NO152842B

NO152842B - OUTPUT MATERIALS FOR THE PREPARATION OF THERAPEUTIC ACTIVE 9-HYDRAZONO-PYRIMIDO- (OR PYRROLO) - (1,2-A) -PYRIMIDINE DERIVATIVES

Info

Publication number: NO152842B
Application number: NO791355A
Authority: NO
Inventors: Istvan Hermecz; Zoltan Meszaros; Istvan Bitter; Agnes Horvath; Lelle Vasvaro
Original assignee: Chinoin Gyogyszer Es Vegyeszet
Priority date: 1979-04-24
Filing date: 1979-04-24
Publication date: 1985-08-19
Also published as: NO791355L; NO152842C

Description

Foreliggende oppfinnelse angår nye utgangsmaterialer for fremstilling av terapeutisk aktive 9-hydrazono-pyrimido-(eller pyrrolo)-[1,2-a]pyrimidinderivater. The present invention relates to new starting materials for the production of therapeutically active 9-hydrazono-pyrimido-(or pyrrolo)-[1,2-a]pyrimidine derivatives.

Det er kjent at 2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-carboxylsyrederivater kan fremstilles ved katalytisk hydrogenering av de tilsvarende umettede forbindelser. [J. Het. Chem. 13, 797 (1976)]. It is known that 2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-carboxylic acid derivatives can be prepared by catalytic hydrogenation of the corresponding unsaturated compounds. [J. Hot. Chem. 13, 797 (1976)].

De nye utgangsmaterialer er kjennetegnet ved at de har generell formel: The new starting materials are characterized by their general formula:

hvori R og R betegner hydrogen eller C,_. alkyl, R 3betegner hydrogen, carboxy, alkalimetallcarboxylat, wherein R and R denote hydrogen or C,_. alkyl, R 3 denotes hydrogen, carboxy, alkali metal carboxylate,

C1-4 alkoxycarbonyl, carbamoyl eller cyano, C1-4 alkoxycarbonyl, carbamoyl or cyano,

n er 0 eller 1, og n is 0 or 1, and

a) hvis R 7 betegner hydrogen, R 5 og R 6 danner en ytterligere binding, betegner R 4 gruppen bestående av a) if R 7 denotes hydrogen, R 5 and R 6 form an additional bond, R 4 denotes the group consisting of

hvori x betegner halogen, where x denotes halogen,

R Qbetegner hydrogen eller C, . alkyl, R Q denotes hydrogen or C, . alkyl,

R 9 betegner hydrogen, C1-4 alkyl, kloracetyl, fenyl som eventuelt er substituert med ett eller flere halogen, R 9 denotes hydrogen, C1-4 alkyl, chloroacetyl, phenyl which is optionally substituted with one or more halogen,

C1-4 alkyl, C1-4 alkoxy eller C1-4 alkoxycarbonyl; eller nafthyl, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkoxycarbonyl; or naphthyl,

R<10> betegner C, . alkyl eller fenyl, og R<10> denotes C, . alkyl or phenyl, and

11 11

R betegner C-^.^ alkyl, eller R denotes C-1-3 alkyl, or

b) hvis R<6> og R^ danner sammen en ytterligere binding, betegner R 4 og R 5 sammen en gruppe beståoende av b) if R<6> and R^ together form an additional bond, R 4 and R 5 together denote a group consisting of

hvori R^, R^, R"*"0, R<1>^" og x har de ovenfor angitte betydninger, wherein R^, R^, R"*"0, R<1>^" and x have the meanings given above,

og p er 2, eller and p is 2, or

c) hvis R^ og R^ danner en ytterligere binding, og R^ betegner hydrogen, betegner R 4en gruppe bestående av c) if R^ and R^ form an additional bond, and R^ denotes hydrogen, R 4 denotes a group consisting of

8 9 8 9

hvori R og R har de ovenfor angitte betydninger, og optisk aktive derivater og salter derav. wherein R and R have the meanings given above, and optically active derivatives and salts thereof.

De nye utgangsmaterialer av generell formel I kan fremstilles ved følgende fremgangsmåter A, B og C: A. For fremstilling av en forbindelse av generell formel (I) The new starting materials of general formula I can be prepared by the following methods A, B and C: A. For the preparation of a compound of general formula (I)

hvori R og R1 betegner hydrogen eller C, , alkyl, in which R and R1 denote hydrogen or C, , alkyl,

3 14 3 14

R betegner hydrogen, carboxy, alkalimetallcarboxylat, R denotes hydrogen, carboxy, alkali metal carboxylate,

C^_4 alkoxycarbonyl, carbamoyl eller cyano, C₁₋₄ alkoxycarbonyl, carbamoyl or cyano,

n er 0 eller 1, og n is 0 or 1, and

a) hvis R^ betegner hydrogen, R^ og R^ danner sammen en ytterligere binding, betegner R 4 en gruppe bestående av a) if R^ denotes hydrogen, R^ and R^ together form an additional bond, R 4 denotes a group consisting of

eller or

hvori X betegner halogen, wherein X denotes halogen,

R Q betegner hydrogen eller C, , alkyl, R Q denotes hydrogen or C, , alkyl,

R 9betegner hydrogen, C-^_4 alkyl, kloracetyl, fenyl som eventuelt er substituert med ett eller flere nalogen, C1-4 alkyl, C1-4 alkoxy eller C1-4 alkoxycarbonyl; R 9 denotes hydrogen, C-1-4 alkyl, chloroacetyl, phenyl which is optionally substituted with one or more analogs, C1-4 alkyl, C1-4 alkoxy or C1-4 alkoxycarbonyl;

eller nafthyl, or naphthyl,

R10 oetegner C alkyl eller fenyl, og R 10 does not represent C alkyl or phenyl, and

11 11

R betegner alkyl eller R denotes alkyl or

6 7 6 7

b) hvis R og R sammen danner en ytterligere binding, betegner R og R^ sammen en gruppe bestående b) if R and R together form an additional bond, R and R^ together denote a group consisting

av of

hvori R^, R9, R"*"0, R^ og X har de ovenfor angitte betydninger, og wherein R^, R9, R"*"0, R^ and X have the meanings indicated above, and

p er 2, p is 2,

at en forbindelse av generell formel II that a compound of general formula II

hvori R, R 1 , R 3 og n har de ovenfor angitte betydninger, omsettes med et dihalogeno-methylen-ammonium-halogenid av formel III in which R, R 1 , R 3 and n have the meanings given above, is reacted with a dihalo-methylene-ammonium halide of formula III

hvori X betegner halogen og R<10> og R"^ har de ovenfor angitte betydninger, in which X denotes halogen and R<10> and R"^ have the meanings indicated above,

og, om ønsket, and, if desired,

- for fremstilling av en forbindelse av formel I - for the preparation of a compound of formula I

1 3 1 3

hvori R, R , R og n har de ovenfor angitte betyd-7 5 6 in which R, R , R and n have the meanings given above-7 5 6

ninger, R betegner hydrogen, R og R danner sammen en ytterligere binding, og R 4 betegner en gruppe nings, R denotes hydrogen, R and R together form a further bond, and R 4 denotes a group

at en således erholdt forbindelse omsettes med en that a connection thus obtained is traded with a

vannholdig alkohol, eller aqueous alcohol, or

- for fremstilling av en forbindelse av formel I hvori R, R 1 , R 3 og n har de ovenfor angitte betydninger, - for the preparation of a compound of formula I in which R, R 1 , R 3 and n have the meanings given above,

6 7 6 7

R og R danner sammen en ytterligere binding, og R and R together form a further bond, and

4 5 4 5

R og R sammen betegner en gruppe R and R together denote a group

hvori p har den ovenfor angitte betydning, at en således erholdt forbindelse omsettes med et diamin av generell formel HNH0-(CHo) -NH~„ hvori p har den ovenfor angitte betydning, fortrinnsvis i nærvær av et inert løsningsmiddel, in which p has the meaning stated above, that a compound thus obtained is reacted with a diamine of the general formula HNH0-(CHo)-NH~„ in which p has the meaning stated above, preferably in the presence of an inert solvent,

eller or

- for fremstilling av en forbindelse av formel I hvori R, r\ R"^ og n har de ovenfor angitte betydninger, - for the preparation of a compound of formula I in which R, r\ R"^ and n have the meanings indicated above,

7 5 6 7 5 6

R betegner hydrogen, R og R danner sammen en ytterligere binding, og R 4 betegner en gruppe hvori R g betegner C^_4 alkyl, at en således erholdt forbindelse omsttes med en alkohol i nærvær av et R denotes hydrogen, R and R together form a further bond, and R 4 denotes a group in which R g denotes C^_4 alkyl, that a compound thus obtained is reacted with an alcohol in the presence of a

alkalialkanoat, eller alkali alkanoate, or

- for fremstilling av en forbindelse av formel I hvori 1 3 - for the preparation of a compound of formula I in which 1 3

R, R , R og n har de tidligere angitte betydninger, R^ betegner hydrogen, R^ og R^ betegner en gruppe R, R , R and n have the previously indicated meanings, R^ denotes hydrogen, R^ and R^ denote a group

