CA1173831A - Process for the manufacture of novel polyazaheterocyclic compounds - Google Patents

Abstract

Abstract of the Disclosure The present invention relates to a process for the manufacture of novel polyazaheterocyclic compounds of the general formula I

Description

1 ~ 7383~

~-:13013 Canada :
:: : Process for the manufacture of novel polyazaheterocyclic :
.
: compounds : ~
: The present invention relates to a process for the manu-: facture of novel polyazaheterocyclic compounds and their acid : addition salts which have valuable pharmacological properties.
; ~ The compounds produced according to the invention correspond to the general formula .

N A

Z~ ~ / \N / (I), . .
.~ .
- ~

I ~ 7 3~3 3 ~

in which R1 and R2 represent, independently of each other, optionally substituted lower aliphatic hydrocarbon radicals, optionally substituted aryl or heteroaryl each having not more than two rings and each being bonded directly or by way of lower alkylene or lower alkenylene, R3 represents hydrogen or lower alkyl, and A represents optionally branchQd lower alkylene or lower alkenylene having 2 to 4 carbon atoms in a direct chain between the adjacent nitrogen atoms, and Zl~ Z2~ Z3 and 24 are members of the unsubstituted or substituted ring B and represent radicals - -CH=, carrying the substituents of ring B, if sucll are present, one o~ which members can however also be the radical -N=, wherein Rl an~ R2 do not both represent methyl or both represent et~yl if R3 repre-sents hydrogen and A represents ethenylene and at the same time, the ring B is unsubstituted.
The invention relates also to the acid addition salts, espe-cially the pharmaceutically acceptable acid addition salts, of the compounds of the gene~al formula I.
In the compounds of the general formula I, the radicals designated "lower" contain, hereinbefore and here-inafter, unlqss statecl otherwise, not more than 7, and pre-ferably not more than 4, carbon atoms.
As lower aliphatic hydrocarbon radicals, Rl and/or R2 are lower alkyl, lower alkenyl or lower alkynyl. Lower alkyl ~1 and/or R2 is, Eor example, pentyl, isopentyl, neopentyl, hexyl, isohexyl or heptyl, and preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl. Rl and R2 having that meaning contain together preferably at least 3 3 8 ~ 1 carbon atoms. Substituents of lower alkyl Rl and/or R2 are, for example, lower alkoxy or lower alkylthio, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy, and methylthio, ethylthio, propylthio, isopropylthio or butylthio, respectively, in any position, but preferably in the 2-position or a higher position, of the lower alkyl, or lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycar-bonyl, propoxycarbonyl, isopropoxycarbonyl or butoxy-carbonyl, in any position, but preferably in the l-position, of the lower alkyl. As lower alkenyl, Rl and/or R2 is, for example, vinyl, l-propenyl, allyl, l-butenyl, 2-methyl-1-propenyl, 2-butenyl, 2-methylallyl, 1-pentenyl, 3-methyl-l-butenyl, 3-methyl-2-butenyl, 3,3-dimethyl-1-butenyl, 1-hexenyl or l-heptenyl and, as lower alkynyl, is, for example, 2-propynyl or 2-butynyl, which can likewise be sub-stituted in the manner mentioned above for lower alkyl.
As an aryl or heteroaryl radical having not more than

2 rings, Rl is, for example, phenyl~ 1- or 2-naphthyl, 5-membered heteroaryl, for example furyl, such as 2- or 3-furyl, thienyl, such as 2- or 3-thienyl, pyrrolyl, such as pyrrol-2-yl or pyrrol-3-yl, pyrazolyl, such as pyrazol-3-yl, pyrazol-4-yl or pyrazol-5-yl, isoxazolyl, such as 3-, 4- or 5-isoxazolyl, isothiazolyl, such as 3-, 4- or 5-isothia-zolyl, oxazolyl, such as 2-, 4- or S-oxazolyl, thiazolyl, such as 2-, 4- or 5-thiazolyl, 6-membered diazaheteroaryl, for example 3-pyridazinyl, pyrimidinyl, such as 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, benzoheteroaryll for example in~olyl, such as 2-, 3 or ar~indolyl, quinolinyl, such as 2-, 3-, 4- or ar-quinolinyl, phthalazinyl, such as 1- or ar-phthalazinyl, quinoxalinyl, such as 2- or ar-quinoxalinyl;
~uinazolinyl, such as 2-, 4- or ar-quinazolinyl, or espe-cially pyridyl, such as 2-, 3- and more especially 4-pyridyl. All oE these radicals can be bonded either by way oE lower alkylene, for example propylene, trimethylen~, tetramethylene, l-methyl- or 2-methyl-trimethylene or espe-cially ethylene or met~ylene, or by way of lower alkenylene, "```` ;~1738,3~

such as propenylene, l-methylethenylene and especially ethenylene (vinylene), or es~ecially directly.
As substituents of aryl or heteroaryl Rl and/or R2 there come into consideration, for example, lower alkyl, such as ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and especially methyl; lower alkoxy, such as ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and especially methoxy; lower alkylthio, such as ethylthio, propylthio, isopropylthio, butylthio and especially methylthio; halogen, especially halogen having an atomic number of not more than 35, i.e. fluorine~ bromine and especially chlorine; tri-fluoromethyl, methylenedioxy, hydroxy, sulphamoyl, nitro, or amino optionally mono- or di-substituted by lower alkyl, or amino substituted by lower alkylene or 3-oxa-1,5-lower alkylene, such as methyl-, ethyl-, propyl-, isopropyl-, butyl- or isobutyl-amino, dimethyl- or diethyl-amino; or 1-pyrrolidinyl, piperidino or morpholino. One or more, but preferably not more than three, such substituents can be present and, in the latter case, can be identical or dif-ferent, wherein, however, not more than two hydroxy or optionally substituted amino groups can be present and, preferably, as with methylenedioxy also, not more than one such group can be present, and not more than two alkylthio or trifluoromethyl gro~ps can be present, and preferably not more than three of each of the other substituents can be present.
R3 as lower alkyl is, for example, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and especially methyl or ethyl.
As optionally branched lower alkylene or lowec alkeny-lene having two carbon atoms in a direct chain between the two nitrogen atoms, A is respectively, ~or example, propylene (l-methylethylene), l,l-dimethylethylene, 1,2-dimethylethylene, l-ethylethylene ~nd especially ethylene, and l-methylethenylene, 1,2-dimethylethenylene and espe-cially ethenylene (vinylene). Radicals A accordin~ to the 1 ~73~ 31 definition having three carbon atoms between the t~o nitro-gen atoms are, Eor example, l-methyl- or 2-meth~l-.rimethyl-ene, 1,2-dimethyl- or 1,3-dimethyl-~rimethylene, 1,1- or 2,2-dimethyltrimethylene, 2- or 3-.~ethylpropenylene, 2,3- or

3,3-dimethylpropenylene and especially trimethylene or pro-penylene, and radicals A according to the definition having

4 carbon atorns between the two nitrogen atoms are, for example, 1- or 2-methyltetramethylene, 1,1- or 2,2-di~ethyl-tetramethylene, 1,4- or 2,3-dimethyltetramethylene, 1,1- or 2,3-dimethyl-2-butenylene and especially tetramethylene or 2-butenylene.
As substituents of the ring ~ or of its ring members Zl to Z4 as -CH=, the same as those in aryl or hetero-aryl Rl, substantially also in the same number, can be present, there coming especially into consideration, in addition to the unsubstituted ring B, especially rings B
that are substitute~ up to three times, but more especially once, by lower alkyl, especially methyl, by lower alkoxy, especially methoxy, and/or by halogen having an atomic number of UQ to 3;, especially chlorine, and also rings ~
that are mono-substituted also by other substituents among those mentioned for aryl or heteroaryl Rl.
As acid addition salts, especially pharmaceutically acceptable acid addition salts, of the compounds of the general formula I there come into consideration, for example, those with suitable inorganic acids, such ~s hydro-halic acids, for example hydrochloric acid or hydrobromic acid, and nitric acid, sulphuric acid or phosphoric acid, or those with sultable organic acids, such as organic carboxylic acids, inter alia optionally hy~roxy-containing lower alkane- or lower alkene-carboxylic acids, for example ace~ic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, Eumaric acid, malic acid, tartaric acid or citric acid, or aryl-, aryl-lower alkane-, aryl-lower alkene- or heterocyclyl-carboxylic acids, for example benzoic acid, cinnamic acid, 3~31 mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sul~honic acids, such as optionally hydroxy-containing lower alkane-sulphonic acids, for example .~ethanesulphonic acid, ethane-sulphonic acid, 2-hydroxyethanesulphonic acid or ethane-1,2-disulphonic acid, or arylsulphonic acids, for example ben-zenesulphonic acid, 4-methylbenzenesulphonic acid or naphthalene-2-sulphonic acid, or other acidic s~bstances, such as ascorbic acid. Corresponding to the close relation-ship between the free bases and their acid addition salts, hereinafter, where appropriate, information concerning ~ree bases relates also to acid addition salts and, conversely, information concerning acid addition salts relates also to free bases.
The novel polyazaheterocyclic co.~pounds of the general formula I and their addition salts with inorganic and organic acids possess valuable pharmacological properties.
In particular, they have a diuretic and natriuretic action on rats in a dosage range of from 10 to 1000 mg/kg ~ os and on dogs in a dosage range of from 5 to 50 mg/kg ~ os, as can be ascertained by collecting the urine for three hours after administration (rats) and hourly for 5 hours after administration (dogs) and determining the urine volume and the sodium, potassium and chlorine ions. In this con-nection, the compounds of the formula I are distin~uished by the absence of any influence on the eliminations of potas-sium, and their good tolerability also should be pointed out. Especially pronounced is the diuretic activity in th~
case o~ those compounds of the general formula I in which A
represents optionally branched lower alkylene having 4, or especially 3, carbon atoms in a direct chain between the adjacent nitrogen atoms, especially trimethylene. Accord-ingly, the compounds of the general formula I, especially those of the kind m~ntioned above, and their pharmaceuti-cally acceptable acid ad~ition salts can be used as potas--- 7 ~

sium-neutral diuretics and anti-hypertensives for the treatment of edematons states and hypertension.
Tnose compounds of the general formula I in which the radical ~ has two car~on atoms in a direct chain between the two nitrogen atoms also possess hypoglycaemic activity, as can be demonstrated in normal-metabolism rats after oral administration of doses starting from 3 mg/kg/ and also in rats in which a diabetes-like metabolic state has been induced by injecting streptozotocin ~cf. A. Junod et al., Proc. Soc. Exp. Biol. Med. 126, 201-205 (1967)]. In con-trast, their diuretic activity is less pronounced. The reduction in the blood sugar level is accompanied neither by hyperlactacidaemia nor, in normally fed rats, by an increase in plasma-insulin. The pharmacological findings charac-terise such compounds of the general formula I and their pharmaceutically acceptable acid addition salts as anti-diabetics that can be used for the oral treatment Gf hyper-glycaemia in mammals, especially for the treatment of diabetes mellitus.
._ _ The compounds of the general formula I possess, in addition, anti-phlogistic and anti-nociceptive activity, which can be demonstrated in the case of oral administra-tion in the kaolin-oedema test on the rat paw and in the writhing syndrome test on mice. They also have a lipid-reducing action, as can be detected, for example, in male rats in the case of administration of 50 mg/kg each day for three successive days and 50 mg/kg twice on the fourth day, by the reduction in the very-low-density lipoproteins (-VLDL) and in the triglycerides in the serum obtained on the fith day.
The invention relates especi~lly to polyazahstero-cyclic compounds of the genera~ formula I in which R1 and R2 represent radicals corresponding to the definition given under formula I which are unsubstituted or substitutsd in the manner stated in detail above, and together and including the optionally present substituents have prefer-ably 3 to 20 carbon atoms and especially S to 15 carbon 3 ~3 3 ~

