GB2127824A - Imidazo[1,2-a]quinolines - Google Patents
Imidazo[1,2-a]quinolines Download PDFInfo
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Abstract
Imidazo[1,2-a]quinolines of formula I <IMAGE> [wherein R1 represents a hydrogen, chlorine or bromine atom; R2 represents a benzoyl group or a group of formula <IMAGE> or <IMAGE> where R6 and R7 represent alkyl groups, R8 represents a hydrogen atom or an alkyl group and Ph represents a phenyl group; R3 represents a hydrogen atom or an alkyl group; R4 represents an alkoxy, hydroxy, acyloxy or alkyl group; and R5 represents an alkyl group; provided that R1 and R3 do not both represent hydrogen atoms when R2 represents a benzoyl group and R4 represents an alkoxy group] and salts thereof have value in the treatment of anxiety and distress. Intermediates of formula V <IMAGE> (wherein R1, R3 and R5 are as defined above and R4 represents an alkoxy, acyloxy or alkyl group) and salts thereof may be used in their preparation.
Description
SPECIFICATION
Imidazo[1 ,2-a]quinolines
The invention relates to new imidazo[1 ,2-a]quinoline derivatives and salts thereof, processes for their preparation, their use as medicaments, pharmaceutical compositions containing them and intermediates for use in the preparation thereof.
The invention provides new imidazo[1 ,2-a]quinolines of the formula (I)
[wherein
R, represents a hydrogen atom or a chlorine or bromine atom:
R2 represents a benzoyl group, a group of formula
(wherein R6 represents a C15 alkyl group), a group of formula
(wherein R7 represents an alkyl (e.g.C1-5 alkyl group) or a group of formula:
(wherein R8 represents a hydrogen atom or an alkyl (e.g. C14 alkyl) group), the symbol Ph representing a phenyl group;
R3 represents a hydrogen atom or a C18 alkyl group;
R4 represents a C18 alkoxy group, a hydroxy group, a C28 acyloxy group or a C18 alkyl group, and
R5 represents a C18 alkyl group; provided that R, and R3 do not both represent hydrogen atoms when R2 represents a benzoyl group and R4 represents a C18 alkoxy group] and salts thereof.
With respect to the general formula (I) and elsewhere in this specification, where C1-5 alkyl groups are referred to these may for example be methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl groups; C18 alkoxy groups may for example be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or octyloxy groups; C28 acyloxy groups may for example be acetoxy, propionyloxy or butyryloxy groups; C18 alkyl groups may for example be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or octyl groups.
Examples of groups which R2 may represent, in addition to the benzoyl group, include acetoxy-i - phenylmethyl, 1-phenylvinyl and 1-hydroxy-1-phenylethyl groups.
The compounds according to the invention possess interesting pharmacological properties as discussed hereinafter. It will be appreciated that, for pharmaceutical use, the salts referred to above will be pharmaceutically acceptable acid addition salts. Other acid addition salts may, however, find use, for example in the preparation of compounds of general formula (I) and their pharmaceutically acceptable acid addition salts. Acid addition salts may be formed with mineral or organic acids. Suitable acids include, for example, hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids such as e.g. methanesulphonic acid and arylsulphonic acids such as e.g.
benzenesulphonic acid.
Preferred compounds according to the invention include those of formula (I) wherein R3 represents a hydrogen atom or a methyl or ethyl group, R4 represents a methoxy, hydroxy, acetoxy or methyl group, B5 represents a methyl or ethyl group and R, and R2 are as defined above; and salts thereof.
In particular there may be mentioned compounds of formula (I) wherein R1 represents a hydrogen atom, R2 represents a benzoyl group or a 1-phenylvinyl group, R3 represents a hydrogen atom or a methyl or ethyl group, R4 represents a methoxy, hydroxy, acetoxy or methyl group and B5 represents an ethyl group; and salts thereof.
Most particularly of interest are compounds of formula (I) wherein R1 represents a hydrogen atom,
R2 represents a benzoyl group, R3 represents a methyl or ethyl group, R4 represents a methoxy group and R5 represents an ethyl group; and salts thereof, particularly the following:
(7-ethyl-5-methoxy-4-methylimidazo[1,2-a]quinolin-2-yl)phenylmethanone, and
4,7-diethyl-5-methoxyimidazol[1 ,2-a]quinolin-2-yl)phenylmethanone; and salts of these compounds.
