GB2119795A

GB2119795A - Condensed cycloaliphatic derivatives of substituted pyrido [1,2-a] pyrimidines

Info

Publication number: GB2119795A
Application number: GB08311648A
Authority: GB
Inventors: Gianfederico Doria; Carlo Passarotti; Pier Paolo Lovisolo; Ada Buttinoni
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1982-04-29
Filing date: 1983-04-28
Publication date: 1983-11-23
Also published as: GB2119795B; GB8311648D0

Abstract

Compounds of the formula <IMAGE> and their pharmaceutically acceptable salts, useful in the prevention and treatment of diseases in which inflammatory and/or anaphylactic mediators are involved, are prepared by reacting the 3-or 4- unsubstituted analogue thereof with RCHO. In formula I, n is 1 or 2, R1 is H, halogen, alkyl, CN, CONH2 or carboxy or esterified carboxy, R2, R3 and R4 independently are H, halogen, alkyl, alkoxy or alkenyloxy, A completes a double bond or, when R1 is carboxy or esterified carboxy, A may also be CH2 (so completing a cyclopropane ring) and R is furyl, thienyl or pyridyl or substituted or unsubstituted phenyl. Compounds where A is CH2 are prepared by cyclopropanating compounds where A completes a double bond.

Description

SPECIFICATION Condensed cycloaliphatic derivatives of substituted pyrido[1 ,2-a]pyrimidines The present invention relates to new condensed cycloaliphatic derivatives of substituted pyrido[1 ,2-a]pyrimidines, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides compounds having the following general formula (I)

wherein n is 1 or2; R, represents a hydrogen or a halogen atom, a C1-C4 alkyl group, a a-CN group, a a-CONH2 group or a a-COOR8 group, wherein R8 represents hydrogen or a C1-C8 alkyl group, unsubstituted or substituted by di(C1-C4)-alkylamino ; each of R2, R3 and R4 independently represents a hydrogen or a halogen atom, a C,C4 alkyl group, a C,C4 alkoxy group or a C3C4 alkenyloxy group; A completes a bond, thereby providing a double bond or, when R, is -COOR8 wherein R8 is as defined above, A may represent also a -OH2- group, thereby providing a cyclopropane ring fused to the pyrido ring; R is a) furyl, thienyl or pyridyl; or b) a group of formula

wherein each of R5, R6 and R7 represents, independently, a hydrogen or a halogen atom, hydroxy, formyloxy, C2-C8 alkanoyloxy, C1-C4 alkyl, C1-C4 alkoxy, nitro or a

group, wherein each of R9 and R10 independently represents hydrogen, C1-C4 alkyl, formyl or C2-C8 alkanoyl, or adjacent groups represented by two of R5, R6 and R7, taken together, form a C,C3 alkylenedioxy group; and the pharmaceutically acceptable salts thereof.

The invention also includes within its scope all the possible isomers, e.g. stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors of the compounds of formula (I).

The numbering used to identify the position in the compounds of formula (I) is the conventional one, as is depicted in the following examples: A) when n=1:

B) when n=2:

From the above definition of the meanings of the symbol A, it is clear that, whichever are the meanings of R1, A can always complete a bond, thereby providing a double bond between the 7- and 8-carbon atoms in the compounds wherein n is one or between the 8- and 9-carbon atoms in the compounds wherein n is two, while, when R1 is -COOR8, A can not only complete a bond but also represent a -OH2- group.

The alkyl, alkoxy, alkanoyl and alkanoyloxy groups may be branched or straight chain groups.

When one or more of R1, R2, Ra and R4 is C,C4 alkyl, this is preferably a methyl group.

When R8 is an unsubstituted C1-C6 alkyl group, it is preferably methyl, ethyl, isopropyl, hexyl, nbutyl.

When one or more of R1, R2, R3, R4 is a halogen atom, it is preferably chlorine or bromine.

When one or more of R5, R8 and R7 is halogen, it is preferably fluorine or chlorine.

When one or more of R5, R6 and R7 is C1-C4 alkyl, it is preferably methyl or ethyl.

When one or more of R5, R6 and R7 is C1-C4 alkoxy, it is preferably methoxy, ethoxy, propoxy and isopropoxy.

When one or both of R9 and R10 is C1-C4 alkyl, it is preferably methyl or ethyl.

Preferred alkanoyloxy groups are acetoxy and propionyloxy.

Preferred alkanoyl groups are acetyl and propionyl.

Preferred compounds of the invention are compounds having formula (I) wherein R, represents hydrogen, chlorine, carboxy, methyl, or (01-04)alkoxy-carbonyl unsubstituted or substituted by a 2 N,N-di(O12)alkyl-amino group; R2 is hydrogen; R3 is hydrogen, chlorine, methyl or methoxy; R4 is hydrogen; A completes a bond, thereby providing a double bond, or when R1 is a free carboxy group, A may represent also a -OH2- group, thereby providing a cyclopropane ring fused to the pyrido ring; n is 1 or 2;R is a) furyl, thienyl or pyridyl; orb) a group of formula

wherein, each of R5, R6 and R7 represents independently hydrogen, chlorine, fluorine, C1-C2 alkyl, O1-C3 alkoxy, amino, dimethylamino, hydroxy or adjacent groups represented by two of R5, R6 and R7, taken together, form a methylenedioxy group; and the pharmaceutically acceptable salts thereof.Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides or with organic bases, such as lysine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, d-(2-ethyl-hexyl)-amine, piperidine, Nethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, 2-phenethylamine, N-benzyl-,8- phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic acids, e.g. hydrochloric, hydrobromic, nitric and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids.

Preferred salts are the sodium and the potassium salts, as well as the hydrochlorides of the basic esters, e.g. the diethylaminoethyl and dimethylaminoethyl esters. Examples of particularly preferred compounds of the invention are: 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7-carboxylic acid; 3-(2-methyl-benzylidene)-1 ,2,3,1 0-tetrahydro-1 O-oxo-cyclopenta [d]pyrido[ 1 ,2-alpyrimidine-7- carboxylic acid; 3-(2,5-dimethoxy-benzylidene)- 1,2,3,1 0-tetrahydro-1 O-oxo-cyclopenta [d] pyrido[ 1,2- a]pyrimidine-7-carboxylic acid; 3-(2,3-dimethoxy-benzylidene)-1 ,2,3, 1 O-tetrahydro- 1 O-oxo-cyclopenta [d] pyrido[1 ,2a]pyrimidine-7-carboxylic acid; 3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2a]pyrimidine-7-carboxylic acid;; 3-(3-methyl-benzylidene)- 1 ,2,3,1 O-tetrahydro- 1 O-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7carboxylic acid; 3-(4-methyl-benzylidene)- 1 ,2,3, 1 O-tetra hydro- 1 0-oxo-cyclopenta[d] pyrido[ 1 ,2-a]pyrimidine-7carboxylic acid; 3-(2-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(3-ethoxy-benzylidene)- 1 ,2,3,1 O-tetrahydro- 1 O-oxo-cyclopenta [d] pyrido[ 1 ,2-ajpyri midine-7- carboxylic acid; 3-(4-methoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7carboxylic acid;; 3-(4-ethoxy-be nzylidene)- 1 ,2,3, 1 O-tetrahydro- 1 O-oxo-cyclopenta [d] pyrido[ 1 ,2-a]pyri m idine-7carboxylic acid; 3-(2-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(3-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-benzylidene-7,8-methylene- 1 ,2,3, 1 O-tetrahydro- 1 O-oxo-cyclopenta [dj pyridol 1 ,2a]pyrimidine-7-carboxylic acid; 3-(2-methyl-benzylidene)-7,8-methylene- 1 ,2,3, 1 O-tetrahydro- 1 O-oxo-cyclopenta [d] pyrido[ 1 ,2a]pyrimidine-7-carboxylic acid;; 4-benzylidene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-methyl-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline-8-ca rboxylic acid; 4-(3-methyl-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline-8-ca rboxyl ic acid; 4-(4-methyl-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8-carboxylic acid; 4-(2-methoxy-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid; 4-(3-methoxy-benzylidene)- 1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8carboxylic acid;; 4-(4-methoxy-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8carboxylic acid; 4-(2-ethoxy-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2, 1 -b]quinazoline-8-ca rboxylic acid; 4-(3-ethoxy-benzylidene)- 1 ,2,3,4-tetrahyd ro- 1 1 -oxo- 11 H-pyrido[2, 1 -b]quinazoline-8-ca rboxylic acid; 4-(4-ethoxy-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8-carboxylic acid; 4-(2,5-dimethyl-benzylidene)- ,2,3,4-tetrahydro- 11 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid; 4-(2,3-dimethoxy-benzylidene)- ,2,3,4-tetrahydro- 11 -oxo-1 1 H-pyrido[2, . -b]quinazoline-8carboxylic acid;; 4-(2,5-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid; 4-(3,4-dichloro-benzylidene)-1 .2,3,4-tetrahydro- 11 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8carboxylic acid; 4-(3,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid; 4-(3,4-methylenedioxy-benzylidene)-1 ,2,3,4-tetrahydro- 11 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline8-carboxylic acid; 4-(4-fluoro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; 4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; ; 4-(3-chloro-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(4-chloro-benzylidene)- 1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-methoxy-3-ethoxy-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo- 11 H-pyrido[2,1 -b]quinazoline- 8-carboxylic acid; 4-(2-thenylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid ; 4-[(2-pyridyl)-methylenel-l ,2,3,4-tetra hydro- 11 -oxo- 11 H-pyrido [2,1 -b]quinazoline-8-carboxylic acid; 4-[(3-pyridyl)-methylene]-1 ,2,3,4-tetrahydro-1 1 -oxo- 1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid;; 4-benzylidene-8,9-methylene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2, 1 -b]quinazoline-8carboxylic acid; 4-benzylidene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2 (N,N-diethylamino)-ethyl ester; 4-benzylidene-8-methyl-1,2,3,4-tetrahydro-11H-pyrido[2,1-b] quinazoline-11-one ; and 3-benzylidene-7-methyl- 1 ,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-1 O-one; and the pharmaceutically acceptable salts thereof, in particular the sodium salts and the hydrochlorides, the basic esters (e.g. those with 2-diethylamino-ethanol) and the C1-C6 alkyl esters thereof, in particular the methyl, ethyl, isopropyl, n-butyl and hexyl esters.The compounds of the invention can be prepared by a process comprising: a) reacting a compound of formula (II)