atoms, wherein Rl and R2, a~ aryl, represent especia.lly phenyl andl as heteroaryl, represent especially pyridyl,:
thienyl or furyl, which radicals are unsubstituted or sub-stituted as stated above, R3 represents hydrogen, or lower alkyl having not more than 4 carbon atoms, and A represents unsubstituted ethylene, trimethylene, ethenylene, pro-penylene or tetramethylene, or ethylene, trimethylene, ethenylene, propenylene or tetramethylene substituted by lower alkyl, especially by one or two methyl groups, wherein substituted ethylene and trimethylen have respectively not more than 4 and 5 carbon atoms, the radicals Zl' Z2' Z3 and Z4 have the meanings given under formula I, an~ the ring is unsubstituted or substituted in the manner state~ in detail further above, and the acid addition salts thereof, especially the pharmaceutically acceptable acid addition salts thereof.
The invention relates more especially to compounds of the general formula I in which Rl represents mono-hetero-cyclic mono-cyclic heteroaryl which is unsubstituted or substituted by lower alkyl, lower alkoxy and/or halogen having an atomic number of up to 35 and is bonded by way of methylene or, preferably, directly, especially unsubstituted pyridyl or pyridyl correspondingly substituted, especially by lower alkyl, such as methyl, or correspondingly substi-tuted or especially unsubstituted thienyl or furyl, R2 represents just such a radical, especially unsubstituted or correspondingly substituted pyridyl, or correspondingly sub stituted or especially unsubstituted thienyl, or unsub~stitu-ted ph~nyl or phenyl substituted as stated above Eor mono~
cycllc heteroaryl Rl, or unsubstituted lower alkyl or lower alkyl substi~uted as stated .Eurther above, especially unsubstituted lower alkyl or lower alkoxycarbonyl-lower alkyl, especially lower alkoxycarbonylmethyl, R3 repre-sents hydrogen or alkyl havin3 not more than 4 carbon atoms, especially methyl or ethyl, and A represents ethylene or trimethylene, the radicals Zl~ Z2~ Z3 and Z4 have ~17383~

the meanings given under formula I and the rin~ B is substi-tuted in the manner stated in ~etail above for Rl, especially, however, by halogen having an atomic number of up to 35, sucn as chlorine, especially at the Z2 ring member, or is especially unsubstituted, and the acid addi-tion salts thereof, especially the pharm~ceutic~lly accept-able acid addition salts thereof.
The invention relates most especially to compounds of the general formula I in ~hich Rl represents unsu~stitute~
pyridyl or pyridyl substituted by lower alkyl, especially methyl, or thienyl, especially 2-thienyl, ~2 represents just such a radical or phenyl substituted by lower alkyl, lower alkoxy or halogen having an atomic number of up to 35, or especially unsubstituted phenyl, lo~er al~yl or lower alkoxycarbonyl-lower alkyl, especially lower alkoxycarbonyl-methyl, R3 represents hydrogen or lower alkyl, especially methyl or ethyl, A represents ethylene or trimethylene, Z2~ Z3 and Z4 represent radicals -CH=, Z2 of which can be substituted by halogen having an atomic number of up to 35~ especially chlorine, and, hence, the ring B is unsub-stituted or correspondingly substituted, and the phacma-ceutically acceptable acid addition salts thereof.
Compounds of the last-mentioned type in which A repre-sents ethylene are, for example, those mentioned below which, in the case of oral administration to rats of the dos-ages each indicated in ~g/kg in parenthesis, bring about a reduction in the blood sugar level of at least 20 ~: S-~ethyl-5-~4-pyridyl)-2,3,5,6-tetrahydro-imidazo~1,2-c]-quinazoline (10), 5-methyl-5-(6-methyl-2-pyridyl-2,3,5,6-~etrahydro-imidazo~1,2-cl~uinazoline ~3~, 5-butyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo~1,2-c]quinazoline (10),

5-methyl-5-~2-pyridyl)-~-chloro-2,3,5,5-tetrahydro-imidazo-[1,2-clquinazoline t3), 5-phenyl-5-~ pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-clquinazoline ~10), an~ 5-~4~pyridyl)-2,3,5,6-tetrahydro-imidazQ[1,2-clcluinazoline-5-acetic acid ethyl ester ~10), a~d 5-propyl-5-t4~pyridyl)-2,3,5,6-tetra-hydro-imidazo~1,2-c]quinazolin~ (3).

' ' . . , ' 3~1 Compounds of the last-mentioned type in which A repre-sents trimethylene are, for example, those mentioned below which, in bitches (nu.~ber of animals = n) in a dosage of 20 mg/~g per os produce, in the first 5 hours after administra-tion, the following average hourly elimina-tion of sodium, potassium and chlorine ions and urine volume (= vol.), expressed as a percentage of the amounts excreted from the same animals in thQ hour immediately before admini-stration: 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[l,2-c]quinazoline (n = 4, Na+ 1224, X+ 114, Cl 1369, vol. 409); 6-phenyl-6-(2-pyridyl)-3,4,6,7-tetra-hydro-~-pyrimido[1,2-c]quinazoline (n = 2, Na+ 392. K+
56, Cl 308, vol. 171); 6-(4-methylphenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2FI-pyrimido[1,2-c]quinazollne methanesul-phonate (n = 2, Na+ 800, K+ 103, Cl 850, vol. 206);

6-(4-chlorophenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[l,2-c3quinazoline (n = 4, Na+ 1673, K+ 92, Cl 868, vol. 301); 6-(4-pyridyl)-6-(2-thienyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline (n = 4, Na+ 1738, K+ 100, Cl- 1233, vol. 514); 7-ethyl-6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido~1,2-c]quinazolin2 fumarate (1:1) (n = 4, Na+ 721, K+ 66, Cl 889, vol.
275). In the case of the first-mentioned compound, the excretions within the first 5 hours after administration of 20 mg/kg per os, as a percentage of the excretions of 10 untreated control animals, determined simultaneously for the same period, were for Na+ 2263, K+ 137, Cl- 751 and vol. 379. All the above tests show, on the one hand, the sh~rp increase in the excretion of sodium and chlorine and also thq increase in the urine volume, whereas, on the other hand, the el.imination o~ potassium is unchanged or, in part, ev~n decreased.
The compounds of the general Eormula I and their acid addition salts can be manueactured in a manner known per se' Eor example by condensing a compound of the general formula II

~ 173~31 N --A

~s~ 4\ i \ N / (II) Z . H
2~ / \ NH

3, Zl, Z2~ Z3~ Z4 and A have the meanings given under formula I and the ring 3, as stated there, can be sub-stituted, or an acid addition salt of the same, with a ketone of the general formula III
; ~ :

.
R - CO - R2 (~II) in which Rl and R2 have the meanings given under formula I, or a reactive functional derivative of the same, if desired introducing lower alkyl as the radical R3 into a compound of the general ~ormula I in which R3 represents hydrogen, and/oc converting a resulting compoun~ o~ the general formula ~ into an acid addition salt or liberating the compound o the g~neral formula I from a resulting acid addition salt.
The condensation of a compound o the general formula II with a ketone oE the general ormula III or a reactive functional derivative thereof can be carried out, Eor example, in the presence of an inert organic solvent, for example in a lower alkanol, such as methanol, ethanol, . ,, . .. , . . :