8 9 10 11 hvori R , R , R , R og X har de ovenfor angitte betydninger, at en således erholdt forbindelse omsettes med et primært eller sekundært amin av formel 8 9 10 11 in which R , R , R , R and X have the meanings given above, that a compound thus obtained is reacted with a primary or secondary amine of formula

8 9 8 9

hvori R og R har de ovenfor angitte betydninger, wherein R and R have the meanings given above,

i nærvær av et inert løsningsmiddel, eller in the presence of an inert solvent, or

R, R , R og n har de ovenfor angitte betydninger, R, R , R and n have the meanings given above,

6 7 6 7

4 5 4 5

R og R betegner sammen en gruppe R and R together denote a group

hvori R^, R9, R"*-0 og R har de ovenfor angitte betydninger, wherein R^, R9, R"*-0 and R have the meanings given above,

at en således erholdt forbindelse omsettes med et basisk reagens, fortrinnsvis med et alkalimetall-carbonat eller hydrocarbonat, that a compound thus obtained is reacted with a basic reagent, preferably with an alkali metal carbonate or hydrocarbonate,

6 7 6 7

4 5 4 5

R og R danner sammen en gruppe av formel R and R together form a group of formula

hvori R''"0, R^ og X har de ovenfor angitte betydninger, at en således erholdt forbindelse omsettes med et tertiært amin i nærvær av et inert løsningsmiddel, fortrinnsvis en ether, eller - hydrolyse eller aminolyse av en forbindelse av formel I hvori R 3 er alkoxycarbonyl eller cyano, under dannelse av en tilsvarende forbindelse av formel I hvori R 3 er carboxy eller et alkalimetallsalt derav eller carbamoyl, eller - omdannelse av en base eller syre av formel I til et farmasøytisk akseptabelt salt derav. B. For fremstilling av en forbindelse av generell formel I in which R""0, R^ and X have the meanings given above, that a compound thus obtained is reacted with a tertiary amine in the presence of an inert solvent, preferably an ether, or - hydrolysis or aminolysis of a compound of formula I in which R 3 is alkoxycarbonyl or cyano, forming a corresponding compound of formula I in which R 3 is carboxy or an alkali metal salt thereof or carbamoyl, or - conversion of a base or acid of formula I to a pharmaceutically acceptable salt thereof. B. For preparation of a compound of general formula I

hvori R og R"*" betegner hydrogen eller C, _. alkyl, wherein R and R"*" denote hydrogen or C, _. alkyl,

R 3 betegner hydrogen, carboxy, alkalimetallcarboxylat, C^_4 alkoxycarbonyl, carbamoyl eller cyano, R 3 denotes hydrogen, carboxy, alkali metal carboxylate, C 1-4 alkoxycarbonyl, carbamoyl or cyano,

n er 0 eller 1, og n is 0 or 1, and

7 5 6 7 5 6

a) hvis R betegner hydrogen, R og R danner sammen en ytterligere binding, betegner R 4 en gruppe a) if R denotes hydrogen, R and R together form a further bond, R 4 denotes a group

hvori R g betegner C^_4 alkyl, eller in which R g denotes C 1 - 4 alkyl, or

b) hvis R 6 og R 7 danner sammen en ytterligere binding, 4 5 b) if R 6 and R 7 together form a further bond, 4 5

betegner R og R sammen en gruppe bestående av R and R together denote a group consisting of

hvori R g betegner hydrogen eller C^_4 alkyl, og p er 2, in which R g denotes hydrogen or C 1-4 alkyl, and p is 2,

og optisk aktive antipoder og salter derav, and optically active antipodes and salts thereof,

at en forbindelse av generell formel II that a compound of general formula II

hvori R, R 1 , R 3 og n er som ovenfor definert, omsettes med et carbondisulfid av formel fortrinnsvis i nærvær av alkaliioner, under dannelse av forbindelser av generell formel Ib) hvori R, r\ R"^ og n er som ovenfor definert, og M betegner et alkaliion, hvoretter, om ønsket, en forbindelse av formel Ib) omsettes med et alkylerings-middel eller et alkylendihalogenid av formel Hlg(CH9z ) P-Hig hvori Hig betegner halogen, og p er som ovenfor definert, under dannelse av en forbindelse av generell formel in which R, R 1 , R 3 and n are as defined above, is reacted with a carbon disulphide of formula preferably in the presence of alkali ions, forming compounds of general formula Ib) in which R, r\ R"^ and n are as defined above , and M denotes an alkali ion, after which, if desired, a compound of formula Ib) is reacted with an alkylating agent or an alkylene dihalide of formula Hlg(CH9z) P-Hig in which Hig denotes halogen, and p is as defined above, forming of a compound of general formula

13 9 13 9

hvori R, R , R , R , n og p er som ovenfor definert, in which R, R , R , R , n and p are as defined above,

3 og/eller at en forbindelse av formel I hvori R er carboxy eller et alkalimetallsalt derav eller carbamoyl, hydrolyseres eller underkastes aminosyre, eller at en base eller syre av formel I omdannes til et farma-søytisk akseptabelt salt. 3 and/or that a compound of formula I in which R is carboxy or an alkali metal salt thereof or carbamoyl, is hydrolysed or subjected to amino acid, or that a base or acid of formula I is converted into a pharmaceutically acceptable salt.

C. For fremstilling av en forbindelse av generell formel I C. For the preparation of a compound of general formula I

hvori R og R"*" betegner hydrogen eller C, . alkyl, in which R and R"*" denote hydrogen or C, . alkyl,

R 3 betegner hydrogen, carboxy, alkalimetallcarboxylat, C^_4 alkoxycarbonyl eller cyano, R 3 denotes hydrogen, carboxy, alkali metal carboxylate, C 1-4 alkoxycarbonyl or cyano,

n er 0 eller 1, og n is 0 or 1, and

7 5 6 7 5 6

a) hvis R betegner hydrogen, R og R danner sammen en ytterligere binding, betegner R 4 en gruppe bestående av a) if R denotes hydrogen, R and R together form a further bond, R 4 denotes a group consisting of

R hv9orbi etR eggnbeer theygnderor gheynd, rCog1-en 4 aellklyer l, Ck, lo- raaclkeytyll,, fenyl som eventuelt er substituert med ett eller flere halogen, C^_4 alkyl, C^_^ alkoxy eller C^_4 alkoxycarbonyl; eller nafthyl, eller R hv9orbi etR eggnbeer theygnderor gheynd, rCog1-en 4 aellklyer l, Ck, lo-raaclkkytyll,, phenyl which is optionally substituted with one or more halogen, C^_4 alkyl, C^_^ lkoxy or C^_4 alkoxycarbonyl; or naphthyl, or

6 7 6 7

b) hvis R og R danner en ytterligere binding og R 5 betegner hydrogen, betegner R 4 en gruppe bestående b) if R and R form an additional bond and R 5 denotes hydrogen, R 4 denotes a group consisting

av of

8 9 hvori R og R er som ovenfor definert, eller 6 7 c) hvis R og R danner sammen en ytterligere binding, 8 9 in which R and R are as defined above, or 6 7 c) if R and R together form a further bond,

4 5 4 5

betegner R og R sammen en gruppe R and R together denote a group

8 9 hvori R og R er som ovenfor definert, og optisk aktive antipoder og salter derav, at en forbindelse av generell formel II hvori R, R 1 , R 3 og n er som ovenfor definert, omsettes med et isocyanat eller isothiocyanat av generell formel 8 9 in which R and R are as defined above, and optically active antipodes and salts thereof, that a compound of general formula II in which R, R 1 , R 3 and n are as defined above, is reacted with an isocyanate or isothiocyanate of general formula

hvori R 9 er som ovenfor definert og Y betegner oxygen eller svovel, in which R 9 is as defined above and Y denotes oxygen or sulphur,

og, om ønsket, at en substituent R"^, R4, R^, R^, R^ omdannes til en annen R<4->, R<5->, R<6->, R<7->substituent, og/eller omdannes til et farmasøytisk akseptabelt salt eller frigis fra dets salt. and, if desired, that a substituent R"^, R4, R^, R^, R^ is converted into another R<4->, R<5->, R<6->, R<7->substituent , and/or is converted to a pharmaceutically acceptable salt or released from its salt.

Ved utførelse av fremgangsmåte A tilsettes forbindelsen av generell formel II, eventuelt løst i et inert løsningsmiddel, til en løsning av dihalogen-methylen-ammonium-halogenider i et inert løsningsmiddel, og reaksjonsblandingen oppvarmes for å fullføre reaksjonen kvantitativt. Ved isolering av forbindelsen av generell formel Ia inntappes reaksjonsblandingen fortrinnsvis ved redusertM:rykk og residuet krystalliseres. When carrying out method A, the compound of general formula II, possibly dissolved in an inert solvent, is added to a solution of dihalogen-methylene-ammonium halides in an inert solvent, and the reaction mixture is heated to complete the reaction quantitatively. When isolating the compound of general formula Ia, the reaction mixture is preferably bottled at reduced pressure and the residue is crystallized.

