CA1208636A - Tricyclic quinazolinones - Google Patents

Abstract

TRICYCLIC QUINAZOLINONES

Abstract Compounds of formula I

I

wherein a) R1 represents one of the following groups wherein m represents 0, 1, 29 3 or 4, p represents 1 or 2, q represents 0, 1 or 2 R7 represents hydrogen or C1-2alkyl, R8 represents hydrogen, halogen or C1-3alkyl, R9 represents hydrogen, halogen, C1-4alkyl, trifluoromethyl or nitro, R2, R3 and R4 represent, independently, hydrogen or C1-2alkyl, R5 represents hydrogen, halogen, C1-4alkyl, trifluoromethyl or nitro and R6 represents hydrogen, halogen or C1-3alkyl, and n represents 0 or 1 whereby at least one of R2, R3 and R4 is hydrogen, or b) R1 represents C1-8alkyl, unsubstituted or substituted by 1 to 3 fluorine atoms R5 is in b-position and represents fluorine, chlorine or trifluoro-methyl, n represents 0 or 1 and R2, R3, R4 and R6 represent hydrogen, with the proviso that R1 is other than methyl when R5 is chlorine and n is 1, or c) R1 represents C3-6alkenyl, C3-6alkynyl, C3-8cycloalkyl, norbornyl or C3-7cycloalkyl-(C1-3)-alkyl, R2, R3 and R4 represent, independently, hydrogen or C1-2alkyl, R5 is in b-position and represents halogen, C1-4alkyl or trifluoro-methyl, R6 represents hydrogen, halogen or C1-3alkyl, n represents 0 or 1, in free base form or in the form of a pharmaceutically acceptable acid addition salt for use as traquillizers.
These compounds are indicated for use as pharmaceuticals, in particular as tranquillizers.

Description

3~i Case 600-6~04/X
TRICYCLIC QUINAZOLINONES

The present invention concerns tricyclic quinazolinones, processes for their production, pharmaceutical connpositions containing them and their use as pharmaceuticals.

5 More particularly the inYention relates to compounds of formula I

~ ~ I
bR ~ ~C~4H ~ 3 wherein a) Rl represents one of the following groups ~(CH)m ~ Rg `Rg Xa Xb -o-(CH2)p ~ Rg -(CH2) Xc Xd wherein m represents 0, 1, 2, 3 or 4, - p represents 1 or 2, q represents 0, 1 or 2 R7 represents hydrogen or Cl 2alkyl, R~ represents hydrogen, halogen or Cl 3alkyl, Rg represents hydrogen, halogen, Cl 4alkyl, trifluoromethyl or nitro, R2, R3 and R4 represent, independently, hydrogen or Cl 2alkyl~
R5 represents hydrogen, halogen, Cl 4alkyl, trifluoromethyl or nitro and .

~ .

,

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R6 represents hydrogen, halogen or Cl 3alkyl, and n represents 0 or 1 ~hereby at least one of R2, R3 and R4 is hydrogen, or b) Rl represents Cl 8alkyl, unsubstituted or substituted by 1 to 3 fluorine atoms on other -~m the ~-carbon atom, R5 is in b-position and represents fluorine, chlorine or trifluoro-methyl, n represents 0 or 1 and R2, R3, R4 and R6 represent hydrogen, with the pro~iso that Rl is other than methyl when R5 is chlorine and n is 1, or c) Rl represents C3 6alkenyl, C3 6alkynyl, C3 8cycloalkyl, norbornyl or C3 7cycloalkyl-(Cl 3)-alkyl, R2, R3 and R4 represent, independently, hydrogen or Cl 2alkyl, R5 is in b-position and represents halogen, Cl 4alkyl or trifluoro-methyl, R6 represents hydrogen, halogen or Cl 3alkyl, n represents 0 or 1, in free base form or in the form of an acid addition salt.
20 Unless otherwise mentioned halogen has an atomic ~eight of from 18 to 80. Alkyl groups may be straight chain or branched. When m = 2 the two resulting ~ groups may be independently of each other hydrogen or Cl 2alkyl.

The compounds of formula I possess pharmaceutical, in particular CNS
25 activity as indicated by their ability to reduce conflicts in the Geller Conflict test in rats (1-20 mg/kg~ by the method basically described by I. Geller, Psychopharmacologia, Vol. 1, pages 482-4~2(1960)(Test A);
by the Flunitrazepam binding assay carried out analcgously to the method described by Chang and Snyder Eur. J. Pharmacol. 48, 213 [1978] slightly modified as follows (Test B):

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Fresh calf brain cortex is homogenized in a l9fold volume of Tris-HCl buffer pH 7.4, using a Brinkman Polytron PT 20 and centrifuged at 50'000 9 for 10 min. The pellets are frozen at -20C and resuspended in a 400fold volume of Tris-buffer pH 7.4 before use for the binding assay. The assay mixtures consist of 1.8 ml of homogenate (corresponding to 4.5 mg of original tissue), 0.1 ml [3H]-Flunitrazepam (final concentration 1.5 nM), and 0.1 ml of buffer for determination of total binding or 0.1 ml of unlabelled Flunitrazepam (final concentration 1 ~IM) for determination of 10 nonspecific binding, respectively. To assess the potency of various drugs in inhibiting specific binding, drugs are added (instead of buffer) to give 5 to 9 different concentrations bet~een 1 nM and 10 ~M, each in duplicate. After incubation for 15 min. at 0C, the assay mixtures are rapidly filtered through 15 Whatman GF/'B filters and washed t~ice with 5 ml of ice cold Tris-buffer. The filters are counted in Rialuma on a LKB Rach-Beta Liquid Sciniillation Counter. IC50 values (concentration of test drug which inhibits specific binding of H-Flunitrazepam by 50%) are determined by linear regression analysis (HILL-Plot).

