DD201594A5 - PROCESS FOR THE PREPARATION OF NEW POLYAZAHETEROCYCLIC COMPOUNDS - Google Patents

Abstract

The present invention relates to a process for the preparation of novel polyazaheterocyclic compounds of the general formula I in which R ind 1 and R ind 2 independently represent optionally substituted, lower aliphatic hydrocarbon radicals, optionally substituted, directly or via lower alkylene or lower alkenylene bonded aryl or heteroaryl with at most two rings, R ind 3 is hydrogen or lower alkyl and A is optionally branched lower alkylene or lower alkenylene having 2 to 4 carbon atoms in the direct chain between the adjacent nitrogen atoms and Z ind 1, Z ind 2, Z ind 3 and Z ind 4 members of the unsubstituted or substituted Ringes B are and radicals -CH =, which carry the substituents of the ring B, if any, instead of one -CH = can also mean the radical -N =, where R ind 1 and R ind 2 are not both methyl or both mean ethyl when R ind 3 is hydrogen and A is Aethenylen and at the same time the ring B is substituted, and their acid addition salts. The compounds of the general formula I have diuretic and antihypertensive activity, which is particularly pronounced in those compounds in whose radical A there are 3 or 4 carbon atoms in direct chain between the adjacent nitrogen atoms. Compounds of the general formula I, in whose radical A 2 carbon atoms are in direct chain between the adjacent nitrogen atoms, are in particular antidiabetic active. formula

Description

232590 5 Berlin, 6.1.1982

AP G 07 D / 232 590/0 (59 596/11)

Process for the preparation of novel polyazaheterocyclic compounds

Field of application of the invention ;

The present invention relates to a process for the preparation of novel polyazaheterocyclic compounds and their acid addition salts, in particular the pharmaceutically acceptable acid addition salts with valuable pharmacological properties, in particular diuretic action. The compounds according to the invention are used as medicaments, in particular as diuretics and antidiuretic drugs.

Characteristic of the known technical solutions

Similar compounds are known which, instead of two substituents R 1 and R _{2, have} only one, such as, for example, 3-p-chlorophenyl and, next to this, hydrogen. They have adrenomimetic properties. Such compounds are the subject of patents by Dr. Ing. Wander 0. G. »Bern with priority of 16.8.1963, see Chemical Abstracts 63, 2984 b and 73617 ζ as well as US-PS 3-309 369.

Furthermore, Chemical Abstracts 70, 76408 e (1968) and 74, 3634 m (1971) describes as a similar compound 5- (p-chlorophenyl) 2,3,5,6-tetrahydroimidazo (1,2-c) quinazoline. «

Furthermore, in H Farmaeo, Ed. Sc. 30 (7), 536-546 (1976) corresponding to Chemical Abstracts 83, 188 196 j, among other compounds, 5,5-dimethyl- and 5,5-diethyl-5,6-dihydro-imidazo (1,2-c) quinazoline described. there

JZ) KJ IJ & AP G 07 L / 232 590/0

6.1.1982 AP G 07 (59 596/11)

is given in terms of their properties that they have no Blatplättchenaggregationshemmende effectiveness »

However, chemically closely related compounds with pharmacological properties similar to those indicated in the present application are not known.

Target of the BrfLadung

The aim of the invention is the provision of better tolerated, in particular potassium neutral biuretics with simultaneous uricosuric efficacy, so v / i 8 of well tolerated widely applicable antidiabetic ·

presentation; the essence of the invention

The invention has for its object to find new compounds with the desired properties and processes for their preparation.

23 2 59 0 5 --T ⁶ · ¹ · ¹⁹⁸²

⁰ AP C 07 D / 232 590/0 (59 596/11)

According to the invention, compounds of the general formula I

YY A

I ³ BIi U ^R 1 (D,

prepared "in v / hich H., H ₂ aad cuiabjaängig one another, optionally substituted, lower aliphatic ^ hydrocarbon radicals, optionally substituted, directly or via ITiederalkylen or Siederalk s ;? 1 is aryl or heteroaryl bonded with at most two rings, R 1 is hydrogen or lower alkyl and A is optionally branched C 2-3 -alkylene or lower-alkenylene having 2 to 4 carbon atoms in direct chain between the adjacent nitrogen atoms and Z-, Z ₂ , Z-, and Z. are members of the unsubstituted or substituted ring B, and radicals -GH =, which carry the substituents of the ring B, if any, one instead of -CH = but may also represent the radical -3J =, where and "R _{2 is} not both methyl or both ethyl when R ^ is hydrogen and A Äthenylen mean and at the same time the ring B is unsubstituted.

232590 5

In the compounds of the general formula I above and below, unless stated otherwise, lower radicals than mentioned contain at most 7 and preferably at most 4 carbon atoms.

As lower aliphatic hydrocarbon radicals R and / or R are lower alkyl, lower alkenyl or lower alkynyl. Niaderaikyl R and / or R "is, for example, petyl, isopentyl, neopentyl, hexyl, isohexyl or heptyl, and preferably methyl, ethyl, propyl, isopropyl ,. Butyl or isobutyl. R and R_ of this meaning together preferably contain at least 3 carbon atoms. Substituents of lower alkyl R and / or R_ are, for example, niaderalkoxy or lower alkylthio, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or isobutoxy, or methylthio, ethylthio, propylthio, isopropylthio or butylthio in any desired, but preferably in the 2-position or higher position lower alkyl, or N-lower alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl / 1 or 3-butoxycarbonyl, in any position, but preferably in the 1-position of the lower alkyl. As lower alkenyl is R, and / or R- z.3. Vinyl, 1-propenyl, allyl, 1-3utenyl, 2-methyl-1-propenyl, 2-3 -utenyl, 2-methylallyl, 1-pentenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3, 3-dimethyl-1-butenyl, 1-hexenyl or 1-heptenyl and as lower alkynyl, for example 2-propynyl or 2-butynyl, which may also be substituted in the manner indicated above for lower alkyl.

As the aryl or heteroaryl group having at most two rings, R is, for example, phenyl, 1- or 2-naphthyl, 5-membered heteroaryl, e.g. Furyl, such as 2- or 3-furyl, thienyl, such as 2- or 3-thienyl, pyrrolyl, such as? Rrol-2-yl or 3-yl, pyrazolyl, such as? Yrazol-3-yl,

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4-yl or 5-yl, isoxazolyl such as 3-, 4- or 5-isoxazolyl, isothiazolyl; such as 3-, 4- or 5-isothiazolyl, oxazolyl such as 2-, 4- or 5-oxazolyl, thiazolyl such as 2-, 4- or 5-thiazolyl, 6-membered diaza-heteroaryl e.g. Pyridazinyl, pyrimidinyl, such as 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, benzoheteroaryl, e.g. Indolyl, 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; Chianzolinyl, like. 2-, 4- or _ar-quinazolinyl 1, or in particular pyridyl, such as 2-, 3- and especially 4-pyridyl. All of these radicals can be either via lower alkylene, e.g. Propylene, trimethylene, tetramethylene, 1-methyl or 2-methyltrimethylene or especially ethylene or ethylene, further via lower alkenylene, such as propenylene, 1-methyläthenylen and especially Aethenylen (vinylene), and in particular be directly bonded.

Suitable substituents of aryl or heteroaryl R and / or R are, for example, arylalkyl, 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, in particular such having an atomic number of at most 35, i. Fluorine, bromine and in particular chlorine, trifluoromethyl, methylenedioxy, hydroxy, sulfamoyl, nitro or optionally mono- or disubstituted by lower alkyl or by lower alkylene or 3-oxa-l, 5-lower alkylene-substituted amino, such as methyl, ethyl, propyl, Isopropyl, butyl or Isobutylamino, dimethyl or Diäthylamino or 1-pyrrolidinyl, piperidino or morpholino, into consideration. Such substituents may be monosubstituted or polysubstituted, preferably at most trisubstituted, and may be the same or different among each other, but hydroxy and optionally substituted amino may be at most twice, and preferably methylthioxy, at most once, lower alkylthio and trifluoromethyl at most twice and remaining substituents may preferably be represented at most three times.

R is lower alkyl, for example, propyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, heptyl and especially methyl or ethyl.

As optionally branched lower alkylene. or lower alkenylene having two carbon atoms in direct chain between the two nitrogen atoms is A, e.g. Propylene (1-methylethylene), 1,1-dimethylethylene, 1,2-dimethylethylene, - 1-Aethyläthylen and especially ethylene, - or 1-methyläthenylen, 1,2-dimethyläthenylen and especially Aethenylen (vinylene). Definite radicals A with three carbon atoms between the two nitrogen atoms are e.g. 1-methyl- or 2-methyltrimethylene, 1,2-dimethyl- or 1,3-dimethyltrimethylene, 1,1- or 2,2-dimethyltrimethylane, 2- or 3-methyl-propenylene, 2,3- or 3,3 -Dimethylpropenylen and especially trimethylene or propenylene and defined radicals A having 4 carbon atoms between the two nitrogen atoms are z.3. 1- or 2-methyltetramethylene, 1,1- or 2,2-Diinethyltetramethylen, 1,4- or 2,3-Diinethyltetramethylen, 1,1- or 2,3-dimethyl-2-butenylene, and especially tetramethylene or 2- Bucenylene.

As substituents of the ring B or of its ring members Z, to Z _f as -CH = may be the same as in the aryl or heteroaryl R ₁ , substantially in the same number, wherein in addition to the unsubstituted ring B in particular by lower alkyl ·, especially Methyl, by lower alkoxy, especially methoxy, and / or halogen to atomic number 35, especially chlorine, up to trisubstituted, but especially monosubstituted rings B and further by other of the substituents monosubstituted for aryl or heteroaryl R monosubstituierta rings 3 particularly considered come.

As acid addition salts, in particular pharmaceutically acceptable acid addition salts of the compounds of general formula I, for example, those with suitable inorganic acids, such as hydrohalic acids, e.g. Hydrochloric acid or hydrobromic acid, furthermore nitric acid, sulfuric acid or phosphoric acid.

32590 5

-y- τ

phosphoric acid, or with suitable organic acids, such as organic carboxylic acids, i.a. optionally hydroxy-containing lower alkane or lower alkene carboxylic acids, z.3. Acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid or citric acid, or aryl-, aryl-lower-alkane-, aryl-lower-alkene- or heterocyclylcarboxylic acids, 2.3. Benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-amino-salicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, or organic sulfonic acids, such as hydroxy-containing niaderalcanesulfonic acids. Z.3. Methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid or ethane-1,2-disulfonic acid, or arylsulfonic acids, e.g. Benzo 1-sulfonic acid, 4-methyl-benzenesulfonic acid or naphthalene-2-sulfonic acid, or other acidic substances, such as ascorbic acid, in question. In accordance with the close relationship between the free bases and their acid addition salts, as far as appropriate, information concerning free acidases also refers to acid addition salts and conversely to acid addition salts also to free bases.