wherein n, R1, R2, R3, R4 are as defined above or a salt thereof, with an aldehyde of formula (III) R-CHO (III) wherein R is as defined above, so obtaining compounds of formula (I) wherein A is a bond; or b) cyclopropanating a compound of formula (IV)

wherein n,R,R2, R3, R4 and R8 are as defined above or a salt thereof, so obtaining compounds of formula (I) wherein R1 is OOR8 wherein R8 is as defined above and A is a -OH2- group; and/or, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers into the single isomers.Preferred salts of a compound of formula (II) are, for example, those with inorganic bases such as sodium, potassium and calcium salts, as well as the salts with inorganic acids such as hydrochloric, hydrobromic and sulphuric acid.

The reaction of a compound of formula (II) with an aldehyde of formula (III) is preferably carried out in the presence of basic condensing agents such as, sodium ethoxide, sodium methoxide, sodium hydride, sodium amide, or potassium tert. butoxide, in a solvent such as methanol, ethanol, dioxane, tert. butanol or their mixtures at a temperature preferably ranging from about OOC to about 1200C.

Preferred salts of a compound of formula (IV) are, for example, those with inorganic bases such as sodium, potassium and calcium salts.

The cyclopropanation of a compound of formula (IV) may be carried out, for example, by reaction with dimethylsulphoxonium methylide (prepared e.g. according to the method described in J. Chem.

Soc., 1967, 2495), operating in an inert organic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide or dioxane or their mixtures; the temperature ranges preferably from OOC to 500C and the reaction time is generaily less than 5 hours, preferably less than 2 hours.Preferably 1-3 moles, in particular 1-1.5 moles, of the reagent are used for one mole of the compound of formula (IV) A compound of formula (I) may be converted, as stated above, into another compound of formula (I) by known methods; for example, the compound of formula (I) wherein R is an esterified carboxy group, may be converted into a compound of formula (I) wherein R, is carboxy by hydrolysis, e.g. basic hydrolysis, using, for example, sodium or potassium hydroxide, in a solvent, such as, water or a lower aliphatic alcohol, and operating at a temperature ranging from room temperature to 1500C;; the same reaction may be also carried out e.g. by treatment with lithium bromide in dimethylformamide at a temperature higher than 50 C or by treatment with hydrochloric or hydrobromic or hydroiodic or sulphuric acid in acetic acid at a temperature higher than 500C.

A compound of formula (I) wherein R1 is a --COOH group may be converted into a compound of formula (I) wherein R, is a -OONH2 group, for example, by reacting the compound of formula (I) wherein R, is carboxy with ethyl chlorocarbonate in the presence of triethylamine in a solvent such as benzene, toluene, dioxane, tetrahydrofurane or dichloroethane at a temperature ranging from 00 to 250C, so obtaining the corresponding mixed anhydride, which in turn is reacted with gaseous ammonia in the same solvents at a temperature varying from about OOC to about 250C.

A compound of formula (I) wherein R1 is a -OONH2 group may be converted into a compound of formula (I) wherein R1 is a --CN group, by dehydrating the amide, e.g. by means of p-toluenesulphonyl chloride in pyridine and dimethylformamide at a temperature ranging from room temperature to about 1000C.

A compound of formula (I) wherein R1 is carboxy may be converted into a compound of formula (I) wherein R, is an esterified carboxy group, e.g. a carbalkoxy group unsubstituted or substituted by a lower dialkylamino group, by conventional methods, for example by reacting an alkaline salt of the acid with a suitable alkyl halide, in an inert solvent, such as, acetone, dioxane, dimethylformamide or hexamethylphosphorotriamide at a temperature ranging from about OOC to about 1000C.

Alternatively a compound of formula (I) wherein R1 is carboxy may be converted into a compound of formula (I) wherein R1 is an esterified carboxy group, as defined above, by reaction with SOCI2 in a solvent such as dioxane or dichloroethane at the reflux temperature so to obtain the corresponding chlorocarbonyl derivative, which in turn is reacted with a suitable alkyl alcohol in a solvent such as benzene, toluene, dioxane, dichloroethane, methylene chloride, chloroform at a temperature ranging from OOC to about 500C.

Free hydroxy groups, as substituents in the phenyl ring may be, for example, etherified by reacting with a suitable alkyl halide in the presence of a base such as NaOH, KOH, Na2CO3, K2CO3, NaH, NaNH2, sodium methoxide or sodium ethoxide, in a solvent such as methanol, ethanol, dioxane, acetone, dimethylformamide, hexamethylphosphorotriamide, tetrahydrofurane or water or their mixtures at a temperature ranging preferably from OOC to about 1 500C.

Furthermore the etherified hydroxy groups may be converted into free hydroxy groups, for example, by treatment with pyridine hydrochloride or with a strong acid such as, HCI, HBr or HI, or with a Lewis acid such as, AICI3 or BBr3.

Furthermore a free hydroxy or amino group, for example, may be converted respectively into a C2C6 alkanoyloxy or C2C8 alkanoylamino group using conventional methods well known in organic chemistry.

A nitro group as substituent on the phenyl ring may be converted into an amino group by treatment, for example, with stannous chloride in concentrated hydrochloric acid, using, if necessary, an organic cosolvent such as acetic acid, dioxane, tetrahydrofuran, at a temperature varying between room temperature and about 1000C.

Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

For example the separation of a mixture of optical isomers into the individual isomers may be carried out by salification with an optically active base and subsequent fractional crystallization.

The compounds of formula (II) may, for example, be prepared by reacting a compound of formula (V)

wherein R1,R2,Ra and R4 are as defined above, with a compound of formula (Vl)

wherein n and R8 are as defined above.The reaction between a compound of formula (V) and a compound of formula (Vl) may, for example, be carried out in the presence of an acid condensing agent such as polyphosphoric acid (polyphosphoric acid means a mixture of equal weights of 99% HYPO4 and P2O5), sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, at a temperature from 500C to 1500C; the reaction may be carried out in an organic solvent such as dimethylformamide, dimethylacetamide, acetic acid, formic acid, benzene, toluene, xylene or ethylene giycol monomethylether, but it is preferably carried out in the absence of a solvent.

The compounds of formula (IV) may, for example, be prepared by reacting a compound of formula (ill)

wherein n,R2, Ra, R4 and R8 are as defined above, and an aldehyde of formula (III), using the same experimental conditions defined above for the reaction between a compound of formula (II) and an aldehyde of formula (lil).

The compounds of formula (VII) may be, for example, prepared by reacting a compound of formula (VIII)

wherein R2,Ra,R4 and R8 are as defined above, with a compound of formula (Vl), using the same experimental conditions defined above for the reaction between a compound of formula (V) and a compound of formula (Vl).

The compounds of formula (III), (V), (Vl) and (VIII) are known compounds and may be prepared by conventional methods: in some cases they are commercially available products.

The compounds of this invention are useful for the prevention and the treatment of all the diseases in which inflammatory and/or anaphylactic mediators are involved, for example, the allergic affections and the inflammatory diseases.

Therefore the compounds of this invention are useful in the prevention and treatment, e.g., of allergic rhinitis, hay fever, urticaria, dermatitis and particularly are effective in the prevention and treatment of the allergic bronchial asthma.

Furthermore the compounds of this invention are useful also in the treatment, e.g., of rheumatoid arthritis and osteoarthrosis.

The activity of the compounds of this invention is shown, e.g., by the fact that they are active in the following biological tests: in vitro 1) test of A 23187 induced SRS production from rat peritoneal cells, according to M. K. Bach and J. R. Brashler (J. Immunol., 113, 2040, 1974); 2) test of antigen induced SRS production from chopped guinea-pig lung, according to W. E.

Brocklehurst (J. Physiol., 151,416, 1960); and in vivo 3) test of the IgG mediated passive peritoneal anaphylaxis in the rat, according to H. C. Morse, K.

J. Bloch and K. F. Austen (Journal Immunology, 101,658,1968); and 4) test of the IgE mediated passive cutaneous anaphylaxis (PCA) in the rat, according to A. M. J.

N. Blair (Immunology, 16, 749, 1969).

The results of these biological tests show that the compounds of the invention are active, for example, as inhibitors of the immunological release of mediators, e.g. histamine, from the mast cells and as inhibitors of the production and/or release of anaphylactic mediators such as "slow reacting substances" (SRS) in the peritoneal and in the pulmonary system, induced by challenge with an ionophore or with an antigen.

As preferred example of compound having antiallergic activity the following can be mentioned; 4-benzylidene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid (internal code FCE 21273).

The following Table I shows, for example, the in vitro inhibition obtained by the compound FCE 21273 of the SRS production from rat peritoneal cells and from chopped guinea-pig lung.

Table I

FCE 21273 Inhibition of SRS Sensitized system mcg/ml production Rat peritoneal cells 1 50% Chopped guinea-pig lung 10 47% Furthermore the compounds of this invention are effective in vivo, for example, in inhibiting the Reversed Passive Arthus Reaction (RPAR) which is a model of immune-complex induced inflammatory reaction initiated by the interaction of antigen and antibody resulting in the formation of precipitating immune-complex, followed by complement fixation and accumulation of PMN in the focal site (D. K.