20 Alternatively the assay can be carried out analogously to the method described by R.C. Speth et.al., Life Science, 22: 859 (1978) again slightly modified as follo~s STest C)a)]

An aliquot of frozen calf caudate tissues is thawed and diluted wilh 0.5M Tris-buffer containing metal ions (120mM NaCl, 5mM KCL, 2mM CaC12 25 and lmM MgC12) to a final concentration of 8 mg/ml, i.e., a ~5 fold dilution. ~his suspension is made homogenous by homogenation ~lith a Brinkmann Polytron using a rheostat se~ting of 8 for 10 seconds.
Ten ~ of H-Flunitrazepam solution is diluted in 0.05M Tris-buffer (pH 7.1 at 37C) to give a concentration of lOn~l (3.13 x 10 ~ mg/ml~.

. , 8~j~3Ç~

4 ~006904/X
A 0.1 ml portion of lOnM I~Flunitrazepam solution is added to 12 x 75 mm borosilicate test tubes along with 0.1 ml of freshly prepared 10~ ethanol solution. This is the control tube for measuring total binding. Non-specific binding is determined by the addition of 2 x 10 5M diazepam (in 10% ethanol) to other tubes in the place of 0.1 ml 10% ethanol. The specific binding is determined by subtraction of the non-specific binding from the total binding. All compounds screened have their results expressed in terms of specific binding and are tested at a final concentration of 1 x 10 6M. Three mg of 10 each compound are placed in 18 x 150 mm borosilicate test tubes. Then 10 ml of absolute ethanol is added and the tubes placed in a Branson Ultrasonic Cleaner for 15 minutes and then vortexed in order to put the compol~nds into solution. If the compound is not in solution 3 drops of 2N HCl is added. If the compound(s) are still not in 15 solution but a cloudy homogenous suspension is found, then the subsequent dilutions are continued. This gives a concentration of 1 x 10 3M. The compound is further diluted by serial dilution as follows: 0.1 ml of the 10 3M solution is added to 0.9 ml of 100% ethanol and vortexed. A 0.1 ml portion 20 of this solution is added to 0.9 ml of water to give 1 X 10 5M solution. A 0.1 ml portion of this solution is added to 12 x 75 mm test tubes for assay. All assays are run in duplicate.
A 0.8 ml portion of caudate tissue is added to all tubes, vortexed, incubated at 2C for 120 minutes, and rapidly filtered under vacuum 25 through Whatman GF/G glass fiber filters. Each tube is rinsed once with 3 ml ice-cold 50mM Tris-Buffer (pH 7.1 at 37C) and the filter subsequently washed once with 6 ml of the same Tris-buffer. The 3H-Flunitrazepam trapped on the filter is counted by liquid scintillation counting on a Beckman LS 8000 after the 30 filters are rapidly shaken for ~5 minutes in the scintillation vials with 10 ml of scintillation cocktail. Results of compounds screened ~L~ 8tj3Ç~

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are calculated by the on-line data reduction system in the Beckman LS 8000, and are expressed as a percent specifically bound compared to control.

The benzodiazepine receptors are obtained from male Holstein calves.
Immediately after exsanguination, the brains are quickly removed and placed in ice. Dissection of the caudate nucleus is completed within 2 hours after sacrifice and the tissue weighed, and homogenized (1:10, W/V) in .05M Tris-buffer (pH 7.1 at 37C) using a ~rinkmann Polytron for 10 seconds ~ith a rheostat setting of 8. The 10 homogenate is centrifuged for 10 minutes at 20,000 RPM in a Sorvall RC2B centrifuge using a SS 34 head. The supernatant ;s decanted and the pellet washed twice to remove endogenous dopamine by resuspension with the use of the Brinkmann Polytron and recentrifuation. The final pellet is resuspended in 0.05~1 Tris buffer 15 (pH 7.1 at 37C) containing 120mM NaCl~ 5mM Kcl, 2mM CaC12, and lmM
MgC12 in a final concentration of 200 mg wet weight starting material/ml of buffer. The homogenate is stored in 4 ml aliquots in glass bottles in liquid nitrogen.

The compounds of the formula I exhibit a relatively high affinity 20 for benzodiazepine receptors in this test.

The compounds are thus indicated for use as minor tranquill-izers particularly for lessening anxiety and/or tension.

However, the compounds of the formula I interact with benzodiazepine receptors of rat brain in a mode which differs from that of benzodia-25 zepine in 2 different test systems.

