GB2105721A - Tricyclic quinazolinones - Google Patents
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Compounds of formula I <IMAGE> wherein a) R<1> represents one of the following groups <IMAGE> wherein m represents 0, 1, 2, 3 or 4, p represents 1 or 2, q represents 0, 1 or 2, R7 represents hydrogen or C1-2 alkyl, R8 represents hydrogen, halogen or C1-3 alkyl, R9 represents hydrogen, halogen, C1-4 alkyl, trifluoromethyl or nitro, R2, R3 and R4 represent, independently, hydrogen or C1-2 alkyl, R5 represents hydrogen, halogen, C1-4 alkyl, trifluoromethyl or nitro and R6 represents hydrogen, halogen or C1-3 alkyl, and n represents 0 or 1 whereby at least one of R2, R3 and R4 is hydrogen, or b) R1 represents C1-8 alkyl, unsubstituted or substituted by 1 to 3 fluorine atoms, R5 is in b-position and represents fluorine, chlorine or trifluoromethyl, 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 C3-6 alkenyl, C3-6 alkynyl, C3-8 cycloalkyl, norbornyl or C3-7 cycloalkyl-(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 pharmaceutically acceptable acid addition salt for use as tranquilizers. These compounds are indicated for use as pharmaceuticals, in particular as tranquilizers.
Description
SPECIFICATION
Tricyclic quinazolinones
The present invention concerns tricyclic quinazolinones, processes for their production, pharmaceutical compositions containing them and their use as pharmaceuticals.
More particularly the invention relates to compounds of formula I
wherein
a) R, 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,
R, represents hydrogen or C,,alkyl, R6 represents hydrogen, halogen or C,,alkyl, R9 represents hydrogen, halogen, C,,alkyl, trifluoromethyl or nitro,
R2, R3 and R4 represent, independently, hydrogen or C,~2alkyl, R5 represents hydrogen, halogen,C14alkyl, 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) R, represents C,~8alkyl, unsubstituted or substituted by 1 to 3 fluorine atoms on other than the alpha-carbon atom.
R5 is in b-position and represents fluorine, chlorine or trifluoromethyl,
n represents 0 or 1, and R2,R3,R4 and R6 represent hydrogen, with the proviso that R, is other than methyl when R5 is chlorine and n is 1, or
c) R, represents C3~6alkenyl, C,,alkynyl, Ca~8cycloalkyl, norbornyl or Ca~7cycloalkyl-(C,~3)-alkyl, R2, R3 and R4 represent, independently, hydrogen or C,,alkyl, R5 is in b-position and represents halogen, C,~4alkyl or trifluoromethyl,
R6 represents hydrogen, halogen or C,~3alkyl, n represents 0 or 1, in free base form or in the form of an acid addition salt.
Unless otherwise mentioned halogen has an atomic weight of from 1 8 to 80. Alkyl groups may be straight chain or branched. When m=2 the two resulting R7 groups may be independently of each other hydrogen or C1-2alkyl.
The compounds of formula I possess pharmaceutical, in particular CNS activity as indicated by their ability to reduce conflicts in the Geller Conflict test in rats (1-20 mg/kg) by the method basicially described by I. Geller, Psychopharmacologia, Vol. 1, pages 482-492 (1960) (Test A); by the
Flunitrazepam binding assay carried out analogously to the method described by Chang and Snyder
Eur. J. Pharmacol. 48, 213 [1978] slightly modified as follows (Test B):
Fresh calf brain cortex is homogenized in a 19 fold volume of Tris-HCI buffer pH 7.4, using a
Brinkman Polyton PT 20 and centrifuged at 50'000 g for 10 min. The pellets are frozen at -200C and resuspended in a 400 fold 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 yM) for determination of 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 between 1 nM and 10 MM, each in duplicate.
After incubation for 15 min. at OOC, the assay mixtures are rapidly filtered through Whatman GF/B filters and washed twice with 5 ml of ice cold Tris-buffer. The filters are counted in Rialuma on a LKB
Rach-Beta Liquid Scintillation Counter. lCsa values (concentration of test drug which inhibits specific binding of 3H-Flunitrazepam by 50%) are determined by linear regression analysis (HlLL-Plot).