Gemmell, J. Cottney and A. J. Lewis, Agents and Actions 9/1 page 107, 1 979).

For example, in the above test in the rat the compound FCE 21 273 gives about a 30% inhibition of RPAR reaction when administered orally at a dosage of 100 mg/kg..

The compounds of the present invention, furthermore, are active on the gastroenterical system, in particular they are endowed with anti-ulcerogenic and anti-secretory activity of the compounds of the therapy, for example, in the prevention and treatment of peptic, e.g., duodenal, gastric and esophageal, ulcers and to inhibit gastric acid secretion. The anti-ulcerogenic acitivity of the compounds of the invention is shown, e.g., by the fact that they are active in the test of inhibition of restraint ulcers in rats, according to the method of Bonfils et al. (ThBrapie, 1960, 15, 1096; Jap. J. Pharmac. 1968, 18, 9).

The following Table shows, for example, the approximate ED50 value of the anti-ulcerogenic activity in the rat obtained for one of the compounds of the invention after oral administration: Table

Compound Anti-ulcerogenic activity 3-benzylidene-1 ,2,3,1 0-tetrahydro-1 0-oxo- 1 OH-cyclopenta [d] pyrido[ 1 ,2-a]pyrimidine- 7-carboxylic acid ED50=12 mg/kg The tested compound was administered per os (p. o.) one hour before the immobilization.

Six Sprague-Dawley male rats (100-1 20 g) fasted 24 hours were used for the experiment: a square flexible small-mesh wire netting was used for the immobilization and 4 hours after the immobilization the rats were sacrificed, their stomachs were removed and the lesions counted under a dissecting microscope.

The compounds of the invention own also antisecretory activity as shown by the fact that after intraduodenal administration, they proved to be active in inhibiting the gastric secretion in rats according to the method of H. Shay et al. (Gastroenter., 1 945, 43, 5).

One of the preferred compounds of the invention having antisecretory activity is, for example, the compound 3-(2-methyl-benzylidene)-1 ,2,3,1 0-tetrahydro-1 0-oxo-1 OH-cyclopenta[d]pyrido[l ,2- a]pyrimidine-7-carboxylic acid, which has an approximate ED25 value of 10 mg/kg in the above test in the rat, after intraduodenal administration.

In view of their high therapeutic index the compounds of the invention can be safely used in medicine. For example, the approximate acute toxicity (LDso) of the compounds 3-benzylidene 1,2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7-carboxylic acid, 3-(2-methylbenzylidene)- 1,2,3,1 0-tetrahydro- 1 0-oxo-1 OH-cyclopenta[d]pyrido[l ,2-a]pyrimidine-7-carboxylic acid and 4-benzylidene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, in the mouse, determined with single administration of increasing doses and measured on the seventh day after the day of treatment, is per os higher than 800 mg/kg.Analogous toxicity data have been found for the other compounds of the invention.

The dosage depends on the age, weight, conditions of the patient and administration route; for example, the dosage adopted for oral administration route; for example, the dosage adopted for oral administration to adult humans may range from about 50 to about 200 mg pro dose, from 1 to 5 times daily. The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form, e.g., in the form of aqueous or oily solutions or suspensions, aerosols, as well as powders, tablets, pills, gelatine capsules, syrups, drops, suppositories, or creams, or lotions for topical use.

Thus, for oral administration, the pharmaceutical compositions containing the compounds of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance, silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone; disaggregating agents, such as starches, alginic acid, alginates, sodium starch glycolate; affervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polyisorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.

Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.

For the treatment of allergic asthma, the compounds of the invention are also administered by inhalation. For such use, suitable compositions may comprise a suspension or solution of the active ingredient, preferably in the form of a salt, such as the sodium salt or the salt with triethanolamine or with tris-(hydroxymethyl)-aminomethane, in water, for administration by means of a conventional nebulizer.

Alternatively, the compositions may comprise a suspension or a solution of the active ingredient in a conventional liquified propellant, such as dichlorodifluoromethane or dichlorotetrafluoroethane to be administered from a pressurized container, i.e., anaerosol dispenser.

When the medicament is not soluble in the propellant, it may be necessary to add a co-solvent, such as, ethanol, dipropylene glycol, isopropyl myristate, and/or surface-active agent to the composition, in order to suspend the medicament in the propellant medium and such surface-active agents may be any of those commonly used for this purpose, such as non-ionic surface-active agents, e.g., lecithin.

The compounds of the invention may also be administered in the form of powders by means of a suitable insufflator device and in this case the fine particle sized powders of the active ingredients may be mixed with a diluent material such as lactose.

Furthermore, the compounds of this invention may also be administered by intradermal or intravenous injection in the conventional manner.

In addition to the internal administration, the compounds of this invention may find use in compositions for topical application, e.g. as creams lotions or pastes for use in dermatological treatments.

For these compositions the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.

The following examples illustrate but do not limit the present invention.

Example 1 2-amino-5-chloro-pyridine (3.8 g) was reacted with ethyl-2-oxo-cyclopentanecarboxylate (9.2 g) in the presence of polyphosphoric acid (38 g, obtained from 18.1 g of P2Os and 19.9 g of 99% HaPO4) under stirring at 1000C for one hour. After cooling the reaction mixture was diluted in ice-water and neutralized to pH=6 using 35% sodium hydroxide.

The precipitate was filtered and crystallized from ethyl acetate to give 7-chloro-1,2,3,10 tetrahydro-cyclopenta[d]pyrido[1 ,2-a]pyrimidine-1 0-one, m.p. 146-1 47C (3.5 g), which was reacted with benzaldehyde (6.7 g) in methanol (140 ml) in the presence of sodium methoxide (3.38 g) under stirring at reflux temperature for 68 hours.

After cooling the precipitate was filtered, washed with water until neutral and crystallized from CH2CI2/acetone to give 3.1 2 g of 3-benzylidene-7-chloro-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[ 1,2- a]pyrimidine-10-one, m.p. 212--213 OC, NMR NMR (CF3COOD) 8 ppm: 3.40 (burs) (4H, 0-1 and C-2 cyclopentane protons), 7.39 (m) (6H, phenyl and methine protons), 8.27 (d) (1 H, C-5 proton), 8.50 (d.d) (1H, C-6 proton), 9.47 (d) (1H, C-8 proton).

By proceeding analogously, starting from suitable halogenated 2-amino-pyridines, the following compounds were prepared: 3-benzylidene-7-bromo-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine-10-one, m.p.

225-226 C ; 3-benzylidene-5,7-dichloro-1 ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[1 ,2-a]pyrimidine- 10-one, m.p. 248-250 C ; and 3-benzylidene-5,7-dibromo-1,2,3,10-tetrahydro-cyclopenta[d]pyrido [1,2-a] pyrimidine-10-one.

Example 2 7-chloro-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine-10-one (4 g), prepared according to Example 1, was reacted with 3,4,5-trimethoxy-benzaldehyde (8.87 g) in methanol (160 ml) in the presence of sodium methoxide (1.65 g) at reflux temperature for 140 hours. After cooling the precipitate was filtered, washed with water until neutral and crystallized from CH2CI2/methanol to give 4.4 g of 7-chloro-3-(3,4,5-trimethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d]pyrido [1,2a] pyrimidine-10-one, m.p. 222-223 C, NMR (CDCI3) S ppm: 3.13 (brs) (4H, cyclopentane protons), 3.95 (br s) (9H-OCH3), 6,82 (s) (2H, phenyl protons), 7.42 (br s) (1 H, =ch-), 7.58 (d) (2H, C-5 and C-6 protons), 9.02 (t) )1H, C-8 proton).

By proceeding analogously the following compounds were prepared: 7-chloro-3-(2-methoxy-benzylidene)-1 ,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[1 ,2-a]pyrimidine- 10-one, m.p. 236-237 C ; 7-chloro-3-(3-methoxy-benzylldene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido[1,2-a] pyrimidine10-one, m.p. 206-207 C ; 7-chloro-3-(4-methoxy-benzylidene)- 1 ,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine- 10-one, m.p. 257-258 C ; 7-chloro-3-(2,3-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido[1,2a]pyrimidine-10-one, m.p. 243-245 C ; 7-chloro-3-(2,5-dimethoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[ 1 2- a]pyrimidine-1 0-one; 7-chloro-3-(3,4-dimethoxy-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2- a]pyrimidine-1 0-one;; 7-chloro-3-(3,4-methylenedioxy-benzylidene)- 1 ,2,3, 1 0-tetrahydro-cyclopenta [d]pyrido[ 1 ,2- a] pyrimidine-10-one ; 7-ch loro-3-(2,3 ,4-tri methoxy-benzylidene)-1 2,3,1 0-tetrahydro-cyclopenta [d] pyrido[ 1 ,2- a] pyrimidine-10-one, m.p. 222-224 C ; 7-chloro-3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one, m.p. 261-262 C ; 7-chloro-3-(4-methyl-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido[1,2-a] pyrimidine10-one, m.p. 235-237 C ; 7-chloro-3-(2-methoxy-3-ethoxy-benzylidene)- 1,2,3,1 0-tetra hydro-cyclopenta [d]pyrido [1,2- a]pyrimidine-1 0-one; 7-chloro-3-(2-ethoxy-3-methoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one;; 7-bromo-3-(2,3-dimethoxy-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2- a]pyrimidine-1 0-one; 7-chloro-3-(2,3-diethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one; 5,7-dichloro-3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one; 5,7-dichloro-3-(2-ethoxy-3-methoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d]pyrido [1,2 a]pyrimidine-1 0-one; 5,7-dichloro-3-(2,3-dimethoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-cyclopenta [d]pyrido[ 1 ,2- a]pydmidine-1 0-one; and 7-chloro-3-(2,4-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one.