Som inerte løsningsmidler ved fremgangsmåte A . anvendes hydrocarboner, fortrinnsvis benzen, toluen, xylen, klorerte hydrocarboner, fortrinnsvis kloroform, diklormethan, klorbenzen osv. Reaksjonen utføres fortrinnsvis ved 0 - 108° C, i særdeles-het ved 10 - 120° C. As inert solvents in method A. hydrocarbons are used, preferably benzene, toluene, xylene, chlorinated hydrocarbons, preferably chloroform, dichloromethane, chlorobenzene, etc. The reaction is preferably carried out at 0 - 108° C, in particular at 10 - 120° C.

Den dannede forbindelse kan også uten iso- The formed compound can also without iso-

lering omsettes for eksempel med et amin til en forbindelse av generell formel I. clay is reacted, for example, with an amine to a compound of general formula I.

Fremgangsmåtealternativ B. utføres fortrinnsvis ved at man til en alkoholisk løsning av forbindelsen av generell formel II og carbondisulfidet av formel IV under mild ytre avkjøling dråpevis tilsetter en alkoholgisk løsning av alkalihydroxyd, og at reaksjonsblandingen omrøres fortrinnsvis ved romtemperatur. Process alternative B. is preferably carried out by adding an alcoholic solution of alkali hydroxide dropwise to an alcoholic solution of the compound of general formula II and the carbon disulphide of formula IV under mild external cooling, and that the reaction mixture is preferably stirred at room temperature.

De under reaksjonen dannede forbindelser av generell formel Ib kan om ønsket isoleres ved fjerning av løsningsmidlet ved redusert trykk. Forbindelsene av generell formel Ib kan også uten isolering, for eksempel ved anvendelse av alkyleringsmidler overføres i forbindelser av generell formel I. The compounds of general formula Ib formed during the reaction can, if desired, be isolated by removing the solvent at reduced pressure. The compounds of general formula Ib can also be converted into compounds of general formula I without isolation, for example by using alkylating agents.

Som alkoholer kan anvendes methanol, ethanol, n- eller iso-propanol eller n-butanol. Som alkalihydroxyder kan anvendes natrium- eller kaliumhydroxyd. Reaksjonen utføres fortrinnsvis ved 0 - 120° C. Til 1 mol forbindelse av generell formel II kan det anvendes 1-5 mol carbondisulfid av formel IV. Methanol, ethanol, n- or iso-propanol or n-butanol can be used as alcohols. Sodium or potassium hydroxide can be used as alkali hydroxides. The reaction is preferably carried out at 0 - 120° C. For 1 mol of compound of general formula II, 1-5 mol of carbon disulphide of formula IV can be used.

Ved fremgangsmåtealternativ C. omsettes en forbindelse av generell formel II uten løsningsmiddel eller i nærvær av et inert løsningsmiddel med isocyanat av generell formel V. Såfremt man arbeider i nærvær av et løsningsmiddel utskilles den dannede forbindelse fra reaksjonsblandingen og kan fjernes ved filtrer-ing. Såfremt den dannede forbindelse ikke utskilles fra blandingen, kan reaksjonsblandingen inndampes ved redusert trykk, In process alternative C., a compound of general formula II is reacted without a solvent or in the presence of an inert solvent with isocyanate of general formula V. If you work in the presence of a solvent, the compound formed is separated from the reaction mixture and can be removed by filtration. If the compound formed is not separated from the mixture, the reaction mixture can be evaporated at reduced pressure,

og det erholdte residuum omkrystalliseres fra et egnet løsnings-middel. Når man arbeider uten løsningsmiddel, kan reaksjonsblandingen etter endt reaksjon, omkrystalliseres i et egnet løsningsmiddel. Reaksjonen utføres ved 0 - 250°C. Reaksjons-temperaturen avhenger av utgangsmaterialene. and the residue obtained is recrystallized from a suitable solvent. When working without a solvent, the reaction mixture can be recrystallized in a suitable solvent after the reaction has finished. The reaction is carried out at 0 - 250°C. The reaction temperature depends on the starting materials.

Man anvender til hvert mol forbindelse av generell formel II 1-3 mol isocyanat av generell formel V. For each mole of compound of general formula II, 1-3 moles of isocyanate of general formula V are used.

De som utgangsmateriale anvendte heterosykliske forbindelser av generell formel II kan fremstilles som beskrevet i ungarsk patentskrift 156 119, 158 089, 162 384, 162 373, 166 577 og i nederlands patentsøknad 72 12286 mens forbindelsene av generell formel III, IV og V og de for fremstilling av disse'anvendte reagenser er handelsprodukter. The heterocyclic compounds of general formula II used as starting material can be prepared as described in Hungarian patent documents 156 119, 158 089, 162 384, 162 373, 166 577 and in Dutch patent application 72 12286, while the compounds of general formula III, IV and V and those for preparation of these' used reagents are commercial products.

Forbindelsene av generell formel I kan på carboxylgrup-pen danne alkalimetallsalter, f.eks. natrium eller kaliumsalter, ammoniumsalter, jordalkalimetallsalter, f.eks. kalsium eller magnesiumsalter eller med salter med organiske aminer, f.eks. triethylamin. The compounds of general formula I can form alkali metal salts on the carboxyl group, e.g. sodium or potassium salts, ammonium salts, alkaline earth metal salts, e.g. calcium or magnesium salts or with salts with organic amines, e.g. triethylamine.

Forbindelsene av generell formel I The compounds of general formula I

anvendes som farmasøytiske utgangsmaterialer. Forbindelsene kan omsettes med aryldiazoniumsalter og overføres i pyrido[1,2-a]-pyrimidinderivater som i 9-stilling er substituert med hydrazono-gruppen, hvilken utviser en rekke farmasøytiske virkninger, f.eks. antiallergisk virkning. are used as pharmaceutical starting materials. The compounds can be reacted with aryldiazonium salts and transferred into pyrido[1,2-a]-pyrimidine derivatives which are substituted in the 9-position with the hydrazono group, which exhibits a number of pharmaceutical effects, e.g. antiallergic effect.

Oppfinnelsen illustreres i de etterfølgende eksempler. The invention is illustrated in the following examples.

Eksempel 1 Example 1

5,9 g 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin og 2,3 ml carbondisulfid ble løst i 35 ml ethanol og til løsningen ble dråpevis tilsatt en løsning av 2,8 g kaliumhydroxyd i 25 ml ethanol ved 25 - 30° C. Reaksjonsblandingen ble omrørt i 1 time ved romtemperatur og ble inndampet ved forminsket trykk. Det ble erholdt 9,8 g 3-ethoxycarbo-nyl-6-methyl-9-[(bis-tiolat)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-dikaliumsalt. 5.9 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidine and 2.3 ml of carbon disulfide were dissolved in 35 ml ethanol and to the solution was added dropwise a solution of 2.8 g of potassium hydroxide in 25 ml of ethanol at 25 - 30° C. The reaction mixture was stirred for 1 hour at room temperature and was evaporated under reduced pressure. 9.8 g of 3-ethoxycarbonyl-6-methyl-9-[(bis-thiolate)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2 -a]pyrimidine dipotassium salt.

E ksempel 2 Example 2

Til en løsning av 9,7 g 3-ethoxycarbonyl-6-methyl-9-[(bis-tiolat)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-dikaliumsalt som ble fremstilt som beskrevet i eksempel 1, i 60 ml ethanol ble under avkjøling dråpevis tilsatt 4,7 ml dimethylsulfat, og reaksjonsblandingen ble omrørt i 1 time ved 40° C. De utskilte gule krystaller ble filtrert fra, vasket med vann og tørket. Det ble erholdt 7,1 g (86 %) 3-ethoxycarbonyl-6-methyl-9-(methylthio-thiocarbonyl)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin, og produktet smeltet etter omkrystallisering fra benzen ved 198 - 199° C. To a solution of 9.7 g of 3-ethoxycarbonyl-6-methyl-9-[(bis-thiolate)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2- α]-pyrimidine dipotassium salt which was prepared as described in Example 1, in 60 ml of ethanol, 4.7 ml of dimethylsulphate was added dropwise while cooling, and the reaction mixture was stirred for 1 hour at 40° C. The separated yellow crystals were filtered from, washed with water and dried. 7.1 g (86%) of 3-ethoxycarbonyl-6-methyl-9-(methylthio-thiocarbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a ]pyrimidine, and the product melted after recrystallization from benzene at 198 - 199° C.