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 follows [Test C)a)].
An aliquot of frozen calf caudate tissues is thawed and diluted with 0.5M Tris-buffer containing
metal ions (120mM NaCI, mM KCL, 2mM CaCI2 and im M MgCl2) to a final concentration of 8 mg/ml,
i.e., a 25 fold dilution. This suspension is made homogenous by homogenation with a Brinkmann
Polytron using a rheostat setting of 8 for 10 seconds. Ten A of 3H-Flunitrazepam solution is diluted in
0.05M Tris-buffer (pH 7.1 at 370C) to give a concentration of 1 OnM (3.1 3 x 10-6 mg/ml).
A0.1 ml portion of 1 OnM 3H-Flunitrazepamsolution is added to 12x75 mm borosilicatetest 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 2x10-5M 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 10-5M. Three
mg of each compound are placed in 18:: 1 50 mm borosilicate test tubes.Then 10 ml of absolute
ethanol is added and the tubes placed in a Branson Ultrasonic Cleaner for 1 5 minutes and then
vortexed in order to put the compounds into solution. If the compound is not in solution 3 drops of 2N
HCI is added. If the compound(s) are still not in solution but a cloudy homogenous suspension is found,
then the subsequent dilutions are continued. This gives a concentration of 1 xl 0-3M. The compound is
further diluted by serial dilution as follows: 0.1 ml of the M solution is added to 0.9 ml of 100%
ethanol and vortexed. A 0.1 ml portion of this solution is added to 0.9 ml of water to give 1 x10-5M solution. A 0.1 ml portion of this solution is added to 12x75 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 20C for 120 minutes, and rapidly filtered under vacuum through Whatman GF/G glass fiber filters.
Each tube is rinsed once with 3 ml ice-cold 50mM Tris-Buffer (pH 7.1 at 370C) 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 filters are rapidly
shaken for 45 minutes in the scintillation vials with 10 ml of scintillation cocktail. Results of
compounds screened 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 370C) using a Brinkmann Polytron for 10 seconds with a rheostat setting of 8.
The homogenate is centrifuged for 10 minutes at 20,000 RPM in a Sorvall RC2B centrifuge-using a SS 34 head. The supernatant is 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 0.05M Tris-buffer (pH 7.1 at 370C) containing 120mM NaCI, 5mM Kcl, 2mM Cacti2, and 1 mM MgCl2 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 for benzodiazepine receptors in
this test.
The compounds are thus indicated for use as minor tranquillizers 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 benzodiazepine in 2 different test systems.
1. In the flunitrazepam receptor binding assay in accordance with 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 labelling 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 values 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.
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 reduction test (Test E). However, at the doses at which the compounds 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 reflex test in cats, the chemically induced convulsions test (in mice with N-sulfamoyl azepine), the Dunham rota rod test and, of further interest, in the variable interval segment of the Geller Conflict test.The compounds I are therefore indicated to have a very specific and desirable mode of action in effecting tranquillization, and in particular are indicated to effect tranquillization with a substantially reduced sedative action which is associated with, e.g drowsiness, in most if not all of the 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 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 pharmaceutically acceptable acid addition salts, e.g. as the hydrochloride. Such salt forms exhibit the same order of activity as the free base forms.
The compounds may be administered with conventional pharmaceutically acceptable diluents and carriers, and, optionally, other excipients and administered in such forms as tablets, capsules or injectable preparations.
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 tranquillizing 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 ,2,3,4-tetrahydropyrimido[2, 1 -b]quinazolin-6-one is known from US Patent 3,598,823 and bronchodilatory 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
wherein R1, R2, R3, R4, R5, R6 and n are as defined for formula I with the proviso that R, is other than methyl or ethyl when R5 is chlorine n is 1 and R2, R3, R4 and R5 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 comprising 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.
1 -Benzyl-1 ,2,3,4-tetrahydropyrimido[2,1 -b]quinazolin-6-one is known from J. Med. Chem. vol.