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1. In the flunitrazepam receptor binding assay in accordance ~lith the method basically described by Speth as above [Test C)b)]
the compounds of the formula I exhibit in contrast to classical benzodiazepines - a higher affinity for benzodiazepine receptors in cerebellum compared to hippocampus suggesting a more potent interaction with type I benzodiazepine receptors than with type II benzodiazepine receptors.

2. The compounds of formula I exhibit a differential interaction with benzodiazepine receptors after photoafFinity labell;ng with flunitrazepam when examined with the method basically described by Karobath and Supavilai. Neuroscience Letters. 31(1982 65-69 (Test D). In this assay conventional benzodiazepines exhibit after photoaffinity labelling with flunitrazepam when compared to untreated membranes a 20-fold and more increased IC50 values after photoaffinity labelling whereas benzodiazepine antagonists exhibit unaltered IC50 values. The compounds of formula I exhibit only up to 4-fold increased IC50 values after photoaffinity labelling of benzodiazepine receptors when compared to the Yalues obtained with control membranes.

In addition compounds of formula I exhibit increased affinity for benzodiazepine receptors of rat cerebral cortex in the presence of 4-aminobutyric acid when compared to their respective affinity in the absence of 4-aminobutyric acid.

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The mode of interaction of the compound of the formula I with benzodiazepine receptors therefore differs from that of conventional benzodiazepines and from that of benzodiazepine antagonists. The compounds of formula I possess an interesting and desirable spectrum of tranquillizer activity, particularly anti-anxiety activity. In addition, the compounds of formula I generally lack CNS depressant effects and they can stimulate behaviour in observation tests.

The compounds of the formula I are also indicated to be active in the well known hexobarbital reductisn test(Test E). However, at the doses at 10 which the co~pounds are indicated to be useful as minor tranquillizers, e.g. by the FBA test and the conflict segment of the Geller Conflict test, the compounds I are generally indicated to be only weakly active or essentially inactive in a number of other standard CNS
depressant tests, such as in sleep studies in monkeys, spinal 15 reflex test in cats, the chemically induced convulsions test (in mice with N-sulfamoyl azepine), the Dunham rotarod test and, of further interest, in the variable interval segment of the Geller Conflict test. The oompounds I are therefore indicated ~o have a very specific and desirable mode of action in effecting tranquil-20 lization, and in particular are indicated to effect tranquillizationwith a substantially reduced sedative action which is associated with, e.g. drowsiness, in most if not all of ~he currently available tranquillizers.

An indicated, suitable daily dosage for use as a minor tranquillizer is from about 10 to 500 mg. If desired this may be administered in .

8~36 divided doses 2 to 4 times daily in unit dosage form containing about 2.5 to 250 mg of the compound or in sustained release form.

The compounds may be used in free base form or in the form of pharma-ceutically acceptable acid addition salts e~g. as the hydrochloride.
Such salt forms exhibit ~he same order of activity as the free base forms.

The compounds may be administered with conventional pharmaceutically acceptable diluents and carriers, and, optionally, other excip,ents and administered in such forms as tablets, capsules or injectable 10 preparations.

.

.

tj 3 ~;

- 9 - 600-6904~X

The invention therefore provides compounds of formula I in free base form or in the form of a pharmaceutically acceptable acid addition salt for use as tranquillizers and a method of tranquilli~ing a subject which comprises administering to a subject in need of such treatment a compound of formula I.in free base form or in the form of a pharmaceutically acceptable acid addition salt.

The compound 8-chloro-1-ethyl-1,2,3,4-tetrahydropyrimido[2,1-b]quin-azolin-6-one is known from US Patent 3,598,823 and bronchodila~ory activity is mentioned therefor.

The remaining compounds of formula I, however, have not previously been disclosed as having pharmaceutical activity and the invention therefore further provides compounds of formula Ic R ~1 6 ~ N ~ N ~ 2 Ic R ~ N~CH)n R3 wherein Rl~ R2, R3, R4, R5, R6 and n are as defined for formula I
with the proviso that Rl is other than methyl or ethyl when R5 is 15 chlorine n is 1 and R2, R3, R4 and R6 are hydrogen, in free base form or in the form of a pharmaceutically acceptable acid addition salt, for use as pharmaceuticals.
The invention further provides a pharmaceutical composition comprisiny 20 a compound of formula Ic in free base form or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable diluent or carrier therefor.

~Z~8~3G

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l-benzyl-1,2,3,4-tetrahydropyrimido[2,1-b]quinazolin-6-one is kno~n from J. Med. Chem. Yol. 18, no. 5, page 447 (1978) and a number of compounds of formula I, wherein Rl is a group of formula Xa and the remaining substituents are hydrogen are S disclosed in J. Chem. Soc. (1960) page 3551. No useful chemotherapeutic activity was observed in these compounds.
The remaining compounds of formula Ic are novel and also form part of the invention.
The invention therefore provides compounds of formula Ip R5 i~l c ~ ~ ~ Ip b ~ N`(CH ~ R3 wherein Rl, R2, R3, R4, R5~ R6 and n are as defined for formula I
with the proviso that Rl is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen and that Rl is other than benzyl when n is 0 or 1 and further that Rl is other 15 than phenyl, p-tolyl or p-chlorophenyl, when n is 0 and in each case the remaining substituents are hydrosen, in free base form or in the form of an acid addition salt.

