CA1331608C

CA1331608C - Tetracyclic quinazoline derivatives, their preparation and use

Info

Publication number: CA1331608C
Application number: CA000576970A
Authority: CA
Inventors: Bernd Ostersehlt; Rainer Schlecker; Beatrice Rendenbach; Gerda Von Philipsborn; Albrecht Franke
Original assignee: BASF SE
Current assignee: BASF SE
Priority date: 1987-09-12
Filing date: 1988-09-09
Publication date: 1994-08-23
Anticipated expiration: 2011-08-23
Also published as: ATE74605T1; DE3730718A1; EP0307814B1; ES2032317T3; JPS6471881A; DE3869886D1; EP0307814A3; EP0307814A2; US5214047A

Abstract

ABSTRACT OF THE DISCLOSURE:
New tetracyclic quinazoline derivatives are disclosed, of the formula I:

Description

1331~8 Tetracyclic quinazoline derivatives, their vreparation and use The present invention relates to novel tetracyclic quinazoline derivatives which have valuable therapeutic, especially antiarrhythmic, properties, to a process for the preparation thereof, and to the use thereof for controlling diseases.
It is known that substituted quinazolines have hypotensive and bronchodilator properties (US Patent 3,441,566, German Laid-Open Application DOS 2,162,590).
We have now found that. tetracyclic quinazoline derivatives of the formula (I):

N ~A
R~ ,X ( I ) N~

where A i6 Cz4-alkylene which may be substituted by C14-alkyl and in which 2~ adjacent methylene groups may be part of a ring which contains 5 to 7 carbon atoms and may be substituted by C14-alkyl, X is a phenyl or naphthyl ring which may be substituted by halogen, nitro, amino, C14-: alkylamino, sulfonylamino, C14-acylamino, hydroxyl, C14-alkoxy, -O(CH2)z4-NR1R2 (with R1 and R2 meaning hydrogen or C1 4-alkyl), C14-alkyl or C14- alkylsulfonyl, or X is a thienyl ring which may be substituted by hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, nitro or hydroxyl and R is hydrogen, halogen, halogen, nitro, amino, C14-alkylamino, sulfonylamino, C14-acylamino, hydroxyl, C14-alkoxy, -o-(CHz~24-NR3R4 (with R3 and R4 meaning hydrogen or C14-alkyl), C14-alkyl or C14~alkylsulfonyl, and the salts thereof with physiologically tolerated acids, surprisingly C

. .
~'. ,; ,. . ' ~ " . ' ' ," . . ' ' . ~ , ' ' , . . . ' ' "
~` ' .' ' . . . ' ' , ~ ' ' ", ' ''. . ' .' ' " " , ' , ' ' . , ' : '. . ' ' ` 1331608 are class III antiarrhythmics. A in formula (I) is preferably Cz3-alkylene which may be substituted by one or two C:l.4-alkyl radicals, and is especially Cz3-alkylene which is substituted by one or two methyl radicals, X is preferably a phenyl or thienyl ring which is substituted by hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, ethocy, nitro or hydroxyl, and ~ is preferably ethoxy and especially hydrogen, - 2 _ 1331~ oO50/394z7 fluorine, ch~orine or methoxy.
The compounds of the formula I can be prepared by a) reacting a compound of the formula Il N Al R~H I I

S where A and R have the stated meanings, ~ith an ~-halogeno ketone of the formula III
o Cl ,!~ I I I
X

where X has the stated meaning, or b) reacting a compound of the formula IV

R ~ X IV

where R and X have the stated meanings, with a diamine of the formula V

where A has the stated meaning, and possibly reacting the resulting compound of the formula I~ if X is a phenyl or naphthyl which is subst;tuted by hydroxyl, with an alkyl halide of the formula Vl Hal-(CH2)2_4-NR R VI

~here Hal is halogen, and R1 and R2 have the stated mean-ings, or with a C1_4-alkylsulfonyl chloride, and subsequently possibly converting the resulting compound into a salt thereof ~ith a physiologically tolerated acid.
In the case of process a), the reac~ions are pref-erably carried out in the presence of a diluent or solvent, for example of a lower alcohol, and expediently at temperatures ` : :