Analyse for formelen C^H^gN20gS2Analysis for the formula C^H^gN20gS2

beregnet: C 51,51 % H 5,56 % N 8,58 % calculated: C 51.51% H 5.56% N 8.58%

Funnet : C 51,70 % H 5,78 % N 8,48 % Found : C 51.70% H 5.78% N 8.48%

Eksempel 3 Example 3

Til en løsning av 9,7 g 3-ethoxycarbonyl-6-methyl-9-[(bis-tiolat)-methylen)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-dikaliumsalt, fremstilt som beskrevet i eksempel 1, i 60 ml ethanol ble tilsatt 4,7 g ethylenbromid. Reaksjonsblandingen ble omrørt i 1 time ved 40° C, og det utskilte natriumbromid ble filtrert fra. Moderluten ble inndampet til halvparten, og de etter avkjøling utskilte krystaller ble filtrert og tørket. 3 g 3-ethoxycarbonyl-6-methyl-9-(1,3-dithiolan-2-yliden)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin ble erholdt, og produktet smeltet etter omkrystallisering fra ethanol ved 205 - 207°C. To a solution of 9.7 g of 3-ethoxycarbonyl-6-methyl-9-[(bis-thiolate)-methylene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2- α]-pyrimidine dipotassium salt, prepared as described in example 1, in 60 ml of ethanol was added 4.7 g of ethylene bromide. The reaction mixture was stirred for 1 hour at 40° C., and the separated sodium bromide was filtered off. The mother liquor was evaporated to half, and the crystals separated after cooling were filtered and dried. 3 g of 3-ethoxycarbonyl-6-methyl-9-(1,3-dithiolan-2-ylidene)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained, and the product melted after recrystallization from ethanol at 205 - 207°C.

Analyse C^H^N^S., Analysis C^H^N^S.,

Beregnet: C 53,23 % H 5,36 % N 8,27 % Calculated: C 53.23% H 5.36% N 8.27%

Funnet: C 53,17 % H 5,41 % N 8,22 % Found: C 53.17% H 5.41% N 8.22%

Eksempel 4 Example 4

3,26 g 3-ethoxycarbonyl-6-methyl-9-(methylthio-thio-carbonyl) -4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin ble kokt i 20 ml eddiksyreanhydrid i 2 timer. Etter avkjøling ble de utskilte krystaller filtrert fra, vasket med benzen og tørket. Det ble erholdt 1,6 g (57,6 %) 3-ethoxycarbonyl-6-methyl-9-[4-(3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-9-yliden)-1,3-dithiethan-2-ylidn)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin som ble omkrystallisert fra dimethylformamid og som smeltet ved 315 - 318° C. 3.26 g of 3-ethoxycarbonyl-6-methyl-9-(methylthio-thio-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine was boiled in 20 ml of acetic anhydride for 2 hours. After cooling, the precipitated crystals were filtered off, washed with benzene and dried. 1.6 g (57.6%) of 3-ethoxycarbonyl-6-methyl-9-[4-(3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H) were obtained -pyrido-[1,2-a]pyrimidin-9-ylidene)-1,3-dithiethan-2-ylidin)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2- a]pyrimidine which was recrystallized from dimethylformamide and which melted at 315 - 318°C.

Analyse C^H^OgS;, Analysis C^H^OgS;,

Beregnet: C 56,10 % H 5,07 % N 10,07 % S 11,52 % Calculated: C 56.10% H 5.07% N 10.07% S 11.52%

Funnet : C 55,89 % H 4,98 % N 10,20 % S 10,80 % Found : C 55.89% H 4.98% N 10.20% S 10.80%

Eksempel 5 Example 5

Til en blanding av .16,3 g fosgen-N,N-dimethyl-immonium-klorid i 50 ml diklormethan ble under omrøring en løsning av 23,6 g 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin i 30 ml diklormethan dråpevis tilsatt, og blandingen ble omrørt i 3 timer. Løsningsmidlet ble destillert fra, og residuet ble krystallisert med ether. 35,2 g av sterkt hygroskopisk 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidinklorid ble inndampet i vakuum. A solution of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7, 8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine in 30 ml of dichloromethane was added dropwise, and the mixture was stirred for 3 hours. The solvent was distilled off and the residue was crystallized with ether. 35.2 g of highly hygroscopic 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]-pyrimidine chloride was evaporated in vacuo.

Analyse C15<H>20N3°3C12Analysis C15<H>20N3°3C12

Beregnet: Cl.. , : 19,6 % Calculated: Cl.. , : 19.6%

^ lonisk ' ^lonic'

Funnet : Cl.. , : <1>9,4%Found : Cl.. , : <1>9.4%

lonisk ' lonic'

Eksempel 6 Example 6

En løsning av 1,8 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidinklorid og 5 mmol natriumacetat i 5 ml vannfri ethanol fikk stå i 24 timer ved romtemperatur, og det utskilte natriumklorid ble filtrert fra og filtratet ble inndampet. Residuet ble løst i vann og pH på løsningen ble innstilt til 7 ved tilsetning av natriumhydrogencarbonat. De utskilte krystaller ble filtrert, vasket med vann og tørket. 0,92 g (60 %) 3,9-diethoxycarbonyl-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin ble erholdt, hvilket smelter ved 138 - 140° C. A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine chloride and 5 mmol of sodium acetate in 5 ml of anhydrous ethanol were allowed to stand for 24 hours at room temperature, and the separated sodium chloride was filtered off and the filtrate was evaporated. The residue was dissolved in water and the pH of the solution was adjusted to 7 by adding sodium bicarbonate. The precipitated crystals were filtered, washed with water and dried. 0.92 g (60%) of 3,9-diethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine was obtained, which melts at 138 - 140° C.

Analyse ci5<H>20<N>2°5 Analysis ci5<H>20<N>2°5

Beregnet: C 58,43 % H 6,54 % N 9,09 % Calculated: C 58.43% H 6.54% N 9.09%

Funnet : C 58,65 % H 6,53 % N 9,06 % Found : C 58.65% H 6.53% N 9.06%

Eksempel 7 Example 7

En løsning av 1,8 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidinklorid og 5 mmol natriumacetat i 5 ml vannfri methanol fikk stå i 24 timer ved romtemperatur, og det utskilte natriumklorid ble filtrert fra og filtratet ble inndampet. Residuet ble løst i vann og pH på løsningen ble innstilt til 7 A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine chloride and 5 mmol of sodium acetate in 5 ml of anhydrous methanol were allowed to stand for 24 hours at room temperature, and the separated sodium chloride was filtered off and the filtrate was evaporated. The residue was dissolved in water and the pH of the solution was adjusted to 7

med natriumcarbonat. De utskilte krystaller ble filtrert fra, vasket med vann og tørket. 0,96 g (65 %) 3-ethoxycarbonyl-6-methyl-9-methoxycarbonyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin ble erholdt som smelter ved 13 6 - 13 9° C. with sodium carbonate. The precipitated crystals were filtered off, washed with water and dried. 0.96 g (65%) of 3-ethoxycarbonyl-6-methyl-9-methoxycarbonyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine was obtained as melting at 13 6 - 13 9° C.

Analyse: c^4<H>i8<N>2°5Analysis: c^4<H>i8<N>2°5

Beregnet: C 57,14 % H 6,17 % N 9,52 % Calculated: C 57.14% H 6.17% N 9.52%

Funnet : C 57,00 % H 6,25 % N 9,52 % Found : C 57.00% H 6.25% N 9.52%

Eksempel 8- 13 Example 8-13

Til en løsning av 3,65 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethylammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid i 15 ml vannfri diklormethan ble tilsatt 0,02 mol amin, og reaksjonsblandingen ble kokt i 1 time. Etter avkjøling ble det utskilte amin-hydroklorid filtrert fra. Filtratet ble inndampet. Det oljeaktige, krystalliserende residuum ble krystallisert med ether. De erholdte krystaller ble filtrert, vasket med ether og tørket. Produktet ble omkrystallisert fra vannfri ethanol. De erholdte produkter og karakteristika er angitt i etterfølgende tabell 1. To a solution of 3.65 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethylammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[ 1,2-a]pyrimidine chloride in 15 ml of anhydrous dichloromethane was added with 0.02 mol of amine, and the reaction mixture was boiled for 1 hour. After cooling, the separated amine hydrochloride was filtered off. The filtrate was evaporated. The oily, crystallizing residue was crystallized with ether. The crystals obtained were filtered, washed with ether and dried. The product was recrystallized from anhydrous ethanol. The obtained products and characteristics are indicated in the following table 1.

Eksempel 14 Example 14

Til en vandig løsning av 4,2 g' 3-ethoxycarbonyl-6-methyl-9-(N-fenyl-N',N'-dimethyl-formamidinium)-4-oxo-l,6,7,8-tetrahydro-4H-pyridotl,2-a]pyrimidin-klorid ble en 20 W/V % kaliumcarbonatløsning tilsatt. De utskilte krystaller ble filtrert, vasket med vann og tørket. Det ble erholdt 3,4 g (89 %) 3- ethoxycarbonyl-6-methyl-9-(N-fenyl-N',N'-dimethyl-formamidino)-4- oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin som etter omkrystallisering fra ethanol smelter ved 193 - 195° C. To an aqueous solution of 4.2 g of 3-ethoxycarbonyl-6-methyl-9-(N-phenyl-N',N'-dimethyl-formamidinium)-4-oxo-1,6,7,8-tetrahydro- 4H-pyridotl,2-a]pyrimidine chloride, a 20 W/V% potassium carbonate solution was added. The precipitated crystals were filtered, washed with water and dried. 3.4 g (89%) of 3-ethoxycarbonyl-6-methyl-9-(N-phenyl-N',N'-dimethyl-formamidino)-4-oxo-1,6,7,8-tetrahydro were obtained -4H-pyrido[1,2-a]pyrimidine which after recrystallization from ethanol melts at 193 - 195° C.