Unless othen~ise mentioned halogen has atomic weight of from 18 to 80. Alkyl groups may be straiyht chain or branched. When m =2 20 the two resulting R7 groups may be independently of each other hydrogen or Cl 2alkyl.

The compounds of formula Ip can be prepared according to the invention by a) by reacting a compound of formula II

2a~ 3~

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6 ~ N ~r Cl ,R3 ,Rz Il R ~ N - (CH) - CH - CH - Cl wherein R2, R3~ R4, R5~ R6 and n are as defined above~ with a a compound of formula III
R~ -NH2 III
wherein Rl is as defined above, b) by reacting a compound of formula IV
R

6 ~ NH2 IV
R ~ COOH

wherein R5 and R6 are as defined above with a compound of formula V
Rl RloS ~ N ~ Rz y N`(CH ~ R3 wherein Rl, R2, R3, R4 and n are as defined above and Rlo represents Cl 4alkyl or benzyl, c) reacting a compound of formula VI
M

CH ~ R3 10 wherein R2, R3, R4, R5, R6 and n are as defined above ~3~6 ~3~

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and M is an alkali metal with a compound of formula VII
X - Rl VII
wherein Rl is as defined above and X is halogen of atomic weight 35 to 130, or d) cyclising a compound of formula VIII

~ ~, ' R5 N JCH - CH - (CH)n YIII
Rl ~ R2 ~ R3 ~ R4 ~ Rs, R6 and n are as def ined above .
Process a) is carried in conventional manner e.g. a~ temperatures of from 20CC to 160C preferably 40C to 90 and in the presence of an inert organic solvent such as dimethylacetamide or a lower alkanol e.g. ethanol.

Process b) is also carried out in conYentional manner at elevated temperatures e.g. 100C to 190C preferably 140C to 180C and in an inert organic solvent e.g. one of higher boiling point such as 15 dimethylformamide or more preferably dimethylacetamide.

Processes c) and d) are of known type and can be carried out as described in US Patents 3,598,823 (for c)); and 3,887,559 and 3,905,976 (for d))-The starting materials of formulae II, III, IV, V, VI, VII and VIII
are either known or can be prepared analogously to known methods.

The compounds may be isolated and purified in conventional mannerand may be recovered in free base form or in the form of an acid addition salt as required. Free base and salt forms may also be 8~

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interconverted in conventional manner.

The known compounds of formulae I and Ic may be prepared in the same manner.

Compounds wherein any of R2, R3~ R4 or R7 is other than hydrogen 5 may exist in diastereomeric or racemic form, the individual isomers of which may be separated in conventional manner.
Unless otherwise stated reference is always made to the racemate.
Examples of particular substituent groups are as follows:
type a Rl = (i) formula Xa = (ii) formula Xb (iii) formula Xc (iv) formula Xd wherein R7 = H or CH3, preferably H
R~ and Rg = H, halogen,-preferably chlorine or alkyl,preferably methyl or ethyl especially methyl 2~ m = 3, 2 or l preferably 2 or l, especially l, R2, R3, R4 an 6 R5 = (i) H, halogen, CF3 each preferably in b-position, ~ii) halogen~
(iii) chlorine in b-position, n = (i) 0 (ii) 19 _ 14 600-6904/X
t~
R1 = (i) Cl 6alkyl particularly Cl ~alkyl optionally Fluorine substituted~ more preferably unsuhstituted (ii) branched C3 6alkyl R5 = (i) chlorine or CF3, (ii) chlorine, type c Rl = (i) C3 6alkenyl particularly allyl, (;i) C3 6alkynyl particularly propargyl, ~iii) C3 8cycloalkyl~
( i V ) C5_ 7CyCl oal kyl, (V) C3 7cycloalkyl-(C1 3)alkyl, (vi ) C5 7cycloalkylmethyl, 15R2, R3, R4, R6 = H
R5 = as for type a~.
These substituent groups and combinations thereof as applied to the compounds of formulae I, Ic and Ip also form part of the invention.

Examples of interesting compound groups are as Follows.
20 A. Compounds of formula 1, wherein Rl represents Cl 8alkyl, R5 represents halogen in b-position, n = 0 or 1 and the remaining substituents represent hydrogen with the proviso that Rl is other than methyl when R5 is chlorine and n is 1, 1~8~3/~

B. Compoullds of formula Ic, wherein all substituents are as defined under A. with the proviso that Rl is other than methyl or ethyl when R5 is chlorine and n is 1.

C. Compounds of formula I, Ic and/or Ip, wherein Rl is represents Cl 8alkyl, R5 represents CF3 in b-position, n = 0 or 1 and the remaining substituents represent hydrogen.