18, no. 5, page 447 (1978) and a number of compounds of formula I wherein R1 is a group of formula
Xa and the remaining substituents are hydrogen are 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
wherein R1, R2, R3, R4, R5, R6 and n are as defined for formula I with the proviso that R, is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen and that R, is other than benzyl when n is O or 1 and further that R, is other than phenyl, p-tolyl orp-chlorophenyl, when n is O and in each case the remaining substituents are hydrogen, in free base form or in the form of an acid addition sait.
Unless otherwise mentioned halogen has atomic weight of from 1 8 to 80. Alkyl groups may be straight chain or branched. When m=2 the two resulting R7 groups may be independently of each other hydrogen or C,~2alkyl.
The compounds of formula Ip can be prepared according to the invention by a) by reacting a compound of formula II
wherein
R2, R3, R4, R5, R6 and n are as defined above, with a compound of formula Ill R1-NH2 Ill wherein
R, is as defined above,
b) by reacting a compound of formula IV
wherein
R5 and R6 are as defined above with a compound of formula V
wherein
R1, R2, R3, R4 and n are as defined above and
R10 represents C,,alkyl or benzyl,
c) reacting a compound of formula VI
wherein
R2, R3, R4, R5, R5 and n are as defined above and M is an alkali metal, with a compound of formula VII X-R1 VII wherein
R1 is as defined above, and
X is halogen of atomic weight 35 to 130, or
d) cyclising a compound of formula VIII
wherein
R1,R2,R3,R4,R5, R6 and N are as defined above.
Process a) is carried in conventional manner e.g. at temperatures of from 20CC to 1 600C preferably 400C to 900 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 conventional manner at elevated temperatures e.g. 1 000C to 1 900C preferably 1 400C to 1 80CC and in an inert organic solvent e.g. one of higher boiling point such as 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 (ford)).
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 manner and 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 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 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
R,=(i) formula Xa
=(ii) formula Xb
(iii) formula Xc
(iv) formula Xd wherein
R7=H or CH3, preferably H R5 and Rg=H, halogen, preferably chlorine or alkyl, preferably methyl or ethyl especially methyl,
m=3, 2 or 1 preferably 2 or 1, especially 1; R2, R3, R4 and R6=H Rs=(i) H, halogen, CF3 each preferably in b-position,
(ii) halogen,
(iii) chlorine in b-position,
n=(i) O
(ii) 1;
Type b
R, (i) C1-6alkyl particularly C1-4alkyl optionally fluorine substitued, more preferably unsubstituted,
(ii) branched C3~6alkyl, R5=(i) chlorine or CF3,
(ii) chlorine;;
Type c
R,=(i) C36alkenyl particularly allyl,
(ii) C3alkynyI particularly propargyl,
(iii) C35cycloaIkyl, (iv) Cs~7cycloalkyl, (v) C3-7cycloalkyl-(C1-3)alkyl,
(vi) Cs~7cycloalkylmethyl, R2, R3, R4, R e=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.
A. Compounds of formula I, wherein
R, represents C,~8alkyl, R5 represents halogen in b-position,
n=O or 1 and the remaining substituents represent hydrogen with the proviso that R, is other than methyl when R5 is chlorine and n is 1;
B. Compounds of form ula Ic, wherein all substituents are as defined underA. with the proviso that R, is other than methyl or ethyl when R5 is chlorine and n is 1.
C. Compounds of formula I, Ic and/or Ip, wherein
R, is represents C,~8alkyl, R5 represents CF3 in b-position,
n=O or 1 and the remaining substituents represent hydrogen.
D. Compounds of formula I, Ic and/or Ip, wherein
R, represents C3~6alkenyl, C35aIkynyl, C3-8cycloalkyl, norbornyl or C3-7cycloalkyl-(C1-3)alkyl,
R2, R3 and R4 represent independently hydrogen or C,~2alkyl, n represents 0 or 1,
R5 represents halogen, C,~4alkyl or trifluoromethyl each in b-position, and
R6 represents hydrogen, halogen or C1~3alkyl.
E. Compounds of formula I, wherein
R1 represents a group Xa, Xb, Xc or Xd as defined above, R2,R3 and R4 represent independently hydrogen or C,~2alkyl, R5 represents hydrogen, halogen C1-3alkyl, and R5 represents hydrogen, halogen C,,alkyl trifluoromethyl, and n=O or 1, m=0, 1 or 2, p=l or2,
q=1 or2; 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
R1 is other than benzyl when n is 1 and the remaining substituents are hydrogen.