- 3 - O.Z. 0050/39427 between 25C and the boiling point of the solvent used~
The reactions are expediently carried out with the addition of a mineral ac;d, eg. HCl, and possiblY in the presence of catalytic amounts of Nal.
The preferred solvent for the reaction of the compounds II and III is ethanol, with the reaction prefer-ably being carr;ed out at the boiling point of the solvent.
Completion of the reaction depends on the reactants and, in general, takes place within 8 to 60 hours. It is possible, in order to complete the reaction, to remove the solvent and to heat the residue at from 90 to 160C, pre-ferably at 110 to 130C, expediently under an N2 atmos-phere, for 2 to 120 hours. The reaction product can be obtained in a conventionaL manner, eg. by filtrat-ion, removaL of the diluent or solvent from the reaction mixture by distillation, or extraction. The resulting compound is purified in a conventional manner, for example by recrystallization from a solvent or conversion into an acid addition compound.
Some of the starting compounds of the general formula II are known or can be prepared by methods known from the literature and as described, for example, in Houben-Weyl, Methoden der organischen Chemie ~Methods of Organic Chemistry), Vol. 11/2, pages 38 et seq.~ G. Thieme Verlag, Stuttgart 1958, by reaction of an appropriate o-amino nitrile with a diamine of the general formula V, preferably uith the addition of catalytic amounts of ammoniu~ sulfide and sulfur.
The ~-halogeno ketones of the general formula III
are known from the literature and can be prepared by Friedel-Cratts acylation of appropriately substituted aromatic compounds with ~-chlorobutyryl ch~oride by methods such as those described, for example, in Pharmazie 35, ~1980), 140 or Industrie Chimique Belge, 9, (1960), 1073. - -Compounds of the general formula III are also obtained by nucleophilic ring opening of appropriately substituted cyclopropyl phenyl ketones with HCl by ~he method described ~, . . , . ~

133~ ~8 - 4 - o.Z. 0050/39427 in Journal of Labelled Compounds and RadioPharmaceuticals 21, (1984), 533.
The reaction of compounds of the general formula IV with a diamine V in process b) can be carried out at room temperature or higher te~peratures, expediently at between 60 and 100C. The starting compounds can be reacted in the presence of an inert, aprotic diluent or solvent. It is also possible to use the diamine V in excess as the diluent or solvent. Subsequently, to carry out the cyclization, after excess diamine and/or solvent has been removed the residue is heated in an inert high-boiling solvent, preferably tetralin, at from 150 to 220C, expediently 180 to 200C. The reaction product is obtained from the reaction mixture in a conventional manner by removing the solvent by distillation. Purific-ation is in a conventional manner, for example by recrys-tallization from a solvent, by column chromatography or by conversion into an acid addit;on compound.
The starting compounds IV can be prepared as follows: an appropriately substituted o-aminobenzoic acid of the general formula VII

R ~ NHOH VII

where R is as defined in the introduction, is reacted with an ~-halogeno ketone of the formuLa III
2S in an inert solvent, eg. benzene, toluene, xylene or chLoro- or dichlorobenzene, expediently in the presence of catalytic amounts of acid, for example p-toluenesulfonic acid. The reaction is expediently carried out at the boiling point of the solvent used ind with a?eotropic removal of the water formed in the reaction. After the reaction is complete, it is possible to obtain the prod-ucts in a conventional manner by removing the solvent by distillation and purify them by recrystallization from a suitabl solvent, preferably an alcohol having 1 to 4 C atoms.
Compounds of the formula I where A and R have the 1331~08 - 5 - O.Z. 0050/39427 stated meanings and X is phenyl or naphthYl which, is sub-stituted by one hydroxyl can be alkylated by known processes.
For alkylation with the aminoalkyl halides VI, for example the anion is, initially formed from the hydroxyl compound S with NaH in an inert aprotic solvent such as dimethyl-formamide, dimethylacetamide, d;methyl sulfoxide or dimeth-oxyethane, and is then reacted with the alkylating agent.
The anion is formed at from O to 100C, preferably from 20 to 50C. The anion is reacted with the alkylating agent at from O to 80C, preferably from room temperature to 50C. The reaction w;th alkylsul-fonyl chlorides is carried out in inert aprotic solvents such as, for example, methylene chloride or chloroform with the addition of an acid-binding agent, preferably a tertiary amine, for example pyridine or triethylamine.
The reaction can be carried out at from -20C to the boiling point of the solvent used, preferably from O
to 60C, especially at room temperature. The products are isolated and purified by conventional methods.
It is possible to convert the resulting compounds according to the invention into the acid addition salts thereof with physiologically tolerated acids. Examples of suitable conventional physiologically tolerated organic or inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzo;c acid. Others can be found in Fortschritte der Arzneimittelforschung, Vol. 10, pages 224 et seq., Birkhauser Verlag, ~asel and Stuttgart, 1966~
The acid addition salts are, as a rule, obtained in a conventional~manner by mixing the free~ base or sol-utions thereof with the appropriate acid or solutions thereof in an organic soLvent, for example a lower alcohol such as methanol, ethanol or propanol, or æn ether such as diethyl ether or methyl t-butylether. It is also pos-sible, to improve deposition of crystals, to use mixtures of the said solvents. Furthermore, pharmaceutically 13316~8 - 6 - o.Z. 0050/39427 acceptable aqueous solutions of acid addition compounds of the compounds I according to the invention can be pre-pared by dissolving the free bases in an aqueous acid solution.
The compounds of the formula I according to the invention have a center of chirality and are obtained as racemates which can be separated by conventional methods, for example by forming diastereomeric salts with optically active acids, into the optically active antipodes.
In some cases, the compounds of the formula I
according to the invention have, depending on the choice of the amines V used, a second asymmetr;c carbon atom and can then be in the form of mixtures of diastereomers which can be separated in a conventional manner using physical/
chemical methods into the pairs of diastereomers.
The noveL compounds are antiarrhythmics. Vaughan ~illiams divides the latter into four groups, as follows:
I. Na channel inhibitors, II. Adrenergic ~-receptor blockers III. K channel inhibitors and IV. Ca antagonists The novel compounds are to be allocated to class III. As such, they a~e preferable to other antiarrhythmics in therapy, because they act on arrhythmias of various etiologies which are otherwise therapy-resistant. They abolish ventricular arrhythmias which occur after myocar-dial infarction and are based on a re-entry mechanism.
In addition, they also act well on atrial dysrhythmias.
Class III antiarrhythmics result in a prolongation of the QT interval in the E~G, without affecting the PQ interval and ~ithout markedly reducing the heart rabe.
The action of the novel substances has been tested as follo~s:
The experimental animals used were male and female Pirbright white guinea pigs weighing 300-500 9. 1.5 g/kg urethane i.p. were used for anesthesia. The substances were administered intravenously. The extremity lead II