" ~ ~7383~
~ 12 -isopropanol or butanol, in an aromatic hydrocarbon, such as benzene, toluene or a xylene or xylene mlxture, or in an N-substituted acid amide, such as dimethylformamide or hexa-methylphosphoric acid triamide, for example at temperatures between approximately O and approximately 180C, pre-ferably at room temperature to approximately 150C and preferably in the presence of an acid or an acid catalyst.
As the acid there may be used, for example, a mineral acid, such as hydrogen chloride or concentrated hydrochloric acid, preferably in a lower alkanol, also polyphosphoric acid, for exa~ple in dimethylformamide or as the sole reaction medium, or a catalytic amount of an arenesulphonic acid, such as p-toluenesulphonic acid, preferably in an aromatic hydrocar-bon, such as toluene, especially at the boiling temperature thereof, while removing the water liberated by azeotropic distillation. As acid catalysts there come into considera-tion, for example, strongly acidic ion-exchange resins, suc~
as, for example, Amberlite IR 120 H ~ - form (trade mark of ~ohm & Haas Co., Philadelphia, ~.S.A.). Instead of acid catalysts`, other agents that promote the liberation of water can also be used, such as silica gel or aluminium oxide, and the condensation can in turn be carried out preferably in a solvent that renders possible the removal of the water liberated by azeotropic distil~ation in a water separator, such as, for example, in toluene at the boiling temperature th~reof. Also polyphosphate ester (PPE) may be used.
The reaction can alternatively be carried out in the absence of solvents or diluents, but preferably at elevated temperatur~s between ~pproximately 120 and 200C and like-wise in the presence oE acids or acid condensation agents, such as, Eor example, a catalytic amount of p-toluenesulpho~
nic acid, or a preferably at least equimolar amount of aluminium chloride to which a solid diluent, such as sodium chloride can have been added. As will be apparent Erom the above and Erom the Examples, the reaction con~i-tions can vary within wide limits. Clearly, more energetic .
, .

``` ~ 1~383:L

conditions than are necessary for achieving as complete a reaction as possible are not used. Within the scope of the above-mentioned range, relatively energetic reactions condi-tions are generally necessary if directly bonded cyclic radicals are present as Rl and R2 in the starting mate-rials of the general ~ormula III e~ployed.
As reactive functional derivatives of ketones of the general formula III there can be used, for example, alcoho-lates, such as lower alkanolates, ketals, such as dimethyl, diethyl and ethylene ketals, or oximes and imines.
The introduction of lower alkyl in place of a hydrogen atom R3 can be effected in a manner known per se, for example by reacting a compound of the general formula I
containing a hydrogen atom as R3 with a reactive ester of a lower alkanol, especially a correspondin~ hydrohalic acid ester, lower alkanesulphonic acid ester or arenesulphonic acid ester, more especially a lower alkyl halide, especially iodide or bromide, such as, for example, methyl or ethyl iodide, or propyl or butyl bromide, in the presence or absence of an organic solvent, for example a lower alkanol, such as methanol, ethanol or isopropanol, a lower alkanone, such as acetone or 2-butanone, a lower alkanoic acid ester or amide, such as ethyl acetate or dimethylformamide, or a low-boiling hydrocarbcn or polyhalohydrocarbon, such as benzene, toluene or methylene chloride, and an acid-binding agent, for example an alkali metal compound, such as sodium hydride, or sodium or lithium amide, a tertiary organic base, such as triethylamine or ethyldiisopropylamine, or an inorganic base, such as potassium or sodium carbonate, pee-~erably at temperatures between 0C and lZ0C and, if necessary, in a closed vessel, especially, however, at room temperature to the boiling temperature o~ the reaction mixture.
OE the starting materials oE the general formula II, some representatives are known and others can be manu~ac-tured analogously to the known compounds. For example, they ""` 1173~31 can be obtained by a reaction sequence described in ~S-PS
3 920 687 for the manufacture of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole and 2-(2-aminophenyl)-4,5-dihydro-5,5-dimethyl-lH-imidazole and in VS PS 3 922 282 for the manu-facture of 2-(2-amino-4-chlorophenyl)-4,5-dihydro-lH-imida-zole, which, for the mentioned compounds, comprises the N-acylation of anthranilic acid methyl ester and 4-chloro-anthranilic acid methyl ester, respectively, with p-methoxy-benzenesulphonyl chloride, boiling of the resulting N-(p-methoxybenzenesulphonyl) derivatives with 1,2-ethanediamine and 2-methyl-1,2-propanediamine, respectively, and heating of the resulting derivatives of 4,5-dihydro-lH-i~idazole with 92 ~ sulphuric acid and freeing of the desired process products with excess aqueous ammonia solution. The 2-(2-aminophenyl3-4,5-dihydro-lH-imidazole was also manufactured according to Zh.Prikl.Khim. 43, 16~1 (1970) (cf. Chem.
Abstr. 73, 77138r) by cond~nsation of anthranilic acid with 1,2-ethanediamine in the presence of a certain cation-exchange resin at room temperature, and according to J. Med.
Chem. 13, 697 (1970) by catalytic hydrogenation of 4,5-dihydro-2-(2-nitrophenyl)-lH-imidazole or 2-(2-nitrophenyl)-lH-imidazole; cf., in connection with the latter, also Il Farmaco, Ed. Sc. 30, 536-546, especially 539 (1975). A
further process that comes into consideration is, for example, the condensation of unsubstituted or ring-sub-stituted 2-aminobenzonitriles, or of corresponding amino-pyridinecarbonitriles having an amino and a cyano group at adjacent ring carbon atoms, with optionally C-lower alkylated 1,2-ethanediamine. ~5 compounds of the general ~ormula II having lower alkyl as R3~ the 4,5-dihydro-2-12-~methylamino)-phenyl]~lH-imidazole and the 4,5-dihydro-2-~2-~ethylamino)-phenyl~--lH imidazole ~ere manu~actured according to Bull. Soc. Chim. France 1975, 2118-20 by reacting th~ corresponding l-lower alkyl-1,2-dihydro-3,1-benzothiazine-4-thiones with 1,2-ethanediamine in a boiling mixture of ethanol/benzene (2:1).

, , ~ .
.
,. . .

J383~

As starting materials of the general formula II in which the radical A contains respectively three and four carbon atoms in a direct chain between the two nitrogen atoms, 2-(2-aminophenyl)-1,4,5,6-tetrahydropyrimidine and 2-~2-aminophenyl)-1,5,6,7-tetrahydro-lH-1,3-diazepine, respectively, have been described by Russell Kwok in J.
Heterocyclic Chem. 15, 877-880 (1978~. Other compounds of that type can be manufactured analogously to the process described in that work, i.e. by heating for several hours optionally ring-substituted 2-aminobenzonitrile with approximately half the molar quantity, in each case, of optionally C-lower alkylated 1,3-propanediamine or 1,4-butanediamine, an~ the bis--4-methylbenzenesulphonates thereof at approximately 200C. Furthermore, correspond-ing starting materials can also be obtained, for example, by heating an optionally ring-substituted 2-aminobenzonitrile, or a corresponding aminopyridinecarbonitrile having an amino and a cyano group at ad]acent ring carbon atoms, with approximately double the molar amount of optionally C-lower alkylated 1,3-propanediamine and a little carbon disulphide at approximately 120 to 170C for some time, for example approximately 2 to 48 hours, while stirring and passing nitrogen through the mixture.
Of the ketones of the general formula III, some are known and others can be manufactured analogously to the known ketones: lower alkyl pyridyl ketones, for example, by reacting the corresponding pyridinecarbonitriles with lower alkylmagnesium halides according to Grignard.
Uependinc3 on the process conditions and the starting materials, the novel compounds are obtaine~ in free form or in the orm o their salts which is likewise included in the scope of the invention, it being possible for the novel compounds or salts thereof also to be in the form of hemi-, mono-, sesqui- or poly hy~rates thereof. Salts of the nov~l compounds can be converted into the free compounds in a manner known per se, fo~ example by treatment with basic ;

~ ~3~3~

agents, such as al<ali metal hydroxides, carbonates or bi-carbonates, or ion-exchangers. On the other hand, resulting free compounds can rorm acid addition salts in a ~anner known 2er se, for example by treatment with organic or inorg~nic acids, such as the acids mentioned above, there beiny used for the manufacture especially those acids which are ~uitable for the formation of pharmaceutically accept-able salts.
These or other acid addition salts of the novel compounds, such as, for example, oxalates, picrates or per-chlorates, can also be used for purifying the resulting free bases by converting the free compounds into salts, separat-ing and purifying these and liberating the bases from the salts again.
Depending on the starting materials and procedures chosen, the novel compounds can be in the form of racemates or optical antipodes or, if they contain at least two centres of asymmetry, also in the form of mixtures of racemates. The starting materials can also be used in the form of certain optical antipodes.
Mixtures of racemates can be separated into the race-mates according to methods kno~n per se' especially by means of physical separating processes, such as fractional adsorp-tion and elution, includin~ chronatography, fractional cey-stallisation and distillation, etc..
Racemates can be separated into the antipodes according to methods known per se, for example by recry-stallisation from an optically active solvent, by tceat~nent with suitable micro-organisms or by reaction with an op~i-cally active compound that Eorms a salt with the racemic compound, especially a corresponding acid, and separation oE
the salt mixture obtainable in that manner, for example on the basis oE die~ering solubility~ into the diastereoiso-rneeic salts, fcom ~hich the eree antipodes can be liberated by the action of s~itable a~ents. Especially custo~aey as optically active acids are, for example, the D- and L-focms ' :
., `

7 3 ~
~ 17 -of tartaric acid, bis-0,0'-(p-toluoyl)-tartaric acid, malic acid, mandelic acidt camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. Advantageously, the more active of the two antipodes is isolated.
The invention relates also to those forms of the process according to which a compound obtainable as an intermediate at any stage of the process is used as start-ing material and the remaining process steps are carried out, or the process is discontinued at any stage, or in which a starting material is formed under the reaction con-ditions, or in which the reactants are optionally in the form of their salts.
For carrying out the reactions according to the invention there are advantageously used those starting materials which res~lt in the groups of end products given special mention at the beginning and in the end products described or emphasised, for example in the Examples.
The starting materials are known or, if they are novel, can be manufactured according to methods known ~
se, as described above, for example in a .manner analogous to that described in the Examples. The invention relates also to novel starting materials. The invention relates also to intermediates that can be obtained in accordance with the process.
The novel compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharma-cologically effective amount of the active sub~tance, optionally together with inorganic or organic, ~olid or liqui~, pharmaceutically acceptable carriers and which are suitable for ente~al, for example oral, administration or parenteral administration. Thus, tablets or gelatine cap-sules are used whiCh Contain the active ~ubstance together with diluents, ~or example lactose, dextrose, sucrose, mannitol, 30rbitol, cellulose and/or glycine, and/or lubricants~ ~or example siliceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, ~ `173~3~

and/or polyethylene glycol. Tablets can also contain binders, for example magnesium aluminium silicate, starches, such as maize, wheat, rice or arrowroot starch, gelatine, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and, if desired, disintegra-tors, for example starches, agar, alginic acid or salts thereof, such as sodium alginate, and/or effervescent mix-tures, or adsorption agents, colouring substances, flavour-ing substances and sweeteners. Furthermore, the novel phar-macologically active compounds can be used in the forrn of parenterally administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, it being possible to manu-facture these before use, for example in the case of lyo-philised preparations which contain the active substance on its own or together with a carrier t for example mannitol.
The pharmaceutical preparations can be sterilised and/or contain adjuncts, for example preservatives, stabilisers, wetting agents and/or emulsifiers, solubilisers, salts for regulating the osmotic pressure and/or buffers. The present pharmaceutical preparations, which, if desired, can contain other pharmacologically active substances, are manufactured in a manner known per se, for example by means of conven-tional mixing, granulating, coating, dissolving or lyophili-sing processes and contain approximately from 0.1 ~ to 100 %, especially from approximately 1 ~ to approximately SO ~, and, in the case of lyophilisates, up to 100 %, of the active substance.