The new polyazaheterocyclic compounds of the general formula 1 and their addition salts with inorganic and organic acids have valuable pharmacological properties. In particular, they act diuretically and natriuretically on the rats in the dose range of 10 to 1000 mg / kg per os and in the dog in the dose range of 5 to 50 mg / kg per os, as by collecting the urine for 3 hours after administration (rat). or hourly for 5 hours after administration (dog) and determination of urine volume and sodium, potassium and chloride ions. In this case, the compounds of formula I are characterized by a lack of influence on the potassium excretion, also highlighting the good compatibility. Particularly pronounced is the diuretic activity in those compounds of general formula I in which Ά optionally branched lower alkylene having 4 or in particular 3 carbon atoms in direct chain between the adjacent nitrogen atoms, which tri all

232590 5

methylene means. Accordingly, the compounds of general formula I, in particular those of the aforementioned type, and their pharmaceutically acceptable acid addition salts can be used as potassium-neutral diuretics and antihypertensives.

Those compounds of the general formula I in which the radical A has two carbon atoms in direct chain between the two nitrogen atoms also have hypoglycemic activity, as in metabolism-normal rats after oral administration of doses from 3 mg / kg and also to rats , which have been converted into a diabetes-like metabolic state by injection of streptozotocin [cf., J. Junod et al., Proc. Soc. Exp. Biol.Med. _L26 ,. 201-205 (1967)]. In contrast, their diuretic efficacy is less pronounced. Lower blood sugar levels are not accompanied by hyperlactatemia nor, in normal fed rats, an increase in plasma insulin. The pharmacological findings characterize those compounds of general formula I and their pharmaceutically acceptable acid addition salts as antidiabetics which can be used for the oral treatment of hyperglycemia in mammals, in particular diabetes mellitus.

The compounds of general formula I also have antiphlogistic and antinocieptive activity, which can be detected by oral administration in the kaolin edema test on the rat paw and in the writhing syndrome test in the mouse, respectively. They also act lipid lowering, e.g. in the male rat, once administered 50 mg / kg each on three consecutive days and twice 50 mg / kg on the fourth day in the fifth day serum on the lowering of lipoproteins very low density (very-low-density lipoproteins) VLDL) and the triglycerides is detectable.

The invention particularly relates to polyazahetero-cyclic compounds of the general formula I in which R and R 1 are radicals corresponding to the definition given under formula I, which

232590 5

-X-

unsubstituted or substituted in the manner specified above and together and including optionally present substituents preferably 3 to. 20. carbon atoms and in particular have 5 to 15 carbon atoms, wherein R and R as aryl above all phenyl and as heteroaryl especially pyridyl, thienyl or furyl, which radicals are unsubstituted or, as indicated above, substituted R hydrogen or lower alkyl not more than 4 carbon atoms and A unsubstituted or 'by lower alkyl, especially one or two methyl, substituted ethylene or trimethylene having a total of at most 4 or 5 carbon atoms, Aethenylen, propenylene or tetramethylene, the radicals Z _n , Z ", Z" and Z. the under the

IL 3 4

Formula I have the meaning given, and the ring B is unsubstituted or substituted in the manner specified above, and their acid addition salts, in particular the pharmaceutically acceptable acid addition salts. More particularly, the invention relates to compounds of general formula I in which R is monohecsrocyclic raonocyclic heteroaryl which is unsubstituted or substituted by lower alkyl, lower alkoxy and / or halogen up to atomic number 35 and is preferably directly attached via methylene or isc, in particular unsubstituted or correspondingly, especially by lower alkyl, such as methyl, substituted pyridyl, or correspondingly substituted or especially unsubstituted thienyl or furyl, R "just such a radical, especially unsubstituted or appropriately substituted pyridyl, or appropriately substituted or especially unsubstituted thienyl, or unsubstituted or, as above for monocyclic heteroaryl · R, substituted phenyl · or unsubstituted or, as indicated above, substituted lower alkyl ,. in particular unsubstituted lower alkyl or lower alkoxycarbonyi-lower aikyl, before a lower alkoxycarbony methyl, R, hydrogen or alkyl having at most 4 carbon atoms, in particular methyl or ethyl, and A denotes ethylene or trimethylene, the radicals Z, Z ₉ , and Z, which have the meaning given under the formula I and the ring B in the manner specified above for R, but in particular by halogen to atomic number 35, such as

232590 5 -

Chlorine, substituted or primarily unsubstituted on the ring member 'Z ₉ , and their acid addition salts, in particular the pharmaceutically acceptable acid addition salts.

In the first place, the invention relates to compounds of the general formula I in which R is unsubstituted or substituted by lower alkyl, in particular methyl, pyridyl, or thienyl, in particular. 2-thienyl, R is likewise a radical or phenyl which is unsubstituted or in particular unsubstituted or substituted by lower alkyl, lower alkoxy or halogen up to atomic number 35, in particular lower alkoxycarbonyl, R "is hydrogen or lower alkyl, in particular methyl or ethyl, A is ethylene or trimethylene , Z ₃ Z ₉ , Z and Z _; Radicals -CH =, of which Z ₉ may be substituted by halogen to atomic number 35, in particular chlorine, and thus the ring B is unsubstituted or appropriately substituted, and their pharmaceutically acceptable acid addition salts.

Compounds of the last indicated type in which A is ethylene are e.g. the following, which give on-orater administration to rats in each case in mg / kg in parentheses cause a lowering of the blood sugar level by at least 20%: 5-methyl-5- (4-pyridyl) -2,3, 5,6-tetrahydroimidazo [1,2-c] quinazoline (10), 5-methyl-5- (6-methyl-2-pyridyl) -2,3,5,6-tetrahydroimidazo [1,2-c] quinazoline (3), 5-butyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline (10), 5-methyl-5-C2- pyridyl) -8-chloro-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazinyl (3), 5-phenyl-5- (4-pyridyl) -2,3,5, 6 Tetrahydro-imidazo [1,2-c] quinazoline (10), 5- (4-pyridyl) -2,3,5,6-tetrahydroimidazole "1> 2-c] quinazolin-5-acetic acid ethyl ester (10) and 5- Propyl 5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline (3)

Compounds of the last-mentioned type in which A is trimethylene are e.g. the following, which are given to female dogs (number of animals = n) in the dosage of 20 mg / kg per os during the first 5 hours after administration

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-, - 41 -

average hourly excretion of sodium, potassium and chloride ions and urine volume (= .Vol.), expressed as a percentage of the amounts excreted from the same animals in the hour immediately prior to administration, gives 6-phenyl-6- (4-pyridyl ) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline (n = 4, Na ⁺ 1224, K ⁺ 114, Cl "1369, Vo1.409); 6-pheny1-6 - (2-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline (n = 2, Na 392, K ⁺ 56, Cl "308, Vol. 171); _6- (4-methylphenyl) -6- (4-pyridy1) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline methanesulphonate (n = 2, Na ⁺ 800, K ⁺ 103, Cl "850, Vol. 206); 6- (4-chlorophenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline (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] quinazolin-fumarate (1 : 1) (n = 4, Na '721, K 66, Cl 889, Vol 275) In the first mentioned compound, excretions within the first 5 hours after administration of 20 mg / kg per os are given as a percentage of those for the same time period determined excretions of 10 untreated control animals for Na """2263, K ⁺ 137, Cl" 751 and vol. 379. All the above experiments show on the one hand the strong increase of excretion of sodium and chlorine, as well as the increase of urine volume, while On the other hand, the potassium excretion is unchanged or even partially reduced.

The compounds of the general formula I and their acid addition salts can be prepared in a manner known per se, for example by reacting a compound of the general formula

II

-A

(ID

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in which R, Z, Z Z, Z, and A have the meaning given to untar of the formula I and the ring B, as indicated therein, may be substituted, or an acid addition salt thereof with a ketone of the general formula III.

R-CO-R ₇ (III)

in which R and R have the meaning given under formula I, or a reactive functional derivative thereof, if desired, into a compound of general formula I in which R represents hydrogen, introduces lower alkyl as radical R- and / or a product obtained Compounds of the general formula I converted into an acid addition salt or releases the compound of general formula I from a resulting acid addition salt.

The condensation of a compound of general formula II with a ketone of general formula III or a reactive functional derivative of such can be, for example, in the presence of an inert organic solvent, for example in a lower alkanol, such as methanol, ethanol, isopropanol or butanol, in an aromatic Hydrocarbon, such as benzene, toluene or a xylene or xylene, or in an N-substituted acid amide, such as dimethylformamide or hexamethylphosphoric triamide, for example at temperatures between atwa 0 ° and about 180 ⁰ C, preferably at room temperature to atwa 150 ⁰ C and vorzugstveisa preferably in the presence an acid or an acidic catalyst. As the acid, for example, a mineral acid such as hydrogen chloride or conc. Hydrochloric acid, preferably in a lower alkanol, further polyphosphoric acid, for example in dimethylformamide or as the sole reaction medium, or a catalytic amount of an arenesulfonic acid, such as p-toluenesulfonic acid, preferably in an aromatic hydrocarbon, such as toluene, in particular at its boiling temperature with removal of the liberated water azeotropic distillery

2 5.9 0 5

tion, be used. As acid catalysts, for example, strongly acidic ion exchange resins such as e.g. Amberlit IR 120 H form (trademark of Rohm & Haas Co., Philadelphia, U.S.A.). Instead of using acidic catalysts, one can also use other agents which promote the release of water, such as silica gel or alumina, and again preferably carry out the condensation in a solvent which allows removal of the liberated water by azeotropic distillation on a water separator, e.g. in toluene at its boiling point. It is also possible to e.g. also use polyphosphate ester (PPE).

Further, the reaction may also be carried out in the absence of solvents or diluents, but preferably at elevated temperatures between about 120 and 200 ° C and also in the presence of acids or acid condensing agents, such as a catalytic amount of p-toluenesulfonic acid, or a preferably at least äauimolaren amount of aluminum chloride to which a solid diluent, such as sodium chloride, may be added. As can be seen from the examples above and the examples, the reaction conditions may vary within wide limits. It is clear that one does not apply more energetic conditions than are necessary to achieve the fullest possible implementation. Within the above range relatively energetic reaction conditions are generally necessary when in the starting materials of general formula III used as. R ₁ and R are directly bonded cyclic radicals.

As reactive functional derivatives of ketones of general formula III, for example, alkoxides, such as lower alkanolates, ketals, such as dimethyl, diethyl and Aethylenketale, or oximes and imines can be used.

The introduction of lower alkyl instead of a hydrogen atom R ~ can be carried out in a manner known per se, for example by reacting a compound of the general formula I which has a hydrogen atom as R, with a reactable ester of a lower alkanol, in particular a corresponding hydrogen halide.

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acid, Niederalkansulfonsäure- or arenesulfonic acid ester, especially a lower alkyl halide, in particular iodide or bromide, such as methyl or ethyl iodide, 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 hydrocarbon or Po ^ halogenated hydrocarbons such as benzene, toluene or methylene chloride, and an acid-binding agent, for example an alkali metal compound, such as sodium hydride, sodium or lithium amide, a tertiary organic BaSe _x such as triethylamine or ethyldiisopropylamine or an inorganic base such as potassium or sodium carbonate, preferably at temperatures between 0 ⁰ C and 12O ⁰ C and, if necessary, in a closed vessel, but especially at Room temperature to boiling temperature of the reac tion mixture.