D. Compounds of formula I, Ic and/or Ip, wherein Rl represents C3 6alkenyl, C3 6alkynyl, C3 8cycloalkyl~
norbornyl or C3 7cycloalkyl-(Cl_3~-alkyl, R2, R3 and R4 represent independently hydrogen or Cl 2alkyl, n represents 0 or 1, R5 represents halogen, Cl 4alkyl or trifluoromethyl each in b-position, and R6 represents hydrogen, halogen or Cl 3alkyl;

E. Compounds of formula I, wherein Rl represents a group Xa, Xb, Xc or Xd-as defined above, R2, R3 and R4 represent independently hydrogen or Cl 2alkyl, R5 represents hydrogen, halogen Cl 3alkyl, and R6 represents hydrogen, halogen Cl 4alkyl or trifluoromethyl and n = C or 1 m = 0, I or 2, p = 1 or 2, q = 1 or 2;
whereby at least one of R2, R3 and R4 is hydrogen.
F. Compounds of formula Ic, wherein all substituents are as defined under E_ with the proviso that Rl is other than benzyl when n is 1 and the remaining substituents are hydrogen;

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G. Compo~nds of formula Ip, wherein all substituents are as defined under E. with the proviso that Rl is other than benzyl l~hen n is 0 or 1 and further that Rl is other than phenyl, p-tolyl or ~chlorophenyl when n is 0 and in each case the remaining substituents are hydrogen;

H. Compounds of formula I, wherein a) Rl represents a yroup of formula - ( CH )m~

wherein m represents 0, 1, 2, 3 or 4 especially 0, 1 ol~ 2, R7 represents hydrogen or Cl 2alkyl, R8 represents hydrogen, halogen or Cl 3alkyl and Rg represents hydrogen, halogen or Cl ~alkyl, R5 represents hydrogen, halogen, CF3 preferably in b-position or Cl 4alkyl, R2, R3, R4 and R6 represent hydrogen, n represents 0 or 1, b) Rl represents Cl 8alkyl, R5 is in b-position and represents fluorine, chlorine or CF3, n represents 0 or 1~
R2, R3, R4 and R6 represent hydrogen with the pro~iso that Rl is other than methyl when R5 is chlorine and n is 1, ~Z~ 3~

c) Rl represents C3 6alkenyl, C3 6alkynyl, C3 8cycloalkyl or C3 7CyCl Oal ~yl - (Cl 3 )-al kyl, R2, R3 and R4 represent independently hydrogen or Cl 2alkyl, R5 is in b-position and represents halosen, Cl 4alkyl or CF3, R6 represents hydrogen, halogen or Cl_3alkyl and n represents 0 or 1.

I. Compounds of formula Ic, ~herein all substituents are as defined under H with the proviso that Rl is other than methyl or ethyl ~hen R5 is chlorine n is 1 and R2, R3, R4 and R6 are hydrogen.

10 J. Compounds of formula Ip, ~herein all substituents are as defined under H.with the pro~iso that Rl is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen and that Rl is other than benzyl when n is 0 or 1 and further that Rl is c,ther than phenyl, p-tolyl or p-chlorophenyl when n is 0 and in each case the remaining substituents are hydrogen.
K. Compounds of formulae I, wherein a) R5 represents hydrogen, halogen or CF3 and the remaining substituents are as defined under H.a~, b~ Rl is Cl 6alkyl and the remaining substituents are as defined under H.b), c) Rl is C3 7cycloalkyl or C3 8cycloalkylalkyl, R5 ;s halogen or CF3 and the remainin~ substituents are as defined under H.c) 3~3 Ç~

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L. Compounds of formulae Ic, wherein all substituents are as defined under K. with the proviso that Rl is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen.

5 M. Compounds of formula Ip, wherein all substituents are as defined under K. with the proviso that Rl is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen and that Rl ~s other than benzyl wh~n n is 0 or i and further that Rl is other than phenyl, p-tolyl or p-chloro-phenyl when n is 0 and in each case the remaining substituents are hydrogen.

N. Compounds of formula I, Ic and Ip, wherein the substit-uents are of the type a) as defined under formula I and subject to the disclaimers in each formula.
15 - Compounds of formula I, Ic and Ip, wherein the substit-uents are of the type b) as defined under formula I and subject to the disclaimers in each formula.
P. Compounds of formula I, Ic and Ip, wherein the substit-uents are of the type c) as defined under formula I.
20 Q. Any of the groups of compounds of formula I, Ic and Ip, wherein at least one of R5 and R6 is other than hydrogen.

The compounds of groups A - Q, which also form part of the invention, may be in free base form or in the form of an acid addition salt.

25 A particularly preferred single compounds is 7-chloro-1-(~-chloro-benzyl)-2,3-dihydroimidazo [2,1-b~ quinazolin-5(1H)-one in free base form or in the form of an acid addition salt.

i2~ 3Çi~

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The following examples illustrate the invention wh2reby all temperatures are given in degrees centigrade.

l-(o-chlorobenzyl)-7-chloro 2,3-dihydro-imidazo[2,1-b]
-5 quinazolin-5(1H)-o~mpound no. la) A solution of 1.0 9 of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g of 2-chlorobenzyl amine in 50 ml of ethanol and 1.0 ml of dimethylacetanlide is stirred and heated at reflux for 12 hours. The solvent is 10 remoYed by evaporation in vacuo and the residue dissol~ed in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chl oride/pentane and filtered to obtain l-(o-chlorobenzyl)-7-chloro-2,3-dihydro-inlidazo [2,1-b~quinazolin-5(1H)-one, m.p. 173 - 174 .