The novel compound3 of the general Eormula I and their pharmaceutically acceptable acid addltion salts are preEer-ably administered perorally. The daily doses vary between 0.5 and 30 mg/kg for mammals and, for mammals weighing approximately 70 kg, are preferably between 50 an~ 1000 mg, especially between 100 and ~00 mg depending on the indi-vidual condition and age. Corresponding oral unit dose forms, for exarnple dragees or tablets or capsules, contain ~ 173831 -- lg --preferably from 25 to S00 mg, especially from 50 to 250 mg, of an active substance according to the invention, i.e. a compound of the general formula I or a pharmaceutically acceptable acid addition salt thereof, together with pharma-ceutical carriers.
The following prescribed method is intended to explain the manufacture of tablets in detail:
a~ 500 g of 5-propyl-5--(4-pyridyl)-2,3,5,6-tetra-hydro-imidazol1,2-c]quinazoline are mixed with 500 g of lac-tose and 340 g of potato starch, the mixture is moistened with an alcoholic solution of 10 g of gelatine and granu-lated by passing it through a sieve. After drying, 60 9 of potato starch, 60 9 of talc, 10 g of magnesium stearate and 20 g of highly disperse silica are mixed in and the mixture is pressed to form 10,000 tablets each weighing 150 mg and containing 50 mg of active substance, which can, if desired, be provided wi~h dividing grooves for finer adjustment of the dosage.
Instead of the above-mentioned active substance, it is also possible to use, for example, 500.0 g of 5-phenyl-5-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c)quinazo-line, its methanesulphonate, its acetate dihydrate or another phar~aceutically acceptable acid addition salt thereof.
The following Examples illustrate in detail the manufacture of the novel compounds o~ the general formula I
and of the starting materials that were not known hitherto, but are not intended to limit the scope of the invention in any way~ The temperatures are given in degrees Centigrade.

-73~331 Example 1 12.11 g (0.1 mol) of methyl 4-pyridyl ketone [cf. J.
Med. Che,n. 14, 551 (1971)] are added at O to a solution of 8.0O 9 (0.05 mol) of 2-(2-aminophenyl)-4.5-dihydro-1~-imidazole (cf. V~-PS 3 920 687) in 125 ml of 1.8N methanolic hydrogen chloride solution. The reaction mixture is stirred at room temperature for 60 hours and is then evaporated to dryness _ vacuo. 125 ml of lN sodium hydroxide solution are a~ded to the residue and the mixture is extrac~ed several times with chloroform. The combined chloroform phases, washed neutral with water and dried over sodiu~
sulphate, are concentrated by evaporation and the residue is recrystallised from isopropanol. The resulting 5-~ethyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imida~o~1,2-c]quinazoline melts at 227-228.
Analogously, using 12.11 y tO.l mol) of ~ethyl 3-pyridyl ketone [cf. Liebigs Ann. Chem. 486, 95 ~1931)1, S-methyl-5-(3-pyridyl)-2,3,5,6-tetrahydro-imidazol1,2-c]-quinazoline having a meltin~ point of 170-171 ~from ethanol/ether) is obtained; and, using 12.11 g (0.1 mol) of methyl 2-pyridyl ketonQ [cf. J. Med. Chem. 14, 551 (1971)], 5-methyl-5-(2-pyridyl)-2,3,5,5-tetrahydro-imidazo[1,2-c~~
~uinazoline having a melting point of 202-203 (from ethanol/ether) is obtained.
The starting material, 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole, can also be obtained, more simply than as described in U~-P~ 3 920 687, in the following manner:
a) A mixture o~ 118~14 ~ (1 mol) of 2-aminobenzonitrile, 120.2 g (2 mol) o~ 2thylensdiamine and 0.5 ml o~ carbon di-sulptlide is heated at 150C for 16 hours while stirring and introducing ni~royen, during which ammonia is evolved.
The reaction mixture is then concentrated by evaporation ln vacuo, the residue is taken up in hot ethyl acetate with the addition of activ~ carbon, the mixture is filtered and hex~ne is added to the ~iltrate while stirring vigorously.
Upon cooling, 2-(2-aminophenyl)-4,5-dihydro~ imidazole ~ 3 ~ 3 1 crystallises out, m.p. 60-64. After recrystallisation from ether/hexane, the product melts at 63-54~.

Example 2 A solution of 8.0~ 9 ~O.OS mol) of 2-(2-aminophenyl)-4,5-dihydro-1~-imidazole, 12.11 g (0.1 mol) oE methyl 4-pyridyl ketone and 0.8 g (0.0042 mol) of ~-toluene-sulphonic acid monohydrate in 200 ml of toluene is boiled under reflux for 15 hours with w3ter being separated. ThQ
mixture is cooled, the precipitate that has formed is filtered off and partitioned between lN sodium hydroxide solution and methyl~ne chloride. The methylene chloride phase, washed neutral with w~ter and dried over sodiu~
sulphate, is concentrated by evaporation. The 5-methyl-S-(4-pyridyl)-2,3,5j6-tetrahy~ro-imidazo~1,2-cJquina~oline obtained after recrystallisation of the residue from isopropanol melts at 228 - 229.

Example 3 Analogously to Example 1, starting from 8.06 g (0.05 mol) of 2-(2-aminophenyl)-4,S-dihydro-lH-imidazole, 12.68 g (0.085 mol) of propyl 4-pyridyl ketone [cf. J. Chem. Soc.
(C) 1969, 2134] and 200 ml of 1.8N methanolic hydrogen chloride solution, 5-peopyl-5-(4-pyridyl)-2,3,5,6-tetra-hydro-imidazo[1,2-c]quinazoline having a melting point of 241 - 242 (from lsopeopanol/ethyl acetate) is obtained.

Example ~
Analogously to Example 1, starting ~rom 8.06 g (O.OS
mol) oE 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole, 8.81 g (0.08 mol) of 2-uryl methyl ketone ~cE. Helv. Chim. Acta 13, 356 ~1930)J and 150 ml o~ 1.8N methanolic hydrogen chloride ~olution, 5-methyl-S-(2-~uryl)-2,3,5,6-~etrahydro-imidazoll,2-c~uinazoline having a melting point o~ l9S -196 (~rom ethanol) is obtained.

1 i 738~1 Example S
Analogously to Example 1, 8.06 g (0.05 mol~ of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole are reacted with 20.22 9 (0.1 mol) of 3-oxoglutaric acid diethyl ester in 240 ml of 1.8N methanolic hydrogen chloride solution. The resulting, crude 5,5-bis-(ethoxycarbonylmethyl)-2,3,5,6-tetrahydro-imidazo~1,2-c]quinazoline is dissolved in 2.1N ethanolic hydrochloric acid. The hydrochloride is precipitated by adding ether. It melts at 213 214.

Exam~_e 6 12.11 9 (0.1 mol) of methyl 4-pyridyl ketone are added at 0 to a solution of 9.78 g (0.05 mol) of 2-(2-amino-~-chlorophenyl)-4,5-dihydro-lH-imidazole (cf. US-PS 3 922 282) in 160 ml of 2.5N methanolic hydrogen chloride solution.
The reaction mixture is boiled under reflux ~or 15 hours and then concentrated ln vacuo. After the addition of ether, a precipitate of the mono- or di-hydrochloride or 5-methyl-S-(4-pyridyl)-8-chloro-2,3,5,6-tetrahydro-imidazo[1,2-c]quina-zoline forms which is filtered off and partitioned between lN sodium hydroxide solution and chloroform. The organic phase is washed neutral with water, dried over sodium sulphate and concentrated by evaporation. Recrystallisation of the residue fro~ acetonitrile/isopropanol yields 5-methyl-5-(4-pyridyl)-8-chloro-2,3,5,6-tetrahydro-imidazo~1,2-c]quinazoline having a melting point of 242 - 244.
~ nalogously, using 12.11 g ~0.1 mol) of methyl 2-pyridyl ketone, 5-methyl-5-~2-pyridyl)-8-chloro-2~3~5~6-tetrahydro-imidazo[l,2-c]quinazoline having a melting point oE 247 - 249 ~rom ethanol) is obtained.

~.

8.06 g ~0.05 mol) of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole ~nd 10.63 9 (0.055 mol) of ~-oxo 4-pyridinepropionic acid ethyl ester ~cf. J. Am. Chem. Soc. 67, 1468 (1945)l are :~ 173~3~3~

heated in 80 ml of 2.1N ethanolic hydrogen chloride solution for 15 hours at 90 in a closed vessel. The reaction mixture is evaporated to dryness and the residue is partitioned between 2~ sodium hydroxide solution and chloroform. The organic phase, washed neutral with ~ater and dried over sodium sulphate, is concentrated by evaporation. The residue is filtered with a mixture of chloroform:methanol:concentrated ammonia = 150:50:1 over silica gel having ~ particle size of 0.0~3 - 0.200 mm.
The fractions containing the desired product are concentrated by evaporation and the residue is recrystallised from iso~ro-panol. The resulting 5-(4-pyridyl)-2,3,$,6-tetr~hydro-imidazo-11,2-c]quinazoline 5-acetic acid ethyl ester melts at ]90 -192. During the above-mentioned filtration through silica gel there is obtained, as by-product, 5-methyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-clquinazoline having a melting point of 226 - 228 (from isopropanol).
Analo~ously, 5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo-~1,2-cJquinazoline 5-acetic acid ethyl ester can also be obtained if, instead of 2-~2-aminophenyl)-4,5-dihydro-lH-imidazole, a corresponding salt, for example 2-(2-amino-phenyl)-4,5-dihydro-lH-imidazole dihydrochloride hydrate (J. Med. Chem. 13, 697-704 (1970)) is used in the reaction.

Example 8 18.22 g (0.1 mol) of benzophenone are added at 0 to a solution oE ~.06 g (O.OS mol) of 2-(2-aminophenyl)-4,5-dihydro-lH-irnidazole in 125 ml of 1.8~ methanolic hydrogen chloride solution. The reaction mixture is stirred Eor 15 hours at room temperature. Ether is added and the resulting precipitate of the hydrochloride of S,5-diphenyl-2,3,5,6-tetrahy~ro-imidazo~1,2-cl~uinazoline is filtered off. The latter i5 recrystallised twice fro~ ethanol~ether. It melts at abova 300 Analogously, using S.8 g (0.1 mol) oE acetone, 5,5-dimethyl-2,3r5,6-tetr~hydro-imidazo[1,2-c]quinazoline hydro-chloride having a melting point of 249 - 2S0 (from ~ 1~38':~

ethanol/ether) is obtained.

Example 9 Analogously to Example 8, 8.06 g ~0. as mol) of 2-~2-aminophenyl)-4,5-dihydro-lFI-imidazole and 8.10 g ~0.06 mol) of methyl 2-pyridylmethyl ketone [cf. Helv. Chim. Acta 45, 729 (1962~l are reacted in 125 ml of 1.8N ~ethanolic hydrogen chloride solution. The reaction mixture is, how-ever, concentrated by evaporation and the residue is recry-stallised from ethanol/ether and chloroform/methanol/ether.
The dihydrochloride of S-methyl-[(2-pyridyl)-methyl~-2,3,5,6-tetrahydro-imidazo[1,2-c]quinazoline begins to decompose at approximately 150.

Example 10 Analogously to Exa~ple S, 8.06 g (0.05 mol) of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole and 6.75 9 (0.05 mol) of methyl 6-methyl-2-pyridyl ketone ~cf. J. Med. Pharm.
Chem. 3, 561 (1961)~ are reacted in 125 ml of 1.8N
methanolic hydrogen chloride solution. The reaction mix-ture is, however, concentrated by evaporation and the resi-due is recrystallised from water and ethanol/ether. The hydrochloride of 5-methyl-5-(6-methyl-2-pyridyl)-2,3,5,5-tetrahydro-imidazol1,2-c~quinazoline melts at 269 - 270.

Example 11 Analogously to Example 8, 8.06 g (0.05 mol) of 2-(2-aminophqnyl)-4,5-dihydro-lH-imidazole and 10.13 g (0.055 mol) of di-~2 pyridyl) ~etone [cf. Rec. trav. chim. 70, 1054 (l9Sl)] are reacted in 2~0 ml o~ 1.8N methallolic hydrogen chloride solution. The reaction mixture is, how-ever, concentrated by evaporation, the residue is dissolved in water and the solution is adjusted to pH 8 with 2N sodium hydroxide sol~tion. The precipitate that has formecl is fil-tered off and recrystallised Erom eth~nol/ether. The resul-ting hydrochloride of 5,5-di-(2-pyridyl)-2,3,5,6-tetrahydro-~ ~7~8~ ~

imidazo[l,2-c]quinazoline ~elts at above 300.

Exam~le 12 A gently boiling, concenteated solution of 2.32 g (0.02 ~ol) of maleic acid is added at the boiling tempera-ture to a likewise gently boiling, concentrated ethanolic solution of 5.28 g (0.02 mol) of S-methyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]quinazoline. After cool-ing, the maleate that has formed is filtered off and recry-stallised from isopropanol, whereupon it melts at 17~ -Analogously, using 2.32 9 (0.02 mol) of fumaric acid, the corresponding fumarate is obtained. After recrystalli-sation from ~ethanol, the fumarate melts at 237 - 239.

Exam~e 13 Analogously to Example 1, 8.06 g (0.05 mol) of 2-(2-amino~henyl)-4,5-dihydro-lH-imidazole and 12.24 g (0.075 mol) of butyl 4-pyridyl ketone [cf. J. Chem. Soc. (C) 1969, 2134] are reacted in lS0 ml o~ 2.7N methanolic hydrogen chloride solution. In working up, instead of 1~ sodium hydroxide solution, dilute aqueous ammonia solution is used.
The resulting 5-butyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[l,2-c]quinazoline melts at 257 - 259 after recrystallisation from ethyl acetate.
Analogously, using 15.40 9 (0.~75 mol) of heptyl 4 pyridyl ketone [cf. J. Med. Chem. 14, SSl (1971)~, 5-heptyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]-quinazoline having a melting point o 161 ~ 163 (from acetone/petroleum ether) is obtained and, usin~ 15.85 9 (0.075 ~ol) of phenethyl ~-pyridyl ketone [cf. J. Chem.
Soc. (C) 1969, 213~1, 5-phenethyl-5- (4-pyridyl)-2,3,5,6-tetrahydro-imidazo~1,2-clquinazoline having a melting point of 187 - 188 (from e~hyl acetate) is obtained.

3 8 3 ~

Example 14 Analogously to Exarnple 13, 6.44 9 (0.04 mol) oE 2-~2-aminophenyl)-4,5-dihydro-lH-imidazo~e and 11.0 9 (0.06 mol) of phenyl 4~pyridyl ketone are reacted, the reaction mixture, however, being stirred for 40 hours at room tem-perature and then boiled for 2 hours under reflux. lrhe resulting 5-phenyl-5-~4-pyridyl)-2,3,5,6-tetrahydro-imidazo-[1,2-c]quinazoline melts at 198 - 200 after recrystalli~
sation from chloroform/ether and then from ethyl acetate.