Of the starting materials of general formula II individual representatives are known and more analogous to the known compounds produced. For example, they may be prepared by a method described in US Pat. No. 3,920,687 for the preparation of 2- (2-aminophenyl) -4,5-dihydro-IH-imidazole and 2- (2-aminophenyl) -4,5-dihydro-imidazole. 5,5-dimethyl-1H-imidazole and in US-PS 3,922,282 for the preparation of 2- (2-amino-4-chlorophenyl) -4,5-dihydro-IH-imidazo 1 described reaction sequence can be obtained for the compounds mentioned in the N-acylation of anthranilic acid or methyl 4-chloroanthranilic acid with p-methoxybenzenesulfonyl chloride, boiling the resulting N- (p-MethoxybenzolsulfonyD derivatives with 1,2-ethanediamine or 2-methyl 1-1 , 2-propanediamine, and heating the resulting derivatives of 4,5-dihydrol-H-imidazole with 92% sulfuric acid and liberating the desired products of the process with excess aqueous ammonia solution The 2- (2-aminophenyl) -4,5-dihydro-1H -imidazole was further prepared by condensation of anthranilic acid with 1,2-ethanediamine in accordance with Zh.Prikl. Kim. 43, 1641 (1970) (see Chem. Abstr. _7_3>? 7138r) Presence of a particular cation exchange resin at room temperature, and according to J.Med.Chem. _L3, 697 (1970) by catalytic hydrogenation

23 2 59 0 5

- yf - is-

of 4,5-dihydro-2- (2-nitrophenyl) -1H-imidazole or 2- (2-nitrophenyl) -1H-imidazole, cf. to the latter also Il Farmaco, Ed. Sc. , 30 , 536-546 ,. especially 539 (1975). Another method is, for example, the condensation of unsubstituted or ring-substituted 2-aminobenzonitriles, or of corresponding Aminopyridincarbonitrilen with amino and cyano group on adjacent ring carbon atoms, optionally with C-lower alkylated 1,2-ethanediamine into consideration. As compounds of the general formula II with lower alkyl as R, the 4,5-dihydro-2- [2- (methylamino) -phenyl] -1H-iniidazole and the 4,5-dihydro-2- [2- (ethylamino) - phenyl] -IH-imidazo1 according to Bull.Soc.Chim. France 1975 ,. 2118-20 prepared by reacting the corresponding 1-Niederalk'yll, 2-dihydro-3, l-benzothiazine-4-thiones with 1,2-ethanediamine in the boiling mixture of ethanol-benzene (2: 1).

As starting materials of the general formula II, in which the radical A contains three or four carbon atoms in direct chain between the two nitrogen atoms, the 2- (2-aminophenyl) -1,1,5,6-tetrahydropyrimidine and the 2- (2- 2-aminophenyl) -l, 5,6,7-tetrahydrolH-1,3-diazepine described by Russell Kwok. In J. Heterocyclic Chem. _L5_, 877-880 (1978). Other compounds of this type can analogously zuu] described therein methods, ie by heating for several hours of optionally ring-substituted 2-aminobenzonitrile, each having about half molar amounts of optionally C-lower alkylated 1,3-propanediamine, or 1,4-butanediamine and bis 4-methylbenzenesulfonates to about 200 ⁰ C, are produced. Furthermore, it is also possible, for example, to obtain appropriate starting materials by reacting an optionally ring-substituted 2-aminobenzonitrile, or a corresponding Aminopyridincarbonitril with amino and cyano group on adjacent ring carbon atoms, with about twice the molar amount of optionally C-lower alkylated 1,3-propanediamine and little Carbon disulfide some time, eg about 2 to. 48 hours, with stirring and passing nitrogen to about 120 to 170 ° C heated.

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Of the ketones of general formula III, some are known and more analogous to the known produced; Lower alkylpyridyl ketones, for example, by reaction of the corresponding Pyridincarbonitrile with Niederalkylmagnesiumhalogeniden according to Grignard.

Depending on the process conditions and starting materials, the novel compounds are obtained in free form or in the form of their salts also encompassed by the invention, whereby the new compounds or salts thereof may also be present as hemi-, mono-, sesqui- or polyhydrates thereof. Salts of the novel compounds can be prepared in a manner known per se, e.g. by treating with basic. Agents, such as alkali metal hydroxides, carbonates or bicarbonates, or ion exchangers are converted into the free compounds. On the other hand, free compounds obtained in a conventional manner, z.3. by treating organic or inorganic acids, such as the abovementioned acids, to form acid addition salts, in particular those acids are used for the preparation, which are suitable for the formation of pharmaceutically acceptable salts.

These or other acid addition salts of the novel compounds, e.g. Oxalates, picrates or perchlorates may also be used to purify the resulting free bases by salifying the free compounds, separating and purifying them, and releasing the bases from the salts.

Depending on the choice of starting materials and procedures, the novel compounds may be present as racemates or optical antipodes or, if they contain at least two asymmetric centers, also as mixtures of racemates. The starting materials can also be used in the form of certain optical antipodes.

Mixtures of racemates can be prepared by methods known per se, in particular by means of physical separation methods,

32590 5

such as fractionated adsorption and elution, including chromatography, fractional crystallization and distillation, etc., into the racemates.

Racemates can be broken down into antipodes by methods known per se, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with a salt-forming optically active compound with the racemic compound, in particular a corresponding acid, and separation of the salt mixture obtained in this way, for example because of different solubilities, into the diastereomeric salts from which the free antipodes can be released by the action of suitable agents. Particularly in use as an optically active acids include the D- and L-forms of tartaric acid, bis-0,0 '- (p ~ toluoyl) - _we ynoic acid, Aapfalsäure, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Advantageously, one isolates the more effective of the two antipodes.

The invention also relates to those embodiments of the method according to which starting from a compound obtainable as an intermediate at any stage of the process and carrying out the missing process steps, or terminating the process at any stage, or wherein forming a starting material under the reaction conditions, or in which the Reaktionskomppnenten optionally present in the form of their salts.

It is expedient to use such starting materials for carrying out the reactions according to the invention _. which lead to the above-mentioned groups of end products and to, for example in the examples, described or highlighted end products.

The starting materials are known or, if new, may be prepared by methods known per se, as above, e.g. analogous

23 2 59 0 5 - ¹⁸ - ⁶ · ¹ ·

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to be obtained in the examples. Heue starting materials likewise form an object of the invention. The invention also relates to intermediates obtainable according to the process.

Particularly valuable properties are possessed by the following compounds prepared according to the invention;

5-Methyl-5- (4-pyridyl) -2,3-i5,6-tetrahydro-imidazo [1,2-c] quinazoline or its pharmaceutically acceptable acid addition salts j

5-Metyl-5- (6-diethlyl-2-pyridy1, 2, 3, 5 »6-tetrahydro-imidazo. [1,2-c] quinazoline or its pharmaceutically acceptable acid addition salts, j.

5-butyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo quinazoline or the 5-propyl-5- (4-pyridyl) -2,3} 5,6-tetra-. hydro-imidazo j.1 »2-eJ quinazoline or its pharmaceutically acceptable acid addition salts»

5-methyl-5-C2-pyridyl) -8-chloro-2,3,5,6-tetrahydroimidazole, 2-cJ-quinazoline or its pharmaceutically acceptable acid addition salts}

5-phenyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [i, 2-c] quinazoline or its pharmaceutically acceptable acid addition salts j

5_ (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [i, 2-c] quinazolin-5-acetic acid ethyl ester or its pharmaceutically acceptable acid addition salts i

6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2E-pyrimido £ i, 2-cj

23 2 590 R - ^ * "6.1.1982

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quinazoline or its pharmaceutically acceptable acid addition salts j

6-phenyl-6- (2-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimidoti, 2-cJ quinazoline or its pharmaceutically acceptable acid addition salts J

6- (4-methylphenyi) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c-quinazoline or its pharmaceutically acceptable acid addition salts

6- (4-chlorophenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2E-pyrimido [1,2-c] quinazoline or its pharmaceutically acceptable acid addition salts j

6- (4-yridyl) -6- (2-thienyl) -3 _} 4,6,7-tetrahyaro-2H-pyrimido-1,2-cJ-quinazoJJLn or its pharmaceutically acceptable acid addition salts

7-ethyl-6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido J.1,2-cJ-quinazoline or its pharmaceutically acceptable acid addition salts

The novel compounds can be used, for example, in the form of pharmaceutical preparations which contain a pharmacologically effective amount of the active substance, optionally together with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral, eg oral, or parenteral administration. Thus tablets or gelatine capsules containing the active ingredient together with diluents, eg lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants, for example silica, are used. Talc, stearic acid or salts thereof, such as

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Magnesium or calcium stearate, and / or polyethylene glycol have. Tablets may also bind, e.g. B, magnesium aluminum silicate, starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. For example, starches, agar, alginic acid or salts thereof, such as itfatriumalginat, and / or effervescent mixtures, or adsorbents, dyes, flavorings and sweeteners. Perner can use the new pharmacologically active compounds in the form of parenterally administered preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which. B. in lyophilized preparations containing the Wirk3ubstanz alone or together with a carrier material, for. B, mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or adjuvants, eg. As preservatives, stabilizers, Hetz- and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain further phacoacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating

3 2 590 5

- yr -

lier, coating, solution or lyophilization process, prepared and contain about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of the active material.

The novel compounds of the general formula I and their pharmaceutically acceptable acid addition salts are preferably administered perorally. The daily doses range between 0.5 and 30 mg / kg for mammals and are preferably between 50 and 1000 mg, in particular between 100 and 500 mg, for those weighing about 70 kg, depending on their individual condition and age. Corresponding oral dosage unit forms, e.g. Dragees or tablets or capsules, preferably contain 25 to 500 mg, especially 50 to 250 mg of an active ingredient according to the invention, i. a compound of general formula I or a pharmaceutically acceptable acid addition salt thereof, together with pharmaceutical excipients.

The following regulation will explain the production of tablets in more detail:

a) 500 g of 5-propyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [l, 2-c] quinazoline are mixed with 500 g of lactose and 340 g of potato starch, the mixture with an alcoholic solution of 10 g of gelatin moistened and granulated through a sieve. After drying, 60 g of potato starch, 60 g of talc, 10 g of magnesium stearate and 20 g of fumed silica are added and the mixture is compressed to 10,000 tablets of 150 mg in weight and 50 mg of active ingredient content, which is desired with finer adjustments the dosage can be provided.

Instead of the aforementioned active ingredient, e.g. also 500.0 g of 5-phenyl-5- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline, its methanesulfonate, its acetate dihydrate or

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of another pharmaceutically acceptable acid addition salt thereof.

embodiment

The following examples illustrate in more detail the preparation of the novel compounds of the general formula I and of starting materials which are hitherto unknown, but are not intended to limit the scope of the invention in any way. The temperatures are given in degrees Centigrade.

Example 1: To a solution of 8.06 g (0.05 mol) of 2- (2-amiaophenyl) -4,5-aihydro-1H-imidazole (cf., U.S. Patent 3,920,687) in 125 ml of 1.8 methanolic hydrogen chloride solution, at 0 ° is added 12.11 g (0.1 mol) of methyl (4-pyrid 37l) ketone (see J.i'ied, Chem., J_4, 551 (1971)). The reaction mixture is stirred for 60 hours at room temperature and then evaporated to dryness in vacuo. The residue is mixed with 125 ml of 1-n. Katronlauge and extracted several times with chloroform. The combined, washed neutral with water chloroform phases are evaporated after drying over lNfatriumsulfat and the residue recrystallized from isopropanol. The resulting 5-methyl-5- (4-pyriäyl) -2,3,5j6-tetrahydro-imidazo [i, 2-c] quinazoline melts at 227-228 °.