G. Compounds of formula Ip, wherein all substituents are as defined under E. with the proviso that that R1 is other than benzyl when n is O or 1 and further that R1 is other than phenyl, p-tolyl orpchlorophenyl when n is 0 and in each case the remaining substituents are hydrogen.
H. Compounds of formula I, wherein
a) R1 represents a group of formula
wherein
m represents 0, 1,2,3 or 4 especially 0, 1 or 2,
R7 represents hydrogen or C1~2alkyl, R5 represents hydrogen, halogen or C1~3alkyl, and R5 represents hydrogen, halogen or C1-4alkyl, R5 represents hydrogen, halogen, CF3 preferably in b-position or C1-4alkyl,
R2, R3, R4 and R5 represent hydrogen,
n represents 0 or 1.
b) R1 represents C1~8alkyl, R is in b-position and represents fluorine, chlorine or CF3, n represents 0 or 1,
R2, R3, R4 and R5 represent hydrogen with the proviso that R1 is other than methyl when R5 is chlorine and n is 1.
c) R1 represents C35alkenyI, C35aIkynyI, C35cycIoalkyI or C3~7cycloalkyl-(C1~3)alkyl, R3, R3 and R4 represent independently hydrogen or C1 2alkyl, R5 is in b-position and represents halogen, C1~4alkyl or CF3,
R6 represents hydrogen, halogen or C1~3alkyl, and
n represents 0 or 1.
/. Compounds of formula Ic, wherein all substituents are as defined under H. with the proviso that
R1 is other than methyl or ethyl when R5 is chlorine n is 1 and R2, R3, R4 and R6 are hydrogen.
J. Compounds of formula Ip, wherein all substituents are as defined under H. with the proviso that
R1 is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen and that
R1 is other than benzyl when n is O or 1 and further that R1 is other than phenyl, p-tolyl or pchlorophenyl 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) R1 is C1~6alkyl and the remaining substituents are as defined under H.b),
c) R1 is C37cycloalkyl or C35cycloalkylalkyI, R5 is halogen or CF3 and the remaining substituents are as defined under H.c).
L. Compounds of formulae Ic, wherein ail substituents are as defined under K. with the proviso that R1 is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R6 are hydrogen.
M. Compounds of formula Ip, wherein all substituents are as defined under K. with the proviso that R1 is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and R5 are hydrogen and that R1 is other than benzyl when n is O or 1 and further that R, is other than phenyl, p-tolyl orpchlorophenyl when n is 0 and in each case the remaining substituents are hydrogen.
N. Compounds of formula I, Ic and Ip, wherein the substituents are of the type a) as defined under formula I and subject to the disclaimers in each formula.
O. Compounds of formula I, Ic and Ip, wherein the substituents 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 substituents are of the type c) as defined under
formula I.
Q. Any of the groups of compounds of formula I, lc 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.
A particularly preferred single compound is 7-chloro-1-(p-chlorobenzyl)-2,3-dihydroimidazo[2,1 - b]quinazolin-5(1 H)-one in free base form or in the form of an acid addition salt.
The following examples illustrate the invention whereby all temperatures are given in degrees centigrade.
Example 1 1-(o-chlorobenzyl)-7-chloro-2,3-dihydro-imidazo[2,1 -b]quinazolin-5(1 H)-one (compound no. 1 a) A solution of 1.0 g of 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydroquinazolin-4-one and 1.5 g of 2chlorobenzylamine in 50 ml of ethanol and 1.0 ml of dimethylacetamide is stirred and heated at reflux for 12 hours.The solvent is removed by evaporation in vacuo and the residue dissolved in methylene chloride, washed with water, treated with charcoal, filtered and concentrated in vacuo to obtain a solid which is recrystallized from methylene chloride/pentane and filtered to obtain 1 -(o-chlorobenzyl)-7- chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1 H)-one, m.p. 173-i 740 The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described.