Example 15 Analogously to Example 1, but observing a reaction period of 15 hours, starting from 3.91 g (0.02 mol) of 2-~2-amino-5-chlorophenyl)-4,5-dihydro-1~-imidazole, 4.47 g (0.03 mol) of propyl 4-pyri~yl ketone and 50 ml of 2 methanolic hydrogen chloride solution, 5-propyl-5-(4-pyridyl)-9-chloro-2,3,5,6-tetrahydro-imidazoEl,2-c}quina-zoline having a melting point of 181.5 - 183 after recrystallisation from chloroform/ether and then from ethyl acetate is obtained.
The 2-(2-amino-5-chlorophenyl)-4,5 dihydro-lH-imidazole is obtained as follows:
a) A solution of 15.26 9 (0.1 mol) of 2-amino-5-chlorobenzonitrile, 6.0 g (0.1 mol) of 1,2-ethan~diamine and 20 ~rops of carbon disulphide in 1~0 ml of ethanol is boiled under reflux for 22 hours. Ater adding a fu~ther 3.0 g ~0.05 mol) o 1,2-ethanediamine and 20 drops of carbon di-sulphide, the mixture is boiled under reflux for a eurther 50 hours, the reaction mlxture is then con~entrated by evapora~ion in vacuo and the residue is recrystallised from methylene chloride/hexane. The resulting 2-(2-amino-5-chlorophenyl)-4,5-dihydro-1~1-imidaæole melts at 105 -107, ~e,~.
Analo~ously to Example 15, startin~ rom 8.Q5 g ~O.Q5 ~1~3~

mol) of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole, 8.15 9 (0.055 mol) of phenyl propyl ketone and 150 ml of 2.5N
methanolic hydrogen chloride solution, 5-phenyl-5-propyl-2,3,5,6-tetrahydro-imidazo[1,2-c]quinazoline having a melt-ing point of 247 - 249 ~from methanol/ether) is obtained.

Example 17 Analogously to Example 1, but with boiling under reflux for 22 hours, starting from 9.46 g (0.05 mol) of 2-(2-amino-4,6-dimethylphenyl)-4,5-dihydro-lH-imidazole, 11.93 g (0.08 ~ol) of propyl 4-pyridyl ketone and 165 ml of 2.5~ methanolic hydrogen chloride solution, 5-propyl-5-~4-pyridyl)-8,10-dimethyl-2,3,5,6-tetrahydro-imidazo[1,2-c]-quinazoline having a melting point of 187 - 189 after recrystallisation from ether and from ethyl acetate/hexane is obtained. Further reaction product can be obtained if the mother liquor is concentrated by evaporation after the first recrystallisation from ether and the resid~e, which still contains starting materials, is boiled under reflux again with 80 ml of 2.SN methanolic hydrogen chloride solu-tion for 15 hours.
The 2-(2-amino-4,6-dimethylphenyl)-4,5-dihydro-lH-imidazole is obtained as follows:
a) A mixture of 21.93 g (0.15 mol) of 2-amino-4,6-dimethylbenzonitrile [cf. Polish Journal of Chemistry 52, 1389 (1978)~ and 34.85 9 (O.lS mol) of 2-aminoethylammoniu~
toluene-4-sulphonate ~cf. J. Chem. Soc., 497 ~1947)] is heated for 3 hours, while stirring, at a bath temperature of 250, during which ammonia is liberated rom thq melt. A
eurther 20 g (0.086 mol) of 2-aminoethylammonium toluene-4-sulphonate are added and the mixt~re is heated for a further 3~ hours at a bath temperature of 250 - 260. After cool-ing, the reaction mixture is partitioned between chloroform and 10 ~ sodium hydroxide solution, the organic phase is washed with water, driad over sodi~m sulphate and concentra-ted by evaporation. After adding ether to the residue, the : : .

?

7 3 ~3 3 1 - ~8 -crude 2-(2-amino-4,S-dimethylphenyl~-4,5-dihydro-1~-imidazole ceystallises out and, after recrystallisation from ethyl acetate, melts at 141 - 142.

Example 18

9.46 (0.05 mol) of 2-(2-amino-4,6-dimethylphenyl)-4,5-dihydro-lH-imidazole ~cf. Example 17a)] and 13.74 g (0.075 mol) of phenyl 4-pyridyl ketone are boiled under reflux in 200 ml of 2.5N methanolic hydrogen chloride solution for 22 hours. After working up analogously to Example 7, the resulting S-phenyl-5-(4-pyridyl~-8,10-dimethyl-2,3f5,6-tetrahydro-imidazo[1,2-c]quinazoline melts at 249 - 251 (from isopropanol/ether).

Example 19 0.28 9 (0.0064 mol) of sodium hydride dispersion (55 ~
in oil) is added to a suspension of 1.32 g (0.005 mol) of 5-methyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]-quinazoline in 13 ml of dimethylformamide and the mixture is stirred for one hour at 70. After cooling to room tem-perature, 0.91 g ~0.0064 mol) of methyl iodide is added dropwise. The mixture is stirred for a further 10 minutes, it is then cooled to 0, 2 ml of water are added dropwise to the reaction mixture, it is concentrated by evaporation in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is ~ashed with water, dried over magnesium sulphate and concentrated by ~vapora-tion. ~fter recrystallisation of the residue Erom ethyl acetate/petroleum ether, pure 5,6-dimethyl-5-(4-pyridyl)-2,3,5,6~tetrahydro-imidazo[1,2-c}quinazoline having a melting point oE 153 - 154 is obtained.

Example 20 .

Analogously to Example l, but with boiling under reflux for 7 hours, using 9.46 g (O.OS mol) of 2-(2-amino-phenyl)-4,4(or 5,5)-dimethyl-4,5-dihydro-lH-imid~zole (cf.

3 ~3 3 1 US 3894040 and ~S 3920687), 9.08 g (0.075 mol) of methyl 4-pyridyl ketone and 160 ml of 2.5N methanolic hydrogen chloride solution, 2,2,5-trimethyl-5-(4-pyridyl)-2,3,5,5-tetrahydro-imidazo[1,2-c]quinazoline having a melting point of 138 - 141 (from ethyl acetate/hexane) is obtained.

Example 21 15.92 g ~0.1 mol) of 2-~2-aminophenyl)-lH-imidazole [cf. Il Farmaco, Ed. Sc. 30, 536 ~1975)] and 20.89 g (0.14 mol) of propyl 4-pyridyl ketone are stirred in 240 ml of 2.5N methanolic hydrogen chloride solution for 15 hours at 20 and then boiled under reflux for a further 12 hoursO
The reaction ~ixture is then evaporated to dryness and the residue is partitioned between 2N sodium hydroxide solution and chloroform. The organic phase is washed with water, dried ovef sodium sulphate and concentra~ed by evaporation.
The 5-propyl-5-~4-pyri~yl)-5,6-dihydro-imidazo[1,2-c]quina-zoline obtained after recrystallisation of the residue from ethyl acetate melts at 199 - 200.

Example 22 Analogously to Example 1, but observing a reaction period of 20 hours at 20, starting from 3.18 g ~0.02 mol) of 2-~2-aminophenyl)-lH-imidazole, 3.63 g (0.03 mol) of methyl 4-pyridyl ketone and 50 ml of 3~ methanolic hydrogen chloride solution, S-methyl-S-(4~pyridyl)-5,6-dihydro-imidazoll,2-c]quinazoline having a melting point of 208 210 (rom chloroform/ether) is obtained~

Example 23 A solution of 8.76 g ~0.05 mol) of 2-(2 aminophenyl)-1,4,5,5-tetrahydro-pyrimidine [c~. J. Heterocyclic Chem.
15, 877 (1978)~ and 13.74 g (0.075 mol) of phenyl 2-pyridyl ketone in 125 ml of 2.5N meth~nolic hydrogen chloride solu-tion is boiled under reflux For 48 hours and then concentra-ted by evaporation. The residue is partitioned between 2N

1 l73a3~

sodium hydroxide solution and chloroform, the organic phase is washed with water anc1, after drying over sodium sulphate, is concentrated by evaporation in vacuo. The oily residue crystallises on being stirred with ether. After recrystal-lisation from ethanol/hexane, the resulting 6-phenyl-6--(2-pyridyl)-3,4,6,7-tetrahydro-2H pyrimido[l,2-c]quinazoline melts at 218 - 219.
Analogously, there are obtained:
using 17.1 9 (0.075 mol) of 3-nitrophenyl 4-pyridyl ketone [cf. ~onatshefte f~r Chemie 107, 1449 tl976)), 6-(3-nitrophenyl)-6-(4-pyridyl)-3/4/6,7-tetrahydro-2H-pyrimido-[1,2-c]quinazoline having a melting point of 115 - 117 (from ethyl acetate; the compound contains one mol of ethyl acetate);
using 13.81 9 (0.075 mol) of 2,2'-dipyridyl ketone -but with ~oiling under reflux in 150 ml of 3N methanolic hydrogen chloride solution for 20 hours - 6,6-di-(2-pyridyl)-3,4,6 r 7-tetrahydro-2~-pyrimido[1,2-c]quinazoline having a melting point of 265 - 266 (from methanol);
using 11.12 9 (0.075 mol) of phenyl propyl ketone -but while heating in a bomb tube at 150 for 4 hours -6-phenyl-6-propyl-3,4,6,7-tetrahydro-2H-pyrimido~1,2-c]-quinazoline having a melting point of 190 - 192 (from ethyl acetate);
and, by reaction of 8.76 g (0.05 mol) of 2-(2-amino-phenyl)-1,4,5,6-tetrahydro-pyrimidine with 8.7 g (0.15 mol) of acetone in 100 ml of 2.SN methanolic hydrogen chlorlde solution for lS hours at 20, 6,6-dimethyl-3,4,6,7-tetra-hydro-2H-pyrimido~1,2-c]quinazolin~ having a melting point of 218 - 220 (from ethyl acetate).
The starting compound, 2-~2-amillophenyl)-1,4,5,6-tetrahydro-pyrimidine can also be obtained in the follow-ing manner:
a) A mixture of 50 g (0.42 mol) of 2-aminobenzo-nitrile, 62.27 g (0.84 mol) of 1,3-propanediamine and 5 drops of carbon disulphide is heated at 150 for 24 hours :

.

1 1~3~33 ~

while stirring and introducing nitrogen, ammonia being evolved. The reaction mixture is then concentrated by evaporation in vacuo and the residue is taken up in ether.
The 2-(2-aminophenyl)-l,g,5,6-tetrahydro-pyrimidine crystallises out of the ethereal solution, m.p. 99 -Example 24 20 g of molecular sieve (3 x 10~1m, pearl form approximately 2 mm; ,~erck) are added to a solution of 34.0 g (0.194 mo~) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimi-dine and 53.3 g (0.291 mol~ of phenyl 4-pyridyl ketone in 300 ml of 3N methanolic hydrogen chloride solution and the reaction mixture is boiled under reflux for 16 hours. The molecular sieve is filtered off, the filtrate is concentra~
ted by evaporation and the residue is worked up analogously to Example 23. The resulting 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]~uinazoline melts at 243 - 245 (from isopropanol/ether).
Analogousll, 6-phenyl-6-(4-pyridyl)-2,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline can also be obtained if, instead of 2-(2-aminophenyl)-1,4,S,6-tetrahydro-pyrimidine, a corresponding salt, for example 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine dihydrochloride (cf. J. Med. Chem. 13, 697-704 (1970)), or, instead of the free ketone, the imine thereof, is used in the reaction.

~me~
A solution of 13.15 g (0.075 mol) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine and 10.41 g (0.086 mol) of methyl 4-pyridyl ketone in 200 ml of 1.83N methanolic hyd~ogen chloride solution is stirred for 2~ days at 20. The reac-tion mixture is subsequently concentrated to approximately half the original volume, ether is added, the precipitate that has formed is filtered off and partitioned between chloroform and lN sodium hydroxide solution. The organic phase, washed with ' ~ ~7 3~

water, is dried over sodium sulphate and concentrated ~y eva-poration, and the residue is recrystallised from isopropanol.
The resulting 5-methyl-~-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[l,2-c]quinazoline melts at 207 209.

Example 26 8.76 g (0.05 mol) of 2-(2-aminophenyl)-1,4,5,6-tetra-hydro-pyrimidine and 13.74 g (0.075 mol) of phenyl 2-pyridyl ketone are stirred in 90 g of polyphosphoric acid for 3 hours at 150. The reaction mixture is cooled, ice-water an~ an exces~ of aqueous ammonia solution are added thereto, the reaction mixture is extracted with chloroform and the organic phase is concentrated by evaporation in vacuo after being dried over sodium sulphate. The oily residue cry-stallises on being stirred with ether. The resultin~ 6-ph~nyl-6-(2-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]-quinazoline melts at 218 - 219 (from ethanol/hexane).
Analogously, starting from 13.74 9 (0.07S mol) of phenyl 4-pyridyl ketone - but with a reaction period of 2 hours at 130 and 4 hours at 150 and using 140 g of polyphosphoric acid - 6-phenyl-5-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c~quinazoline having a melting point of 243 - 246 (from isopropanol/ether) is obtained.

A solution of 8.76 g (0.05 mol) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine and 11.18 g (0.075 mol) of propyl 4-pyridyl ketone in 200 ml of 2N methanolic hydrogen chloride solution is boiled under reflux for 2 days and worked up analogously to ~xample 23. Th~ resulting 6-propyl-6-~-pyridyl)-3,~,6t7-tetrahydro-2H-pyrimido~1,2-c]-quinazoline melts at 221 - 2~3 (from ethanol/ether).
~ he mother liquor obtained in recrystallisation, which still contains starting materials, is concentrated by eva-poration and the residue is stirred with 60 9 of poly?hos-phoric acid ~or one hour at 120. 'rhe reaction mixture is ~ ~738~3~

cooled, ice-water and an excess of aqueous ammoni3 solution are added, the reaction mixture is extracted with chloroform and the organic phase i5 concentrated by evaporation after being dried over sodium sulphate. The residue is recrystallised from ethanol/ether. In this manner, a second batch of 6-propyl-6-~4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[l,2-c~quinazoline having a melting point of 221 -223 is obtained.
Analogously, using 12.24 g (0.075 mol) of butyl 4-pyridyl ketone, 6-butyl-6-~4-pyridyl)-3,4,6,7-tetra;nydro-2H-pyrimido[1,2-c]quinazoline having a melting point of 197 - 199 (from chloroform/hexane) is obtained.

Example 28 A mixture of 17.52 g (0.1 mol) of 2-(2-aminophenyl)-1,4,5,5-tetrahydro-pyrimidine, 27.48 g (0.15 mol) oF phenyl 4-pyridyl ketone and 0.3 9 of toluene 4-sulphonic acid mono-hydrate is stirred for 24 hours at 180 and under a pres-sure of approximately 270 mbar. After cooling, the melt is taken up in ethyl acetate. In so doing, crude 6-phenyl-~-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline precipitates which, after recrystallisation from isopro-panol/ether, melts at 243 - 245.