Analogously, using 12.11 g (0.1 mol) of ethyl (3-pyridyl) ketone (see Liebigs Ann. Chem. 486 , 95 (1931)), 5-methyl-5- (3-pyridyl ) -2,3,5,6-tetrahydro-imida2; o [1,2-c-quinazoline, snip * 170-171 ° (from ethanol ether);

and using 12.11 g (0.1 mol) of methyl (2-pyridyl) ketone (see J.Med.Chem.t4, 551 (1971)), the 5-methyl-5- (2-pyridyl ) -2,3,5,6-tetrahydro-imidazo] i, 2-c] quinazoline, ämp. 202-203 ° (from ethanol-ether).

2 3 2 5 9 0 5 ->& - 6.1.1932

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The starting material 2- (2-aminophenyl) -4,5-dihydro-1H · imidazo! icann, more easily than described in the Ua-PS 3 920 687, can also be prepared as follows:

232590 5

a) A mixture of 118.14 g (1 mol) of 2-amino-benzonitrile, 120.2 g (2 mol) of ethylenediamine and 0.5 ml of carbon disulfide is heated to 150 ⁰ C while stirring and introducing nitrogen for 16 hours , where ammonia is developed. Then the reaction mixture is evaporated in vacuo, the residue is added with addition of activated charcoal in hot ethyl acetate, filtered and the filtrate is added with vigorous stirring with hexane. On cooling, the 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole crystallizes, mp 60-64 °. After recrystallization from ether / hexane, the product melts at 63-64 °.

Example 2: A solution of 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole, 12.11 g (0.1 mol) of methyl (4-pyridyl ) -ketone and 0.8 g (D, 0042 mol) of p-toluenesulfonic acid monohydrate in 200 ml of toluene is refluxed for 15 hours with water separation to boiling. It is cooled, filtered from the precipitate formed and distributed between 1-n. Matron lye and methylene chloride. The washed neutral with water and dried over sodium sulfate methylene chloride phase is evaporated. The 5-methyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline obtained after crystallization of the residue from isopropanol melts at 228-229 °.

Example 3: Starting from 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole, 12.68 g (0.085 mol) of propyl (4 pyridyl) ketone [cf. J. Chem. Soc. (C) 1969, 2134] and 200 ml of 1,8-n. methanolic hydrogen chloride solution, the 5-Propy1-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, mp. 241-242 ° (from isopropanol-ethyl acetate).

Example 4 : Starting from 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole, 8.81 g (0.08 mol) (2 -Furyl) methyl ketone [cf. Helv.Chim.Acta L3, 356 (193O)] and 150 ml of 1,8-n. methanolic hydrogen chloride solution, the 5-methyl-5- (2-furyl) -2,3, 5,6-cetrahydro-imidazo [l, 2-c] quinazoline, mp 195-196 ° (from ethanol).

2 590 5

Example 5: Analogously to Example 1, 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole with 20.22 g (0.1 mol) of diethyl 3-0xoglutarate in 240 ml of 1,8-n. ethanolic hydrogen chloride solution implemented. The resulting crude 5,5-bis (ethoxycarbonylmethyl) -2,3,5,6-tetrahydroimidazo [1,2-c] quinazoline is dissolved in 2,1-n. dissolved ethanolic hydrochloric acid. By adding ether, the hydrochloride is precipitated. It melts at 213 - 214 °.

Example 6 :. To a solution of 9.78 g (0.05 mole) of 2- (2-amino-4-chlorophenyl) -4,5-dihydro-1H-imidazole (see US Patent 3,922,282) in 160 ml of 2.5 -n. methanolic hydrogen chloride solution is added at 0 ° 12.11 g (0.1 mol) of methyl (4-pyridyl) ketone. The reaction mixture is refluxed for 15 hours and then concentrated in vacuo. After addition of ether, a precipitate of mono- or dihydrochloride forms of 5-methyl-5- (4-pyridyl) -S-chloro-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, which is filtered off and between 1-n. Sodium hydroxide and chloroform are distributed. The organic phase is washed neutral with water, dried over sodium sulfate and evaporated. Umkristailisation of the residue from acetonitrile / isopropanol gives the 5-methyl-5- (4-pyridyl) -8-chloro-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, mp. 242 - 244 °.

Analogously, using 12.11 g (0.1 mol) of methyl (2-pyridyl) ketone, the 5-methyl-5- (2-pyridyl) -8-chloro-2,3,5,6- tetrahydro-imidazoCl ^ -c-quinazoline, mp 247-249 ° (from ethanol).

Example 7: 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole and 10.63 g (0.055 mol) of β-oxo-4-pyridinepropionic acid ethyl ester [cf. J.Am.Chem. Soc. 67, 1468 (1945)] are dissolved in 80 ml of 2,1-n. ethanolic hydrogen chloride solution heated for 15 hours at 90 ° in a closed vessel. The reaction mixture is evaporated to dryness and the residue is partitioned between 2-n. Sodium hydroxide solution and chloroform are distributed. The neutral washed with water and dried over sodium sulfate organic phase is evaporated. The residue is filtered

232590 5

with a mixture of chloroform: methanol: conc. Ammonia = 150: 50: 1 over silica gel of particle size 0.063 - 0.200 mm. The fractions containing the desired product are evaporated and the residue recrystallized from isopropanol. The resulting 5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline-5-acetic acid ethyl ester melts at 190-192 °. In the above filtration through silica gel is as a by-product 5-methyl-5- (4-pyridyl) -2, 3, 5, 6-tetrahydro-imidazo [l, 2-c] quinazoline, mp 226-228 ° (from isopropanol ) receive.

Similarly, the 5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline-S-acetic acid ethyl ester can also be obtained by reacting in the reaction instead of 2- (2 Aminophenyl) -4,5-dihydro-1H-imidazole, a corresponding salt, for example the 2- (2-aminophenyl) -4,5-dihydro-1H-inimidazole dihydrochloride hydrate (J.Med.Chem. 697-704 (197O)).

Example 8: To a solution of 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-IH-imidazo-1 in 125 ml of 1,8-n. Methanolic Chlorvassarstoff solution is added at 0 ° 18.22 g (0.1 mol) of benzophenone. The reaction mixture is stirred for 15 hours at room temperature. Ether is added and the resulting precipitate of the hydrochloride is filtered off from 5,5-diphenyl-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline. This is recrystallized twice from ethanol / ether. It melts above 300 °.

Analogously, using 5.8 g (0.1 mol) of acetone, the 5,5-dimethyl-1,2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline hydrochloride, mp 249-250 ° (from AethanoL ether).

Example 9: Analogously to Example 8, 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole and 8.10 g (0.06 mol) of methyl [(2 -pyridyl) -methyl] -ketone [cf. Helv. Chim. Acta 45, 729 (1962).]

23259

in 125 ml of 1,8-n. methanolic hydrogen chloride solution implemented. The reaction mixture is evaporated and the residue recrystallized from ethanol / ether and chloroforin / methanol / ether. The dihydrochloride of 5-methyl-5 - [(2-pyridyl) methyl] -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline begins to decompose at about 150 ° C.

Example 10 Analogously to Example 8, 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole and 6.75 g (0.05 mol) of methyl (6) methyl-2-pyridyl) ketone [cf. J. Med. Pharm. Chem. 3_, 561 (1961)] in 125 ml of 1,8-n. methanolic hydrogen chloride solution implemented. The reaction mixture is evaporated and the residue recrystallized from water and ethanol / ether. The hydrochloride of 5-methyl-5- (6-methyl-2-pyridyl) -2,3,5,6-tetrahydroimidazo [1,2-c] quinazoline melts at 269-270 °,

Example 11: Analogously to Example 8, 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-IH-imidazo 1 and 10.13 g (0.055 mol) of di- (2-pyridyl ) ketone [cf. Rec. Trav. chim. 7Ό, 1054 (1951)] in 240 ml of 1,8-n. methanolic hydrogen chloride solution implemented. The reaction mixture is, however, evaporated, the residue dissolved in water and the solution with 2-n. Sodium hydroxide solution adjusted to pH 8. The precipitate formed is filtered off and recrystallized from ethanol / ether. The resulting hydrochloride of 5, 5-di- (2-pyridyl) -2,3,5, ö-tetrahydro-imidazoCl ^ -clchinazolin melts above 300 °.

Example 12: To a concentrated, low-boiling ethanolic solution of 5.28 g (0.02 mol) of 5-methyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1, 2] c] quinazoline is added at boiling heat to a likewise low-boiling, concentrated solution of 2.32 g (0.02 mol) of maleic acid. After cooling, the maleate formed is filtered off and recrystallized from isopropanol, whereupon it melts at 170 171 °.

9 0 5

Analogously, the corresponding fumarate is obtained using 2.32 g (0.02 mol) of fumaric acid. This melts after Ümkristallisation from methanol at 237 - 239 °.

Example 13 Analogously to Example 1, 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole and 12.24 g (0.075 mol) of butyl (4-pyridyl) ketone [cf. J. Chem. Soc. (C) 1969, 2134] in 150ml 2,7-n. methanolic hydrogen chloride solution implemented. In the work-up, instead of 1-n. Sodium hydroxide dilute aqueous ammonia solution used. The resulting 5-butyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [l, 2-c] quinazoline melts after ümkristallisation of ethyl acetate at 257-259 °.

Analogously, using 15.40 g (0.075 mol) of heptyl (4-pyridyl) ketone [cf. J. Med. _14, 551 (1971)], the 5-heptyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [l, 2-c] quinazoline, mp. 161-163 ° (from Acetoa / Patrol ether), and using 15.35 g (0.075 mol) of phenethyl (4-pyridyl) ketone [cf. J. Chem. Soc. (C) 1969, 2134 1, the 5-phenethyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, mp. 187-188 ° (from ethyl acetate.

Example 14: Analogously to Example 13, 6.44 g (0.04 mol) of 2- (2-aminophenyl-4,5-dihydro-1H-imidazole and 11.0 g (0.06 mol) of phenyl (4-pyridyl However, the reaction mixture is stirred for 40 hours at room temperature and then refluxed for 2 hours to give the resulting 5-phenyl-5- (4-pyridyl) -2,3,5, ö-tetrahydro-imidazofl ^. CYCHINAZOLE melts after crystallization from chloroform ether and then from ethyl acetate at 198-200 °.

2 59 0 5.

Example 15 Analogously to Example 1, but with a reaction time of 15 hours, starting from 3.91 g (0.02 mol) of 2- (2-amino-5-chlorophenyl) -4,5-dihydro-1H iinidazole, 4.47 g (0.03 mol) of propyl (4-pyridyl) ketone and 50 ml of 2-n. Methanoliseher hydrogen chloride solution, the 5-propyl-5- (4-pyridyl) -9-chloro-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, mp. 181.5 - 183 ° after Recrystallization from chloroform-ether and then from ethyl acetate.

The 2- (2-amino-5-chlorophenyl) -4,5-dihydro-1H-imidazole is obtained as follows:

a) A solution of 15.26 g (0.1 mol) of 2-amino-5-chloro-benzonitrile, 6.0 g (0.1 mol) of 1,2-ethanediamine and 20 drops of carbon disulfide in 100 ml of ethanol becomes 22 Cooked under reflux for hours. After renewed addition of 3.0 g (0.05 mol) of 1,2-ethanediamine and 20 drops of carbon disulfide, the mixture is boiled for a further 50 hours under reflux, then the reaction mixture is evaporated in vacuo and the residue is recrystallized from methylene chloride-hexane , The resulting 2- (2-amino-5-chloropnenyl) -4,5-dihydro-IH-imidazoI melts at 105-107 °.