Table A
(n=O, R,=Xa (m=1), R3=R6=H, R5 in b-position)
Cmpd.no. R5 R7 R8 R9 R2 m.p.
1b chloro H H H H 162-164 ic chloro H H H -CH3 143-145 id chloro GH3 H H H 143145 (-)-isomer 1e chloro H p-chloro H H 151--153 if chloro -CH3 H H H 144--145 (+)-isomer 1g -CF3 H o-chloro- H H 114--116 lh CF3 H H H H 145-1470 1i chloro H m-methyl H H 144-146 li chloro H m-chloro H H 170172 1k chloro H m-chloro p-methyl : H 138-141 11 chloro H o-chloro p-chloro H 1881900 I m chloro H m-chloro p-chloro H 206-208 in chloro -CH3 p-chloro H H 128-130 lo H . p-chloro H H 119--121 Compound 1 c 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.
Example 2
The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described.
Table B
(n=O, R=Xa (m=O), R3=R6=H, R5 in b-position)
Cmpd.no. R5 R8 R9 R2 m.p.
2a chloro p-fluoro H H 226-2270 2b chloro p-chloro H H 222223 2c chloro m < F3 H H 175-1770 2d chloro o-chloro p-methyl H 145-147 Example 3
The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described.
Table C
(n=1, R1=Xa (m=1), R3=R4=R6=H, R5 in b-position)
(Cmpd.no. R, R, R, Rg R, m.p.
3b chloro H p-chloro H H 202-205 3a chloro H H H H 147--151 3b chloro H p-chloro H H 202--205 3e chloro H m-chloro 3f chloro H o-chloro H H 193195 Example 4
The following compounds of formula I may be prepared analogously to example 1 or as otherwise hereinbefore described.
Table D
(n=1, R1=Xa (m=O), R2=R3=R4=R6=H, R5 in b-position)
Cmpd.no. R5 R8 R9 m.p.
4a chloro m-CF3 H 185-187 4b chloro p-fluoro H 199200 4c chloro p-methyl H 172-173 4d chloro p-chloro H Example 5
The following compounds of formula I may be prepared analogously to Example 1 or as otherwise hereinbefore described.
Table E
Cmpd.no. R1 n R2 R3 R4 R5 R6 m.p.
5a 4-pyridylmethyl O H H - chloro (b-pos.) H 136138 5b phenylcyclopropyl 0 H H - chloro (b-pos.) H 136.5-1380 Sc phenylmethoxy 0 H H - chloro (b-pos.) H 7880 5d o-chlorn-p-phenethyl 0 H H - chloro (b-pos.) H 116118 5e 3-pyridylmethyl O H H - chloro (b-pos.) H 153155 5f 2-pyridylmethyl O H H - chloro (b-pos.) H 170--173 5g y-phenylpropyl 0 H H - chloro (b-pos.) H 111-113 5h S-phenylbutyl O H H - chloro (b-pos.) H 104106 5i y-phenylpropyl 1 H H H chloro (b-pos.) H 8082 5j 4-pyridyl O H H - chloro (b-pos.) H 151-154 5k benzyl 1 H H H nitro (c-pos.) H 258-261 Example 6 1-Allyl-7-chloro-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1H)one (compound no. 6a)
a) The 3-(2-chloroethyl)-2,6-dichloro-3,4-dihydro-quinazolin-4-one is obtained by refluxing a solution of 1 7.3 g of 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 mixture is diluted with methylene chloride, filtered with carbon, the filtrate concentrated and chromatographed through silica gel by first adding in a minor portion of 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. 1611630.
b) A solution 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 dissolve any remaining solid starting material. After heating at reflux for about 5 hours the resulting reaction mixture is allowed to cool, the mixture stripped down to a dimethylacetamide 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 is washed with pentane to obtain 1-allyl-7-chloro-2,3- dihydro-imidazo[2,1-b]quinazolin-5(1 H)-one, m.p. 91--93 .
The following compounds of formula I may be prepared analogously to example 1 or 6 or as otherwise hereinbefore described.
Table F
Cmpd.no. A1 n R2 R3 R4 R5 R9 m.p.