Example 3 7-chloro-1,2,3,10-tetrahydro-cyclopenta[d]pyrido[1,2-a]pyrimidine-10-one (3.5 g), prepared according to Example 1, was reacted with 2-chlorobenzaldehyde (3.4 g) in methanol (150 ml) in the presence of sodium methoxide (1.73 g) under stirring at reflux temperature for 36 hours.

After cooling the precipitate was filtered, washed with water until neutral and crystallized from chloroform to give 3 g of 7-chioro-3-(2-chloro-benzylidene)-l ,2,3,1 O-tetrahydro- cyclopenta[d] pyrido [1,2-a] pyrimidine-10-one, m.p. 249-250 C, NMR (CF3COOD) $ ppm : 3.34 (s) (4H, 0-1 and C-2 protons), 7.45 (m) (3H, 3-, and 5-phenyl protons), 7.70 (m) (1 H, 6-phenyl proton), 7.91 (m) (1 H, =CH-), 8.25 (d) (1 H, C-S proton), 8.50 (d.d) (1 H, C-6 proton) 9.48 (d) (1 H, C-8 proton).

By proceeding analogously, reacting suitable halogenated 1,2,3,1 0-tetrahydro- cyclopenta[d] pyrido[1,2-a] pyrimidines with suitable substituted benzaldehydes, the following compounds were prepared: 7-chloro-3-(3-chloro-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta [d]pyrido[l ,2-a]pyrimidine- 10-one, m.p. 270-272 C ; 7-chioro-3-(4-chloro-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2-a]pyrimidine- 10-one, m.p. 253-256 C ; 7-chloro-3-(2,6-dichloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2a] pyrimidine-10-one, m.p. 234-236 C ; 7-chloro-3-(2,4-dichloro-benzylidene)-1 ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[1 ,2- a] pyrimidine-10-one, m.p. 298-300 C ;; 7-chloro-3-(3,40dichloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2a] pyrimidine-10-one, m.p. 279-280 C ; 7-bromo-3-(2-chloro-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2-a]pyrimidine- 10-one; 7-bromo-3-(3-chloro-benzylidene)-1 ,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[1 2-aipyrimidine- 10-one ; 7-bromo-3-(4-chloro-benzy7lidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one; 7-bromo-3-(2,6-dichloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2a] pyrimidine-10-one, m.p. 233-234 C ; 7-bromo-3-(2,4-dichloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2a] pyrimidine-10-one ; 5,7-dichloro-3-(2,6-dichloro-benzylidene)-1 ,2,3, 1 0-tetrahydrn-cyclopenta[d]pyrido[1 ,2- a] pyrimidine-10-one, m.p. 164-166 C ;; 5,7-dichloro-3-(2-chloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one; 5,7-dichloro-3-(3-chloro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2a] pyrimidine-10-one ; S,7-dichloro-3-(4-chloro-benzylidene)-1 ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[ 1,2- a] pyrimidine-10-one ; 7-chloro-3-(4-fluoro-benzylidene)- 1 ,2,3, 1 0-tetrahydro-cyclopenta [d]pyrido[ 1 ,2-a]pyrimidine- 1 0- one; 7-bromo-3-(4-fluoro-benzylidene)-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2-a]pyrimidine-l 0- one; 5,7-dichloro-3-(4-fluoro-benzylidene)-1 ,2,3, 1 0-tetrahydro-cyclopenta[djpyrido[1 2-aipyrimidine- 10-one; 5,7-dibromo-3-(4-fluoro-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one;; 7-chloro-3-(4-N,N-dimethylamino-benzylidene)- 1,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[ 1,2- a]pyrimidine-1 0-one; 7-bromo-3-(4-N,N-dimethylamino-benzylidene)-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2 a]pyrimidine-1 0-one; and 5,7-dichloro-3-(4-N,N-dimethylamino-benzylidene)-1,2,3,10-tetrahydrocyclopenta[d] pyrido [1,2-a] pyrimidine-10-one.

Example 4 1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid methyl ester, m.p. 153-154 C (3.3 g) g) was reacted with 3-methoxybenzaldehyde (5.52 g) in methanol (145 g) in the presence of sodium methoxide (2.97 g) under stirring at reflux temperature for 144 hours.

After cooling the precipitate was filtered and treated with formic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2/methanol to give 2.73 g of 3-(3-methoxy-benzylidene)-1 2,3,1 0-tetrahydro-1 0-oxocyclopenta[d] pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 310-312 C, NMR (CF3COOD) $ ppm: 3.42 (br) (4H, cyclopentane protons), 4.11 (s) (3H, OCHa), 7.2-7.6 (m) (4H, phenyl protons), 7.61 (br) (1 H, OH-), 8.41(d) (1H, (1 H, C-S proton), 9.11 (d.d) (1 H, C-6 proton), 10.20 (d) (1 H, C-8 proton).

By proceeding analogously the following compounds were prepared: 3-(2-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid, m.p. 322-324 C ; 3-(4-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid, m.p. 368-370 C ; 3-(2-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(2,3-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a] pyrimidine-7-carboxylic acid, m.p. 3093110C; 3-(3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] yrido [1,2-a] pyrimidine-7carboxylic acid, m.p. 328-332 C ; 3-(2,5-dimethoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[djpyrido[ 1 2- a]pyrimidine-7-carboxylic acid; and 3-(3,4-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxylic acid.

Example 5 1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid methyl ester, m.p. 153-154 C (5 g) in methanol (300 ml) containing 6.45 g of sodium methoxide was reacted with 10.9 g of benzaldehyde under stirring at reflux temperature for 96 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and treated with acetic acid and then with water; the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2/methanol and then from dioxane to give 3.25 g of 3-benzylidene 1,2,3,1 O-tetrahydro-l O-oxo-cyclopenta[d]pyrido[ 1,2-a] pyrimidine-7-carboxylic acia, m.p. 309- 310 C, NMR (CF3COOD) 8 ppm: 3.44 (m) (4H, cyclopentane protons),7.68 (6H, OH- and phenyl protons), 8.44 (d) (1 H, C-5 proton), 9.1 5 (d.d) (1 H, C-6 proton), 10.23 (d) (1 H, C-8 proton).

By proceeding analogously the following compounds were prepared: 3-(3-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(4-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(2,5-dimethyl-benzylidene)- 1,2,3,10-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine- 7-carboxylic acid; 3-(2,4-dimethyl-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[1 ,2-a]pyrimidine- 7-carboxylic acid; 3-(4-fluoro-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(3-chloro-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta [d]pyrido[ 1 ,2-ajpyrimidine-7- carboxylic acid, m.p. 318-320 C ;; 3-(2-methyl-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid, m.p. 300-302 C ; 3-(2,6-dichloro-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine7-carboxylic acid, m.p. 292-295 C ; 3-(2,4-dichloro-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine7-carboxylic acid; 3-(3,4-dichloro-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine7-carboxylic acid; 3-(4-N,N-dimethylamino-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxylic acid, m.p. 330-340 C dec.; and 3-(2-chloro-benzylidene)- 1,2,3,1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid.

Example 6 1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid (3.12 g) in methanol (145 ml) containing 2.9 g of sodium methoxide was reacted with 4.86 g of 2-methylbenzaldehyde under stirring at reflux temperature for 144 hours. After cooling and concentration in vacuo to a small volume, the precipitate was filtered and treated with acetic acid and then with water: the crude compound was recovered by filtration, washed with water until neutral and crystallized from CH2Cl2/methanol and then from dioxane to give 1.9 g 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro- 10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 300-302 C, NMR (CF3COOD) # ppm: 2.49 (s) (3H, -CH3), 3.36 (s) (4H, cyclopentane protons), 7.42 (m) (3H, phenyl protons),7.64 (m) (1 H, phenyl proton), 7.81 (bs) (1 H, =CH-), 8.40 (d) (1 H, C-S proton), 9.11 (dd) (1 H, C-6 proton), 10.23(d) (1H, C-8 proton).

By proceeding analogously the following compounds were prepared: 3-(4-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] prrimidine-7carboxylic acid; 3-(3,4-methylenedioxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxylic acid; and 3-(2,3,4-trimethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxylic acid.

Example 7 3-(3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta [d] pyrido [1,2-a] pyrimidine-ycarboxylic acid (2.7 g), prepared according to Example 4, was heated with 37% HCI (54 ml) in acetic acid (54 mi) under stirring at reflux temperature for 20 hours. After cooling the precipitate was filtered, washed with water and then treated with aqueous sodium acetate under stirring: filtration and crystallization of the precipitate from dimethylformamide gave 1 ,85 g of 3-(3-hydroxy-benzylidene) 1,2,3,1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[1 ,2-a]pyrimidine-7-carboxylic acid, m.p. > 320 C.

Example 8 7-methyl-1,2,3,1 O-tetrahydro-cyclopenta [d]pyrido[l ,2-a]pyrimidine-l O-one (5 g) was reacted with benzaldehyde (13.2 g) in methanol (200 ml) in the presence of sodium methoxide (6.8 g) at reflux temperature for 96 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and washed with water until neutral; crystallization from CH2CI2/methanol gave 3benzylidene-7-methyl- 1,2,3,1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-ajpyrimidine-1 0-one, m.p. 197- 199 C, NMR (CDCI3) a ppm: 2.45 (s) (3H, CH3), 3.10 (bs) (4H, C-i and C-2 protons), 7.2-7.7 (m) (8H, =CH-- and C-S and C-6 and phenyl protons), 8.80 (bs) (1 H, C-8 proton).

