defined in claim 1).

26. A process according to claim 25, wherein in the starting material of the general Formula Vlll stands for a halogen atom or a methanesulphonyloxy, p-toluene-sulphonyloxy, p-bromophenylsulphonyloxy, acetoxy or hydroxy group.

27. A process for the preparation of a compound of general 5 Formula 1 as defined in claim 1, wherein R is hydrogen, 10 which comprises reacting a compound of the general Formula X 12 3 (wherein R, R , R , R , Z, n and the dotted line have the meanings defined in claim 1) with a compound of the general Formula XI 15 0 = N — R XI (wherein R has the meaning defined in claim 1).

28. A process according to claim 27 wherein the reaction is carried out in an inert solvent in the presence of a dehydrating agent. - 73

29. A process according to claim 28 wherein said dehydrating agent is dicyclohexylcarbodiimide.

30. A process for the preparation of compounds of the general Formula 1 as defined in claim 1 wherein R is an 5 5 optionally substituted aryl or heteroaryl group and R is hydrogen which comprises reacting a compound of the general Formula Xll 12 3 (wherein R, R , R , R , Z, n and the dotted line have the 10 meanings as defined in claim 1 and K stands for a leaving group) with a diazonium salt of the general Formula 111 as defined in claim 13 or a reactive derivative thereof and removing the group K from the intermediate product thus formed after or without isolation. 15

31. A process according to claim 30 wherein K stands for a formyl, lower alkanoyl group, or an optionally substituted aroyl or heteroaroyl group, or a carboxylic group or a derivative thereof.

32. A process according to claim 30 or 31 wherein the K 20 group is removed from the said intermediate product of the general Formula XVI - 74 N-Ar the meanings defined in claim 1 and K is a leaving group) by acidic or alkaline treatment. 5

33. A process according to any of claims 13—32 including the step of subjecting a compound of the general Formula 1 thus obtained to one or more of the following subsequent 1234,. 5 transformations: converting an E , R , E , R and/or R 1 2 3 4 5 group into another R , R , R , R and/or R group by methods 10 known per se; converting a compound of the general formula which contains an acidic group into a salt formed with a pharmaceutically acceptable base; converting a base compound of the general Formula 1 into an addition salt formed with a pharmaceutically acceptable acid; setting free a com15 pound of the general Formula 1 from its salt formed with an acid or a base; separating a racemic compound of the general Formula 1 into the optically active antipodes.

34. A process according to claim 33 wherein a carboxylic 1 2 3 group standing for R , R , R or being present in the group 4 5 20 R or R is converted into an alkoxycarbonyl, aryloxycarbonyl or araIkoxycarbonyl group by means of esterification; or is converted into the corresponding amide by reacting with an amine; or is removed by thermal decarboxylation. - 75

35. A process according to claim 33 wherein a carboxylic 12 3 acid ester group standing for R , R or R , or being present 4 5 in the group R or R is converted into another carboxylic acid ester group by transesterification; or is transformed into a carboxylic group by hydrolysis with an acid or an alkali; or is converted into an amide by treatment with ammonia or into the corresponding hydrazide by treatment with an optionally substituted hydrazine.

36. A process according to claim 33 wherein a cyano group 12 3 4 standing for R , R or R or being present in the group R or R is converted, into a carbamoyl or carboxylic group by alkaline or acidic hydrolysis.

37. A process according to claim 33 wherein a carbamoyl 12 3 4 group standing for R , R or R or being present in the R g or R group is converted into a carboxylic group by alkaline or acidic hydrolysis.

38. A process according to claim 33 wherein a carboxylic 12 3 acid hydrazido group standing for R , R or R , or being 4 5 present in group R or R is converted into a carboxylic group by alkaline or acidic treatment.

39. A process according to claim 33 wherein a compound of the general Formula 1, wherein R is hydrogen is converted into the corresponding compound of the general Formula 1, wherein R stands for a formyl, alkanoyl, or optionally substituted aroyl or heteroaroyl group by acylation.

40. A process according to claim 33 wherein a compound of 4 5 the general Formula 1, wherein R and R are hydrogen is converted into the corresponding compound of the general Formula 4 5 1, wherein —NR R stands for a grouping of the general 6 7 6 7 Formula —N=CR R (wherein R and R have the meanings - 76 defined in claim 1) by condensing with an aldehyde or a ketone.

41. A process according to claim 33 wherein a compound of the general Formula 1, wherein R stands for a phenyl group is nitrated, followed if desired by reducing the nitrophenyl derivative thus obtained and if desired acylating or alkylating the amino derivative thus formed.

42. A process according to any of claims 13—41 for the preparation of optically active compounds of the general Formula 1, which comprises using as starting material an optically active compound of the general Formulae 11, V, Vll, Vlll, X or Xll, or resolving an obtained racemic compound of the general Formula 1 into its optically active antipodes.

43. A process according to any of claims 13—42 including the step of converting a compound of the general Formula 1 obtained into its acid addition salt formed with hydrochloric acid, hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid or succinic acid.

44. A process according to any of claims 13—42 including the step of converting an obtained compound of the general Formula 1, containing a carboxyl or sulfonyl acid group into its alkali metal, alkaline earth metal or ammonium salt or its salt formed with triethylamine or triethanolamine.

45. A process according to any of claims 13—44 substantially as described herein and as illustrated in the Examples.

46. Pharmaceutical compositions comprising as active ingredient a compound according to any of claims 1—8 or 11, in admixture with inert solid or liquid pharmaceutical carriers. - 77

47. Pharmaceutical compositions according to claim 46 comprising the compound of claim 9.

48. Pharmaceutical compositions according to claim 46 comprising the compound of claim 10.

49. Pharmaceutical compositions according to claim 46 comprising a compound of claim 12.

50. The compounds of claims 1—12 for use as anti-allergic agents in human therapy.

51. 9-(p-Bromo-phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

52. 9-(p-Chloro-phenyl~hydrazono)-6~methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

53. 6-Methyl-9-(3-pyridyl-hydrazono)-4-oxo-6,7,8,9-tetrahydro-4H~pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

54. 9-Hydrazono~6~methyl-4-oxo-6,7,8,9-tetrahydro-4Hpyrido-(l,2-a)pyrimidine-3~carboxylic acid and its pharmaceutically acceptable salts.

55. 9-(g-Ethoxyphenyl)-hydrazono)-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

56. 9-(3,4-Dichloro-phenyl-hydrazono)-6-methyl-4-oxo6,7,8,9-tetrahydro-4H-pyr ido(1,2-a)pyr imidine-3-carboxylic acid and its pharmaceutically acceptable salts.

57. 9-(3-Nitro-phenyl)-hydrazono-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts. - 78

58. 9-(3-Chloro-phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

59. 9-(4-Carboxy-phenyl-hydrazono)-6~methyl-4-oxo-6,7,8,95 tetrahydro-4H-pyrido(l,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts.

60. 9-(3-Methyl-phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylic acid and its pharmaceutically acceptable salts. 10

61. Pharmaceutical compositions according to claim 46 comprising a compound of any of claims 5 to 60.

62. Compounds of any of claims 5 to 60 for use as antiallergic agents in human therapy.