1331~08 - 7 - 0.~. 0050t39427 was recorded to measure the ECG conduct;on t;mes and the heart rate. The ~easured variables were the QT and PQ
;ntervals and the heart rate. 4-6 an;~als were used for each dose. The criterion for a class III action was an increase in the QT ;nterval compared with the values before administration of the substance. A PQ increase and a ~arge decrease in the heart rate were used as exclusion criter;a. The ED20% is calculated from the linear relation between log dose tmg/kg) of the substance and the relative prolongation of the QT interval (~ X). The table shows the values obtained, together with the potency related to that of d-sotalol.
TAaLE
Prolongation of Potency relative to the QT interval that of d-sotalol Substance f ED2o% = 1.0 Example No. mg/kg 1 1.0 3.6 2 1.1 3.3 4 0.21 17 1.0 3.5 7 0.86 4.3 8 0.61 6.0 9 1.5 2.4 11 0.40 9.0 13 0.99 3.7 0.43 8.5 19 1.4 2.6 21 0.46 8.0 22 0.56 6.5 24 0.29 12 0.58 6.2 26 1.5 2.4 27 0.42 8.7 28 0.94 3.9 29 0.55 6.6 1.0 3.6 133~08 - 8 - o.Z. 0050/39427 Prolongat;on of Potency relative to the QT interval that of d-sotaLol Substance of ED20% = 1.0 Example Ho. mg/kg 31 0.56 6.5 33 1.5 2.4 34 0.61 6.0 0.63 5.7 37 0.69 5.3 38 0.83 4.4 41 0.46 7.8 42 0.78 4.7 43 0.60 6.1 44 0.49 7.4 0.59 6.2 46 0.55 6.7 47 0.52 7.0 48 0.31 11.8 49 0.32 11 2Q 50 0.25 15 53 1.0 3.6 d-sota~ol 3.6 1.0 The table shows that in terms of QT prolongation the substances according to the invention are 2.4 to 17 times as effective as the known class III antiarrhythmic d-sotalol.
The compounds according to the invention can be administered orally or parenterally (subcutaneously, in-travenously, intramuscularly or intraperitoneally) in a conventional manner. Administration can also take place with vapors or sp~ays ~hrough the nasophary~ngeal space.
The dosage depends on the age, condition and weight of the patient and on the mode of administration.
As a rule, the daily dose of active compound is from about 10 to 500 mg per patient and day on oral administration and from about 1 to 50 mg per patient and day on parenteral administration.