The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described.

Table A (n = 0, Rl = Xa (m = 1)~ R3 = R6 = H, R5 in 20 b-position) Cmpd.no. R5 R7 _ R9 R2 m.p.
.
lb chloro H H H H 162-164 lc chloro H H 5~ -CH3 143-145 ld chlo ro -CH H H H 143-145 (-)-isomer 3 _ chloro H p-chloro H 151-153 ¢3 8 ~3 ~

_ _ , Cmpdmlo. R5 ¦ 7 L R8 Rg R2m.p.
lf chloro -CH3 H H H144_145 (~)-isomer 19 -CF3 H o-chloro H H 114-1150 lh -CF3 H H H H 145-147 li chloro H m-methyl H H 144-146 lj chloro H m-chloro H H170-172 G
lk chlorQ H m-chloro p-methyl H 1 38-141 11 chloro H o-chloro p-chloro H 188-190 lm chloro H m-chloro p-chloro H 206-2Q8 ln chloro -CH3 p-chloro H H 128-130 lo H H p-chloro H l~119-121 __ _ _ Compound lc is also prepared by preparing the corresponding compound of formula VI by the procedure of example 1 and reacting this first with NaH and then with phenylmethyl bromide in dimethylacetamide at room temperature for 15 hours and then recrystallizing from ethanol.

The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described~

Table B (n = 0, Rl = Xa (m = 0), R3 = R~ = H, R5 in b-position) Cmpd.no. _ ~ _ Rg R2 - -_ , ~ ~. _ 2a chloro p-fluoro H H 226-227 2b chloro p-chloro H H 222 223 2c chloro m-CF3 H H 175-177 2d chloro o chloro p-methyl _ . 145-147 ~ ~ __ __ 36~3~

The following compounds of ,orrnula I may be prepared analogously to example 1 or as otherwise hereinbefore descri bed.

Tabl e ~ ( n = 1, Rl = Xa ( m = 1 ) ~ R3 = R4 = R5 = H, R5 i n b-posi ti on ) .
Cmpd . no . R~; R7 R8 R~ R2 m . p .
3a chl oro H H H H 147-151 3b chl oro H p-chl oro H ~ 202-205 ~
3c chl o ro H p-fl uoro H H 166-1 68 3d chloro H o-chl oro p-Cl H
3e chl oro H m-chl oro p-Cl H
3f chl oro H o-chl oro H H 193-195 EXAM?LE 4 The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore descri bed.

Table D (n = 1, Rl = Xa (rn= 0), R2 ~ R3 = R~ = R6 = H~
, _ R5 in b-position) Cmpd. no . R5 --R8 R
, _ _ 4a - chl oro m-CF3 H 185 ~187 4b chloro p-fl uoro H 199-200 4c chl oro p-methyl H 172 -1 73 4d chl oro p-chl oro ~2¢~86~6 - 22 - 600-6~0-4!X

The following compounds of formula I may bP prepared analog-ously to Example l or as otherwise hereinbefore described.

TABLE E
__ Cmpd.no. Rl n R2 R3 R4 R5 R6 m.p 5a 4-pyridyl- 0 H H _ chloro H 136-138 methyl (b-pos.) 5b phenylcyclo- 0 H H _ chloro H 136.5-138 propyl (b-pos.) 5c phenylmethoxy 0 H H _ (hblpors.) H 78-80 5d o-chloro-~- 0 H H chloro H 116-118 phenethyl (b-pos.) 5e 3-pyridyl- 0 H H _ chloro H 153-155 methyl (b-pos.) 5f 2-pyridyl- 0 H H chloro H 170-173 methyl (b-pos.) 5g ~-phenyl- 0 H H _ chloro H lll-113 propyl (b-pos.) 5h ~-phenylbutyl 0 H H (blpors.) H 104 106 Si ~-pnhenyl- l H H H chloro H 80-82 propyl ~b-pos.) 5j 4-pyridyl 0 H H ......... (blpors.) H 15~ 4 5k benzyl 1 H H H nitro H 258^261 _-allyl-7-chloro 2,3-di_ydro-imidazot2,1-b~quinazolin-5(1H)-one (compound no.~

a) The 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydro-quinazolin 4-one is obtained by refluxing a solution of 17.3 g o~

~3g~36 4-(2-chloroethoxy)-2,6-dichloroquinazoline in 50 g of trichlorobenzene for 3 hours and continuing the reflux for 2 more hours after washing the deposit in the tube back into the reaction mixture with methylene chloride.
The resulting m-ixture is diluted with methylene chloride, filtered with carbon, the filtrate concentrated and chromatographed through silica gel by first adding in a minor portion o-f a 50 : 50 mixture of methylene chloride and pentane, eluding the trichlorobenzene spot with pure pentane and eluting the product out with methylene chloride which is then stripped off to a solid product, m.p. 161 - 163 Q.