By proceeding analogously, the following compounds were prepared: 3-(3-methoxy-benzylidene)-7-methyl-1,2,3,10-tetrahydro-cyclopenta[d] pyrido[1,2-a] pyrimidine10-one ; 3-(2-methoxy-benzylidene)-7-methyl-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one; 3-(4-methoxy-benzylidene)-7-methyl-l ,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2-a]pyrimidine- 10-one; 3-(2,6-dichloro-benzylidene)-7-methyl-1,2,3,10-tetrahydro-cyclopenta[d] pyrido[1,2a] pyrimidine-10-one, m.p. 210-211 C ; 3-(2-methyl-benzylidene)-7-methyl-1 ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine- 10-one; 3-(3-methyl-benzylidene)-7-methyl-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one, and 3-(4-methyl-benzylidene)-7-methyl-1,2,3,10-tetrahydro-cyclopenta[d] pyrido [1,2-a] pyrimidine10-one.

Example 9 5-methoxy-1,2,3,1 O-tetrahydro-cyclopenta[d]pyrido[l ,2-a]pyrimidine-l O-one, m.p. 212- 2140C, (4 g) was reacted with benzaldehyde (8 g) in methanol (150 ml) in the presence of sodium methoxide (4 g) at reflux temperature for 150 hours. After cooling and concentration in vacuo to a small volume the precipitate was filtered and washed with water until neutral: crystallization from dioxane gave 2.5 g of 3-benzylidene-5-methoxy-l ,2,3,1 O-tetra hydro-cyclopenta [d]pyrido[l ,2- a]pyrimidine-1 0-one, m.p. 229-230 C, NMR (DMSO d6) 8 ppm: 3.26 (bs) (4H, C-i and C-2 protons), 4.20 (s) (3H, OCHa), 7.5-7.9 (m) (8H, =CH, C-6 and C-7 and phenyl protons), 8.90 (d.d) (1 H, C-8 proton).

By proceeding analogously the following compounds were prepared: 3-(2-chlorobenzylidene)-5-methoxy-i ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine- 10-one; and 3-(2,6-dichlorobenzylidene)-5-methoxy-1 ,2,3, 1 0-tetrahydro-cyclopenta[djpyrido[ 1,2- a] pyrimidine-10-one, m.p. 247-248 C.

Example 10 Trimethyl-sulphoxonium iodide (1.8 g) was reacted with 50% sodium hydride (0.39 g) in dimethyl formamide (30 ml) under stirring at room temperature for 60 minutes, then a solution of 3 benzylidene- 1 ,2 ,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a] pyrimidine-7-carboxylic acid methyl ester, m.p. 248-250 C, (2.49 g) in dimethylformamide (30 ml) was added. The mixture was allowed to react at room temperature for 1 hour then it was diluted with ice water and neutralized with acetic acid. The precipitate was filtered and washed with water to give 2.55 g of 3-benzylidene-7,8 methylene- 1 ,2 3,1 0-tetrahydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2-a]pyri midine-7-carboxylic acid methyl ester, m.p. 185-187 C, which was treated with 0.5% KOH in 95% ethanol solution (90 ml) at reflux temperature for 15 minutes.After cooling the reaction mixture was acidified with acetic acid and diluted with water: the precipitate was filtered, washed with water until neutral and crystallized from CH2CI2/methanol to give 1.8 g of 3-benzylidene-7,8-methylene-1,2,3,10-tetrahjydro-10-oxo- cyclopenta[d] pyrido [1,2-a] pyrimidine-7-carboxylic acid, m.p. 230-240 C dec., NMR (CF3COOD)# ppm: 1.19 (t) (1H, 7,8-methylene proton), 2.91 (d.d) (iH, 7,8-methylene proton), 3.32 (burs) (4H, cyclopentane protons), 3.51 (d.d) (1H, C-8 proton), 7.01 (d) (1H, C-5 proton), 7.45 (m) 1H, = CH-), 7.58 (br s) (5H, phenyl protons), 8.26 (d) (1 H, C-6 proton).

By proceeding analogously the following compounds were prepared: 3-(2-methyl-benzylidene)-7,8-methylene- 1 ,2,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid, m.p. 254-2 56C C; 3-(2-methoxy-benzylidene)-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopejnta[d] pyrido[1,2 a]pyrimidine-7-carboxylic acid; 3-(3-methoxy-benzylidene)-7,8-methylene-1,2,3,10-tetrahydro-10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2 a]pyrimidine-7-carboxylic acid; 3-(4-methoxy-benzylidene)-7,8-methylene- 1,2,3,10-tetrahydro- 1 0-oxo-cyclopenta [d] pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid; 3-(2,3-dimethoxy-benzylidene)-7,8-methylene-1,2,3,10-tetrahydro-10-oxo cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid ;; 3-(4-fluoro-benzylidene)-7,8-methylene- 1 ,2,3, 1 0-tetrahydro-i 0-oxo-cyclopenta[d]pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid; 3-(3-methyl-benzylidene)-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2 a]pynmidine-7-carboxylic acid; 3-(4-methyl-benzylidene)-7,8-methylene- 1 ,2,3, 1 0-tetra hydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid; and 3-(2-ethoxy-benzylidene)-7,8-methylene-1- ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[dipyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid.

Example 11 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid (3.2 g) suspended in dioxane (70 ml) and tetrahydrofurane (30 ml) was reacted with ethyl chlorocarbonate (4.55 g) in the presence of triethylamine (4.05 g) under stirring at 15 C for 2 hours.

Then the reaction mixture was treated with dioxane (200 ml) saturated with gaseous ammonia for 30 minutes under stirring. After dilution with ice water and neutralization with HCI, the precipitate was filtered and purified by washing with dimethylformamide to give 2.52 g of 3-benzylidene-1,2,3,10- tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxamide, m.p. 350-357 C, NMR (CF3COOD) 8 ppm: 3.40 (bs) (4H, 0-1 and C-2 protons), 7.60 (m) (6H, =CH-- and phenyl protons), 8.42 (d) (1 H, C-S proton), 9.03 (dd) (1 H, C-6 proton), 10.09 (d) (1 H, C-8 proton).

Example 12 3-benzylidene-i ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-7-carboxamide (1.9 g) was reacted with p-toluenesulphonyl chloride (2.28 g) in dimethylformamide (80 ml) in the presence of pyridine (2 ml) under stirring at room temperature for 24 hours. Dilution with ice water gave a precipitate which was filtered and crystallized with CH2Cl2/isopropyl ether to give 1.25 g of 3 benzylidene-7-cyano-i ,2,3, 1 0-tetrahydro-cyclopenta[d]pyrido[ 1 ,2-a]pyrimidine-1 0-one, m.p. 285- 287 C, NMR (CF3COOD/CDCI3) 8 ppm: 3.34 (bs) (4H, C-i and C-2 protons), 7.52 (bs) (6H, =CH-- and phenyl protons), 8.45 (m) (2H, C-S and C-6 protons), 9.76 (bs) (1 H, C-8 proton).

Example 13 3-benzylidene- 1 ,2 ,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2-ajpyri midi ne-7-ca rboxylic acid (1 g) was reacted with ethyl iodide (3.75 g) and anhydrous K2CO3 (3.3 g) in dimethylformamide (10 ml) under stirring at 1000C for 72 hours. After cooling and dilution with ice water the precipitate was filtered and washed with water until neutral: 0.9 g of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo- cyclopenta[d] pyrido[1,2-a] pyrimidine-7-carboxylic acid, ethyl ester, m.p. 225-227 C, were obtained.

By proceeding analogously the following compounds were prepared: 3-(2-methoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-i 0-oxo-cyclopenta[djpyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid, ethyl ester; 4-(3-methoxy-benzylidene)- 1 ,2 ,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d] pyrido[ 1 ,2-a]pyri midi ne-7- carboxylic acid, ethyl ester; 3-(2,3-dimethoxy-benzylidene)-1 ,2,3, 1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 2- a]pyrimidine-7-carboxylic acid, ethyl ester; 3-(4-fluoro-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta [d] pyrido [1,2-a] pyrimidine-7carboxylic acid, ethyl ester; 3-benzylidene-7,8-methylene- 1 ,2,3, 10-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid, ethyl ester; ; 3-(4-methoxy-benzylidene)- 1 ,2,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d] pyrido[ 1 ,2-a] pyrimidine-7- carboxylic acid, ethyl ester; and 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta [d] pyrido [1,2-a] pyrimidine-7carboxylic acid, ethyl ester.

Example 14 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a] pyrimidine-7-carboxylic acid was treated with the stoichiometric amount of sodium methoxide in methanol at 600C for 10 minutes.

After concentration in vacuo to a small volume the precipitate was filtered and washed with a little amount of cold methanol and then with hexane: 3-benzylidene-1,2,3,10-tetrahydro-10-oxo- cyclopenta[d]pyrido[1 ,2-a]pyrimidine-7-carboxylic acid, sodium salt, m.p. > 3000C was obtained.

By proceeding analogously the following compounds were prepared: 3-(2-methoxy-benzylidene)- 1,2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta[d]pyddo[i ,2-aipyrimidine-7- carboxylic acid, sodium salt; 3-(3-methoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7carboxylic acid, sodium salt; 3-(4-methoxy-benzylidene)- 1 2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta[djpyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid, sodium salt; 3-(4-fl uoro-benzylidene)- 1 ,2,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid, sodium salt; 3-benzylidene-7,8-methylene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxylic acid, sodium salt;; 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid, sodium salt, and 3-(2,3-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a]pyrimidine-7-carboxyiic acid, sodium salt.