Example 29 While stirring and introducing nitrogen, a mixture of 20 g (0.114 mol) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine and 31.2 g (0.170 mol) of phenyl 4-pyridyl ketone is introduced at 160Q into a melt consisting of 100 g of anhydrous aluminium chloride and 50 g of sodium chloride, the temperature temporarily rising to 205. When the a~dition is complete, the reaction mixture is stirred for a further 20 minutes at 180 and the melt is then allowed to solidify while cooling. The reaction material is dissolved in 700 ml of hot water. Washing with chloroform is carried out and 500 ml of concentrated aqueous ammonia solution are 1173~31 ~ 34 -added to the aqueous phase. The alkaline phase is stirred thoroughly with 500 ml of chloroform for 3 hours and, after the addition of 300 g of kieselguhr, the mixture is filtered.
The chloroform phase of the filtrate is dried over sodium sulphate and concentrated by evaporation ln vacuo. After recrystallisation of the residue from ethyl acetate and from isopropanol/et~er, the resulting 6-phenyl-5-~4-pyridyl)-3,4,6,7-tetrahydro-2a-pyrimido~1,2-c]quinazoline melts at 243 - 245.

Example 30 1.92 9 (0.02 mol) of methanesulphonic acid is added to a solution of 6.8 g (0.02 mol~ of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido~1,2-c]quinazollne in methanol.
The mixture is concentrated by evaporation and the residue is receystallised from ethanol/ethyl acetate. The resulting 6-phenyl-6-(4-pyridyl~-3,4,6,7-tetrahydro-2~-pyrimido[1,2-c]-quin~zoline methanesulphonate melts at 249 - 250.
Upon recrystallising the above methanesulphonate from ethanol with a little water, adding hexane until the mixture becomes opaque, filtering and drying, depending on the method of drying the methanesulphonate monohydrate or the methanesulphonate dihydrate i3 obtained both of which melt at Z48 - 251 ~with sintering from 100).

Example 31 Analogously to Example 23, starting from 8.76 g ~0.05 mol) oE 2-(2-aminophenyl)~1,4,5,6-tetrahydro-pyrimidine ~nd 13.74 g (0.075 mol) of phenyl 3-pyridyl ketone, crude 6-phenyl-6-(3-pyridyl)-3,~,6,7-tetrahydro-2H-pyrLmido~1,2-c]-~uinazoline is obtained which is filtered over silica gel havlng a particle size oE 0.063 - 0.200 m~ with a mixture of chloroform:methanol:concentrated ammonia - 40:10:1. The fractions containing the desired product are concentrated by evaporation and the oily residue is dissolved in methanol.
To this solution is added a methanolic solution of an equi-~ ~ "l 3 ~ 3 ~

molar amount of ~u~aric acid. After concentration by eva-poeation in vacuo, the residue is recrystallised from methanol/ ethyl acetate. The resulting 6-phenyl-&-~3-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido~1,2-c3quinazoline fumarate contains 1.5 mol of fumaric acid and melts at 223 -225.

Example 32 Analogously to Example 25, starting from 17.52 g (0.1 mol) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine, 29.55 g (0.15 mol) of 4-methyl~henyl 4-pyridyl ketone [cf.
~elv. Chim. Acta 52, 262 (1969)], 150 ml of 2.5~ methanolic hydrogen chloride solution an~ 15 g of molecular sieve (3 x 10 10m, pearl form approximately 2 mm; Merck), crude 6-(4-methylphenyl)-6-(4-pyridyl)-3,4,6,7-tetr~hydro-2~-pyrimidoll,2-c]quinazoline is obtained which is chromato-graphed over silica gel having a par~icle size of 0.063 -0.200 mm with a mixture of chloroform:methanol:concentrated ammonia - 40:10:1 as solvents and eluants. The uniform fractions containing the desired product are concentrated by evaporation. The residue is dissolved in ethanol and an equivalent amount of methanesulphonic acid is added to the ethanolic solution. After renewed concentration by evapora-tion and recrystallisation o~ the residue from ethanol/
hexane, the resulting 6-(4-methylphenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2a-pyrimido[1,2-c]quinazoline methane-sulphonate melts ~t 257 - 259.

A mixture of 17~52 g (0.1 mol) o~ 2-~2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine, 18.32 g (0.1 mol) of phenyl 4-pyridyl ketone, 500 ml oE toluene and ~0 g of silica gel having a particle size o~ 0.063 - 0.200 mm i5 ~oiled in a water ~eparator, while stirriny, for 18 hours, then a further 20 g of silica gel are added and the mixture is boiled for a further 15 hours in the water separator. After ~17~31 filtration and washing of the filter material with a chloro-form/methanol mixture (1:1), the filtrate is concentrated by evaporation ln vacuo and ethyl aceta~e is added to the residue, whereu~on 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[1,2-c]quinazoline precipitates ~hich melts at 234 - 237.

Example 34 Analogously to Example 19, 12.75 g ~0.0375 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]-quinazoline, 2.19 g (0.05 mol) of sodium hydride dispersion 155 % in oil) and 7.`3 g (0~05 mol) of ethyl iodide are reac-ted in 110 ml of dimethylformamide. Stirring is, however, carried out for 12 hours at room temperature, 10 ml of water are then added dropwise to the reaction mixture, while cool-ing, the reaction mixture is concentrated by evaporation ln vacuo and the residue is partitioned between chloroform and lN sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulph~te and concentrated by evaporation. The residue is chromatographed over silica gel having a particle size of 0.0~3 - 0.200 mm with a mixture of chloroform:methanol:concentrated ammoni~ = 14:6:1 as solvents and eluants. The uniform fractions containing the desired product are concentrated by evaporation and the residue is recrystallised from ethanol/hexane. The resulting 6-phenyl-6-(4-pyridyl)-7-ethyl-3,4,6,7-tetrahydro-~H-pyrimido[1,2-c]quinazoline me}t~ at 230 - 231. The fumarate manufactured therefrom with Eumaric acid melts at 252 - 25~ (~rom ethanol~methanol 10~1).

Example 35 Analogously to Example 1, but with boiling under reflux eor 5 hours, starting from 11.16 g (0.059 mol) of 2-~2-aminophenyl)-4,4(or 5,5)-dimethyl-4,5-dihydro-lH-imidazole, 13.27 g (0.089 mol) of propyl 4-pyridyl keton2 and 150 ml of 3N metnanolic hydrogen chloride solution, ~.17~3~

2,2-dimethyl-S-propyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[l,2-c]quinazoline having a melting point of 224 -226 after recrystallisation from ethyl acetate and then from ethanol/ether is obtained.

Example 36 Analogously to Exaimple 33, using 16.32 g (0.1 mol~ of 2-(2-aminophenyl)-4,5-dihydro-lH-imidazole ~nd 21.83 9 ~0.1 mol~ of 4-methoxyphenyl 2-thienyl ketone, but with boiling under reflux for 7 days and chromatography of the crude product over silica gel having a particle size of 0.063 -~.200 mm with a mixtur~ of chloroform:methanol = 9:1, 5-(4-methoxyphenyl)-5-(2-thienyl)-2,3,5,6-tetrahydro-imidazo-[1,2-c~quinazoline having a melting point of 207 - 208 ~from acetone and ethyl acetate) is obtained.

Example 37 11.68 g ~0.05 mol) of 2-chloro-5-acetyl-benzenesul-phonamide [Arzneimittelforsch. 13, 269-280 (1963)] are added to a solution of 8.06 9 (0.05 mol) of 2-(2 aminophenyl)-4,5-dihydro-lH-imidazole in 1~0 ml of 2.6N methanolic hydrogen chloride solution and the reaction mixture is stirred for 72 hours at 20. The precipitate that has formed is Eiltered of~ and suspended in 360 ml of water, and the suspension is stirred for ~ hour at room temperature with an excess of 30 % aqueous ammonia solution. After filtration and recry-stallisation of the residue from methanol, the resulting S-(4 chloro-3-sulphamoyl-phenyl)-5-methyl-2,3,5,6-tetrahydro-imidazoEl,2-c3quinazoline melts at 274 (with decomposi-tion).

17.52 9 (0.1 mol) of 2-(2-aminophenyl)-1,4,5,6-tetrahydro-pyrimidine, 21.32 9 (0.1 mol) of 4-methoxyphenyl 4-pyridyl ketone (J. Pharm. Sci. 62, 847-9 (1973)) and 43.2 9 ~0.1 mol) of polyphosphate ester (PPE, Fieser & Fieser, ~ ~3~33 Reagents for Ocganic Synthesis, New York 1967, page 892) are boiled un~er reflux in 250 ml of chloroform for 96 hours.
The reaction mixture is subsequently stirred with an excess of 2~ sodium hydroxide solution. The organic pAase is then separated, washed with a littl~ water, dri~d over sodium sulpha~e and concentrated by evaporation. Ethylene c-nloride is added to the residue, whereupon the desired 5-(4-methoxy-phenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2'~-pyrimido[1,2-c]-quinazoline precipitate~. It melts at 236 - 238 (fro ethylene chloride~.

Exam~e 39 17.52 g (0.1 mol) of 2-(2-aminophenyl)-1,4,5,6-tetra-hydro-pyrimidine, 18.32 g (0.1 mol) of phenyl 4-pyridyl ketone and 43.2 g (0.1 mol) of polyphosph~te ester are ~oile~ under reflux for 45 hours in 150 ml of chloroform while stirring and gently introducing nitrogen. After cool-ing the reaction mixture and adding 253 ml of 2~ sodium hydroxide solution and 200 ml of chloroform, the reaction mixture is stirred for a further 15 minutes at room tempera-ture, the chloroform phase is subse~uently separated and the aqueous phase is extracted another two times with 150 ml of chloroform each time. The combined organic phases, ~ashed with a little ~ater and dried over sodium sulphate, are con-centrated by evaporation and the oily residu~ is stirred with 100 ml of ethyl acetate, whereupon the desired 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimidotl,2-cl-~uinazoline precipitates which, after washing with ethyl acetate and ether, melts at 237 - 239. Ater an acldi-tional recrystallisation Erom ethanol/hexane, the product mel~s at 240 - 242.

17.52 ~ (0.1 mol) o~ 2-(2-~minophenyl)-1,~,5,6-tetrahydro-pyrimidine, 23.93 g (0.1 mol) o~ 4-(1,1-dlmethyl-ethyl)-phenyl 4-pyridyl ketone E~. Pharm. Sci. 62, 847-349 ~ 3 ~ 3 1 (1973)] and 43.2 g (0.1 mol) of polyphosphate ester are boiled under reflux in 250 ml of chloroform for 24 hours.
The reaction mixture is cooled and, while stirring vigor-ously, 260 ml of semi-concentrated (approx. 12.5 ~ in water) ammonia solution are added. After stirring for 15 minutes, the c~loroform phase is separated off, dried over sodium sulphate and concentrated by evaporation. The residue is filtered over silica gel having a particle size o~ 0.063 -0.200 m~ with a mixture of chloroform:methanol:concentrated ammonia = 40:10:1 and the fractions containing the desired product are concentrated by eva~oration. After recrystal-lisation from acetonitrile and methylene chloride/hexane the resulting 6-[4-(1,1-dimethylethyl)-phenyl]-6-14-pyridyl]-3,4,6,7-tetrahydro-2a-pyrimido[1,2-c]quinazoline ~elts at 142 - 145.

Example 41 600 ml of xylene are added to 70 g of silica gel H
according to Stahl (for example of E. ~erck AG, Darmstadt) and the mixture is heated, while stirring, in a ~ater separator until no more watet separates. The mixture is cooled, 17.52 g (0.1 mol) of 2-(2~aminophenyl)-1,4,5,6-tetrahydro-pyrimidine and 18.32 g (0.1 mol) of phenyl 4-pyridyl ketone are added and the reaction mixture is boiled in a water separator for 95 hours. After filtration and washing of the filtration residue with ether, the filter material is continuously extracted with chloroor~. The ~xtract is concentrated by evaporation and ethyl acetate is added to the resulting re~i~ue, whereupon 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H pyrimido~l,2-clquinazoline precipitates which melts at 241 - 243.

Example 42 Analogously to Exa~ple 41, but using toluene as solvent and heating the reaction mixture for 40 hours, s~arting from 17.52 g (0.1 mol) of 2-(2-aminophenyl)-~ ~ 7 ~

1,4,5,6-tetrahydro-pyrimidine and 21.77 g (0.1 mol) of 4-chlorophenyl 4-pyridyl ketone, 6-(4-chlorophenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline is obtained which, after recrystallisation from ethylene chloride and acetonitrile, melts at 215 ~ 217.

Example 43 Analogously to Example 41, but using toluene and heating for 72 hours, 8.76 g (0.05 mol) of 2-(2-amino-phenyl)-1,4,5,6-tetrahydro-pyrlmidine and 9.46 9 (0.05 mol) of 4-pyridyl 2-thienyl ketone (J. Med. Chem. 12, 1093-6 (1969~) are reacted. After filtration and washing of the filtee material with a solvent mixture of chloroform:
methanol = 1:1, the filtrate is concentrated by evaporation.
Ethyl acetate is added to the residue, whereupon crude 6-(4-pyridyl)-6-(2-thienyl)-3,4,6,7-tetrahydro-2H-pyrimido-[1,2-c]quinazoline precipitates which, after recrystallisa-tion from ethanol/hexane, melts at 208 - 21~.

Example 44 Analogously to Example 41, 17.52 g (0.1 mol) of 2-(2-aminophenyl)-1,4,5,5-tetrahydro-pyrimidine and 19.92 g (0.1 mol) of 4-hydroxyphenyl 4-pyridyl ketone are reacted using 500 ml of chlorobenzene as solvent. After ~iltration and washing of the silica gel with ether, the filter material is stirred three times, while heating, with 300 ml of a mixture oE chloroform:methanol = 1:1 each time and then filtered.
The combined filtrates are concentrated by avaporatioll and the residue is puri~ied by chromatography over silica gel with a mixture oE chloroform:methanol:concentrated ammonia =
40:10:1. The Eractions containing the desired product are combined and concentrated by evaporation. 'rhe crystalline residua is boiled in methanol, cooled and Eiltered. The resulting 6-(4-hydroxyphenyl)-6-~4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline hemihydrate melts at 287 - 289 (with decomposition).

, ' :3 173~3.1 ~ he starting compound~ 4-hydroxyphenyl 4-pyridyl ketone, is manufactured as follows:
A solution o~ 187.9 g (0.75 mol) o boron tribromide in 750 ml of methylene chloride is added dropwise at 5, while stirring, to a solution of S3.3 g (0.25 mol) of 4-methoxyphenyl 4-pyridyl ketone in 500 ml of methylene chloride. The reaction mixture is stirred at room tempera ture for 15 hours and su~sequently extracted with an excess of 2N sodium hydroxide solution. The alkaline phase is washed with chloroform and is subsequently rendered acidic (pH approx. 5) with glacial acetic acid. The precipitate that has formed is filtered off and the filter material is washed with isopropanol. After recrystallisation from dimethylformamidejwater, the resulting 4-hy~roxyphenyl 4-pyridyl ketone melts at 257 - 259. (cf. Heterocycles 2, 423-426 (1974)).