13316~8 _ 9 _ o.~. 0050/39427 The novel compounds can be used in conventional solid or liquid pharmaceut,cal administration forms, eg. as tablets, film-coated tablets, capsules, po~ders, granules, sugar-coated tablets, suppositories, solutions or sprays. These are prepared in a conventional manner.
It is possible in this connection for the active compounds to be processed with the customary pharmaceutical auxil-iaries such as tablet binders, fillers, preservatives, tablet disintegrants, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, retardants, antioxidants and/or propellant gases (cf.
H. Sucker et al.: Pharmazeutische Technologie (Pharma-ceutical Technology), Thieme Verlag, Stuttgart, 1978).
The administration forms obtained in this way normally contain fro0 1 to 99~ by weight of the active compound.
The Examples which follow are intended to explain the invention ;n detail.
EXAMPLE 1:
2,3,5,6,7,8-Hexahydro-5-(4-methylphenyl)imidazoC1,2-c]-Z0 pyrrolo~1,2-a~quina2Oline A mixture of 10.2 9 of 4-chloro-1-(4-methylphenyl)-1-butanone, 8.1 9 of 2-~2-aminophenyl)-4,5-dihydroimidazole, 0.5 9 of sodium iodide and 250 mL of ethanol at roo~ tem-perature was mixed with 5.5 ml of 12 N HCl and then re-fluxed for 30 h. The solvent was removed, and the residuewas heated at 120C under an N2 atmosphere for 4 h.
After cooling, the residue was partitioned in H20tmethyl t-butyl ether, and the insoluble constituents were removed by filtration wi~h suction. The phases were separated, and the aqueous phase was basified with 5 N sodium hydr-oxide sol;ution, rèsulting in the formation of a yellow-brown substance in the form of an oil, which was extracted by shaking three times with methylene chloride. The solution was dried with MgS04 and then fiLtered, the solvent was removed by distillation, and the crude product (13.1 9) was dissolved in hot ethyl acetate. The product separated out in the form of colorless crystals on cooling.

133~ 608 - 10 - 0.~. OOS0/3942 Yield: 10.8 9 (71%), melting point 187-189C;
C20H21N3 (3Q3.4) calc. C 79.17 H 6.98 N 13.85 found C 78.9 H 7.1 N 13.8 The following ~ere prepared in analogy to Example 5 1:
Z. 5-(4-Chlorophenyl)-2,3,5,6,7,8-hexahydroimidazoC1,2-c~pyrrolo~1,2-a~quinazoline Yield: 7.2 9 (36%), melting point 158-160C (ethanol) 3. 12-Chloro-2,3,5,6,7,8-hexahydro-S-phenylimidazoC1,2-c~pyrroloC1,2-a]quinazoline Yield: 8.9 9 (54~), melting point 249-250C (ethanol) 4. 5-(4-Fluorophenyl)-2,3,5,6,7,8-hexahydroimidazoC1,2-c~pyrrolo[1,2-a]quinazoline Yield: 10.5 9 (68%), melting point 177C (decomposition) 5. 2,3,5,6,7,8-Hexahydro-11,12-dimethoxy-5-phenylimi-dazot1,2-c]pyrroloC1,2-a]qu;nazoline Yield: 4.8 9 (SlX), melting point 171C (ethanol) 6. 2,3,5,6,7,8-Hexahydro-11,12-dimethoxy-5-(3,4-dimethoxyphenyl)imidazoC1,2-c]pyrroloC1,Z-a]quinazoline hydrochloride Yield: 4.5 g ~62X), melting point 221C (decomposition) ~i~opropanol) 7. 2,3,5,6,7,8-Hexahydro-5-(4-hydroxyphenyl)imidazo-C1,2-c]pyrroloCI,2-a]quinazoline hydrochloride Yield: 25.3 9 (74%), melting point 275-277C (decompos-ition) (methanol/ethanol) 8. 2,3,5,6,7,8-Hexahydro-5-(4-methoxyphenyl)imidazo-C1,2-c]pyrroloC1,2-a]quinazoline Yield: 7.7 9 (48X), melting point 110-112C
9. 5-(3,4-Dichlorophenyl)-2,3,5,6,7,8-hexahydroimi-dazotl,2-c]pyrroLoC1,2-ajquinazoline Yield: 4.4 9 (71%), melting point 213-222C
10. 2,3,5,6,7,8-Hexahydro-5-(2,4-dimethylphenyl)imi-dazoC1,2-c]pyrroloC1,2-a]quinazoLine Yield: 5.0 9 (32%), meltin~ point 175-180C (decomposition) 11. 11-Chloro-2,3,5,6,7,8-hexahydro-S-phenylimidazo-C1,2-c~pyrroloC1,2-a]quinazoline 13316~8 - 11 - o.z. OOS0/39427 Yield: 10.0 9 (62%), melting point 177-181C