Example 15 1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid, methyl ester, m.p.

123-124 C, (9 g), was reacted with benzaldehyde (11 g) in methanol (250 ml) in the presence of sodium methyl ate (7.3 g) under stirring at reflux temperature for 140 hours. After cooling the solution was concentrated in vacuo to a small volume: the precipitate was filtered and washed with little methanol and then dissolved in water.

Acidification with acetic acid gave a precipitate which was filtered, washed with water and dissolved in acetone: treatment with the stoichiometric amount of 37% HCI formed the sparingly soluble 4-benzylidene-1,2,3 ,4-tetrahydro-l l-oxo-l 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, hydrochloride, m.p. > 3000 C, which was recovered by filtration and thoroughly washed with acetone.

Treatment with aqueous potassium carbonate to obtain the free compound and then crystallization from CH2CI2-methanol gave 2.9 g of 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11 1H- pyrido[2,1 -b]quinazoline-8-carboxylic acid, m.p. 261-263 C, NMR (CF3COOD) 8 ppm: 2.10(m) (2H, C-2 protons), 3.06 (m) (4H, 0-1 and C-3 protons), 7.55 (bs) 5H, phenyl protons), 7.76 (bs) (1H, CH-), 8.39 (d) (1H, C-6 proton), 9.06 (dd) (1H, C-7 proton), 10.13 (d) (1H, C-9 proton).

Example 16 1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, methyl ester (2.5 g) was reacted with 2-methoxy-benzaldehyde (2.6 g) in tert. butanol (75 ml) in the presence of potassium tert. butylate (4.3 g) under stirring at reflux temperature for 8 hours. After cooling the solution was concentrated in vacuo to a small volume and the precipitate was filtered and washed with little methanol and then dissolved in water containing NaHCO3: the solution was acidified with 23% HCI to pH=4 and the precipitate was filtered and washed with water until neutral.Crystallization from acetone gave 1.1 g of 4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1b]quinazoline-8-carboxylic acid, m.p. 300 C (dec.), N.M.R. (0D03-CF3COOD) 8 ppm: 1.93 (m) (2H, C-2 protons),2.84 (4H, 0-1 and C-3 protons),3.81 (3H, -OCH3), 6.80-7.50 (m) (4H, phenyl protons), 7.70 (bs) (1H, OH-), 8.17(d) (iH, C-6 proton), 8.69 (dd) (iH, C-7 proton), 9.73 (d) (1H, C-9 proton).

Example 17 By proceeding according to Example 15 and 16 the following compounds were prepared: 4-(3-methyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, m.p. 281-284 C ; 4-(4-methyl-benzylidene)- ,2,3,4-tetrahydro-1 11 -oxo- 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-methyl-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, m.p. 295-300 C dec ; 4-(3-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid, m.p. 239-243 C ; 4-(4-methoxy-benzylidene)- 1 ,2,3,4-tetra hydro- 11 -oxo- ii H-pyrido [2,1 -b]quinazo line-8carboxylic acid, m.p. 263-267 C ;; 4-(2-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid, m.p. 26927i0C; 4-(3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, m.p. 257-260 C ; 4-(4-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, m.p. 285-288 C ; 4-(2,5-dimethyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, m.p. 225-227 C ; 4-(2,3-dimethoxy-benzylidene)-l ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, m.p. 280-5 C dec; 4-(2,5-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-1 11 -oxo-11 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid, m.p. 265-8 C;; 4-(3,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, m.p. 266-8 C ; 4-(3,4-dimethylenedioxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline8-carboxylic acid, m.p. 294-297 C ; 4-(4-fluoro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-caboxylic acid, m.p. 270-274 C ; 4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, m.p. 245-247 C ; 4-(3-chloro-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 I H-pyrido[2, 1 -b]quinazoline-8-carboxyilc acid, m.p. 285-293 C ; 4-(4-chloro-benzylidene)-1 2,3,4-tetrahydro- 11 -oxo- ii H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, m.p. 320-327 C ;; 4-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline8-carboxylic acid, m.p. 210-212 C ; 4-(2-thenylidene)-1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, m.p. 296-299 C ; 4-[(2-pyridyl)-methylene]- 1,2,3,4-tetrahydro- 11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-[(3-pyridyl)-methylene]-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; 4-[(4-pyridyl)-methylene]-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; 4-(2-furfurylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid ;; 4-(2,4-dimethoxy-benzylidene)- 1,2,3,4-tetrahydro- ll-oxo-ll H-pyrido[2,1-b]quinazoiine-8- carboxylic acid, 4-(3,5-dimethoxy-benzylidene)-1 ,2,3,4-tetrahydro- 11 -oxo- 1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid; 4-(2-ethoxy-3-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline8-carboxylic acid; 4-(2,3 ,4-trimethoxy-benzylidene)-l ,2,3,4-tetrahydro-l l-oxo-11H-pyrido[2, -b]quinazoline-8carboxylic acid, m.p. 225-230 C (dec); 4-(3,4,5-trimethoxy-benzylidene)-l ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, m.p. 259261cO;; 4-(2,4,5-trimethoxy-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8carboxylic acid; 4-(3-hydroxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(4-hydroxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b= quinazoline-8carboxylic acid; 4-(2-nitro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [1,2-b] quinazoline-8-carboxylic acid; 4-(3-nitro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid; 4-(4-nitro-benzylidene)- 1,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoli ne-8-carboxylic acid; 4-(4-dimethylamino-benzylidene)-l ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid, m.p. 262-267 C ; ; 4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, m.p. 320-330 C, dec.; 4-(3,4-dichioro-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, m.p. 285-290 (dec); 4-(2,4-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, m.p. 260-265 C (dec); 4-(2,4-dimethyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(2-isopropoxy-benzylidene)- 1,2,3,4-tetrahydro- 11-oxo-11H-pyrido [2,1 -b]quinazoline-8carboxylic acid; 4-(3-isopropoxy-benjzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid; 4-(4-isopropoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid ;; 4-(2-propoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid; 4-(3-propoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; and 4-(4-propoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8carboxylic acid.

Example 18 By proceeding according to Example 15, starting from 1,2,3,10-tetrahydro-10-oxo cyclopenta[d]pyrido[1 ,2-a]pyrimidine-7-carboxylic acid, methyl ester and using suitable heterocyclic aldehydes, the following compounds were prepared: 3-(2-thenylidene)-1 ,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[ 1 ,2-ajpyrimidine-7- carboxylic acid, m.p. 325-327 C ; 3-[(2-pyridyl)-methylene]-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido[1,2-a] pyrimidine-7carboxylic acid ; 3-[(3-pyridyl)-methylene]-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [2,1-a] pyrimidine-7carboxylic acid; 3-[(4-pyridyl)-methylene]-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid; and 3-(2-furfurylidene)- 1 ,2,3,i 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[i ,2-a]pydmidine-7- carboxylic acid.

Example 19 By proceeding according to Examples 1 5 and 16, starting from suitable substituted 1,2,3,4tetrahydro-1 1 H-pyrido[2,1-b] quinazoline-11-ones, the following compounds were prepared: 4-benzylidene-1,2,3,4-tetrahydo-11H-pyrido[2,1-b] quinazoline-11-one ; 4-(2-methyl-benzylidene)-1,2,l3,4-tetrahydro-11H-pyrido[2,1-b] quinazoline-11-one, m.p. 130 1310C; 4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one, m.p. 145146 C ; 4-benzylidene-8-chloro-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-chloro-4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one, m.p. 189-190 C ; 8-chloro-4-[(3-pyridyl)-methylene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one, m.p. 201-202 C ; 4-benzylidene-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ;; 4-benzylidene-7-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 4-(2-methoxy-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 4-(3-methoxy-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 4-(2,6-dichloro-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11one; 4-(4-methoxy-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 4-(2,3-dimethoxy-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11one; 4-(2,5-dimethoxy-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11one; 4-(2-methoxy-3-ethoxy-benzyl idene)-8-methyl- 1,2,3,4-tetrahydro- ii H-pyrido[2, b]quinazoline-i i-one; 4-(2,5-dimethyl-benzylidene)-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11one;; 8-methyl-4-(2-methyl-benzylidene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-methyl-4-(3-methyl-benzylidene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-methyl-4-(4-methyl-benzylidene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-methyl-4-(2-thenylidene)-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-methyl-4-[(2-pyridyl)-methylene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; 8-methyl-4-[(3-pyridyl)-methylene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one ; and 8-methyl-4-[(4-pyridyl)-methylene]-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one.

Example 20 4-benzsylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid (1 g) was reacted with methyl iodide (1.25 g) and anhydrous K2CO3 (1.15 g) in dimethylformamide (40 ml) under stirring at room temperature for 24 hours. Dilution with ice water gave a precipitate which was filtered and washed with water until neutral: 0.9 g of 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11 H pyrido[2,1 -b]quinazoline-8-carboxylic acid, methyl ester were obtained, m.p. 166-168 C.

By proceeding analogously the following compounds were prepared: 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, ethyl ester; 4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid, methyl ester; 4-(3-methyl-benzylidene)- 1,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8-ca rboxylic acid, methyl ester; 4-(4-methyl-benzylidene)- 1,2,3,4-tetrahydro- ii oxo- ii H-pyrido[2, 1 -b]quinazoline-8-ca rboxylic acid, methyl ester; 4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, methyl ester; 4-(3-methoxy-benzylidene)- 1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, methyl ester; and 4-(4-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, methyl ester.

Example 21 Trimethyl-sulphoxonium iodide (1.8 g) was reacted with 50% sodium hydride (0.39 g) in dimethylformamide (20 ml) under stirring at room temperature for 60 minutes, then a solution of 4benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid methyl ester (2.7 g) in dimethylformamide (30 ml) was added.