~xample 45 Analogously to Example 19, 12.75 9 (0.0375 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido~1,2-c~-quinazoline, 2.19 g (0.05 mol) of sodium hydride dispersion (55 % in oil) and 7.1 g (0.05 mol) of methyl iodide are reacted in 110 ml of dimethylformamide. Stirring is, how-ever, carried out for 12 hours at room temperature, 10 ml of water are then added dropwise to the reaction mixture, while cooling, the reaction mixture is concentrated by evaporation in VACUo and the residue is partitioned between chloroform and 15 ~ sodium hydroxide solution. The organic phase, wash~d with water and dried over sodium sulph~te, is concen-trat~d by evaporation ~nd the residue is chromatographed over silica gal with a mix~ure of chloroform:meth~nol:con-cantrated ammonia ~ 40:10:1. The ~ractions containing the desired product are concentrated by evaporation and the residue is recrystallised from chloroform/ether. The resulting ~-phenyl-6-(4-pyridyl)-7-methyl-3,4,6,7-tetrahydro-2H-pyrimido[1,2~clquinazoline melts at 183 - 184.

.

-` ~ 17383~

Exam~e 46 Analogously to Example 12, using equivalent amounts of 5-propyl-5-~4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]-quinazoline and ethanolic hydrogen chloride solution, the corresponding hydrochloride is obtained ~hich, after recry-stallisation from ethanol/ether, melts at 278 - 280.
Analogously, when an eql~ivalent amount of fumaric acid is used, 5-propyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-i~idazo-[1,2-clquinazoline fumarate having a melting point of 215 -217 (with decomposition~ is obtained.

Example 47 34.04 g (0.1 mol) of 6-phenyl-6-~4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimidoll,2-c]quinazoline is dissolved, while heati~g, in 390 ml of ethanol and then, while cooling, a solution of 10022 g of 96 ~ sulphuric acid (0.1 mol~ in 19.5 g of water is added. The sulphate which precipitates on cooling melts, after recrystallisation from ethanol/methanol - 1:3 and drying at 150 in a high vacuum, at 321 - 322 (with decomposition).
Recrystallisation of the above sulphate from water yields, after drying at 160 in a high vacuu~, a sulphate (crystal modification) that melts at 278 - 280. This can be re-converted by renewed recrystallisation from methanol/
ether into the sulphate that melts at 321 - 322.

Example 48 a) 3.33 ml of 15N sulphuric acid (0.025 mol) are added to a gently boiling solution o 17.02 g (O.OS mol) of 6-phenyl-6~4-pycidyl)-3,4~6,7-tetrahydro-2H-pyrimido~1,2-c]-quinazoline in 150 ml of ethanol. After the addition oE
active carbon and subsequent filtration, 100 ml of ether are added dropwise, while stirring, to the filtrate. ~he mixture i9 allowed to cool slowly to approximately 5, and the precipitated salt is filtered oEf and wa,hed with a ~ixture ~1~3~31 of ethanol:ether - 1:1. After drying over sodium hydroxide in a high vacuu~ at 160, the resulting bis-[6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazolinel sulphate monohydrate melts at 300 - 303.
b) A solution of 2.55 g of 96 % sul~huric acid ~0.025 mol) in 10 ml of water is added, while stirring, to a sus-pension of 17.02 g (0.05 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[1,2-c]quinazoline in 30 ml of water. The resulting solution having a temperature of approximately 40 i9 filtered. The filtrate is allowed to cool slowly to 0 in the course of 4 hours and th~ product that has precipitated is filtered off. The mother liquor is concentrated ln vacuo and, after cooling and filtration, a further batch of product is obtained. After drying the combined batches at room temperature, the bis-[6-phenyl-~-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline]-sulphate has a water content of 11.63 ~ and melts at 235 -240. (Samples having a water content of 8.7 % and 7O6 likewise melt at 235 - 240).

Example 49 1.7 g (0.005 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido[1,2-c]quinazoline and 0.79 g (0.005 mol) of benzenesulphonic acid are heated to 100 in 280 ml of water. The mixture is then filtered and the filtrate is allowed to cool to 5. The product that precipitates during cooling is filtered off, washed with water and dried. Tha resulting benzenesulphonate monohydrate decomposes at 164 - 166.

Exam~e 50 A solution oi 3.05 9 (0.025 mol) of benzoic acid in 10 ml of ethanol is added to a boiling solution o a . 51 g ~0.025 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2r]-pyrimido~l,2-c]quinazoline in 70 ml of ethanol. After the a~dition of 120 ml of ethar and cooling to 5 the preci-:' ' ~' . .. :

,: . ' .

-~ 173~31 Qitated product is filtered off, washed with a mixture of ethanol:ether = 2:3 ~nd then dried. The resulting benzoate melts at 241 - 243.

Example Sl 3.40 g (0.01 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2~-pyrimido~1,2-c~quinazoline are heated in a solution of 0.72 g ~0.012 mol) of acetic acid in S ml of water. After cooling the solution in an ice bath, the pre-cipitated product is filtered off, washed with a little ice-cold water and dried. The resulting acetate dihydrate melts at approximatel~ 132-137 (with sintering from 120).

Exam~le 52 Analogously to Example 12, usiny 3.40 g (0.01 mol) of 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2B-pyrimido[1,2-c}-quinazoline and 1.16 9 (0.01 ~ol) of fumaric acid, the cor-responding fumarate is obtained which, after recrystallisa-tion fro.m methanol, decomposes at a~proximately 230.
This salt still contains 2.9 ~ of water.
~ pon recrystallisation from water, 6-phenyl-~-(4-pyridyl)-3,4,6,7-tetrahydro-2~3-pyrimido[1,2-c~quina%oline-l~-fumarate is obtained which decomposes at 232 - 235.

Example 53 L~ mixture of 9.1 g (0.056 mol) of 2-amino-3-(4,5-dihydro-l~-imidazol-2-yl)-pyridine, 12.5 g (0.08~ mol) of propyl 4~pyridyl ketone and 70 g oE polyphosphoric ~cid is stirred at 150 for 18 hours. Ater working up analogously to Example 26, the resulting crude product is purified by filtration over silica gel with a solvent mix~ure of chloroform:methanol - 9:1. The fractions containing the desired product are concentrated by evaporation and the residue is recrystallised from ethyl acetate. The resulting 5-propyl~5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c~pyridol3,2-e]2yrimidine melts at ' . .
.

~73~3.

182 - 183.5.
Analogously, using 9.16 g (0.05 mol) of phenyl 4-pyridyl ketone, but with a reaction period of 24 hours at 140C and subsequently 24 hours at 180C, 5-phenyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]pyrido[3,2-e]-pyrimidine is obtained which, after recrystallisation from ethyl acetate/hexane, melts at 240 - 241. The hydro-chloride, prepared with hydrochloric acid in water, melts at 312 - 314 (water content 1.2 %).
The 2-amino-3-(4,5-dihydro-lH-imida2O1-2-yl)-pyridine used as starting material is manufactured as ~ollows:
A mixture of 23.8 g (0.2 mol) of 2-amino-3-pyridine-carbonitrile EJ. Heterocyclic Chem. 15, 877-~80 (1975)], 24 g (0.4 mol) of ethylenediamine and 6 drops of carbon disulphide is stirred for 2 hours at 150 and then concen-trated by evaporation ln vacuo. The crystalline residue is taken up in 200 ml of ice-cold ether. After filtration of the ether solution, the crude product obtained therefrom is recrystallised from hexane and ethanol/ether. The resulting 2-amino-3-(~,5-dihydro-lH-imidazol-2-yl)-pyridine ~elts at 155 - 157.

Example 54 A mixture of 14.08 g ~0.08 mol) of 4-amino-3-(1,4,5,6-tetrahydro-2-pyrimidinyl)-pyridine, 17.53 9 (0.096 mol) of phenyl 4-pyridyl ketone and 240 g of polyphosphoric acid is heated, while stirring, for 43 hours at 170, 17 hours at 180 and 24 hours at 200. The reaction mixture is cooled, ice-water and an exc~ss of 30 ~ sodium hydroxide solution are adcled thereto, the reaction mixture is extracted with chloroform and the organic phase is concentrated by evaporation ln vacuo after being dried over sodium sulphate. For purification, the residue is chromatographed ov~r silica gel with a solvent mixture of chloroform:methanol:concentrated ammonia = 40:10:1. The ractions containing the desired product are concentrated by ~ ~ ~3~

evaporation and the residue is recrystallised from ethanol/
ethyl acetate/ether. The resulting 5-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrido[3,4-e]pyrimido[1,2-c~pyrimidine melts at 199 - 201 (water content: 3 ~).
The starting compound, 4-amino-3-~1,4,5,6-tetrahydro-2-pyrimidinyl)-pyridine, is manufactured as follows:
A mixture of 35.7 g ~0.3 mol) of 4-amino-3-pyridine-carbonitrile (US-PS 3 517 021), 44.5 g (95 mol) o~ propylene-diamine and approximately 10 drops oE carbon disulphide is stirred Eor 20 houes at 140. After concentration of the reaction mixture oy evaporation in vacuo, the residue is recrystallised from ethanol. The resulting 4-amino-3 (1,4,5,6-tetrahydro-2-pyrimidinyl)-pyridine melts at 208 - 210.

Example 55 A mixture of 8.1 g (0.05 mol) of 4-amino-3-t4,5-dihydro-lH-imidazol-2-yl)-pyridine, 11.2 g (0.075 mol) of propyl 4-pyridyl ketone and 150 g of polyphosphoric acid is stirred for 30 ~ours at 150, a further 5.6 9 of propyl 4-pyridyl ketone are added and the mixture is stirred for a further 16 ~ours at 150. After working up analogously to Example 26, the desired 5-propyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidine ls obtained which, after recrystallisation from ethyl acetate, melts at 238 - 240.
The starting compound, 4-amino-3-(4,5-dihydro-lH-imidazol-2-yl)-pyridine, is obtained as follows:
A mixture of 23.8 g (0.2 mol) of 4-amino-3-pyridine-carbonitrile, 24 g (0.4 mol) of ethylenediamine and approxi-mately 8 drops of carbon disulphide is stirred for 1.5 hours at 120. A furth~r 15 ml of ethylenediamine are added to the reaction mixture, it is heated ~or a furthec ~ hours at 120 and then concentrated by evaporation in vacuo. After recry.stallisation from ethanol, the resulting 4-amino-3-~4,5-dihydro lM-imida~ol-2-yl)-pyrimidine melts at L98 - 199.

~ 173~3:l Example 56 8.75 g (0.05 mol) of 2-~2-aminophenyl)-1,4,5,6-tetra-hydro-pyrimidine and 10.4 9 (0.05 mol) oE phenyl styryl ketone (2-benzylideneacetophenone) are added to a solution of 21.7 g of polyphosphate ester in 75 ml of chloroform and the reaction mixture }s boiled under reflux for 16 hours.
The oily residue obtaine~ after working up analogously to Example 39 is chromatographed over silica gel with a solvent mixture of chloroform:methanol:conc~ntrated aqueous ammonia solution = 70:30:5. The fractions containing the desired product are concentrated by evaporation and the residue is recrystallised from acetonitrile. The 6-phenyl-6-styryl-3,4,6,7-tetrahydro-2~-pyrimido~1,2-c]quinazoline so obtained melts at 143 - 145 after drying in a high vacuum at 100.

Example 57 -50 ml of l-n. hydrochloric acid are added while stirring to a suspension of 17.0~ (O,05 mol) of 6-phenyl-6-(4-pyridyl~-3,4,6,7-tetrahydro-2H-pyrimido[1,2-c]quinazoline in lOO ml of water. The suspension is brought to the boil and water is added until a solution is formed. The latter is filtered after addition of charcoal, and the filtrate is concentrated until crystallisation begins. After cooling to 5, the salt is filtered off and washed with a small amount of ice-cold water.
~he 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido-~1,2-c]quinazollne hydrochloride dlhydrate so obtained de-composes a-t 345 to 347a.

Claims (33)

Patent Claims

1. Process for the manufacture of polyazaheterocyclic compounds of the general formula I

(I), in which Rl and R2 represent, independently of each other, lower aliphatic hydrocarbon radicals optionally sub-stituted by lower alkoxy, lower alkylthio or lower alkoxycarbonyl, aryl or heteroaryl each having not more than 2 rings optionally substi-tuted by lower alkyl, lower alkoxy, lower alkyl-thio, halogen having an atomic number of not more than 35, trifluoromethyl, methylenedioxy, hydroxy, sulphamoyl, nitro or by amino optionally mono-or di-substituted by lower alkyl or amino substi-tuted by lower alkylene or 3-oxa-1,5-lower alkylene, and each being bonded directly or by way of lower alkylene or lower alkenylene, R3 represents hydrogen or lower alkyl, and A represents optionally branched lower alkylene or lower alkenylene having 2 to 4 carbon atoms in a direct chain between the adjacent nitrogen atoms, and Z1, Z2, Z3 and Z4 are members of the ring B, which is unsub-tituted or substituted in the manner stated above for aryl Rl and R2, and represent radicals -CH=
carrying the substituents of ring B, if such are present, one of which members can however also be the radical -N=, wherein Rl and R2 do not both represent methyl or both represent ethyl if R3 represents hydrogen and A represents ethenylene and, at the same time, the ring B is unsubstituted, and their acid addition salts, characterised in that a com-pound of the general formula II

(II) in which R3, Z1, Z2, Z3, Z4 and A have the meanings given above and the ring B, as stated there, can be substituted, or an acid addition salt of the same, is condensed with a ketone of the general formula III