6b cyclopentyl 0 H H - chloro (b-pos.) H 142--146 6c cyclohexyl 0 H H - chloro (b-pos.) H 181-183 6d cyclohexylmethyl 0 H H - chloro (b-pos.) H 125-1270 6e cycloheptyl 0 H H - chloro (b-pos.) H 157-159 6f cyclohexylmethyl 0 CH3 H - chloro (b-pos.) H 152-153 6g norbornyl 0 H H - chloro (b-pos.) H 155157 6h cyclooctyl 0 H H - chloro (b-pos.) H 107110 6i allyl 1 H H H chloro (b-pos.) H 100102 6j cyclohexylmethyl 1 H H H chloro (b-pos.) H 120-121 6k ally 0 H H - CF3 (b-pos.) H 122-124 61 propargyl 1 H H H chloro (b-pos.) H 165-1670 6m cyclopentyl 1 H H H chloro (b-pos.) H 6265 Example 7 7-Chloro-1-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 dimethylacetamide is refluxed for 12 hours and then the reaction mixture is concentrated in
vacuo. The residue is dissolved in methylene chloride, washed first with 2N sodium hydroxide and then
with 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(1 H)-one, m.p. 86890.
The following compounds may be prepared e.g. analogously to example 7.
8-Chloro- 1 -ethyl- ,2,3,4-tetrahydro-pyrimido[2, 1 -b]quinazolin-6-one, m.p. 96--97 (cmpd.no.
7b)
1 -Ethyl-7-trifluoromethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5( 1 H)-one (cmpd.no. 7c) Example 8
1 -Butyl-7-chloro-2,3-dihydro-imidazo [2,1 -b]quinazolin-5(1 H)-one (compound no. 8a) To a flask equipped with an aspirator is charged 1.5 g of 4-(2-chloroethoxy)-2,6dichloroquinazoline followed by aspiration to a pressure of 1 5 mm and thus heating to a temperature of 240+100 for 3 hours. After the flask has cooled to room temperature the resulting solid residue is crystallized to obtain 3-(2-chloroethyl)-2,6-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(1 H)-one, m.p. 92- 93 .
The 3-(2-chloroethyl)-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.
Table G
(R2=R3=R4=R6=H)
Cmpd.no. R, n R5 m.p. 8b n-propyi ch oro 112--114 8c isopropyl 0 chloro 141-142 8d n-pentyl 0 chloro 98100 8e n-octyl 0 chloro 77-78 8f n-butyl 1 chloro 120--165 89 isopentyl 0 chloro 9294 8h methyl 0 chloro 153155 8i isobutyl 0 chloro 112-115 8j ethyl 0 fluoro 124-127 8k sec.-butyl 0 chloro 9395 o 81 tert.-butyl 0 chloro 154--156 8m jB-fluorethyl 0 chloro 120-122
Example 9 1 -n-Butyl-7-trifluoromethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1 H)-one (compound no. 9a)
A mixture of 2.0 g of 7-trifluoromethyl-2,3-dihydroimidazo[2,1 -b]quinazolin-5(1 H)-one in 25 ml dimethylacetamide is treated with 450 mg of sodium hydride and heated at 500 for 3-5 hours. The resulting solution is then treated by addition of 1.6 g of bromobutane 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(1 H)-one, m.p. 67--68 .
The 7-Trifluoromethyl-2,3-dihydro-imidazo[2,1-b]quinazolin-5(1 H)-one employed in this Example is obtained analogously to process a) by reacting 13 g of ammonia with 30 g of the corresponding compound Il 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 methanol, treatment with charcoal, filtering, concentration to a volume of 100 ml and cooling to crystallize (2 hours with stirring) the 7-trifluoromethyl-2,3-dihydroimidazo[2,1-b]quinazolin5(1H)-one, m.p. 2740.
Claims (9)
1. Compounds of formula I
wherein
a) R, represents one of the following groups
wherein
m represents 0, 1,2, 3 or 4,
p rep resents 1 or 2,
q represents 0, 1 or 2,
R7 represents hydrogen or C1~2alkyl, R5 represents hydrogen, halogen or C,~3alkyl, R5 represents hydrogen, halogen, C1 4alkyl, trifluoromethyl or nitro, R2,R3 and R4 represent, independently, hydrogen or C,~2alkyl, R5 represents hydrogen, halogen, C, 4alkyl, trifluoromethyl or nitro, and R5 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) R, represents C,~8alkyl, unsubstituted or substituted by 1 to 3 fluorine atoms on other than the alpha-carbon atom.