12. 2,3,5,6,7,8-Hexahydro-5-t2-thienyl)imidazo[1,2-c]py-rroloC1,2-a]quinazoline Yield: 7.5 9 (51i), melting point 159-161C
S 13. 5-(2,4-Dichlorophenyl)-2,3,5,6,7,8-hexahydroimi-dazot1,2-c~pyrroloC1,2-a]quinazoline hydrochloride Yield: lO.l 9 (51%), melting point 200C (decomposition) (ethanol/methyl t-butyl ether) 14. 5-(4-~romophenyl)-2,3,5,6,7,8-hexahydroimidazo-C1,Z-c~pyrrolot1,2-a]quinazoline hydrochloride Yield: 8.2 9 (52%), melting point 273-274C
(ethanol/methyl t-butyL ether) 15. 11-Chloro-5-(4-fluorophenyl)-2,3,5,6,7,8-hexahy-droim;dazoC1,2-c]pyrroloC1,2-a]quinazoline hydrochloride IS Yield: 16.9 9 (82%), melting point 240-243C
(ethanol/methyl t-butyl ether) 16. 5-(4-Aminophenyl)-2,3,5,6,7,8-hexahydroimidazo-t1,2-c~pyrroloC1,2-a]quinazoline hydrochloride Yield: 3.9 9 t32%), melting point 259-261C
~thanol/diethyL ether) 17. 2,3,5,6,7,8-Hexahydro-5-(a-naphthyl)imidazoC1,2-c~pyrrolot1,2-a~quinazoline Yield: 6.4 9 (61%), melting point 216-217C (decomposition) 18. 2,3,5,6,7,8-Hexahydro-5-(3-nitrophenyl)imidazo-C1,2-c]pyrroloC1,2-a}quinazoline hydrochloride Yield: 8.0 9 (86%), melting point 297-298C
(ethanol/methyl t-butyl ether) 19. 5-(2-(5-Chlorothienyl))-2,3,5,6,7,8-hexahydroimi-dazoC1,2-c]pyrrolo[1,2-a]quinazoline hydrochloride Yield: 13.4 g (73%), melting point 245-248C
(ethanol/diethyl ether) 20. 2,3,5,6,7,8-Hexahydro-5-(4-methylsulfonylamino-phenyl)imidazoC1,Z-c]pyrroloC1,2-a]quinazoline hydrochloride Yield: 8.4 9 (59%), melting point 296-297C ~methanol~
21. 2,3,5,6,7,8-Hexahydro-S-(4-nitrophenyl)imidazo-t1,2-c]pyrrolot1,2-a]quinazoLine hydrochloride ~ . , ~ , - 12 - O.Z. 0050/39427 Yield: 1.5 9 t51%), melting point 295C (decomposition) ~ethanol) 22. 2,3,5,6,7,8-Hexahydro-2,3-tetramethylene-S-phen-ylimidazot1,2-c]pyrroloC1,2-a~uinazoline S Yield: 3.9 9 (51Z), melting po;nt 168-170C
23. 2,3,5,6,7,8-Hexahydro-5-~4-fluoropheny~)-2,3-tetramethyleneimidazoC1,2-c~pyrroloC1,2-a]quinazoline hydrochloride Yield: 5.7 9 (67%), melting point 160C (decomposition) (ethanol) 24. 2,3,5,6,7,8-Hexahydro-3-methyl-S-phenylimidazo-C1,2-c~pyrroloC1,2-a]quinazoline hydrochloride Yield: 2.8 9 (29%), melting point 238-240C (ethanol/
methyl t-butyl ether) 25. 2,3,6,7,8,9-Hexahydro-6-(2-thienyl)-2H-pyrimidoC1, 2-c]pyrroloC1,2-a]quinazoline Yield: 5.2 9 (34X), melting point 136-138C
26. 6-(4-Chlorophenyl)-2,3,6,7,8,9-hexahydro-2H-py-rimidoC1,2-c]pyrroloC1,2-a]quinazoline Yield: 10.3 9 (61Z), melting point 148-150C