Rl - CO - R2 (III) in which R1 and R2 have the meanings given above, or a re-active functional derivative of the same, if required lower alkyl is introduced as a radical R3 into a compound of the general formula I in which R3 represents hydrogen, and/or a resulting compound of the general formula I is converted into an acid addition salt, or the compound of the general formula I is liberated from a resulting acid addition salt.

2, A process according to claim 1, characterised in that Rl and R2 represent radicals corresponding to the defini-tion given in claim 1 which are unsubstituted or, as lower aliphatic hydrocarbon radical , are mono- or poly--substi-tuted by lower alkoxy, lower alkylthio or lower alkoxy-carbonyl or, as aryl or heteroaryl radicals each having not more than 2 rings, are mono- or polysubstituted by lower alkyl, lower alkoxy, lower alkylthio, halogen having an atomic number of not more than 35, trifluoromethyl, methylenedioxy, hydroxy, sulphamoyl, nitro or by amino optionally mono- or di-substituted by lower alkyl or amino substituted by lower alkylene or 3-oxa-1,5-lower alkylene, and together and including the optionally present substituents have from 3 to 20 carbon atoms, R3 represents hydrogen or lower alkyl having not more than 4 carbon atoms and A represents unsubstituted ethylene, trimethylene, ethenylene, propylene or tetramethylene, or ethylene, trimethylene, ethenylene, propenylene or tetramethylene substituted by lower alkyl, wherein substituted ethylene and trimethylene have a total of not more than 4 and 5 carbon atoms, respectively, the radicals Z1, Z2, Z3 and Z4 have the meanings given under formula I, and the ring is unsubstituted or can be substituted in the manner stated above for aryl Rl and R2.

3. A process according to claim 1, characterised in that Rl represents monoheterocyclic monocyclic heteroaryl which is unsubstituted or substituted by lower alkyl, lower alkoxy and/or halogen having an atomic number of up to 35 and is bonded by way of methylene or directly, R2 represents just such a radical or represents unsubstituted phenyl or phenyl substituted as stated above for monocyclic heteroaryl R1, or unsubstituted lower alkyl or lower alkyl mono- or poly-substituted by lower alkoxy, lower alkylthio or lower alkoxy carbonyl, R3 represents hydrogen or alkyl having not more than 4 carbon atoms, and A represents ethylene or trimethylene, the radicals Zl, Z2, Z3 and Z4 have the meanings given in claim 1 and the ring B is unsubstituted or substituted in the manner stated above for Rl.

4. A process according to claim 1, characterised in that Rl represents unsubstituted pyridyl or pyridyl substituted by lower alkyl, lower alkoxy and/or halogen having an atomic number of up to 35, which is bonded directly or by way of methylene, or represents unsubstituted or correspondingly substituted thienyl or furyl, R2 represents just such a radical. or unsubstituted phenyl or phenyl substituted as stated above for pyridyl Rl, or lower alkyl or lower alkoxycarbonyl-lower alkyl, R3 represents hydrogen or alkyl having not more than 4 carbon atoms, and A represents ethylene or trimethylene, the radicals Zl' Z2' Z3 and Z4 have the meanings given in claim 1 and the ring B is unsubstituted or substituted in the manner stated above for Rl.

5. A process according to claim 1, characterised in that Rl represents unsubstituted pyridyl or pyridyl substituted by lower alkyl, or thienyl, R2 represents just such a radical or unsubstituted phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen having an atomic number of up to 35, or lower alkyl or lower alkoxycarbonyl-lower alkyl, R3 represents hydrogen or lower alkyl, A represents ethylene or trimethylene and Zl, Z2, Z3 and Z4 represent radicals -CH=, of which Z2 can be substituted by halogen having an atomic number of up to 35, and, hence the ring B is unsubstituted or correspondingly substituted.

6. A process according to claim 1, characterised in that Rl represents unsubstituted pyridyl or pyridyl substituted by methyl, or 2-thienyl, R2 represents just such a radical or unsubstituted phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen having an atomic number of up to 35, or lower alkyl or lower alkoxycarbonylmethyl, R3 represents hydrogen, methyl or ethyl, A represents ethylene or trimethylene, and Zl, Z2, Z3 and Z4 represent radicals -CH=, of which Z2 can be substituted by chlorine and, hence J the ring B is unsubstituted or correspondingly substituted.

7. A process according to claim 1, characterised in that Rl represents unsubstituted pyridyl or pyridyl substituted by methyl, or 2-thienyl, R2 represents just such a radical or unsubstituted phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen having an atomic number of up to 35, or lower alkyl or lower alkoxycarbonylmethyl, R3 represents hydrogen, methyl or ethyl, A represents ethylene, and Z1, Z2, Z3 and Z4 represent radicals -CH=, of which Z2 can be substituted by chlorine and, hence, the ring B is unsubstituted or correspondingly substituted.

8. A process according to claim 1, characterised in that Rl represents unsubstituted pyridyl or pyridyl substituted by methyl, or 2-thienyl, R2 represents just such a radical or unsubstituted phenyl or phenyl substituted by lower alkyl, lower alkoxy or halogen having an atomic number of up to 35, or lower alkyl or lower alkoxycarbonylmethyl, R3 re-presents hydrogen, methyl or ethyl, A represents trimethyl-ene, and Z1, Z2, Z3 and Z4 represent radicals -CH=, of which Z2 can be substituted by chlorine, and hence, the ring B is unsubstituted or correspondingly substituted.

9. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Z1, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, Rl is methyl and R2 is 4-pyridyl so as to pro-duce the 5-methyl-5-(4-pyridyl)-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline or a pharmaceutically acceptable acid addition salt thereof.

10. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, R1 is methyl and R2 is 6-methyl-2-pyridyl so as to produce the 5-methyl-5-(6-methyl-2-pyridyl)-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

11. A process according to claim 1, characterised in that starting materials of the formulae II and III are used wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, R1 is butyl and R2 is 4-pyridyl, so as to pro-duce the 5-butyl-5-(4-pyridyl)-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline or a pharmaceutically acceptable acid addition salt thereof.

12. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Z1, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, Rl is propyl and R2 is 4-pyridyl, so as to produce the 5-propyl-5-(4-pyridyl)-2,3,5,6-tetrahydroimid-azo[l,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

13. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Z1, Z3 and Z4 are each -CH=, Z2 is -CC1=, R3 is hydrogen, A is ethylene, Rl is methyl and R2 is 2-pyridyl, so as to produce the 5-methyl-5-(2-pyridyl)-8-chloro-2,3,5,6-tetrahydroimidazo[1,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

14. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Z1, Z2. Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, Rl is phenyl and R2 is 4-pyrldyl, so as to produce the 5-phenyl-5-(4-pyridyl)-2,3,5,6-tetrahydro-imidazo-[1,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

15. A process according to claim 1, characterised in that starting materials of the formulae II and III are used, wherein Z1, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is ethylene, Rl is ethoxycarbonylmethyl and R2 is 4-pyridyl, so as to produce the 5-(4-pyridyl)-2,3,5,6-tetrahydro-imid-azo[l,2-c]-quinazoline-5-acetic acid ethyl ester or a pharmaceutically acceptable acid addition salt thereof.

16. A process according to claim l, characterised in that starting materials of the formulae II and III are used, wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
propylene, R1 is phenyl and R2 is 4-pyridyl, so as to pro-duce the 6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyr-imido[l,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

17. A process according to claim l, characterised in that starting materials of the formulae II and III are used, wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is propylene, Rl is phenyl and R2 is 2-pyridyl, so as to produce the 6-phenyl-6-(2-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[l,2-c]quinazoline or a pharmaceutically acceptable acid addition salt thereof.

18. A process according to claim l, characterised in that starting materials of the formulae II and III are used, wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is propylene, Rl is 4-methylphenyl and R2 is 4-pyridyl, so as to produce the 6-(4-methylphenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido-[1,2-c]quinazoline or a pharmaceuti-cally acceptable acid addition salts thereof.

19. A process according to claim l, characterised in that starting materials of the formulae II and III are used, wherein Zl, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is propylene, Rl is 4-chlorophenyl and R2 is 4-pyridyl, so as to produce the 6-(4-chlorophenyl)-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido [1,2-c)quinazoline or a pharmaceutlcally acceptable acid addition salt thereof.

- 54a -

20. A process according to claim 1, characterised in that starting materials of the formulae II and III are used wherein Z1, Z2, Z3 and Z4 are each -CH=, R3 is hydrogen, A
is propylene, Rl is 2-thienyl and R2 is 4-pyridyl, so as to produce the 6-(4-pyridyl)-6-(2-thienyl)-3-4,6,7 tetrahydro-2H-pyrimido[1,2-c]quinazoline or a pharmaceutically accept-able acid addition salt thereof.

21. A process according to claim 1, characterised in that a compound of the formula I is used, wherein Zl, Z2, Z3 and Z4 are each -CH=X, R3 is hydrogen, A is propylene, Rl is phenyl and R2 is 4-pyridyl, so as to produce the 7-ethyl-6-phenyl-6-(4-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido[1,2-cl-quinazoline or a pharmaceutically acceptable acid addition salt thereof.

22. Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Zl, Z2, Z3 and Z4 have the meanings defined there, and the ring B is unsubstituted or substituted and the acid addition salts thereof, whenever prepared by a process as claimed in claim 1, or by an obvious chemical equivalent thereof.

23. Compounds of the general formula I given in claim 1, wherein Rl, R2, R3, A, Zl, Z2, Z3 and Z4 have the meanings defined in claim 2, and the ring B is unsubstituted or substituted as defined in claim 2, and the acid addition salts thereof, whenever prepared by a process as claimed in claim Z, or by an obvious chemical equivalent thereof.

24. Compounds of the general formula I given in claim 1, wherein Rl, R2, R3, A Z1, Z2, Z3 and Z4 have the meanings defined in claim 3, and the ring B is unsubstituted or sub-stituted as defined in claim 3, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 3, or by an obvious chemical equivalent thereof.

25. Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Z1, Z2, Z3 and Z4 have the meanings defined in claim 4, and the ring B is unsubstituted or sub-stituted as defined in claim 4, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 4, or by an obvious chemical equivalent thereof.

26. Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Zl, Z2, Z3 and Z4 have the meanings defined in claim 5, and the ring B is unsubstituted or sub-stituted as defined in claim 5, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 5, or by an obvious chemical equivalent thereof.

27. Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Zl,Z2, Z3 and Z4 have the meanings defined in claim 6, and the ring B is unsubstituted or substituted as defined in claim 6, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 6, or by an obvious chemical equivalent thereof.

28. Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Z1,Z2, Z3 and Z4 have the meanings defined in claim 7, and the ring B is unsubstituted or substituted as defined in claim 7, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 7, or by an obvious chemical equivalent thereof.

29, Compounds of the general formula I given in claim 1, wherein R1, R2, R3, A, Zl,Z2, Z3 and Z4 have the meanings defined in claim 8 and the ring B is unsubstituted or sub-stituted as defined in claim 8, and the acid addition salts thereof, whenever prepared by a process as claimed in claim 8, or by an obvious chemical equivalent thereof.

30. 5-Propyl-5-(4-pyridyl)-2,3,5,6-tetrahydroimidazo-[l,2-c]quinazoline and its pharmaceutically acceptable acid addition salts, whenever prepared by a process as claimed in claim 12, or by an obvious chemical equivalent thereof.

31. 5-(4-Pyridyl)-2,3,5,6-tetrahydro-imidazo[1,2-c]-quinazoline-5-acetic acid ethyl ester and its pharmaceutically acceptable acid addition salts, whenever prepared by a process as claimed in claim 15, or by an obvious chemical equivalent thereof.

32. 6-Phenyl-6-(2-pyridyl)-3,4,6,7-tetrahydro-2H-pyrimido-[1,2-c]quinazoline and its pharmaceutically acceptable acid addition salts, whenever prepared by a process as claimed in claim 17, or by an obvious chemical equivalent thereof.

33. A process according to claim 5 wherein the halogen substituent in Z2 is chlorine.