The mixture was allowed to react at room temperature for 1 hour then it was diluted with ice water and neutralized with acetic acid. The precipitate was filtered and washed with water to give 2.25 g of 4-benzylidene-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1-b]quinazoline-8- carboxylic acid methyl ester, m.p. 228-230 C, which was treated with 0.5% KOH in 95% ethanol solution (80 ml) at reflux temperature for 1 5 minutes. After cooling the reaction mixture was acidified with acetic acid and diluted with water: the precipitate was filtered, washed with water until neutral and crystallized from CH2CI2/methanol to give 1.3 g of 4-benzylidene-8,9-methylene-1 2,3,4- tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, m.p. 240-243 C.

By proceeding analogously the following compounds were prepared: 4-(2-methoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; 4-(3-methoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1 b]quinazoli ne-8-carboxylic acid; 4-(4-methyl-benzylidene)-8,9-methylene- 1,2,3 ,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 b]quinazoline-8-carboxylic acid; 4-(2-methoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; 4-(3-methoxy-benzylidene)-8,9-methylene- 1,2,3,4-tetrahydro- 1 -oxo-1 1 H-pyrido[2,1 - b]quinazoline-8-carboxylic acid; 4-(4-methoxy-benzylidene)-8,9-methylene- 1,2,3,4-tetrahydro- 1 -oxo-1 1 H-pyrido[2, 1 - b]quinazoline-8-carboxylic acid;; 4-(2-ethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; 4-(3-ethoxy-be nzylidene)-8,9-methylene-1,2,3,4-tetrahydro- ii -oxo- 11 H-pyrido[2,1 b]quinazoline-8-carboxylic acid; 4-(4-ethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; 4-(2,5-dimethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1 b]quinazoline-8-carboxylic acid; 4-(2,3-dimethoxy-benzylidene)-8,9-methylene-1 ,2,3,4-tetrahydro-1 1 oxo- ii H-pyrido[2, 1 - biquinazoline-8-carboxylic acid; 4-(2,5-dimethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; ; 4-(3,4-dimethoxy-benzylidene)-8,9-methylene-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 b]quinazoline-8-carboxylic acid; 4-(2,3,4-trimethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1b]quinazoline-8-carboxylic acid; 4-(3,4,5-trimethoxy-benzylidene)-8,9-methylene- ,2,3,4-tetrahydro-11-oxo-1 1 H-prydo[2,1 - b]quinazoline-8-carboxylic acid; 4-(3,4-methylenedioxy-benzylidene)-8,9-methylene- 1 2,3,4-tetrahydro- 11oxo- ii H-pyrido [2,1 b]quinazoline-8-carboxylic acid; 4-(4-fluoro-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid;; 4-(2-chloro-benzylidene)-8,9-methylene-1 1,2,3,4-tetrahydro- 1 -oxo-i 1 H-pyrido[2,1 - biquinazoline-8-carboxylic acid; 4-(3-chloro-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid; 4-(4-chloro-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoli ne-8-ca rboxylic acid; 4-(2,6-dichloro-benzylidene)-8,9-methylene- 1,2,3,4-tetrahydro-11 -oxo- 11 H-pyrido[2, 1 b]quinazoline-8-carboxylic acid; 4-(3,4-dichloro-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid; 4-(2-methoxy-3-ethoxy-benzylidene)-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoli ne-8-carboxylic acid;; 4-(2-thenylidene)-8,9-methylene- 1,2,3,4-tetrahydro- 1 -oxo-i 1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid; 4-[(2-pyridyl)-methylene]-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid; 4-[(3-pyridyl)-methylene]-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid; and 4-[(4-pyridyl)-methylene]-8,9-methylene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1b]quinazoline-8-carboxylic acid.

Example 22 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b]quinazoline-8-carboxylic acid (0.5 g) was reacted with SOCI2 (0.25 g) in dioxane (250 ml) at the reflux temperature for 2 hours. After cooling the reaction mixture was evaporated in vacuo to dryness and the residue was dissolved in dioxane (70 ml) and reacted with 2-(N,N-diethylamino)-ethanol (3.5 g) under stirring at room temperature for 20 hours.

The reaction mixture was concentrated in vacuo to a small volume and then diluted with ice water: the precipitate was extracted with chloroform and the organic solution was evaporated in vacuo to dryness.

Crystallization of the residue from CH2CI2-isopropyl ether gave 2.9 g of 4-benzylidene-1 ,2,3,4- tetrahydro-i 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2-(N,N-diethjylamino)-ethyl ester, m.p. 95-97 C NMR (CDCI3) 8 ppm: 1.08 (t) (6H, -CH2-CH3), 1.84 (m) (2H, C-2 protons), 2.62 (q) (4H, -CH2-CH3), 2.85 (m) (6H; 0-1 and C-3 protons ; -COOCH2CH2-N < ), 4.41 (t) (2H, -COOCH2CH2N < ), 7.35 (m) (5H, phenyl protons), 7.48 (d) (1H, C-6 proton), 7.98 (dd) (1H, C-7 proton), 8.12 (bs) (1H, =CH-), 9.50 (d) (1H, C-9 proton).

By proceeding analogously, the following compounds were prepared: 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2 (N,N-dimethylamino)-ethyl ester; 4-(2-thenylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido]2,1-b] quinazoline-8-carboxylic acid, 2 (N ,N-diethyla mino)-ethyl ester; 4-[(2-pyridyl)-methylene]-1,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-[(3-pyridyl )-methylene]- ,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-ca rboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(2-methyl-benzyflidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-caboxylic acid, 2-(N,N-diethylamino)-ethyl ester ;; 4-(3-methyl-benzylidene)- 1 ,2,3,4-tetra hydro- 11 -oxo- 11 H-pyrido [2,1 -b]qu inazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(4-methyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(2-methoxy-benzylidene)- 1,2,3,4-tetrahydro-1 1 oxo-i 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester; 4-(3-methoxy-benzylidene)- ,2,3,4-tetrahydro-11-oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(4-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ;; 4-(2-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11 -oxo- ii H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-H-pyrido [2,1-b] quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(4-ethoxy-benzylidene)- 1 ,2,3,4-tetrahydro- ii -oxo- ii H-pyrido[2, 1 -b] quinazoline-8-ca rboxylic acid, 24N,N-diethylamino)-ethyl ester; 4-(2,5-dimethyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(2,3-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ;; 4-(2,5-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(3,4-dimethoxy-benzylidene)- 1,2,3,4-tetrahydro- 11 -oxo- 11- H-pyrido[2,1 -b]quinazoline-8- carboxylic acid, 2-(N,N-diethylamino)-ethyl ester; 4-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline 8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(3-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid, 2-(N,N-diethylamino)-ethyl ester;; 4-(4-chloro-benzylidene)- 1,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8-ca rboxylic acid, 2-(N,N-diethyiamino)-ethyl ester; 4-(2,6-dichloro-benzylidene)- 1,2,3,4-tetrahydro- ll-oxo-ll H-pyrido[2,1 -b]quinazoiine-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester ; 4-(3,4-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester; and 4-(2,4-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, 2-(N,N-diethylamino)-ethyl ester.

Example 23 4-(4-nitro-benzylidene)-1,2,3,4-tetrahydro-11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8-ca rboxylic acid, methyl ester (3.23 g), was reacted with SnOl2. 2H20 (17 g) in 37% HCI (12.5 ml) and acetic acid (40 ml) under stirring at 600C for 2 hours. After cooling the precipitate, 4-(4-amino-benzylidene) 1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid methyl ester, was filtered and washed with water and then dissolved in dimethylformamide (60 ml) and treated with 2N NaOH (15 ml) at room temperature for 3 hours.After acidification with acetic acid and dilution with ice water the precipitate that formed was filtered and washed with water: crystallization from dimethylformamide gave 2.1 g of 4-(4-amino-benzylidene)-l ,2,3,4-tetrahydro-l l-oxo-l 1H- pyrido [2,1-b] quinazoline-8-carboxylic acid.

By proceeding analogously the following compounds were prepared: 4-(3-amino-benzylidene)-l ,2,3,4-tetrahydro-l l-oxo-l 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-amino-benzylidene)-1 ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; and 4-(4-amino-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11-one.

Example 24 4-(4-amino-benzylidene)- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid (1 g) in dimethylformamide (40 ml) was reacted with acetic anhydride (4 ml) in the presence of pyridine (8 ml) at 60 C for 7 hours. After cooling and dilution with ice water, the precipitate was filtered and washed with water: crystallization from dimethylformamide-ethanol gave 0.7 9 of 4-(4 acetylamino-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-ca rboxylic acid.

By proceeding analogously the following compounds were prepared: 4-(3-acetylamino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(2-acetylamino-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(4-acetoxy-benzylidene)- 1,2,3,4-tetrahydro- 11-oxo-11 H-pyrido[2,1 -b]quinazoline-8carboxylic acid; 4-(3-acetoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; and 4-(4-acetylamino-benzylidene)-8-methyl-1,2,3,4-tetrahydro-11H-pyrido [2,1-b] quinazoline-11one.

Example 25 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid was treated with the stoichiometric amount of sodium methoxide in methanol at 600C for 10 minutes.

After concentration in vacuo to a small volume the precipitate was filtered and washed with a little amount of cold methanol and then with hexane: 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11 H pyrido[2,1 -b]quinazoline-8-carboxylic acid, sodium salt, m.p. > 3000C was obtained.

By proceeding analogously the following compounds were prepared: 4-(2-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, sodium salt; 4-(3-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, sodium salt; 4-(4-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, sodium salt; 4-(2,3-di methoxy-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid, sodium salt; 4-(2-methyl-benzylidene)- 1 ,2,3,4-tetrahydro- ii -oxo-11 H-pyrido[2, 1 -b]quinazoline-8-ca rboxylic acid, sodium salt; and 4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid, sodium salt.