Analyse: C2lH26N4C>3 Analysis: C21H26N4C>3

Beregnet: C 65,98 % H 6,81 % N 14,65 % Calculated: C 65.98% H 6.81% N 14.65%

Funnet : C 65,89 % H 6,79 % N 14,69 % Found : C 65.89% H 6.79% N 14.69%

Eksempel 15 Example 15

Til en blanding av 2 2,1 g fosgen-N-methyl-N-fenyl-immoniumklorid i 50 ml diklormethan ble dråpevis tilsatt til en løsning av 23,6 g 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin i 30 ml diklormethan, og reaksjons-balndingen ble kokt i 3 timer. Etter destillering av blandingen ble residuet krystallisert i ether. Det ble erholdt 41,2 g sterkt hygroskopisk 3-ethoxycarbonyl-6-methyl-9-[(klor-N-methyl-N-fenyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] - pyrimidin-klorid som ble tørket i vakuum. To a mixture of 2 2.1 g of phosgene-N-methyl-N-phenyl-ammonium chloride in 50 ml of dichloromethane was added dropwise to a solution of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7 ,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine in 30 ml of dichloromethane, and the reaction mixture was boiled for 3 hours. After distilling the mixture, the residue was crystallized in ether. 41.2 g of strongly hygroscopic 3-ethoxycarbonyl-6-methyl-9-[(chloro-N-methyl-N-phenyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro were obtained -4H-pyrido[1,2-a]-pyrimidine chloride which was dried in vacuo.

Analyse: C2oH23N3<0>3Cl2Analysis: C2oH23N3<0>3Cl2

Beregnet: Cl.^.^: 8,36 Calculated: Cl.^.^: 8.36

Funnet : Cllonisk<s><8,>45%Found : Cllonic<s><8,>45%

Eksempel 16 Example 16

Til en løsning av 3-ethoxycarbonyl-6-methyl-9-[(klor-N-methyl-N-f enylammonio) -methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid i 20 ml vannfri diklormethan ble tilsatt 0,2 ml anilin, og reaksjonsblandingen ble kokt 1 time. Etter avkjøling ble det utskilte anilin-hydroklorid filtrert fra. Den diklormethan-holdige moderlut ble inndampet. Residuet ble krystallisert med ether. De utskilte krystaller ble filtrert, vasket med ether og tørket. Det ble erholdt 25,9 g (54 %) 3-ethoxycarbonyl-6-methyl-9-(N<1>,N-difenyl-N-methyl-formamidinium)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid som etter omkrystallisering fra ethanol og under spaltning smelter ved 186 - 188° C. To a solution of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N-methyl-N-phenylammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2 -α]pyrimidine chloride in 20 ml of anhydrous dichloromethane was added with 0.2 ml of aniline, and the reaction mixture was boiled for 1 hour. After cooling, the separated aniline hydrochloride was filtered off. The dichloromethane-containing mother liquor was evaporated. The residue was crystallized with ether. The precipitated crystals were filtered, washed with ether and dried. 25.9 g (54%) of 3-ethoxycarbonyl-6-methyl-9-(N<1>,N-diphenyl-N-methyl-formamidinium)-4-oxo-1,6,7,8- tetrahydro-4H-pyrido[1,2-a]pyrimidine chloride which after recrystallization from ethanol and during cleavage melts at 186 - 188° C.

Analyse: C2<gH>2<gN>403<Cl>Analysis: C2<gH>2<gN>403<Cl>

Beregnet: C 64,95 % H 6,04 % N 11,66 % Calculated: C 64.95% H 6.04% N 11.66%

Funnet : C 64,76 % H 6,09 % N 11,26 % Found : C 64.76% H 6.09% N 11.26%

Eksempel 17 Example 17

Til en vandig løsning av 24 g 3-ethoxycarbonyl-6-methyl-9- (N,N'-difenyl-N-methyl-formamidinium)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[l,2-a]pyridinium-klorid ble tilsatt en 20 W/V % kalium-carbonatløsning. De utskilte krystaller ble filtrert fra, vasket med vann og tørket. Det ble erholdt 16,7 g (75 %) 3-ethoxycarbo-nyl-6-methyl-9-(N,N'-difenyl-N-methyl-formamidino)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin som etter omkrystallisering fra ethanol smelter ved 199 - 202° C. To an aqueous solution of 24 g of 3-ethoxycarbonyl-6-methyl-9-(N,N'-diphenyl-N-methyl-formamidinium)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[ 1,2-a]pyridinium chloride was added to a 20 W/V% potassium carbonate solution. The precipitated crystals were filtered off, washed with water and dried. 16.7 g (75%) of 3-ethoxycarbonyl-6-methyl-9-(N,N'-diphenyl-N-methyl-formamidino)-4-oxo-1,6,7,8- tetrahydro-4H-pyrido[1,2-a]pyrimidine which after recrystallization from ethanol melts at 199 - 202° C.

Analyse C^h^N^ Analysis C^h^N^

Beregnet: C 70,25 % H 6,31 % N 12,61 % Calculated: C 70.25% H 6.31% N 12.61%

Funnet : C 69,97 % H 6,27 % N 12,42 % Found : C 69.97% H 6.27% N 12.42%

Eksempel 18 Example 18

Til en løsning av 21 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N-methyl-N-fenyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin-klorid i 20 ml vannfri diklormethan ble tilsatt 0,2 mol 4-kloranilin, og reaksjonsblandingen ble kokt 1 time. Etter avkjøling ble det utskilte 4-kloranilin-hydroklorid filtrert fra. Den diklormethan-holdige moderlut ble inndampet. Det erholdte 3-ethoxycarbonyl-6-methyl-9-[N-(4-klor-fenyl)-N'-fenyl-N'-methyl-formamidinium]-4-oxo-l,6,7,8-tetra-hydro-4H-pyrido[1,2-a]pyrimidin-klorid ble løst i vann og til løsningen ble tilsatt en 20 W/V % kaliumcarbonatløsning. De utskilte krystaller ble filtrert, vasket med vann og tørket. Det ble erholdt 13,5 g (55,5 %) 3-ethoxycarbonyl-6-methyl-9-[N-(4-klorfenyl)-N'-fenyl-N'-methylformamidino]-4-oxo-l,6,7,8-tetra-hydro-4H-pyrido[1,2-a]pyrimidin som etter omkrystallisering fra ethanol smelter ved 194 - 196° C. To a solution of 21 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N-methyl-N-phenyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetra-hydro- 4H-pyrido[1,2-a]pyrimidine chloride in 20 ml of anhydrous dichloromethane was added to 0.2 mol of 4-chloroaniline, and the reaction mixture was boiled for 1 hour. After cooling, the separated 4-chloroaniline hydrochloride was filtered off. The dichloromethane-containing mother liquor was evaporated. There was obtained 3-ethoxycarbonyl-6-methyl-9-[N-(4-chloro-phenyl)-N'-phenyl-N'-methyl-formamidinium]-4-oxo-1,6,7,8-tetra- hydro-4H-pyrido[1,2-a]pyrimidine chloride was dissolved in water and to the solution was added a 20 W/V% potassium carbonate solution. The precipitated crystals were filtered, washed with water and dried. 13.5 g (55.5%) of 3-ethoxycarbonyl-6-methyl-9-[N-(4-chlorophenyl)-N'-phenyl-N'-methylformamidino]-4-oxo-1,6 ,7,8-tetra-hydro-4H-pyrido[1,2-a]pyrimidine which after recrystallization from ethanol melts at 194 - 196° C.

Analyse C26H27<N>403C1 Analysis C26H27<N>403C1

Beregnet: C 65,15 % H 5,65 % N 11,71 % Calculated: C 65.15% H 5.65% N 11.71%

Funnet : C 64,85 % H 5,83 % N 11,66 % Found : C 64.85% H 5.83% N 11.66%

Eksempel 19 Example 19

Til en løsning av 21 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N-methyl-N-fenyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin-klorid i vannfri diklormethan ble tilsatt 0,2 mol 4-methyl-anilin, og reaksjonsblandingen ble kokt 1 1 time. Etter avkjøling ble det utskilte 4-methyl-anilin-hydroklorid filtrert fra. Diklormethan-filtratet ble inndampet. Det erholdte 3-ethoxycarbonyl-6-methyl-9-[N-(4-methyl-fenyl)-N'-fenyl-N'-methyl-formamidinium]-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin-klorid ble løst i vann. Den vandige løsning ble tilsatt en 20 W/V % kaliumcarbonatløsning. De utskilte krystaller ble filtrert, vasket med vann og tørket. Det ble erholdt 14,7 g (64 %) 3-ethoxycarbonyl-6-metyl-9-[N'-(4-methyl-fenyl)-N'-fenyl-N<1->methyl-formamidino]-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin og produktet smelter ved 161 - 163° C etter omkrystallisering fra ethanol. To a solution of 21 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N-methyl-N-phenyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetra-hydro- 4H-pyrido[1,2-a]pyrimidine chloride in anhydrous dichloromethane was added with 0.2 mol of 4-methylaniline, and the reaction mixture was boiled for 11 hours. After cooling, the separated 4-methyl-aniline hydrochloride was filtered off. The dichloromethane filtrate was evaporated. There was obtained 3-ethoxycarbonyl-6-methyl-9-[N-(4-methyl-phenyl)-N'-phenyl-N'-methyl-formamidinium]-4-oxo-1,6,7,8-tetrahydro- 4H-pyrido-[1,2-a]pyrimidine chloride was dissolved in water. To the aqueous solution was added a 20 W/V% potassium carbonate solution. The precipitated crystals were filtered, washed with water and dried. 14.7 g (64%) of 3-ethoxycarbonyl-6-methyl-9-[N'-(4-methyl-phenyl)-N'-phenyl-N<1->methyl-formamidino]-4- oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine and the product melts at 161 - 163° C after recrystallization from ethanol.