R5 is in b-position and represents fluorine, chlorine or trifluoromethyl,
n represents 0 or 1, and
R2, R3, R4 and R5 represent hydrogen, with the proviso that R, is other than methyl when R5 is chlorine and n is 1, or
c) R, represents C36alkenyl, C35aIkynyl, C,,cycloalkyl, norbornyl or C3~7cycloalkyl-(C,~3)-alkyl, R2,R3 and R4 represent, independently, hydrogen or C,~2alkyl, R5 is in b-position and represents halogen, C C,~4alkyl on trifluoromethyl, R6 represents hydrogen, halogen or C, 3alkyl,
n represents 0 or 1, in free base form or in the form of a Dharmaceutically accepable acid addition salt for use as tranquillizers.
2. A method of tranquillizing a subject which comprises administering to a subject in need of such treatment a compound of formula I as described in Claim 1 in free base form or in the form of a pharmaceutically acceptable acid addition salt.
3. Compounds of formula Ic
wherein R1, R2, R3, R4, R5, R8 andnare as defined in Claim 1, with the proviso that R1 is other than methyl or ethyl when R5 is chlorine, n island R2, R3, R4 and R5 are hydrogen, in free base form or in the form of a pharmaceutically acceptable acid addition salt, for use as pharmaceuticals.
4. A pharmaceutical composition comprising a compound formula Ic as defined in Claim 3 in free base form or in the form of a pharmaceutically acceptable acid addition salt, together with a pharmaceutically acceptable diluent or carrier therefor.
5. Compounds of formula Ip
wherein
R1, R2, R3, R4, R5, R6 and n are as defined in Claim 1 with the proviso that R, is other than methyl or ethyl when R5 is chlorine, n is 1 and R2, R3, R4 and Re are hydrogen and that R, is other than benzyl when n is O or 1 and further that R1 is other than phenyl, p-tolyl or p-chlorophenyl, when n is 0 and in each case the remaining substituents are hydrogen, in free base form or in the form of an acid addition salt.
6. A process for preparing compounds according to Claim 5 which comprises
a) reacting a compound of formula II
wherein R2, R3, R4, R5, R6 and n are as defined in Claim 5 with a compound of formula Ill R1-NH2 Ill wherein
R1 is as defined in Claim 5,
b) reacting a compound of formula IV
wherein
R5 and R6 are as defined in Claim 5, with a compound of formula V
wherein R1,R2,R3, R4 and n are as defined in Claim 5, and R10 represents C,,alkyl or benzyl,
c) reacting a compound of formula VI
wherein
R2, R3, R4, R5, R5 and n are as defined in Claim 5 and M is an alkali metal, with a compound of formula VII X--R, VII wherein
R, is as defined in Claim 5 and,
X is halogen of atomic weight 35 to 130, or
d) cyclising a compound of formula VIII
wherein
R,, R2, R3, R4, R5, R6 and n are as defined in Claim 5 and recovering the compounds thus obtained in free base form or in the form of an acid addition salt as required.
7. A compound according to any one of Claims 1, 3 or 5, a method according to Claim 2 or a composition according to Claim 4, whereby in the compound involved the substituents are as hereinbefore defined in any of the groups A to Q.
8. A compound according to Claim 1 or 3, a method according to Claim 2 or a composition according to Claim 4, whereby the compound involved is 7-chloro-1-(p-chloro-benzyl)-2,3 dihydroimidazo[2,1 -b]quinazolin-5-(1 H)-one in free base form or in the form of a pharmaceutically acceptable acid addition salt thereof.
9. The compound 7-chloro- 1 -(p-chloro-benzyl)-2,3-dihydroimidazo[2,1 -b]quinazolin-5-(1 H)-one in free base form or in the form of an acid addition salt.