Example 26 Tablets, each weighing 200 mg and containing 100 mg of the active substance were manufactured as follows: Composition (for 10,000 tablets) 3-benzylidene- 1,2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta [d]pyrido[1,2- a]pyrimidine-7-carboxylic acid 1000 g lactose 710 g corn starch 237.5 g talc powder 37.5 g magnesium stearate 15 g The 3-benzylidene- 1 2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta[d]pyrido[ 1 ,2-aipyrimidine-7- carboxylic acid, lactose and half the corn starch were mixed. The mixture was then forced through a sieve having 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried and comminuted on a sieve having 1.4 mm openings.The remaining starch, talc and magnesium stearate were added, carefully mixed and processed into tablets using punches of 8 mm diameter.

Example 27 Tablets, each weighing 200 mg and containing 100 mg of the active substance were manufactured as follows: Composition (for 10,000 tablets) 4-benzylidene- ,2,3,4-tetrahydro-1 11 -oxo-11 H-pyrido[2,1 -b]quinazoline- 8-carboxylic acid 1000 g Lactose 710 9 Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15g The 4-benzylidene-1 ,2,3,4-tetrahydro-1 1 -oxo-i 1 H-pyrido [2,1-b] quinazoline-8-carboxylic acid, lactose and half the corn starch were mixed. The mixture was then forced through a sieve having 0.5 mm openings. Corn starch (18 g) was suspended in warm water (180 ml). The resulting paste was used to granulate the powder. The granules were dried and comminuted on a sieve having 1.4 mm opening. The remaining starch, talc and magnesium stearate were added, carefully mixed and processed into tablets using punches of 8 mm diameter.

Claims

1. A compound of general formula (I)

wherein n is 1 or 2; R represents a hydrogen or a halogen atom, a C1-C4 alkyl group, a -CN group, a -CONH2 group or a -COOR8 group, wherein R8 represents hydrogen or a C1-C6 alkyl group, unsubstituted or substituted by di (C1-C4) -alkylamino; each of R2, R3 and R4 independently represents a hydrogen or a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group or a C3-C4 alkenyloxy group ; A completes a bond, thereby providing a double bond or, when R1 is -COOR8 wherein R8 is as defined above, A may represent also a -OH2- group, thereby providing a cyclopropane ring fused to the pyrido ring; R is a) furyl, thienyl or pyridyl; or b) a group of formula

group, wherein each of R9 and R10 independently represents hydrogen, C1-C4 alkyl, formyl or C2-C8 alkanoyl, or adjacent groups represented by two of R5, R6 and R7, taken together, form a C1-C3 alkylenedioxy group ; and the pharmaceutically accentable salts thereof.

2. A compound of formula (I), according to claim 1, wherein R represents hydrogen, chlorine, carboxy, methyl, or (C1-C4) alkoxy-carbonyl unsubstituted or substituted by a 2-N,N-di (C1-C2) alkyl-amino group ; R2 is hydrogen ; R3 is hydrogen, chlorine, methyl or methoxy ; R4 is hydrogen ; A completes a bond, thereby provinding a double bond, or when R1 is a free carboxy group, A may represent also a -OH2- group, thereby providing a cyclopropane ring fused to the pyrido ring; n is 1 or 2; R is a) furyl, thienyl or pyridyl; orb) a group of formula

wherein, each of R5, R6 and R7 represents independently hydrogen, chlorine, fluorine, C1-C2 alkyl, C1-C3 alkoxy, amino, dimethylamino, hydroxy or adjacent groups represented by two of R5, R6 and R7, taken together, form a methylenedioxy group; and the pharmaceutically acceptable salts thereof.

3 3-be nzylidene- 1 ,2,3, 1 0-tetrahydro-i 0-oxo-cyclopenta[d]pyrido[ 1 ,2-a] pyrimidine-7-carboxylic acid; and the pharmaceutically acceptable salts thereof.

4. A compound selected from the group consisting of : 3-(2-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid ; 3-(2,5-di methoxy-benzylidene)- 1 ,2,3, 1 0-tetrahydro- 1 0-oxo-cyclopenta [d] pyrido[ 1 ,2- a]pyrimidine-7-carboxylic acid; 3-(2,3-dimethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a] pyrimidine-7-carboxylic acid ; 3-(2-methoxy-3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2a] pyrimidine-7-carboxylic acid ; 3-(3-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid ; 3-(4-methyl-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d] pyrido [1,2-a] pyrimidine-7carboxylic acid ;; 3-(2-ethoxy-benzylidene)- 1,2,3,1 0-tetrahydro-1 0-oxo-cyclopenta [d] pyrido [1,2-a] pyri midine-7carboxylic acid; 3-(3-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta [d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(4methoxy-benzylidene)- 1,2,3,1 0-tetrahydro-i Ooxo-cyclopenta[dipyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid; 3-(4-ethoxy-benzylidene)-1,2,3,10-tetrahydro-10-oxo-cyclopenta [d] pyrido [1,2-a] pyrimidine-7carboxylic acid; 3-(2-methoxy-benzylidene)- 1 2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta [djpyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid; 3-(3-methoxy-benzylidene)- 1 2,3,1 0-tetra hydro- 1 0-oxo-cyclopenta [d]pyrido[ 1 ,2-a]pyrimidine-7- carboxylic acid;; 3-benzylidene-7,8-methylene- 1 2,3,1 0-tetrahydro-1 0-oxo-cyclopenta[d]pyrido[ 1,2- a]pyrimidine-7-carboxylic acid; 3-(2-methyl-benzylidene)-7,8-methylene- 1,2,3,1 0-tetrahydro- 1 0-oxo-cyclopenta [d] pyrido[ 1,2- a]pyrimidine-7-carboxylic acid; 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazolline-8-carboxylic acid ; 4-(2-methyl-benzylidene)-1,2,3,4-tetrahydro-11 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(3-methyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [[2,1-b] quinazoline-8-carboxylic acid; 4-(4-methyl-benzylidene)- 1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-methoxy-benzylidene)- 1,2,3,4-tetrahydro- 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid;; 4-(3-methoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [[2,1-b] quinazoline-8carboxylic acid; 4-(4-methoxy-benzylidene)- ,2,3,4-tetrahydro-1 1 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8carboxylic acid; 4-(2-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[[2,1-b] quinazoline-8-carboxylic acid; 4-(3-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[[2,1-b] quinazoline-8-carboxylic acid; 4-(4-ethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[[2,1-b] quinazoline-8-carboxylic acid; 4-(2,5-dimethyl-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(2,3-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(2,5-dimethoxy-benzylidene-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid;; 4-(2,6-dichloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(3,4-dichloro-benzylidene)- 1,2,3,4-tetra hydroxy 11 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8- carboxylic acid; 4-(3,4-dimethoxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8carboxylic acid; 4-(3,4-methylenedioxy-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline8-carboxylic acid; 4-(4-fluoro-benzylidene)-l ,2,3,4-tetrahydro-l l-oxo-l 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; 4-(3-chloro-benzylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido [2,1-b] quinazoline-8-carboxylic acid; ; 4-(4-chloro-benzylidene)- ,2,3,4-tetrahydro-11 -oxo-1 1 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-(2-methoxy-3-ethoxy-benzylidene)- 1,2,3,4-tetrahydro- 1 -oxo-1 1 H-pyrido[2,1 -b] quinazoline- 8-carboxylic acid; 4-(2-thenylidene)-1,2,3,4-tetrahydro-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid ; 4-[(2-pyridyl)-methylene]-1,2,3,4-tetrahydro-11 -oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-[(3-pyridyl)-methylene]- 1 ,2,3,4-tetrahydro- 11 -oxo- 11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid; 4-benylidene-8,9-methylene- ,2,3,4-tetrahydro-i 1 -oxo-i I H-pyrido[2,1 -b]quinazoline-8- carboxylic acid;; 4-benzylidene-1,2,3,4-tetrahydro-11-oxo-11 H-pyrido[2,1 -b]quinazoline-8-carboxylic acid, 2 (N,N-diethylamino)-ethyl ester; 4-benzylidene-8-methyl- 1 2,3,4-tetrahydro- 11 H-pyrido[2,1 -b] quinazoline-11 -one; and 3-benzylidene-7-methyl- 2,3,1 O-tetrahydro-cyclopenta[d] pyrido[1,2-a] pyrimidine- 10-one, and the pharmaceutically acceptable salts thereof.

5. A process for the preparation of a compound of formula (I), as claimed in claim 1, said process comprising: a reacting a compound of formula (II)

wherein n, R1, R2, R3, R4 are as defined in claim 1 or a salt thereof, with an aldehyde of formula (III) R--CHO (III) wherein R is as defined in claim 1, so obtaining compounds of formula (I) wherein A is a bond; or b) cyclopropanating a compound of formula (IV)

wherein n, R, R2, R3, R4 and R8 are as defined in claim 1 or a salt thereof, so obtaining compounds of formula (I) wherein R1 is --COOR, wherein R8 is as defined in claim 1 and A is a -OH2- group; and/or, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt and/or, if desired, converting a salt into a free compound and/or, if desired, separating a mixture of isomers into the single isomers.

6. A pharmaceutical composition containing a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 hereinbefore specifically mentioned.

8. A process according to claim 5 substantially as hereinbefore described with reference to any one of the Examples 1 to 25.

9. A composition according to claim 5 substantially as hereinbefore described with reference to Examples 26 or 27.

10. A compound according to any one of claims 1 4 or 7 or a composition according to claim 6 or 9 for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.