Example 16 Analogously to Example 15, starting from 3.05 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole, 8.15 g (0.055 mol) of phenyl-propyl ketone and 150 ml of 2,5-n. methanolic hydrogen chloride solution, the 5-? -enyl-5-propyl-2,3,5,6-tetrahydroimidazo [l, 2-c] quinazoline, mp. 247-249 ° (from methanol-ether).

Example 17 Analogously to Example 1, but with refluxing for 22 hours, starting from 9.46 g (0.05 mol) of 2- (2-amino-4,6-dimethylphenyl) -4,5-dihydro- 1H-imidazole, 11.93 g (0.08 mol) of propyl (4-pyridyl) ketone and 165 ml of 2,5-n. methanolic hydrogen chloride solution, the 5-propyl-5- (4-pyridyl) -8,10-dimethyl-2,3,5,6-tetrahydro-imidazo [l, 2-c] quinazoline, mp. 187 - 189 ° after Uinkristallisation from Aether and from ethyl acetate-hexane. WEI

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-ZS. -30-

TeTes reaction product can be obtained by evaporating the mother liquor after the first recrystallization from ether and the residue, which still contains starting materials, again with 80 ml of 2,5-n. Methanolic hydrogen chloride solution for 15 hours under reflux boils.

The. 2- (2-Amino-4,6-diynethylphenyl) -4,5-dihydro-IH-imidazo 1 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 5_2_, 1389 (1978)] and 34.85 g (0.15 mol) of 2-aminoethyl-ammonium-toluene-4-sulfonate [cf. J. Chem. Soc., 497 (1947)] is heated for 3 hours with stirring at a bath temperature of 250 °, wherein "from the

Melt ammonia is released. A further 20 g (0.086 mol) of 2-Aininoäthyl-aiamonium-collo-4-sulfonate .zu and erhiczt another 3 1/2 hours at a bath temperature of 250 - 260 °. After cooling, the reaction mixture is partitioned between chloroform and 10% sodium hydroxide solution, the organic phase is washed with water, dried over sodium sulfate and evaporated. After the residue has been treated with ether, the crude 2- (2-amino-4,6-dimethylphenyl) -4,5-dihydro-1H-imidazole crystallizes out, which, after crystallization from ethyl acetate, melts at 141-142 °.

Example 18: 9.46 (0.05 mol) of 2- (2-amino-4,6-dimethylphenyl) -4,5-dihydro-1H-imidazole [cf. Example 17a) and 13.74 g (0.075 mol) of phenyl (4-pyridyl) ketone are dissolved in 200 ml of 2,5-n. Methanolic hydrogen chloride solution boiled under reflux for 22 hours. After working up analogously to Example 7, the resulting 5-phenyl-5- (4-pyridyl) -8,1O-dimethyl-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline melts at 249. 251 ° (from isopropanol ether).

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Example 19: To a suspension of 1.32 g (0.005 mol) of 5-methyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [i, 2-c] quinazoline in 13 ml of dimethylformamide 0.28 g (0.0064 mol) Matriumshydrid Diapersion (55% in oil) and the mixture is stirred for one hour at 70 °. After cooling to room temperature, 0.91 g (0.0064 mol) of methyl iodide are added dropwise. The mixture is stirred for a further 10 minutes, then it is cooled to 0 °, 2 ml of water are added dropwise to the reaction mixture, evaporated in vacuo and the residue is partitioned between ethyl acetate and 7% water. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The recrystallization of the residue from ethyl acetate-petroleum ether gives the pure 5,6-dimethyl-5- (4-pyridyi) -2,3,5,6-tetrahydro- imidaao [1,2-cJ-quinazoline, Snip, 153 154 °

EXAMPLE 20 Analogously to Example 1, but with refluxing for 7 hours, 9.46 g (0.05 mol) of 2- (2-aminophenyl) -4,4 (or 5,5) - dimethyl -4,5-dinydro-IH-imidazole (cf., U.S. Patent 3,894,040 and U.S. Patent 3,920,687), 9.08 g (0.075 mole) of methyl (4-pyridyl) ketone and 160 ml of 2 Hydrochloric acid solution containing 2,2,5-trimethyl-5- (4-pyridyl) -2,3,5,6-tetrahydroimidazoj.1 »2-c-quinazoline, mp, 138-141 ° (from ethyl acetate hexane) ·

Example 21; 15 "92 g (0.1 mol) of 2- (2-aminophenyl) -1H-imidazole (compare H Parmaco, Bd. Sc., 30, 536. (1975)) and 20.89 g (0.14 mol) Propvl- (4-P3 ^r ridyl) ketone in 240 ml of 2,5-be n. stirred methanolic hydrogen chloride solution for 15 hours at 20 ° and then boiled for a further 12 'hours under reflux. The reaction mixture is then evaporated to dryness and the residue is partitioned between 2-n. Caustic soda and

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Chloroform. The organic phase is washed with water, dried over sodium sulfate and evaporated. The 5-propyl-5- (4-pyridyl) -5j 6-dihydro-imidazoj, 2-cJ-quinazoline obtained after crystallization of the residue from ethyl acetate melts at 199-200 °.

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Example 22: Analogously to Example 1, but maintaining a reaction time of 20 hours at 20 °, starting from 3.18 g (0.02 mol) of 2- (2-aminophenyl) -1-imidazole, 3.63 g ( 0.03 mol) of methyl '(4-pyridyl) ketone and 50 ml of 3-n. methanolic hydrogen chloride solution, the 5-methyl-5- (4-pyridyl) -5,6-dihydro-iinidazo [1,2-c] quinazoline, mp 208-210 ° (from chloroform ether).

Example 23: A solution of 8.76 g (0.05 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine [cf. J. Heterocyclic Chem. _L5_, 877 (1978)] and 13.74 g (0.075 mol) of phenyl (2-pyridyl) ketone in 125 ml of 2,5-n. Methanolic hydrogen chloride solution is refluxed for 48 hours and then evaporated. Distribute the residue between 2-n. Sodium hydroxide solution and chloroform, the organic phase is washed with water and evaporated after drying over sodium sulfate in vacuo. The oligs residue crystallized on stirring with ether. Recrystallization from ethanol-sexan melts the resulting 6-pheny1-5- (2-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimidof1,2-c] quinazoline at 218-219 °.

Analogously you get:

Using 17.1 g (0.075 mol) of (3-nitrophenyl) - (4-pyridyl) ketone [cf. Monatshefte für Chemie 107 , 1449 (1976)] reported the 6- (3-nitrophenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline, m.p. 115-117 ° (from ethyl acetate, the compound contains one mole of ethyl acetate);

using 13.81 g (0.075 mol) of 2,2'-dipyridyl ketone but with refluxing in 150 ml of 3-n. Methanolic hydrogen chloride solution for 20 hours, the 6,6-di- (2-pyridyl) -3,4,6, .7-tetrahydro-2H-pyrimido [1,2-c] quinazoline, mp. 265 266 ° (from methanol );

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-ysr-

using 11.12 g (0.075 mol) of phenylpropyl-katone

but with heating in the bomb tube at 150 ° for 4 hours, the 6-phenyl-6-propyl-3,4,6 -, 7-tetrahydro-2E-pyrimido [1,2-c] quinazoline, mp 190 -. 192 ° (from ethyl acetate);

and by reacting 8.76 g (0.05 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine with 8.7 g (0.15 mol) of acetone in 100 ml of 2, 5-n. methanolic hydrogen chloride solution for 15 hours at 20 °, the 6,6-dimethyl-3,4,6,7-tetrahydro-2H-pyrimido [l, 2-c] quinazoline, mp 218-220 ° (from ethyl acetate).

The starting compound, 2- (2-aminophenyl) -1,1,5,6-tetrahydropyrimidine can also be obtained as follows:

a) A mixture of 50 g (0.42 mol) of 2-amino-benzonitrile, 62.27 g (0.34 mol) of 1, .3 Propanediamine and 5 drops of carbon disulfide is stirred for 24 hours while introducing nitrogen Heated to 150 °, with ammonia is developed. The rejection mixture is then evaporated in vacuo and the residue is taken up in ether. The 2- (2-aminophenyl) -l, 4,5,6-tetrahydro-pyrimidine crystallized from the ethereal solution, mp. 99 - 101 °.

Example 24: To a solution of 34.0 g (0.194 mol) of 2- (2-aminophenyl) - !, 4,5,6-tetrahydropyrimidine and 53.3 g (0.291 mol) of phenyl- (4-pyridyl ) -ketone in 300 ml of 3-n. methanolic hydrogen chloride solution is added 20 g of molecular sieve (3.10 m _, bead form about 2 mm, Merck) and the reaction mixture is refluxed for 16 hours. The molecular sieve is filtered off, the filtrate evaporated and the residue worked up in analogy to Example 23. The resulting 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazole melts at 243-245 ° (from isopropanol ether).

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Similarly, the 6-phenyl-6- (4-pyridyl) -2,4,6,7-tetrahydro-2H-pyrimido [L, 2-c] quinazoline can also be obtained by substituting in the reaction for. 2- (2-aminophenyl) -1,1,5,6-tetrahydro-pyrimidine a corresponding salt, z.3. 2- (2-aminophenyl) -l, 4,5,6-tetrahydropyrimidine dihydrochloride (see J. Med. Chem. , 697-704 (1970) or instead of the free ketone of which imine is used.

Example 25 : A solution of 13.15 g (0.075 mol) of 2- (2-amiriophenyl) 1,4,5 _} 6-tetrahydropyrimidine and 10.41 g (0.086 mol) of methyl (4-pyridyl) ketone in 200 ml of 1.83-n. methanolic hydrogen chloride solution is stirred for 2 1/2 days at 20 °. The mixture is then concentrated to about half the original volume. Add ether, filter off the precipitate formed and partition it between chloroform and 1-n. Sodium hydroxide solution. The washed with water organic phase is dried over sodium sulfate, evaporated and the residue from isopropanol unicrystallized. The resulting 6-methyl-o- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline melts at 207-209 °.

Example 26: 8.76 g (0.05 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine and 13.74 g (0.075 mol) of phenyl (2-pyridyl) ketone are dissolved in 90 g of polyphosphoric acid for 3 hours at 150 °. It is cooled, the reaction mixture is mixed with ice-water and an excess of aqueous ammonia solution, extracted with chloroform and the organic phase is evaporated after drying over sodium sulfate in vacuo. The oily residue crystallizes on stirring with ether. The resulting 6-phenyl-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 g (0.075 mol) of phenyl (4-pyridyl) ketone - but at a reaction time of 2 hours at 130 ° and 4 hours at 150 ° and using 140 g of polyphosphoric acid - the 6- phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-

23 259 0 5

2H-pyrimido [1,2-quinazoline, Stnp. 243-246 ° (from isopropanol ether).