1 0. The steps, features, compositions and compounds referred to or indicated in the specification and/or claims of this application, individually or collectively, and any and all combinations or any two or more of said steps or features.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US30248681A | 1981-09-16 | 1981-09-16 | |
US30248581A | 1981-09-16 | 1981-09-16 | |
US30248381A | 1981-09-16 | 1981-09-16 | |
US30248481A | 1981-09-16 | 1981-09-16 |
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Publication Number | Publication Date |
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GB2105721A true GB2105721A (en) | 1983-03-30 |
GB2105721B GB2105721B (en) | 1985-11-13 |
Family
ID=27501816
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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GB08226008A Expired GB2105721B (en) | 1981-09-16 | 1982-09-13 | Tricyclic quinazolinones |
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AU (1) | AU8838582A (en) |
DE (1) | DE3233766A1 (en) |
DK (1) | DK410782A (en) |
ES (1) | ES8402838A1 (en) |
FI (1) | FI823207L (en) |
FR (1) | FR2512674B1 (en) |
GB (1) | GB2105721B (en) |
IT (1) | IT1189355B (en) |
NL (1) | NL8203587A (en) |
NZ (1) | NZ201915A (en) |
PT (1) | PT75555B (en) |
SE (1) | SE8205256L (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2186574A (en) * | 1986-02-13 | 1987-08-19 | Sandoz Ltd | Tetracyclic quinazolinones |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US4490371A (en) * | 1983-02-16 | 1984-12-25 | Syntex (U.S.A.) Inc. | N,N-Disubstituted-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-B]quinazolinyl)oxyalkylamides |
CA2113115A1 (en) * | 1991-07-29 | 1993-02-18 | Vlad E. Gregor | Quinazoline derivatives as acetylcholinesterase inhibitors |
Family Cites Families (1)
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US3631046A (en) * | 1969-05-28 | 1971-12-28 | Sandoz Ag | Tetracyclic quinazolin-ones |
-
1982
- 1982-09-10 FR FR8215474A patent/FR2512674B1/en not_active Expired
- 1982-09-11 DE DE19823233766 patent/DE3233766A1/en not_active Withdrawn
- 1982-09-13 GB GB08226008A patent/GB2105721B/en not_active Expired
- 1982-09-14 ES ES515693A patent/ES8402838A1/en not_active Expired
- 1982-09-14 SE SE8205256A patent/SE8205256L/en not_active Application Discontinuation
- 1982-09-14 DK DK410782A patent/DK410782A/en not_active Application Discontinuation
- 1982-09-14 PT PT75555A patent/PT75555B/en unknown
- 1982-09-14 AU AU88385/82A patent/AU8838582A/en not_active Abandoned
- 1982-09-14 NZ NZ201915A patent/NZ201915A/en unknown
- 1982-09-15 IT IT49124/82A patent/IT1189355B/en active
- 1982-09-16 FI FI823207A patent/FI823207L/en not_active Application Discontinuation
- 1982-09-16 NL NL8203587A patent/NL8203587A/en not_active Application Discontinuation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2186574A (en) * | 1986-02-13 | 1987-08-19 | Sandoz Ltd | Tetracyclic quinazolinones |
GB2186574B (en) * | 1986-02-13 | 1990-03-28 | Sandoz Ltd | Tetracyclic quinazolinones |
Also Published As
Publication number | Publication date |
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PT75555B (en) | 1985-05-31 |
FI823207L (en) | 1983-03-17 |
NL8203587A (en) | 1983-04-18 |
ES515693A0 (en) | 1984-03-01 |
FI823207A0 (en) | 1982-09-16 |
SE8205256L (en) | 1983-03-17 |
NZ201915A (en) | 1985-11-08 |
ES8402838A1 (en) | 1984-03-01 |
FR2512674B1 (en) | 1986-01-10 |
SE8205256D0 (en) | 1982-09-14 |
PT75555A (en) | 1982-10-01 |
IT8249124A0 (en) | 1982-09-15 |
DK410782A (en) | 1983-03-17 |
FR2512674A1 (en) | 1983-03-18 |
IT1189355B (en) | 1988-02-04 |
GB2105721B (en) | 1985-11-13 |
DE3233766A1 (en) | 1983-03-31 |
AU8838582A (en) | 1983-03-24 |
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