Analyse C^H^N^O^ Analysis C^H^N^O^

Beregnet: C 70,75 % H 6,56 % N 12,21 % Calculated: C 70.75% H 6.56% N 12.21%

Funnet : C 70,35 % H 6,62 % N 11,91 % Found : C 70.35% H 6.62% N 11.91%

Eksempel 20 - 23 Example 20 - 23

I en løsning av 0,05 mol pyrido[1,2-a]pyrimidin-utgangsmateriale i diklormethan ble 0,055 mol isocyanat dråpevis tilsatt ved romtemperatur. Reaksjonsblandingen ble kokt i 10 timer og fikk stå i 2 dager ved romtemperatur, hvoretter løsnings-midlet ble destillert fra. Residuet ble krystallisert fra ethanol. De fremstilte forbindelser er angitt i etterfølgende tabell 2 . In a solution of 0.05 mol of pyrido[1,2-a]pyrimidine starting material in dichloromethane, 0.055 mol of isocyanate was added dropwise at room temperature. The reaction mixture was boiled for 10 hours and allowed to stand for 2 days at room temperature, after which the solvent was distilled off. The residue was crystallized from ethanol. The compounds produced are listed in the following table 2.

Eksempel 22 - 26 Example 22 - 26

En blanding av 23,6 g 3-ethoxycarbonyl-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin og 0,1 mol isocyanat ble omrørt i 72 timer ved 40 - 50° C. Den dannede tykke viskøse reaksjonsblan-ding ble suspendert i 200 ml ethanol, filtrert og vasket med ethanol. (Såfremt reaksjonen ble gjennomført ved anvendelse av n-butyl-isocyanat ble denne utført ved 80 - 100° C). A mixture of 23.6 g of 3-ethoxycarbonyl-6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine and 0.1 mol of isocyanate was stirred for 72 hours at 40-50° C. The formed thick viscous reaction mixture was suspended in 200 ml of ethanol, filtered and washed with ethanol. (If the reaction was carried out using n-butyl isocyanate, this was carried out at 80 - 100° C).

De fremstilte forbindelser er angitt i tabell 3. The prepared compounds are listed in Table 3.

Eksempel 2 7 Example 2 7

En løsning av 1,8 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethylammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid i 5 ml ethanol ble kokt i 30 minutter. Etter avkjøling ble de utskilte krystaller filtrert fra, vasket med ethanol og tørket. Det ble erholdt 1,08 g (63 %) 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-hydroklorid som etter omkrystallisering fra ethanol smelter ved 166 - 168° C under spaltning. A solution of 1.8 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethylammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine chloride in 5 ml of ethanol was boiled for 30 minutes. After cooling, the precipitated crystals were filtered off, washed with ethanol and dried. 1.08 g (63%) of 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine hydrochloride which, after recrystallization from ethanol, melts at 166 - 168° C during decomposition.

Analyse C-^I^N-jC^Cl Analysis C-^I^N-jC^Cl

Eksempel 28 Example 28

3,26 g 3-ethoxycarbonyl-6-methyl-9-(methylthio-thiocar-bonyl) -4-oxo-l , 6 , 7 ,8-tetrahydro-4H-pyrido [1 ,a-2] pyrimidin og 0,6 g ethylendiamin ble kokt i 50 ml benzen i 10 timer. Etter avkjø-ling ble de utskilte gule krystaller filtrert fra, dekket med benzen og tørket. Det ble erholdt 1,9 g (62 %) 3-ethoxycarbonyl-6-methyl-9-(2-imidazoliden)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin som etter omkrystallisering fra dimethylformamid smelter ved 252 - 254° C. 3.26 g of 3-ethoxycarbonyl-6-methyl-9-(methylthio-thiocarbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,a-2]pyrimidine and 0, 6 g of ethylenediamine was boiled in 50 ml of benzene for 10 hours. After cooling, the separated yellow crystals were filtered off, covered with benzene and dried. 1.9 g (62%) of 3-ethoxycarbonyl-6-methyl-9-(2-imidazolide)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2- a]pyrimidine which after recrystallization from dimethylformamide melts at 252 - 254° C.

Analyse ci5Hi8<N>4°3 Analysis ci5Hi8<N>4°3

Eksempel 29 Example 29

1,0 g 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidin)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin ble løst i 10 ml ethanol. Løsningen ble mettet med hydrogenkloridgass og inndampet. Residuet ble omkrystallisert fra en blanding av ether og ethanol. Det ble .erholdt 0,9 g 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidin)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-bis-hydroklorid som smelter ved 190° C under spaltning. 1.0 g of 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidine)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was dissolved in 10 ml ethanol. The solution was saturated with hydrogen chloride gas and evaporated. The residue was recrystallized from a mixture of ether and ethanol. 0.9 g of 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidine)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine- bis-hydrochloride which melts at 190° C during decomposition.

Analyse C15<H>2Q<N>4<0>3C12Analysis C15<H>2Q<N>4<0>3C12

Eksempel 3 O Example 3 O

3,6 g 3-ethoxycarbonyl-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin-klorid og 1,2 g ethylendiamin i 40 ml dimethylformamid ble omrørt ved 40° C, og de etter avkjøling utskilte krystaller ble filtrert fra, vasket med vann og tørket. Det ble erholdt 1,0 g 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidin)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin som smelter ved 252 - 254° C. 3.6 g of 3-ethoxycarbonyl-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1, 2-a]-pyrimidine chloride and 1.2 g of ethylenediamine in 40 ml of dimethylformamide were stirred at 40° C., and the crystals separated after cooling were filtered off, washed with water and dried. 1.0 g of 3-ethoxycarbonyl-6-methyl-9-(2-imidazolidine)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained which melts at 252 - 254° C.

Eksempel 3 1 Example 3 1

En blanding av 2,0 g 3-amino-carbonyl-2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin og 2,2 g fenylisocyanat ble oppvarmet til 80° C, og den erholdte løsning ble omrørt ved 50 - 6 0° C. Reaksjonsblandingen ble etter avkjøling behandlet med 30 ml ether, de utskilte krystaller ble løst i ethanol, filtrert og filtratet fikk krystallisere i kjøleskap hvoretter de utskilte krystaller ble filtrert fra, vasket med ethanol. Det ble erholdt 1,4 g 3-aminocarbonyl-9-(fenyl-amino-carbonyl)-2,6-dimethyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]-pyrimidin med sm.p. 187 - 188° C. A mixture of 2.0 g of 3-amino-carbonyl-2,6-dimethyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine and 2.2 g of phenyl isocyanate was heated to 80° C, and the resulting solution was stirred at 50 - 60° C. After cooling, the reaction mixture was treated with 30 ml of ether, the separated crystals were dissolved in ethanol, filtered and the filtrate was allowed to crystallize in a refrigerator, after which the separated crystals was filtered off, washed with ethanol. 1.4 g of 3-aminocarbonyl-9-(phenyl-amino-carbonyl)-2,6-dimethyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a ]-pyrimidine with m.p. 187 - 188° C.

Analyse C18<H>20<N>4O3Analysis C18<H>20<N>4O3

Eksempel 3 2 Example 3 2

1,6 g kaliumhydroxyd ble løst i 20 ml ethanol. Til den ethanoliske løsning av kaliumhydroxydet ble tilsatt en ethanolisk løsning av 3,6 g 3-ethoxycarbonyl-9-(fenyl-aminocarbonyl)-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin. Reaksjonsblandingen ble kokt i 30 timer, og de etter avkjøling ufkry-stalliserte krystaller ble filtrert fra, vasket med kloroform og tørket. Det ble erholdt 3,1 g kalium-9-(fenylamino-carbonyl)-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxylat som smelter ved 276 - 280° C under spaltning. 1.6 g of potassium hydroxide was dissolved in 20 ml of ethanol. To the ethanolic solution of the potassium hydroxide was added an ethanolic solution of 3.6 g of 3-ethoxycarbonyl-9-(phenyl-aminocarbonyl)-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[ 1,2-a]pyrimidine. The reaction mixture was boiled for 30 hours, and the uncrystallised crystals after cooling were filtered off, washed with chloroform and dried. 3.1 g of potassium 9-(phenylamino-carbonyl)-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate were obtained which melts at 276 - 280° C during decomposition.