Example 27: A solution of 8.76 g (0.05 mol). 2- (2-Aminophanyl) -1,4,5,6-tetrahydropyrimidine and 11.18 g (0.075 mol) of propyl (4-pyridyl) ketone in 200 ml of 2-n. methanolic hydrogen chloride solution is boiled under reflux for 2 days and worked up analogously to Example 23. The obtained 6-ropyl-o- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline melts at 221-223 ° (from Aathanoi ether). ,

The mother liquor obtained in the crystallization, which still contains starting materials, is evaporated and the residue is stirred with 60 g of polyphosphoric acid for one hour at 120 °. It is cooled, the reaction mixture is mixed with ice-water and an excess of aqueous ammonia solution, extracted with chloroform and the organic phase is evaporated after drying over sodium sulfate in vacuo. The residue is recrystallized from ethanol-ether. This gives a second batch of 6-ropyi-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline, mp 221-223 °.

Analogously, using 12.24 g (0.075 mol) of butyl (4-pyridyl) ketone, the 6-butyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido is obtained. 1,2-c] quinazoline, mp 197-199 ° (from chloroform-hexane).

Example 28: A mixture of 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine, 27.48 g (0.15 mol) of phenyl (4 -pyridyl) ketone and 0.3 g of toluene-4-sulfonic acid monohydrate is stirred for 24 hours at 180 ° and a pressure of about 270 mbar. After cooling, the melt is taken up in ethyl acetate. This precipitates crude 6-phenyl-o- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido- [L, 2-c] quinazoline, which, after crystallization from isopropanol ether at 243-245 ° melts.

Example 29: Untar stirring and introducing nitrogen into a melt of 100 g of anhydrous aluminum chloride and 50 g of sodium chloride at 160 ° 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, wherein the temperature temporarily rises to 205 °. After completion of the addition, the reaction mixture is stirred. 20 minutes at 180 ° and then allowed to solidify the melt with cooling. The reaction mixture is dissolved in 700 ml of hot water. It is washed with chloroform and the aqueous phase is mixed with 500 ml of concentrated aqueous ammonia solution. The alkaline phase is stirred well with 500 ml of chloroform for 3 hours and the mixture filtered after addition of 300 g of diatomaceous earth. The chloroform phase of the filtrate is dried over sodium sulfate and evaporated in vacuo. Recrystallization of the residue from ethyl acetate and from isopropanol ether melts the resulting 3-phenylene-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline 243 - 245 °.

Example 30: To a solution of 6.8 g (0.02 mol) of 6-ethyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline in methanol is added 1.92 g (0.02 mol) of methanesulfonic acid. The mixture is evaporated and the residue recrystallized from ethanol-ethyl acetate. The resulting 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline methanesulfonate melts at 249-250 °.

In the recrystallization of the above Mechansulfonates from ethanol with a little water and adding hexane to turbidity, filtering off and drying, depending on the type of drying Methansulf onat monohydrate or methanesulfonate dihydrate, both at 248-251 ° (with sintering from 100 °). melt.

23259

Example 31 Analogously to Example 23, starting from 8.76 g (0.05 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine and 13.74 g (0.075 mol) of phenyl (3-pyridyl) ketone crude 6-phenyl-6- (3-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline ₇ which is treated with a mixture of chloroform: methanol : conc. ammonia = 40: 10: 1 filtered through silica gel of particle size 0.063 - 0.200 mm. The fractions containing the desired product are evaporated and the oily residue is dissolved in methanol. To this solution is added the methanolic solution of an equimolar amount of fumaric acid. After evaporation in vacuo, the residue is recrystallized from methanol-ethyl acetate. The obtained 6-phenyl-6- (3-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline fumarate contains 1.5 mol of fumaric acid and melts at 223-225 ° ,

Example 32: AnaTog Example 25 is obtained starting from 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine, 29.55 g (0.15 mol) (4-methylphenyl) - (4-pyridyl) ketone [cf. Helv. Chim. Acta 5.2, 262 (1969)], 150 ml of 2,5-n. methanolic hydrogen chloride solution and 15 g of molecular sieve (3.10 m, bead form about 2 mm, Merck) of crude 6- (4-methyl-phenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2 -c] -quinazoline _x which is mixed with a mixture of chloroform: methanol; conc. Ammonia = 40: 10: 1 as solvent and eluent on silica gel of particle size 0.063. - 0.200 mm chromatographed. The uniform fractions containing the desired product are evaporated. The residue is dissolved in ethanol and added to the ethanolic Solu _n g _m it an equivalent amount of methanesulfonic acid. After renewed evaporation and recrystallization of the residue from ethanol-hexane, the resulting 6- (4-methylphenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido melts [l, 2- c] quinazoline methanesulfonate at 257-259 °.

Example 33: A mixture of 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine, 18.32 g (0.1 mol) of phenyl (4 -pyridyl) -ketone, 500 ml of toluene and 70 g of silica gel of particle size 0.063 - 0.200 mm is boiled for 18 hours with stirring on a water separator, then

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once again mixed with 20 g of silica gel and cooked for a further 15 hours on a water separator. After filtration and washing of the filter material with a chloroform-methanol mixture (1: 1), the filtrate is evaporated in vacuo and the residue is treated with ethyl acetate, whereby 6-phenyl-6- (4-pyridy1) -3,4,6,7 Tetrahydro-2H-pyrimido [1,2-c] quinazoline precipitates, which 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 (55% in OeI) and 7.8 g (0.05 mol) of ethyl iodide in 110 ml of dimethylformamide. The mixture is stirred for 12 hours at room temperature, then added dropwise with cooling 10 ml of water in the reaction mixture, it is evaporated in vacuo and the residue is partitioned between chloroform and 1-n. Sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed with a mixture of chloroform: methanol: conc. Ammonia = 14: 6: 1 as a solvent and eluant on silica gel of particle size 0.063 - 0.200 mm. The uniform fractions containing the desired product are evaporated and the residue recrystallized from ethanol-hexane. The obtained 6-phenyl-6- (4-pyridy 1) -7-ethyl 1-3, 4, 6, 7-tetrahydro-2H-pyrimido [1,2-c] quinazoline melts at 230-231 °. The fumarate produced therefrom with fumaric acid melts at 252-254 ° (from ethanol-methanol 10: 1).

Example 35 Analogously to Example 1, but with refluxing for 5 hours, starting from 11.16 g (0.059 mol) of 2- (2-aminophenyl) -4,4 (or 5,5) -dimethyl-4 , 5-dihydro-1H-imidazole, 13.27 g (0.089 mol) of propyl (4-pyridyl) ketone and 150 ml of 3-n.methanolic hydrogen chloride solution, the 2,2-dimethyl-5-propyl-5- (4 -pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline, mp 224-226 ° after recrystallization from ethyl acetate and then from ethanol-ether.

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_ co-

EXAMPLE 36 Analogously to Example 33, 16.32 g (0.1 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole and 21.83 g (0.1 mol) of ( 4-methoxyphenyl) - (2-thienyl) ketone, but with refluxing for 7 days and chromatography of the crude product with a mixture of chloroform: methanol = 9: 1 over silica gel of particle size 0.063-0.200 mm, containing 5- (4- Methoxyphenyl) -5- (2-thienyl) -2,3,5,6-tetrahydro-imidazo (1,2-c] quinazoline, m.p. 207-208 ° (from acetone and ethyl acetate).

Example 37 : To a solution of 8.06 g (0.05 mol) of 2- (2-aminophenyl) -4,5-dihydro-1H-imidazole in 140 ml of 2,6-n.methanolic hydrogen chloride solution is added 11, 68 g (0.05 mol) of 2-chloro-5-acetyl-benzenesulfonamide [Arzneimittelforsch. L3, 269-280 (1963)] and stirred the Reaktionsgemi sch 72 hours at 20 °. The precipitate formed is filtered off, suspended in 360 ml of water and the suspension is stirred with an excess of 30% aqueous ammonia solution for L / 2 hour at room temperature. After filtration and recrystallization of the residue from methanol, the resulting 5- (4-chloro-3-sulfamoyl-phenyl) -5-methyl-2,3,5,6-tetrahydro-imidazo [1,2-c] quinazoline melts at 274 ° (Zers.).

Example 38 : 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1, 4,5,6-tetrahydropyrimidine, 21.32 g (0.1 mol) of 4-methoxyphenyl (4-pyridyl) ketone (J. Pharm. Sci. 62, 847-9 (1973) and 43.2 g (0.1 mol) polyphosphate ester (PPE, Fieser & Fieser, Reagents for Organic Synthesis, New York 1967, page 892) are dissolved in 250 ml of chloroform The reaction mixture is then refluxed for 96 hours, the reaction mixture is then stirred with an excess of 2N sodium hydroxide solution, then the organic phase is separated off, washed with a little water, dried over sodium sulphate and concentrated by evaporation 6- (4-methoxyphenyl) -6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline precipitates and melts at 236-238 ° (from ethylene chloride). ,

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Example 39 : 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1, 4,5,6-tetrahydropyrimidine, 18.32 g (0.1 mol) of phenyl (4-pyridyl) ketone and 43.2 g (0.1 mol) of polyphosphate ester are refluxed in 150 ml of chloroform with stirring and sparging with nitrogen for 45 hours. After cooling and addition of 250 ml of 2-n. Sodium hydroxide solution and 200 ml of chloroform are stirred into the reaction mixture for a further 15 minutes at room temperature, then the chloroform phase is separated off and the aqueous phase is extracted twice more with 150 ml of chloroform each time. The combined, washed with a little water and dried over sodium sulfate organic phases are evaporated and the oily residue with 100 ml. Aethylacetat stirred to give the desired 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro -2H ~ pyrimido- [1,2-c] quinazoline precipitates, which melts after washing with ethyl acetate and ether at 237-239 °. After an additional recrystallization from ethanol / hexane melts: the product at 240-242 °,

Example 40 : 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1, 4,5,6-tetrahydropyrimidine, 23.93 g (0.1 mol) of 4- (1,1-dimethylethyl) -phenyl - (. 4-pyridyl) ketone [J.Pharm.Sci. 62, 847-849 (1973)] and 43.2 g (0.1 mol) of polyphosphate ester are refluxed in 250 ml of chloroform for 24 hours. The reaction mixture is cooled, and 260 ml of semi-concentrated (about 12.5% in water) of ammonia solution are added with vigorous stirring. After stirring for 15 minutes, the chloroform phase is separated off,

dried over sodium sulfate and evaporated. The residue is filtered through silica gel of particle size 0.063-0.200 mm with a mixture of chloroform: methanol: conc. Ammonia = 40: 10: 1 and the fractions containing the desired product are evaporated. After recrystallization from acetonitrile and methylene chloride-hexane, the resulting 6- [4- (1,1-dimethylethyl) phenyl] -6- [4-pyridyl] -3,4,6,7-tetrahydro-2H-pyrimido melts [1 , 2-c] quinazoline at 142-145 °.

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Example 41 : 70 g of silica gel H to steel (for example from E. Merck AG, Darmstadt) are mixed with 600 ml of xylene and heated with stirring on a water separator until no more water separates. It is cooled, then gives 17,52 g (0.1 mol) of 2- (2-aminophenyl) -1,4,5,6-tetrahydropyrimidine and 18.32 g (0.1 mol) of phenyl (0.1 mol) 4-pyridyl) ketone and the reaction mixture is boiled for 95 hours on a water. After filtration and washing the Nutschrückstandes with ether, the filter material is extracted with chloroform continuously. The extract is evaporated and the residue obtained is treated with ethyl acetate to give 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline, cf. at 241-243 ° melts.