27. 6-~4-Fluorophenyl)-2,3,5,6,7,8-hexahydro-2H-py-rimidoC1,2-c~pyrroloC1,2-a]quinazoline Yield: 9.1 9 (57X), melting point 154-156t 28. 6-~3,4-Dichlorophenyl)-2,3,5,6,7,8-hexahydro-2H-pyrimidoC1,2-c]pyrroloC1,2-a]quinazoline Yield: 3.5 g (51X), melting point 155-157C
29. 13-Chloro-2,3,5,6,7,8-hexahydro-6-phenyl-2H-pyrimidoC1,2-c]pyrroloC1,2-a]quinazoline hydrochloride Yie~d: 4.5 g (24X), melting point 320C (decomposition) (ethanol~methy~ t-butyl ether) 30. 13-Chloro-6-(4-fluorophenyl)-2,3,5,6,7,8-hexahydro-2H-pyrimidoC1,2-c]pyrroloC1,2-a~quinazoline Yield: 9.3 g t53Z), melting point 197-201C
31. Z,3,5,6,7,8-Hexahydro-6-(3-nitrophenyl)-2H-py-rimidoC1,2-c]pyrroloC1,2-a]quinazol;ne Yield: 7.5 9 (47%), melting point 141-143C
32. 2,3,5,6,7,8-Hexahydro-6-(4-methylsulfonylaminophenyl)- -i331~08 - 13 - o.Z. 0050/39427 2H-pyrimidot1,2-c]pyrroloC1,2-a]quinazoline hydrochloride Yield: 5.6 9 (41~), meLting point 175-177C (decomposition) (acetone/water) 33. 6-(2-(5-Chlorothienyl))-2,3,5,6,7,8-hexahydro-2H-pyrimidot1,2-c]pyrroloC1,2-a]quinazoline Yield: 5.6 9 (33X), melting point 245C tdecomposition) ~ethanol/diethyl ether) 34. 2,3,5,6,7,8-Hexahydro-6-(4-nitrophenyl)-ZH-pyrimidoC1,2-c]pyrroloC1,2-a]quinazoline YieLd: 9.6 9 (61%), melting point 287C (decomposition) (methanol) 35. 2,3,5,6~7,8-Hexahydro-6-(4-methoxyphenyl)-2H-pyrimidot1,2-c]pyrroloC1,2-a]quinazoline hydrochloride Yie~d: 4.1 9 (22X), melting point Z47C (ethanol/methyl t-butyl ether) 36. 6-(2,4-Dichlorophenyl)-2,3,5,6,7,8-hexahydro-2H-pyrimido[1,2-c]pyrroloC1,2-a]qu;nazoline fumarate Yield: 6.0 9 (40~), melting point 207-209C (decomposition) ~ethanol/methyl t-butyl ether) 37. 12-Chloro-2,3,5,6,7,8-hexahydro-6-phenyl-2H-pyrimido~1,2-c]pyrroloC1,2-a~quinazoline hydrochloride Yield: 10.8 9 (58%), melting point 289-292C (ethanol) 38. 2-Chloro-6-(4-fluorophenyl)-2,3,5,6,7,8-hexahydro-2H-pyrimidoCI,2-c]pyrroloC1,2-a~quinazoline hydrochloride Yield: 6.9 9 (35X), melting point 271-273C (ethanol) 39. 2,3,5,6,7,8-Hexahydro-6-(4-hydroxyphenyl)-2H-pyrimidoC1,2-G]pyrroloC1,2-a]quinazoline hydrochloride Yield: 11.0 9 (62X), melting point 150C (decomposition) (ethanol) 40. 6-(4-Bromophenyl)-2,3,5,6,7,8-hexahydro-2H-py-rimidoC1,2-c]pyrrolot1,2-a]quinazoline hydrochloride Yield: 7.0 9 (43X), melting point 298-302C (decomposition) (ethanol/methyl t-butyl ether) 41. 2,3,5,6,7,8-Hexahydro-3,3-dimethyl-6-phenyl-2H-pyrimidoC1,2-c]pyrroloCI,2-a]quinazoline hydrochloride Yield: 8.9 9 (49X), melting point 304-306C (ethanol) 42. 2,3,5,6,7,8-He~ahydro-3,3-dimethyL-6-(4-nitrophenyl)-1331~08 - 14 - O.Z. OO50t39427 2~-pyrimidoC1,2-c]pyrrolo~1,2-a]~uinazoline hydrochloride YieLd: 2.6 9 t63~), melting point 326C (ethanol) 43. 