Analyse Cl7<HlgN>3<0>4<K>Analysis Cl7<HlgN>3<0>4<K>

Eksempel 3 3 Example 3 3

3,1 g kalium-9-(fenylamino-carbonyl)-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin-3-carboxylat ble løst i 250 ml vann under oppvarming. pH på løsningen ble ved 40 - 50° C innstilt til 1 med 38 W/V % saltsyreløsning. De utskilte krystaller etter avkjøling ble filtrert fra, vasket med vann og tørket. Det ble erholdt 2,2 g krystaller som ble omkrystallisert fra acetonitril. Det ble erholdt 9-(fenyl-amino-carbonyl)-3-carboxy-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin med et utbytte på 25 %. 3.1 g of potassium 9-(phenylamino-carbonyl)-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate were dissolved in 250 ml of water while heating. The pH of the solution was set at 40 - 50° C to 1 with 38 W/V % hydrochloric acid solution. The precipitated crystals after cooling were filtered off, washed with water and dried. 2.2 g of crystals were obtained which were recrystallized from acetonitrile. 9-(phenyl-amino-carbonyl)-3-carboxy-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine was obtained in a yield of 25%.

Analyse C]_7H^7N3°4 Analysis C]_7H^7N3°4

Eksempel 3 4 Example 3 4

2 g 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidin ble omsatt med fosgen-N,N-dimethyl-immoniumklorid som angitt i eksempel 5. Det ble erholdt et sterkt hygroskopisk 6-methyl-9[(klor-N,N-dimethyl-ammonio)-methylen]-4~oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid som ble tørket i vakuum. 2 g of 6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]-pyrimidine was reacted with phosgene-N,N-dimethyl-ammonium chloride as indicated in Example 5. A highly hygroscopic 6-methyl-9[(chloro-N,N-dimethyl-ammonio)-methylene]-4~oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a ]pyrimidine chloride which was dried in vacuo.

Analyse <C>12<H>17<N>3<0>C12Analysis <C>12<H>17<N>3<0>C12

Beregnet: Cl.. ,: 12,22 % Calculated: Cl.. ,: 12.22%

3 lonisk 3 lonic

Funnet : Cl.. , : 12,10 % Found : Cl.. , : 12.10%

lonisk lonic

Eksempel 3 5 Example 3 5

6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid ble oppvarmet i ethanol i 3 0 minutter. Reaksjonsblandingen ble inndampet, og det erholdte 6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-hydroklorid ble på vanlig måte overført til base. Basen ble krystallisert fra petrolether. Det ble erholdt 6-methyl-9-[(N,N-dimethylamino)-carbonyl]-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin. 6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine chloride was heated in ethanol for 30 minutes. The reaction mixture was evaporated to give 6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine hydrochloride was transferred to base in the usual way. The base was crystallized from petroleum ether. 6-Methyl-9-[(N,N-dimethylamino)-carbonyl]-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained.

Analyse C]_2H17N3°2 Analysis C]_2H17N3°2

Eksempel 36 Example 36

3-cyano-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin som beskrevet i eksempel 5, ble omsatt med fosgen-N,N-dimethyl-immoniumklorid. Det ble erholdt sterkt hygroskopisk 3-cyano-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid. 3-cyano-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine as described in Example 5 was reacted with phosgene-N,N-dimethyl -ammonium chloride. Highly hygroscopic 3-cyano-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine chloride.

Analyse <C>13<H>16<N>4<0>C12Analysis <C>13<H>16<N>4<0>C12

Beregnet: Cl.. , : 10,70 % Calculated: Cl.. , : 10.70%

3 lonisk 3 lonic

Funnet : Cl...: <10>,52%Found : Cl...: <10>,52%

lonisk lonic

Eksempel 3 7 Example 3 7

3-cyano-6-methyl-9-[(klor-N,N-dimethyl-ammonio)-methylen]-4-OXO-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-klorid ble behandlet som beskrevet i eksempel 29. 3-cyano-6-methyl-9-[(chloro-N,N-dimethyl-ammonio)-methylene]-4-OXO-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] Pyrimidine chloride was treated as described in Example 29.

Den ethanoliske løsning ble inndampet og residuet ble krystallisert fra ethylacetat. Det ble erholdt 3-cyano-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin, utbytte: 60 %. The ethanolic solution was evaporated and the residue was crystallized from ethyl acetate. 3-cyano-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine was obtained, yield: 60%.

Analyse ci3Hi6<N>4°2 Analysis ci3Hi6<N>4°2

Eksempel 38 Example 38

3,4 g 3-ethoxycarbonyl-6-methyl-8-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-hydroklorid ble løst i 20 ml vann, og løsningen ble nøytralisert med en 5 W/V % natriumbicarbonatløsning. Reaksjonsblandingen ble utristet med kloroform. Kloroformløsningen ble tørket over natriumsulfat, filtrert og inndampet. Residuet ble omkrystallisert fra en blanding av ethanol og vann. Det ble erholdt 2,1 g 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin. 3.4 g of 3-ethoxycarbonyl-6-methyl-8-(N,N-dimethylamino-carbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine- hydrochloride was dissolved in 20 mL of water, and the solution was neutralized with a 5 W/V% sodium bicarbonate solution. The reaction mixture was shaken with chloroform. The chloroform solution was dried over sodium sulfate, filtered and evaporated. The residue was recrystallized from a mixture of ethanol and water. 2.1 g of 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a ]pyrimidine.

Analyse C, CH.-.,N,0. Analysis C, CH.-.,N,0.

J 15 21 3 4 J 15 21 3 4

E ksempel 39 Example 39

3,07 g 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidin ble løst i ethanol. Til den erholdte løsning ble tilsatt en 20 W/V % løsning av ammoniakk, og reaksjonsblandingen fikk stå i 3 dager i et lukket kar. De utskilte krystaller ble filtrert fra og vasket med ethanol. Det ble erholdt 1,18 g 3-aminocarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin med sm.p. 220° C. 3.07 g of 3-ethoxycarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2-a]pyrimidine was dissolved in ethanol. A 20 W/V % solution of ammonia was added to the solution obtained, and the reaction mixture was allowed to stand for 3 days in a closed vessel. The precipitated crystals were filtered off and washed with ethanol. 1.18 g of 3-aminocarbonyl-6-methyl-9-(N,N-dimethylamino-carbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2- a]pyrimidine with m.p. 220°C.

Analyse C]_3Hi8N4° Analysis C]_3Hi8N4°

Eksempel 40 Example 40

3,6-diethoxycarbonyl-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyridin[1,2-a]pyrimidin ble behandlet som beskrevet i eksempel 41 med ammoniakk i ethanol. Det ble erholdt 1,51 g 3-aminocarbo-nyl-9-ethoxycarbonyl-6-methyl-4-oxo-l,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidin som smelter ved 251° C. 3,6-diethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyridine[1,2-a]pyrimidine was treated as described in Example 41 with ammonia in ethanol. 1.51 g of 3-aminocarbonyl-9-ethoxycarbonyl-6-methyl-4-oxo-1,6,7,8-tetrahydro-4H-pyrido-[1,2-a]pyrimidine was obtained which melts at 251°C.

Analyse ci3<H>i7<N>3°4 Analysis ci3<H>i7<N>3°4

Eksempel 41 Example 41

0,416 g 3-ethoxycarbonyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,a-a]pyrimidin ble løst i 4 ml benzen og til løsningen ble tilsatt 0,24 g fenylisocyanat. Reaksjonsblandingen fikk stå i 5 dager ved romtemperatur, og de utskilte krystaller ble filtrert og vasket med benzen. Det ble erholdt 0,50 g (76,5 %) 3-ethoxycarbonyl-8-(N-fenyl-amino-carbonyl)-4-oxo-l,4,6,7-tetrahyd-ro-pyrrolo[1,2-a]pyrimidin som smelter ved 240 - 241° C. 0.416 g of 3-ethoxycarbonyl-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,a-a]pyrimidine was dissolved in 4 ml of benzene and 0.24 g of phenyl isocyanate was added to the solution. The reaction mixture was allowed to stand for 5 days at room temperature, and the precipitated crystals were filtered and washed with benzene. 0.50 g (76.5%) of 3-ethoxycarbonyl-8-(N-phenyl-amino-carbonyl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[1,2 -a]pyrimidine which melts at 240 - 241° C.