b) A soiution of 1.0 g of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one in 50 ml of ethanol is combined with a solution of 0.62 g of allylamine in 10 ml of dimethylacetamide and the resulting mixture heated to reflux with dimethylacetamide being added as required to d-issolve any remaining solid starting material. After heating at reflux for about 5 hours the resulting reaction mixture is ~0 allowed to cool, the mixture stripped down to a dimethyl-acetamide slurry and pentane added. A white solid form which dissolves upon addition of water after which the organic layer is dried and concentrated in vacuo to a solid residue which ;s washed with pentane to obtain l-allyl-7-chloro-2,3-dihydro-imidazo~2,1-b]quinazolin-5(lH)-one, m.p. 91 - 93 .

The following compounds of formula I may be prepared analogously to exampie 1 or 6 or as otherwise hereinbefore described.

- 24 - 600-6904/~
Table F

Cmpd.no.¦ Rl n R2 ~ R3 ~ ~ ~ ;p.
_ I _ I __ __ 6b cyclopentyl 0 H H (Chblpors.) H 142-146 6c cyclohexyl 0 H H (Chblpos.) H 181-183 6d cyclohexyl- 0 ~ H chloro H 125-127 methyl (b-pos.) 6e cycloheptyl 0 H H chloro ~l 157-159 (b-pos.) 6f cyclohexyl- CH3 H _ chloro H 152-153 methyl (b-pos.) 69 norbornyl 0 H H (hblpoOro5.) H 155-157 6h cyclooctyl 0 H H (hlpors.) H 107-110 6i allyl 1 H H H (Chblpors.) H 100-102 6j cyclohexyl- 1 H U H chloro H 120-121 methyl . (b-pos.) 6k allyl 0 H H _ Cg3 H 122-124 61 propargyl 1 H H H (cblpoOr5o.) H 1 b5-1 67 6m cyclop tyl 1 H H H ~ PDD- ) H 62-65 7-Chloro-l-ethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one (compound no. 7a) .

A solution of 2.2 g of 1-ethyl-2-methylthioimidazoline, 2.5 g of 2-amino-5-chlorobenzoic acid and 25 ml of dimethyl-acetamide is refluxed for 12 hours and then the reaction ~Z~38~3~

- 25 - 600-69~4/X
mixture is concentrated in vacuo. The residue is dissolved in methylene chloride9 washed first with 2N sodium hydroxide and then ~ith water, dried over magnesium sulfate, filtered and chromatographed on silica gel to obtain 7-chloro-1-ethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one, m.p. 86 - 89 .

The following compounds may be prepared e.g. analogously to example 7.

8-chloro-1-ethyl-1,2,3,4-tetrahydro-pyrimido[2,1-b]
quinazolin-6-one, m.p. 96 - 97 ~ (cmpd.no. 7b) l-ethyl 7-trifluoromethyl-2,3-dihydro-imidazo[2~1-b]
quinazolin-5(1H)-one (cmpd.no. 7c) l-Butyl-7-chloro-2,3-clihydro-imidazo[2,1-b]quinazolin-5(1H)-one (compound no. 8a) ~o a flask equipped with an aspirator is charged 1.5 g of 4-(2-chloroethoxy~--2,6-dichloroquinazoline followed by aspiration to a pressure of 15 mm and thus heating to a temperature of 240 + 10 for 3 hours. After the flask has cooled to room temperature the resulting solid residue is crystallized to obtain 3-(2-chloroethyl)-296-dichloro-3,4-dihydroquinazolin-4-one which is then dissolved in ethanol and treated by addition of 3 mol equivalents of n-butylamine.
After refluxing the resulting mixture for 3 hours the ethanol is removed in vacuo and the residue crystallized from ethanol/
water to obtain 1-butyl-7-chloro-2,3-dihydro-imidazo[2,1-b]
quinazolin-5(1H)-one, m.p. 92 - 93 .

3~

The 3-~2-chloroethyl3-2,6-dichloro-3,4-dihydroquinazolin-4-one is also obtained as described in example 6a.

The following compounds may be prepared e.g. analogously to example 7 or 8.
i Table G (R2 = R3 = R4 R6 H~

_ Cmpd.no. Rl n R5 m. p .
_ 8b n-propyl 0 chloro 112 -114 8c isopropyl 0 chloro 141-142 8d n-pentyl 0 chloro 98-lOU
8e n-octyl 0 chloro 77-78 8f n-butyl 1 chloro 120-165 89 isopentyl 0 chloro 92-94 8h methyl 0 chloro 153-155 8i isobutyl 0 chloro 112-115 8j ethyl 0 fluoro 124-127 8k sec.-butyl 0 chloro 93~9so 81 tert.-butyl 0 chloro 154-156 Bm ~ 0 chloro 120-122 - 27 - 600-6~04/X