2,3,5,6,7,8-Hexahydro-3,3-dimethyl-5-phenyLimi-dazoC1,2-c]pyrroloC1,2-a]quinazoLine hydrochloride YieLd: 15.0 9 (80Z), meLting point 269C (ethanol) 44. 2,3,5,6,7,8-Hexahydro-4,4-dimethyl-6-phenyl-2H-pyrimidot1,2-c]pyrroloC1,2-a~quinazoline hydrochloride Yield: 6.5 9 ~72~), melt;ng point 287C (ethanoL/~ethyl t butyl ether) 45. 5-(4-Fluorophenyl)-2,3,5,6,7,8-hexahydro-3,3-dimethyLimidazoC1,2-c]pyr oLoC1,2-a]quinazoline hydrochLoride Yield: 3.9 9 (35~), melting point 251C (ethanoL) 46. 2,3,5,6,7,8-Hexahydro-3,3-dimethyl-5-(4-nitro-phenyl)imidazol1,2-c]pyrrolo~1,2-a]quinazoline hydrochloride Yield: 5.3 9 t46~), melting point >300C (ethanol) 47. 2,3,5,6,7,8-Hexahydro-4,4 dimethyl-6-(4-nitro-phenyl)-2H-pyrimidoC1,2-c]pyrroloC1,2-aJquinazoline hydrochloride Yield: 5.0 9 ~47X), melting point >300C (ethanol) 48. 2,3,5,6,7,8-Hexahydro-3-methyl-5-(4-nitrophenyl)-imidazoC1,2-c]pyrroloC1,2-a]quinazoline hydrochLoride Yield: 5.1 9 (46%), melting point 283-285C (ethanol) 2,3,5,6,7,8-Hexahydro-6-phenyl-2H-pyrimido~1,2-c]pyrrolo-C1,2-a~quinazoline hydrochloride a) 1,2,3,3a-Tetrahydro-3a-phenyl-SH-pyrroloC1,2-a~-3,1-benzoxazin-5-one (Formula IV, R3 = H, X = C6Hs) A mixture of 26.1 9 of 2-aminobenzoic acid, 36.5 9 of 4-chloro-1-phenyl-1-butanone~ 0.5 9 of p-toluenesul-fonic aci!d and 250 ml of xylene were refluxed with a water trap. After the reaction was complete, the solvent was removed by distillation and the remaining solid was re-crystallized from ethanol. Yield: 41.1 9 (81.5~), melt-ing point 152C.b) 2,3,5,6,7,8-Hexahydro-6-phenyl-2H-pyrimidoC1,2-c]-pyrroloC1,2-a~quinazoline hydrochloride - 15 - O.Z. OOS0/39427 6.Z g of 1,2,3,3a-tetrahydro-3a-phenyl-SH-pyrrolo-~1,2-a~-3,1-benzoxazin-S-one were dissolved in 15 ml of 1,3-diaminopropane and stirred at 80C for 3 h. Then 35 ml of tetralin were added to this solution, the inter-S nal temperature was increased to 190C within 30 min,and the excess diamine was removed by distillation. After 6 h, the mixture was concentrated at 190C under reduced pressure, and the residue was allowed to cool to about 70C and was dissolved in 15 ml of ethanol.
The crude product which slowly crystallized out after addition of 8 ml of 3 N ethereal HCl was filtered off with suction and washed with a little ethanol.
Yield: 4.4 9 (55.5%), melting point 285-286C
The follo~ing was prepared in analogy to Example 49:
S0. 2,3,5,6,7,8-Hexahydro-S-phenylimidazo~1,2-c]-pyrrolo~1,2-a~quinazoline hydrochloride Yield: 3.6 9 t45X); melting point 308-3~0C