Example 42 Analogously to Example 41, but using toluene as solvent and heating the reaction mixture for 40 hours, starting from 17.52 g (0.1 mol) of 2- (2-aminophenyl) -1, 4, 5,6-tetrahydro-pyrimidine and 21.77 g (0.1 mol) of (4-chlorophenyl) - (4-pyridyl) -ketone is 6- (4-chlorophenyl) -6- (4-pyridyl) -3 , 4, 6, 7-tetrahydro-2H-pyrimido [-l, 2-c] quinazoline, which melts after recrystallization from ethylene chloride and acetonitrile 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-aminophenyl) -1, 4,5,6-tetrahydropyrimidine and 9 , 46 g (0.05 mol) (4-pyridyl) · (2-thienyl) ketone (J.Med.Chein. JL2_, 1093-6 (1969) was reacted. After filtration and washing of the filter material with a solvent mixture of chloroform j Methanol = 1: 1, the filtrate is evaporated and the residue is treated with ethyl acetate to give crude 6- (4-pyridyl) -6- (2-thienyl) -3,4,6,7-tetrahydro-2H-pyrimido [ L, 2-c] quinazoline precipitates, which melts after recrystallization from ethanol-hexane at 208-210 °.

Example 44 Analogously to Example 41, 17.52 g (0.1 mol) of 2- (2-aminophenyI) -I, 4,5,6-tetrahydropyrimidine and 19.92 g (0.1 mol) Hydroxyphenyl) - (4-pyridyl) -ketone using 500 ml chlorobenzene as solvent. After filtration and washing of the silica gel

[32590 5 -χ - «-

gels with ether, the filter material is stirred three times with 300 ml of a mixture of chloroform: methanol = 1: 1 with warming and then filtered. The combined filtrates are evaporated and the residue is purified by chromatography on silica gel with a mixture of chloroform: methanol: conc. Ammonia = 40: 10: 1. The fractions containing the desired product are combined and evaporated. The crystalline residue is boiled in methanol, cooled and filtered. The resulting 6- (4-hydroxyphenyl) -o- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline hemihydrate melts at 287-289 ° (dec. ).

The starting compound, the (4-hydroxyphenyl) - (4-pyridyl) ketone, is prepared as follows:

To a solution of 53.3 g (0.25 mol) of (4-methoxyphenyl) - (4-pyridyl) ketone in 500 ml of methylene chloride is added dropwise with stirring at 5 °, a solution of 187.9 g (0.75 mol Boron tribromide in 750 ml of methylene chloride. The reaction mixture is stirred for 15 hours at room temperature and then with. an excess of 2-n. Natronlauge'extrahiert. The alkaline phase is washed with chloroform and then acidified with glacial acetic acid (pH approx. 5). The formed precipitate is filtered off and the filter material is washed with isopropanol. After recrystallization from dimethylformamide-water, the resulting (4-hydroxyphenyl) - (4-pyridyl) -ketone melts at 257-259 °. (See Heterocycles _2, 423-426 (1974)).

Example 45 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 (55% in OeI) and 7.1 g (0.05 mol) of methyl iodide in 110 ml of dimethylformamide. The mixture is stirred for 12 hours at room temperature, then added dropwise with cooling 10 ml of water in the reaction mixture, it is evaporated in vacuo and the residue is partitioned between chloroform and 15% sodium hydroxide solution. The washed with water and dried over sodium sulfate organic phase is evaporated and the residue with a mixture of chloroform: methanol: conc. Ammonia = 40: 10: 1 on silica gel chromatographiart. The the

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desired product-containing fractions are evaporated and the residue recrystallized from chloroform-ether. The resulting 6-phenyl-6- (4-pyridyl) -7-methyl-3,4,6,7-tetrahydro-2H-pyrimido- [1,2-c] quinazoline melts at 183-184 °.

Example 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 one is obtained Hydrochloride, which melts after recrystallization from ethanol-ether at 278-280 °.

Similarly, using an equivalent amount of fumaric acid, 5-propyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] quinazole fumarate, m.p. 215-217 ° (dec.) Is obtained. ,

Example 47 : In 300 ml of Aechanol is dissolved with heating 34.04 g (0.1 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2 -c] quinazoline and then, with cooling, a solution of 10.22 g of 96% sulfuric acid (0.1 mol) in 19.5 g of water. The precipitated on cooling sulfate melts after recrystallization from Aethano! -Methanol = 1: 3 and drying at 150 ° in a high vacuum at 321-322 ° (dec.).

In the recrystallization of the above sulfate from water is obtained after drying at 160 ° in a high vacuum, a sulfate (crystal modification), which melts at 278-280 °. This can be converted by re-recrystallization from methanol ether again in the melting at 321-322 ° sulphate.

Example 48:

a) To a low-boiling solution of 17.02 g (0.05 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline in 150 ml of ethanol is added 3.33 ml of 15-n. Sulfuric acid (0.025 mol). After addition of activated carbon and subsequent filtration, the filtrate is added dropwise with stirring with 100 ml of ether. The mixture is allowed to cool slowly to about 5 °, the precipitated salt is filtered off and washed with a mixture of ethanol: ether = 1: 1. To

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- ns

Drying over sodium hydroxide in a high vacuum at 160 °, the resulting bis [6-phenyl-6- (4-pyridyl) -J, 4,6,7-tetrahydro-2H-pyrimido- [1,2-c] quinazoline] - sulphate monohydrate at 300-303 °.

b) To a suspension of 17.02 g (0.05 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline A solution of 2.55 g of 96% sulfuric acid (0.025 mol) in 10 ml of water is added with stirring to 30 ml of water. The resulting about 40 ° heat solution is filtered. The filtrate is allowed to cool slowly over 4 hours to 0 ° and then filtered from the precipitated product. The mother liquor is concentrated in vacuo, after which, after cooling and filtration, another batch of product is obtained. After drying the combined batches at room temperature, the bis [6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline] sulfate has a water content of 11.63% and melts at 235-240 °. (Samples with a water content of 8.7% and 7.6%, respectively, also melt at 235-240 ° C).

Example 49 : 1.7 g (0.005 mol) of 6-phenyl-o- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline and 0.79 g ( 0.005 mol) of benzenesulfonic acid are heated to 100 ° C in 280 ml of water. It is then filtered and the filtrate is allowed to cool to 5 °. The precipitated product is filtered off, washed with water and dried. The resulting benzenesulfonate monohydrate decomposes at 164-166 °.

Example 50 : To a boiling solution of 8.51 g (0.025 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline 70 ml of ethanol are added to a solution of 3.05 g (0.025 mol) of benzoic acid in 10 ml of ethanol. After addition of 120 ml of ether and cooling to 5 °, the precipitated product is filtered off, washed with a mixture of ethanol: ether = 2: 3 and then dried. The resulting benzoate melts at 241-243 °.

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Example 51 : 3.40 g (0.01 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline are heated in one Solution of 0.72 g (0.012 mol) of acetic acid in 5 ml of water. After cooling the solution in an ice bath, the precipitated product is filtered off, washed with a little ice-cold water and dried. The resulting acetate dihydrate melts at about 132-137 ° (with sintering from 120 °).

Example 52 :. Analogously to Example 12, using 3.40 g (0.01 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline and 1.16 g (0.01 mol) of fumaric acid the corresponding Fuinarat, which decomposes after recrystallization from methanol at about 230 °. This salt still contains 2.9% water.

Recrystallization from water gives the 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1, 2-c] chinazo1in-1 1/2 fumarate which decomposes at 232-235 °.

Example 53 : A mixture of 9.1 g (0.056 mol) of 2-amino-3- (4,5-dihydrol-H-imidazol-2-yl) -pyridine, 12.5 g (0.084 mol) of propyl- (4-pyridyl ) -ketone ~ and 70 g of polyphosphoric acid is stirred for 18 hours at 150 °. After working up analogously to Example .26, the crude product obtained is purified by filtration through silica gel with a solvent mixture of chloroform: methanol = 9: 1. The fractions containing the desired product are evaporated and the residue recrystallized from ethyl acetate. The obtained 5-ropyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] pyrido [3,2-e] pyrimidine melts at 182-183.5 ° ,

Analogously obtained using 9.16 g (0.05 mol) of phenyl (4-pyridyl) ketone, but at a reaction time of 24 hours at 14O ⁰ C and then 24 hours at 180 ° C, the 5-Pheny1 -5- (4-pyridyl) -2, 3,5, 6-tetrahydro-imidazo [l, 2-c] pyrido [[3,2-e] pyrimidine, which after recrystallization from ethyl acetate / hexane at. 240-241 ° melts. The hydrochloride prepared with hydrochloric acid in water melts at 312-314 ° (water content 1.2%).

2 59 0 5

The starting 2-amino-3- (4,5-dihydro-1H-imidazdl-2-yl) -pyridine is prepared as follows: A mixture of 23.8 g (0.2 mol) of 2-amino-3 pyridinecarbonitrile [J. Heterocyclic Chem. 15, 877-880 (1975)], 24 g (0.4 mol) of ethylenediamine and 6 drops of carbon disulfide are stirred for 2 hours at 150 ° and then evaporated in vacuo. The crystalline residue is taken up in 200 ml of ice-cold ether. After filtration of the ether solution, the resulting crude product from hexane and ethanol / ether is recrystallized. The resulting 2-amino-3- (4,5-dihydro-1H-imidazol-2-yl) -pyridine melts 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, 17.58 g (0.096 mol) of phenyl (4-pyridyl) ketone and 240 g of polyphosphoric acid is heated with stirring for 43 hours at 170 °, 17 hours at 180 ° and 24 hours at 200 °. It is cooled, the reaction mixture is mixed with ice-water and an excess of 30% sodium hydroxide solution, extracted with chloroform and the organic phase is evaporated after drying over sodium sulfate in vacuo. For purification, the residue is mixed with a solvent mixture of chloroform: methanol: conc. Ammonia = 40: 10: 1 chromatographed on silica gel. The fractions containing the desired product are evaporated and the residue recrystallized from ethanol / ethyl acetate / ether. The resulting 6-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 prepared as follows:

A mixture of 35.7 grams (0.3 mole) of 4-amino-3-pyridinecarbonitrile (U.S. Patent 3,517,021), 44.5 grams (95 moles) of propylene diamine, and about 10 drops of carbon disulfide is heated at 140 ° C for 20 hours touched. After evaporation of the reaction mixture in vacuo, the residue is recrystallized from ethanol. The resulting 4-amino-3- (l, 4,5,6-tetrahydro-2-pyrimidinyl) -pyridine melts at 208-210 °.

2 59 0 5

Example 55 : A mixture of 8.1 g (0.05 mol) of 4-amino-3- (4,5-dihydro-1H-imidazol-2-yl) -pyridine, 11.2 g (0.075 mol), is stirred. Propyl (4-pyridyl) ketone and 150 g of polyphosphoric acid for 30 hours at 150 ° ,. is again 5.6 g of propyl (4-pyridyl) ketone and stirred for a further 16 hours at 150 °. After working up analogously to Example. 26 gives the desired 5-propyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c] pyrido [3,4-e] pyrimidine, which after recrystallization from Aethylacetat melts at 238-240 °.