l-n-butyl-7-trifluoromethyl-2,3-dihydro-imid~zo[2,1-b]
quinazolin-5(1H)-one (compound no. 9a) A mixture of 2.0 g of 7-trifluoromethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)-one in 25 ml dimethyl-acetamide is treated ~ith 450 mg of sodium hydride and heated at 50 for 3 - 5 hours. The resulting solution is then treated by addition of 1.6 9 of bro~obutane in 10 ml of dimethylacetamide and stirred for 15 hours at room temperature. The resulting mixture is evaporated to a small volume, dissolved in methylene chloride and water, the organic layer separated, washed with water, dried and evaporated to an oil which is treated with carbon, filtered through Celite and dissolved in hot pentane to crystallize on cooling 1-n-butyl-7-trifluoromethyl-2,3-dihydro-imidazo~2,1-b]
quinazolin-5(1H)-one, m.p. 67 - 68 .
The 7-trifluoromethyl-2,3-dihydro-imida20[2,1-b]
quinazolin-5(1H)-one employed in this Example is obtained analogously to process a) b~ reacting 13 9 of ammonia with 30 9 of the corresponding compound II
under nitrogen for 20 hours followed by evaporation to a thick oil, treatment with methylene chloride/
water, washing of the separated organic layer with water, drying, evaporation, dissolution with meth-anol, treatment with charcoal, filtering, concen-tration to a volume of 100 ml and cooling to crystallize (2 hours with stirring) the 7-trifluoro-methyl-2,3-dihydroimidazo[2tl-b]quinazolin-5(1H)-one, m.p. 274.

Claims (8)

Claims:
1. A process for producing compounds of formula I

wherein a) R1 represents one of the following groups wherein m represents 0, 1, 2, 3 or 4 p represents 1 or 2, q represents 0, 1 or 2 R7 represents hydrogen or C1-2alkyl, R8 represents hydrogen, halogen or C1-3alkyl, R9 represents hydrogen, halogen, C1-4alkyl, trifluoromethyl or nitro, R2, R3 and R4 represent, independently, hydrogen or C1-2alkyl, R5 represents hydrogen, halogen , C1-4alkyl, trifluoromethyl or nitro and R6 represents hydrogen, halogen or C1-3alkyl, and n represents 0 or l whereby at least one of R2, R3 and R4 is hydrogen, or b) R1 represents C3-6alkenyl,C3-6 alkynyl,C3-8cycloalkyl, norbornyl or C3-7cycloalkyl-(C1-3)-alkyl, R2, R3 and R4 represent, independently, hydrogen or C1-2alkyl, R5 is in b-position and represents halogen, C1-4alkyl or trifluoromethyl, R6 represents hydrogen, halogen or C1-3alkyl, n represents 0 or 1, in free base form or in the form of a pharmaceuti-cally acceptable acid addition salt for use as tran-quilizers, which comprises a) reacting a compound of formula II

II

wherein R2, R3, R4, R5, R6 and n are as defined in claim 1 with a compound of formula III

wherein R1 is as defined in claim 1, b) reacting a compound of formula IV

IV

wherein R5 and R6 are as defined in claim 1, with a compound of formula V

V

wherein R1, R2, R3, R4 and n are as defined in claim 1 and R10 represents C1-4alkyl or benzyl, c) reacting a compound of formula VI

VI

wherein R2, R3, R4, R5, R6 and n are as defined in claim 1 and M is an alkali metal with a compound of formula VII

wherein R1 is as defined in claim 1 and X is halogen of atomic weight 35 to 130, or d) cyclising a compound of formula VIII

VIII

wherein R1, R2, R3, R4, R5, R6 and n are as defined in
1. claim 1 and recovering the compounds thus obtained in free base form or in the form of an acid addition salt as re-quired.
2. 2. Compounds of formula I as defined in claim 1 whenever produced by the process claimed in claim 1 or an obvious chemical equivalent.
3. 3. A process according to claim 1 wherein n is 0, R
   is Xa where m is 1, each of R2, R3, R6, R7 and R9 is H, R5 is chloro in the b-position and R8 is p-chloro.
4. 4. The compound 7-chloro-l-(p-chloro-benzyl)-2,3-di-hydroimidazo [2,1-b] quinazolin-5-(1H)-one in free base form or in the form of an acid addition salt, whenever produced by the process claimed in claim 3 or an obvious chemical equivalent.
5. 5. A process according to claim 1 wherein n is 0, R1 is Xa where m is 1, each of R2, R3, R6, R7, R8 and R9 is H, and R5 is -CF3 in b-position.
6. 6. A compound of formula I as defined in claim 1 wherein n is 0, R1 is Xa where m is 1, each of R2, R3, R6, R7, R8 and R9 is H, and R5 is -CF3 in b-position, whenever produced by the process claimed in claim 5 or an obvious chemical equivalent.
7. 7. A process according to claim 1 wherein n is 0, R1 is cyclohexylmethyl, each of R2, R3 and R6 is H and R5 is chloro in b-position.
8. 8. A compound of formula I as defined in claim 1 wherein n is 0, R1 is cyclohexylmethyl, each of R2, R3 and R6 is H and R5 is chloro in b-position, whenever produced by the process claimed in claim 7 or an obvious chemical equivalent.