Analyse C]_7H]_7N3°4 Analysis C]_7H]_7N3°4

Eksempel 4 2 Example 4 2

Til en løsning av 0,8 g 3-cyano-4-oxo-4,6,7,8-tetra-hydro-pyrrolo[1,2-a]pyrimidin og 0,6 ml carbondisulfid i 10 ml ethanol ble dråpevis tilsatt en løsning av 0,6 g kaliumhydroxyd i 10 ral ethanol. Reaksjonsblandingen ble omrørt i 1 time ved romtemperatur, og inndampet under redusert trykk. Det ble erholdt et dikaliumsalt av 3-cyano-8-[(bis-tiolat)-methylen]-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin. To a solution of 0.8 g of 3-cyano-4-oxo-4,6,7,8-tetra-hydro-pyrrolo[1,2-a]pyrimidine and 0.6 ml of carbon disulfide in 10 ml of ethanol was added dropwise a solution of 0.6 g potassium hydroxide in 10 ral ethanol. The reaction mixture was stirred for 1 hour at room temperature and evaporated under reduced pressure. A dipotassium salt of 3-cyano-8-[(bis-thiolate)-methylene]-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine was obtained.

Eksempel 4 3 Example 4 3

Et dikaliumsalt av cyano-9-[(bis-thiolat)-methylen]-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidin, fremstilt som beskrevet i eksempel 44, ble løst i 20 ml ethanol og ble deretter tilsatt 1,25 g dimethylsulfat hvoretter reaksjonsblandingen ble omrørt i 1 time ved 40° C. De utskilte krystaller ble filtrert fra, vasket med ethanol. Det ble erholdt 0,46 g (36,5 %) 3-cyano-8-(methylthio-thiocarbonyl)-4-oxo-l,4,6,7-tetrahydro-pyrrolo-[1,2-a]pyrimidin som smelter ved 202 - 203° C. A dipotassium salt of cyano-9-[(bis-thiolate)-methylene]-4-oxo-4,6,7,8-tetrahydro-pyrrolo[1,2-a]pyrimidine, prepared as described in Example 44, was dissolved in 20 ml of ethanol and then 1.25 g of dimethylsulphate was added, after which the reaction mixture was stirred for 1 hour at 40° C. The separated crystals were filtered off, washed with ethanol. 0.46 g (36.5%) of 3-cyano-8-(methylthio-thiocarbonyl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo-[1,2-a]pyrimidine was obtained as melts at 202 - 203° C.

Analyse C10HgN3O<S>2Analysis C10HgN3O<S>2

Eksempel 44 Example 44

0,66 g av en 80 %-ig oljeaktig natriumhydridsuspensjon ble tilsatt til 50 ml benzen, og deretter ble en løsning av 4,72 0.66 g of an 80% oily sodium hydride suspension was added to 50 ml of benzene, and then a solution of 4.72

g 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin i 15 ml benzen dråpevis tilsatt. Etter 30 minut-ters omrøring ble en løsning av 2,96 g methylthioisocyanat i 10 ml benzen tilsatt i løpet av 10 minutter ved en temperatur på 25 - 35° C. Reaksjonsblandingen ble omrørt i 2 timer og etter tilsetning av 80 ml ether utskiltes natriumsaltet av 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin i oljeaktig form. Løsningsmidlet ble dekantert fra, residuet ble revet med ether og tørket i vakuum i eksikator. På denne måte ble det erholdt 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin i form av natriumsaltet. g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidine in 15 ml of benzene added dropwise. After stirring for 30 minutes, a solution of 2.96 g of methylthioisocyanate in 10 ml of benzene was added over 10 minutes at a temperature of 25 - 35° C. The reaction mixture was stirred for 2 hours and after the addition of 80 ml of ether, the sodium salt separated of 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine in oily form. The solvent was decanted off, the residue was triturated with ether and dried in a vacuum in a desiccator. In this way, 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained in the form of the sodium salt.

Eksempel 4 5 Example 4 5

Det ifølge eksempel 46 fremstilte natriumsalt av 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin ble tilsatt 15 ml aceton og deretter 130 ml vann, og pH-verdien på den erholdte løsning ble stilt på 3 - 4 ved hjelp av eddiksyre. De utskilte krystaller ble filtrert fra, vasket med vann, tørket og omkrystallisert fra ethanol. Det ble erholdt 3,2 g (52 %) 3-ethoxycarbo-nyl-6-methyi-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetra-hydro-4H-pyrido[1,2-a]pyrimidin med sm.p. 199 - 200° C. The sodium salt of 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine prepared according to example 46 was added 15 ml of acetone and then 130 ml of water, and the pH value of the resulting solution was set to 3 - 4 using acetic acid. The precipitated crystals were filtered off, washed with water, dried and recrystallized from ethanol. 3.2 g (52%) of 3-ethoxycarbonyl-6-methyl-9-(methylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1 ,2-a]pyrimidine with m.p. 199 - 200° C.

Analyse C14HigN3<0>3<S:>Analysis C14HigN3<0>3<S:>

Eksempel 4 6 Example 4 6

0,66 g av en 80 %-ig oljeaktig natriumhydridsuspensjon ble tilsatt til 50 ml benzen, og deretter ble en løsning av 4,72 g 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a]pyrimidin i 15 ml benzen dråpevis tilsatt. Etter 30 minut-ters omrøring ble en løsning av 5,4 g fenylthioisocyanat i 10 ml benzen i løpet av 10 minutter og ved en temperatur på 25 - 35° C tilsatt. Reaksjonsblandingen ble omrørt i 2 timer, og etter tilsetning av 80 ml ether utskiltes natriumsaltet av 3-ethoxycarbo-nyl-6-methyl-9-(fenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin i oljeaktig form. Løsningsmidlet ble dekantert fra, residuet ble revet med ether og tørket i vakuum-eksikator. På denne måte ble det erholdt natriumsaltet av 3-ethoxycarbonyl-6-methyl-9-(fenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin med et utbytte på 6,1 g (76 %) . 0.66 g of an 80% oily sodium hydride suspension was added to 50 ml of benzene, and then a solution of 4.72 g of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro -4H-pyrido-[1,2-a]pyrimidine in 15 ml of benzene added dropwise. After stirring for 30 minutes, a solution of 5.4 g of phenylthioisocyanate in 10 ml of benzene was added over the course of 10 minutes and at a temperature of 25 - 35° C. The reaction mixture was stirred for 2 hours, and after the addition of 80 ml of ether, the sodium salt of 3-ethoxycarbonyl-6-methyl-9-(phenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H was separated -pyrido[1,2-a]pyrimidine in oily form. The solvent was decanted off, the residue was triturated with ether and dried in a vacuum desiccator. In this way the sodium salt of 3-ethoxycarbonyl-6-methyl-9-(phenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine was obtained with a yield of 6.1 g (76%).

Eksempel 4 7 Example 4 7

Det i eksempel 48 fremstilte natriumsalt av 3-ethoxy-carbonyl-6-methyl-9-(fenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4PI-pyrido [1, 2-a] pyrimidin ble tilsatt 15 ml aceton og 130 ml vann, og pH-verdien på den erholdte løsning ble innstilt på 3 - 4 med eddiksyre. De utskilte krystaller ble filtrert, vasket med vann, tørket og omkrystallisert fra acetonitril. The sodium salt of 3-ethoxy-carbonyl-6-methyl-9-(phenylamino-thiocarbonyl)-4-oxo-6,7,8,9-tetrahydro-4PI-pyrido[1,2-a]pyrimidine prepared in example 48 15 ml of acetone and 130 ml of water were added, and the pH value of the resulting solution was adjusted to 3 - 4 with acetic acid. The precipitated crystals were filtered, washed with water, dried and recrystallized from acetonitrile.

Det ble erholdt 3,2 g (52 %) 3-ethoxycarbonyl-6-methyl-9-(fenyl-amino-thiocarbonyl ) -4-oxo-l,6,7,8-tetrahydro-4H-pyrido[1,2-a]-pyrimidin. Sm.p.: 173 - 175° C. 3.2 g (52%) of 3-ethoxycarbonyl-6-methyl-9-(phenyl-amino-thiocarbonyl)-4-oxo-1,6,7,8-tetrahydro-4H-pyrido[1,2 -α]-pyrimidine. Melting point: 173 - 175° C.

Analyse: CjgH^NUCKS: Analysis: CjgH^NUCKS:

Claims

Starting materials for the production of therapeutically active 9-hydrazono-pyrimido-(or pyrrolo)-[1,2-a]pyrimidine derivatives, characterized in that they have the general formula:

wherein R and R denote hydrogen or C, . alkyl,

R 3 denotes hydrogen, carboxy, alkali metal carboxylate, C--4 alkoxycarbonyl, carbamoyl or cyano,

n is 0 or 1, and a) if R 7 represents hydrogen, R 5 and R 6 form an additional bond, R 4 represents the group consisting of

where x denotes halogen,

R gdenotes hydrogen or C, . alkyl,

R 9 denotes hydrogen, C 1-4 alkyl, chloroacetyl, phenyl which is optionally substituted by one or more halogen, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkoxycarbonyl; or naphthyl, R"*"0 denotes C,_. alkyl or phenyl, and 11

R denotes C^_^ alkyl, or b) if R^ and R<7> together form a further bond, denotes 4 5

R and R together a group consisting of

wherein R^, R^, R10, R1"1* and x have the meanings given above, and p is 2, or 6 7 5 c) if R and R form an additional bond, and R denotes hydrogen, R denotes a group consisting of 8 9

wherein R and R have the meanings given above, and optically active derivatives and salts thereof.