2û 2,3,5,6,7,8-Hexahydro-5-(4-~2-dimethylaminoethoxy)phenyl)-imidazo~1,2-c]pyrrolo~1,2-a]quinazoline hydrochloride S g of 2,3,5,6,7,8-hexahydro-5-~4-hydroxyphenyl)imi-dazoC1,2-c]pyrroloC1,2-a~quinazoline hydrochloride (Ex-ample 7) suspended in 200 ml of dimethylformamide were slowly added at room temperature to a suspension of 1.5 9 of sodium hydride in 100 ml dimethylformamide. After evol-ution of gas was complete, 3 9 of 2-chloroethyldimethyl-amine were added, and the mixture was stirred at room temperature for 20 h. The reaction solution was mixed with H2O and extracted with methylene chloride. The organic phase was wafshed with H20, dried over magnes;um sulfate and concentrated. The remaining oily residue was taken up in a little isopropanol, 4.5 ml of 3 N ethereal HCl were added, and the solid which separated out was recrystallized from ethanol/methyl t-butyl ether. Yield:
2.0 ~ (33X); melting point 304C (decomposition).
The follo~ing was prepared by a similar method:

~ . .. ~

1331S~8 - 16 - o.Z. OO50t39427 52. 2,3,5,6,7,8-Hexahydro-5-(4-(2-pyrrolidinoethoxy)-phenyl)imidazol1,2-c]pyrrolo~1,2-a]quina~oline dihydro-chloride Yield: 6.1 9 (43%); melting point 289C (methanol/methyl t-b~tyl ether) 53. 2,3,5,6,7,8-Hexahydro-5-(4-methylsulfonyloxyphenyl)-imidazo~1,2-c]pyrrolo~1,2-a]quinazoline hydrochloride 6 ml of methylsulfonyl chloride were added drop-wise at 0-5C to a vigorously stirred suspension of 8.55 9 of 2,3,5,6,7,8-hexahydro-5-(4-hydroxyphenyl)imidazo-l1,2-c]pyrrolo~1,2-a~quinazoline hydrochloride in 100 ml of methylene chloride and 25 ml of pyridine, and the reac-tion mixture was stirred at room temperature for 70 h.
The solvent was removed by distillation and then 1 ~ HCl was added, and the resulting precipitate was recrystallized from ethanoltmethyl t-butyl ether. Yield: 8.0 9 (76%);
melting point 241-242C (decomposition).
Examples of pharmàceutical administration forms:
A) Tablets of the following composition are compressed in a tabletting press in a conventional manner:
mg of substance of Example 28 120 mg of corn starch 13.5 mg of gelatin 4~ mg of lactose 2.25 mg of Aerosil(R) (chemically pure silica in sub-microscopically fine distribution) 6.~5 mg of potato starch (as 6~ paste) ~) Sugar-coated tablets of the following composition are prepared in a conventional manner:
20 mg of substance of Example 42 60 mg of core composition 60 mg of sugar-coating composition The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of Luviskol(R) VA
; 35 64 (60:40 copolymer of vinylpyrrolidone/vinyl acetate, cf. Pharm. Ind. 1962, 586)~ The sugar-coating composition consists of 5 parts of sucrose, 2 parts of corn starch, ~ . , .. , , . . ~ . .

- 17 - o.Z. 005~/39427 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets prepared in this way are then provided ~ith an enteric coating.
C) 10 9 of substance of Example 41 are dissolved in 5000 ml of water with the addition of NaCl, and the pH
is adjusted to 6.0 with 0.1 N NaOH so that a solution which is isotonic with blood is produced. l ml portions of this solution are dispensed into ampoules and sterili~ed.

Claims

1. A tetracyclic quinazoline derivative of the formula (I):

(I) where A is C2-4-alkylene which may be substituted by C1-4-alkyl and in which two adjacent methylene groups may additionally be part of a ring which contains 5 to 7 carbon atoms and may be substituted by C1-4-alkyl, X is a phenyl or naphthyl ring which may be substituted by halogen, nitro, amino, C1-4-alkyl-amino, sulfonylamino, C1-4-acylamino, hydroxyl, C1-4-alkoxy, -O(CH2)2-4-NR1R2 (with R1 and R2 meaning hydrogen or C1-4-alkyl), C1-4-alkyl or C1-4-alkylsulfonyl, or X is a thienyl ring which may be substituted by hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, nitro or hydroxyl and R is hydrogen, halogen, nitro, amino, C1-4-alkylamino, sulfonylamino, C14-acylamino, hydroxyl, C1-4-alkoxy, -O-(CH2)2-4-NR3R4 (with R3 and R4 meaning hydrogen or C1-4-alkyl), C1-4-alkyl or C1-4-alkylsulfonyl, and the salts thereof with physiologically tolerated acids.

2. A tetracyclic quinazoline derivative of the formula (I) as claimed in claim 1, wherein A is C2-3-alkylene which may be substituted by one or two C1-4-alkyl radicals, X is a phenyl or thienyl ring which is substituted by hydrogen, chlorine, fluorine, methyl, ethyl, methoxy, ethoxy, nitro or hydroxyl, and R is hydrogen, fluorine, chlorine, methoxy or ethoxy.

3. A tetracyclic quinazoline derivative as claimed in claim 2, wherein A is C2-3-alkylene which is substituted by one or two methyl radicals.

4. A process for the preparation of a tetracyclic quinazoline derivative of the formula (I) as claimed in claim 1, which comprises:
a) reacting a compound of the formula (II):

(II) where A and R are as defined in claim 1, with an .omega.-halogeno-ketone of the formula (III):

t III ) where X is as defined in claim 1, or b) reacting a compound of the formula (IV):

( IV ) where R and X are as defined in claim 1, with a diamine of the formula (V):

H2N-A-NH2 (V) , where A is as defined in claim 1, and, if desired, reacting the resulting compound of the formula (I), if X is a phenyl or naphthyl which is substituted by hydroxyl, with an alkyl halide of the formula (VI):

Hal-(CH2)2-4-NR1R2 (VI) where Hal is halogen, and R1 and R2 are as defined in claim 1, or with a C1-4-alkylsulfonyl chloride, and subsequently, if desired, converting the resulting compound into a salt thereof with a physiologically tolerated acid.

5. A tetracyclic quinazoline derivative of the formula (I) as claimed in claim 1, 2 or 3, for use for controlling atrial and ventricular dysrhythmias.

6. The use of a tetracyclic quinazoline deriva-tive of the formula (I) as claimed in claim 1, 2 or 3, for preparing drugs for controlling atrial and ventricular dysrhythmias.