The starting compound, the 4-amino-3- (4,5-dihydro-1H-imidazol-2-yl) -pyridine, is obtained as follows: A mixture of 23.8 g (0.2 mol) of 4-amino 3-pyridinecarbonitrile, 24 g (0.4 mol) of ethylenediamine and about 8 drops of dibasic carbon are stirred for 1.5 hours at 120 °. A further 15 ml of ethylenediamine are added to the reaction mixture, and the mixture is heated at 120 ° for a further 2 hours and then evaporated in vacuo. After recrystallization from ethanol, the resulting 4-amino-3- (4,5-dihydro-1H-imidazol-2-yl) -pyrimidine melts at 198-199 ° ..

Example 56 :. 8.75 g (0.05 mol) of 2- (2-aminophenyl) -l, 4,5, o-tetrahydropyrimides and 10.4 g (0.05 mol) of phenyl styry! Ketone (2-3enzylidenacetophenone) in a solution of 21.7 g of polyphosphate ester in 75 ml of chloroform and the reaction mixture was refluxed for 16 hours. The oily residue obtained after working up analogously to Example 39 is mixed with a solvent mixture of chloroform: methanol: conc. aqueous ammonia solution = 70: 30: 5 on silica gel chrotaatographiert. The fractions containing the desired product are evaporated and the residue is recrystallized from acetonitrile. The resulting o-phenyl-o-styryl-3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline melts at 143-145 °, after drying under high vacuum at 100 °.

232590 5

Example 57 : To a suspension of 17.02 g (0.05 mol) of 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido [1,2-c] quinazoline in 100 ml of water is added with stirring 50 ml of 1-n. Hydrochloric acid and enough water until a solution has formed on heating to boiling. This is filtered through activated charcoal and the filtrate concentrated to incipient crystallization. After cooling to about 5 °, the precipitated salt is filtered off and washed with a little ice-cold water. The obtained 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-pyrimido- [1,2-c] quinazoline hydrochloride dihydrate decomposes at 345-347 °.

Claims (7)

2 3 2 5 9 0 5 -βΆ- 50 - 6.1.1982 AP C 07 D / 232 590/0 (59 596/11) invention claim 1 _# Veriahren for the preparation of novel polyazaheterocyclic compounds of the general formula I. (D, in which R. and R ₂ are each independently optionally substituted lower aliphatic hydrocarbon radicals, optionally substituted, either directly or through lower alkylene or liiederalkenylen aryl or heteroaryl bonded with more than two rings, R ^ is hydrogen or Efiederalkyl and A represents optionally branched lower alkylene or Hiederalkenylen having 2 to 4 Mean carbon atoms in the direct chain between the adjacent nitrogen atoms and Z ^, Z ₂ , Ζ-, and Z. are members of the unsubstituted or substituted ring B and radicals -CH =, which carry the substituents of the ring B, if any, but instead of -CH = can also mean the radical -N =, where R ^ and R ₂ 'are not both methyl or both ethyl, when R is hydrogen and A Äthenylen and at the same time the ring B is unsubstituted, and their acid addition salts, characterized in that a compound of general formula II 23 2 59 0 5 i ^ - ⁵¹ - 6.1.1982 AP C 07 D / 232 590/0 (59 596/11) in which IU, Z 1, Z ₂ , Z 1, Z ₃ and A have the meaning given under formula I and the ring B may be substituted as indicated there, or an acid addition salt thereof with a ketone of the general formula III, R ₁ -CO-R ₂ (III) in which R .. and R ₂ have the meaning given under formula I, or condensed thereof a reactive functional derivative, if desired, in a compound of general formula I in which R ~ is hydrogen, introducing ITiederalkyl as radical R, and / or an obtained 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. , Method according to item 1, characterized in that compounds of the general formula I indicated in point 1, in which R ₁ and R _{2 are} radicals corresponding to the definition given in point 1, which are unsubstituted or as lower aliphatic ^ hydrocarbon radicals by lower alkoxy, lower alkylthio or Hiederalkoxycarbonyl and as, or in aryl or heteroaryl radicals having at most two rings by lower alkyl, lower alkoxy, Hiederalkylthio, halogen having an atomic number of at most 35 ₉ trifluoromethyl, methylenedioxy, hydroxy, sulfamoyl, IJitro or optionally mono- or disubstituted by lower alkyl or substituted by Uiederalkylen or 3-oxa-1,5-lower alkylene amino substituted or polysubstituted and together and including optionally present substituents 3 to 20 carbon atoms, R is hydrogen or lower alkyl having at most 4 Carbon atoms and A unsubstituted 23 2 59 0 5 "- ^ - ** ⁶ · ¹ · ¹⁹⁸² AP C 07 D / 232 590/0 (59 596/11) or by Hiederalkyl substituted ethylene or trimethylene having a total of at most 4 or 5 carbon atoms, Äthenylen, propenylene or tetramethylene, the radicals ZJ, Z ₂ , Z and Z. Have the meaning given under the formula I, and the ring B is unaubstituiert or in the manner indicated above for aryl R and R ₂ , and their acid addition salts " 3. The method according to item 1, characterized in that compounds of the general formula I given in point 1, in which R. monoheterocyclisches mono Cycle before heteroaryl, which is unsubstituted or substituted by iäiederalkyl, Sfiederalkoxy and / or halogen to atomic number 35 is and is attached via methylene or directly, R _{2 is} just such a radical, or unsubstituted or, as above, for mono-cyclic heteroaryl R-. substituted, substituted phenyl or unsubstituted or, as indicated in point 2, substituted lower alkyl, R is hydrogen or alkyl having at most 4 carbon atoms, and A is ethylene or trimethylene, the radicals Z, Z ₂ , Z and Z, in the point 1 have meaning given and the ring B is unsubstituted or substituted in the manner indicated above for R-, or produces their acid addition salts. 4, Method according to item 1, characterized in that compounds of the general formula I given in point 1, in which R is unsubstituted or substituted by alkyl, Hiederalkoxy and / or halogen to Atomrmmmer 35 it pyridyl which is bonded directly or via methylene , or unsubstituted or correspondingly substituted thienyl or furyl, R _{2 is also} a radical or unsubstituted or, as indicated above for R 1, sub- 232590 5 - 6.1.1982 AP G 07 D / 232 590/0 (59 596/11) atituiertes phenyl, or lower alkyl or lower alkoxycarbonyl lower alkyl, R is hydrogen or alkyl having at most 4 carbon atoms, and A is ethylene or trimethylene, the radicals Z ₁ , Z ₂ , Z_ and Z ^ have the meaning given in point 1 and the ring B unsubstituted or is substituted in the manner indicated above for R ₁ , or produces their acid addition salts · Process according to item 1, characterized in that compounds of the general formula I given in point 1, in which R _{1 is} unsubstituted or by lower alkyl substituted pyridyl, or thienyl, R _{2 is} just such a radical or unsubstituted or by lower alkyl, xliederalkosy or halogen bis Atomic number 35 substituted phenyl, or lower alkyl or itfiederalkoxycarbonylniederalkyl, R is hydrogen or allyalkyl, A is ethylene or trimethylene and Z, Z ₂ , Z and Z are radicals -GH =, of which Z ₂ by halogen to atomic number 35 »in particular chlorine , may be substituted and thus the ring B is unsubstituted or appropriately substituted, or produces their pharmaceutically acceptable acid addition salts. A method according to item 1, characterized in that compounds of the general formula I given in point .1, in which R _{1 is} unsubstituted or substituted by methyl pyridyl, or 2-thienyl, R ₂ just such a radical or unsubstituted or by lower alkyl, lower alkoxy or Halogen to atomic number 35 substituted phenyl, or itfiederalkyl or Miederalkoxy-, carbonyl! Methyl, R _{3 is} hydrogen, methyl or ethyl, A is ethylene or trimethylene and Z ₁ , Z ₂ , Z_ and Z ^ radicals -GH = - 6.1.1982 AP C 07 D / 232 590/0 (59 596/11) Z, of which Z ₂ may be substituted by chlorine, and thus the ring B is unsubstituted or substituted iat appropriately, or produces their pharmaceutically acceptable Säureadaitionssalze, 7. A process according to any one of items 3 to β, characterized in that corresponding compounds of general formula I in which A is ethylene or their pharmaceutically acceptable acid addition salts are prepared. 8. A process as claimed in any one of items 3 to 6, characterized in that aian is corresponding compounds of the general formula I in which A is trimethylene, or produces their pharmaceutically acceptable acid addition salts, 9 «method according to item T, characterized in that the 5-MetJiyl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo. f \ , 2-cj quinazoline or its pharmaceutically acceptable acid addition salts, 10, Process according to item 1, characterized in that the 5-Meth5'l-5- (6-methyl-2-pyridyl-2,3,5,6-tetrah5'droimidazol [i, 2-cJ-quinazoline or produces its pharmaceutically acceptable acid addition salts. 11. A method according to PunK: t 1, characterized in that the 5-But5rl-5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [i, 2-cJ quinazoline or the 5-propyl -5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo [1,2-c-quinazoline or their pharmaceutically acceptable acid addition salts. 23 2 59 0 5 - & - & ~ β.1.1982 AP G 07 D / 232 590/0 (59 596/11) Method according to item 1, characterized in that the 5-metfayl-5- (2-pyridyl) -8-chloro-2,3,5,6-tetrahydroimidazo j_1,2-cJ-quinazoline or its pharmaceutically
produces acceptable acid addition salts. Process according to item 1, characterized in that there is 5-phenyl-5- (4-pyridyl) -2,3 »5,6-tetrahydro-imidazo
1, 2-cinquinazoline or its pharmaceutically acceptable acid addition salts, 14 * Method according to item 1, characterized in that the 5- (4-pyridyl) -2,3,5,6-tetrahydro-imidazo Π j2-cj
quinazolin-5-acetic acid ethyl ester or its pharmaceutically acceptable acid addition salts. 15. A method according to item 1, characterized in that the 6-phenyl-6- (4-pyridyl) -3,4,6,7-tetrahydro-2H-p7rimidojj, 2-cchinazoline or its pharmaceutically acceptable acid addition salts are prepared, 16. The method according to item 1, characterized in that the ö-phenyl-ö- (2-pyridy1) -3,4,6,7-t et rahydro-2H-pyrimido JJl, 2-clchinazoline or its pharmaceutically acceptable acid addition salts manufactures. 17. Method according to. Item 1, characterized in that the 6- (4-methylphenyl) -6- (4-pyridyl) -3,4, β, 7-tetrahydro-2H-pyrimido [i, 2-cJ-quinazoline or its pharmaceutically acceptable Produces acid addition salts. Process according to item 1, characterized in that the 6- (4-chlorophenyl) -6- (4-propyl) -3,4,6,7-tetrahydro-2H-pyrimido [i], 2 -c3-quinazoline or its pharmaceutical 73 2 59 0 5 AP C 07 D / 232 590/0 (59 596/11) produces acceptable acid addition salts. Process according to item 1, characterized in that the 6- (4-pyridyl) -6- (2-tertoxy) -3,4,6,7- "FeyraJaydro-2H-pyrimido ^ 1,2-cJ -quinazoline or its pharmaceutically-acceptable acid addition salts. 20. The method according to item 1, characterized in that the 7-ethyl-6-phenyl-6- (4-P3 ^r ridyl) -3,4,6,7-tetrahydro-2H-pyrimido | j, 2-cj quinazoline or its acceptable acid addition salts.