In a further aspect the invention provides processes for the preparation of the compounds of formula (I).
For example, compounds of formula (I) wherein R1 represents a hydrogen atom, R2 represents a benzoyl group, R4 represents a C18 alkoxy group or a C15 alkyl group and R3 and R5 have the abovedefined meanings, and acid addition salts thereof may be prepared by a process which comprises cyclising a compound of formula (IV)::
(wherein R3 and R5 are as defined above, R4 represents a C18 alkoxy or C18 alkyl group and Xe represents an anion, e.g. a halogen anion) to form a compound of formula (IA)
(wherein R3, R4 and R6 are as hereinbefore defined) followed, if desired, by isolation of the compound of formula (IA) optionally in the form of an acid addition salt thereof.
The cyclisation of the compound of formula (IV) is preferably effected by heating the compound in the presence of an organic solvent, e.g. ethanol.
In general, the above cyclisation reaction will lead to the formation of an acid addition salt of the compound of formula (I) i.e. with the acid HX. The free base of formula (I) may be obtained therefrom, if desired without previous isolation, by treatment with a base such as, for example an alkali metal hydroxide or carbonate e.g. potassium carbonate.
Compounds of formula (IV) may be prepared for example by reaction of a compound of formula (II):
(wherein R3, R4 and R5a are as hereinbefore defined) with a compound of formula (III):
(wherein X represents a group capable of elimination to form the anion Xe, for example a halogen atom). The reaction of the compounds of formulae (II) and (III) is desirably carried out in the presence of an organic solvent such as dimethoxymethane. The reaction of the compounds of formulae (II) and (III) can be carried out if desired in such a way as to lead the compound of formula (IA) directly without intermediate isolation of the compound of formula (IV).
An alternative method for the preparation of compounds of formula (I) having the formula
(wherein R,, R3, R4 and B5 are as hereinbefore defined) and acid addition salts thereof comprises oxidation of a compound of formula (VIII):
(wherein R,, R3, R4 and B5 are as hereinbefore defined) followed, if desired, by isolation of the compound of formula (IB), optionally in the form of an acid addition salt thereof.
Oxidation of the compound of formula (VIII) may be performed using conventional oxidising agents. The use of manganese dioxide is preferred but alternative oxidising agents which may be used include nitric acid, ferric chloride and chromic oxide/pyridine. Oxidation may alternatively be effected by an Oppenauer oxidation or by dehydrogenation over a copper catalyst.
Compounds of formula (VIII) may be prepared for example from compounds of formula (IX)
(wherein R,, R3, R4 and R5 are as hereinbefore defined) by reaction with a Grignard reagent formed from a compound of formula (X)
(wherein Y represents a chlorine, bromine or iodine atom, preferably a bromine atom) or with phenyllithium. The reaction may be performed under anhydrous conditions in a suitable organic solvent, preferably tetrahydrofuran.
Compounds of formula (IX) may be prepared for example by oxidation of compounds of formula (Xl)
(wherein R,, R3, R4 and B5 are as hereinbefore defined). The oxidation may be performed using conventional oxidising agents, for example manganese dioxide or one of the alternative oxidising agents or oxidising techniques set out above.
Compounds of formula (Xl) may be prepared for example from compounds of the formula (XII)
(wherein R,, R3, R4 and B5 are as hereinbefore defined and Q represents an esterified carboxy group, e.g.
an alkoxycarbonyl or aralkoxycarbonyl group, preferably an alkoxycarbonyl group in which the alkoxy moiety contains 1 to 3 carbon atoms) by reduction using conventional reducing agents. The use of lithium aluminium hydride is preferred but other reducing agents which may alternatively be used include sodium borohydride/aluminium chloride and lithium borohydride.
Starting materials of formula (XII) may generally be prepared by the method disclosed in our
British Patent No. 1596652 or by analogous methods.
Compounds of formula (I) wherein R, represents a chlorine or bromine atom and R2, R3, R4 and B5 are as hereinbefore defined and acid addition salts thereof may be prepared by halogenation of a corresponding compound wherein R1 represents hydrogen, to obtain a compound of formula (I')
(wherein R; represents a chlorine or bromine atom and R2, R3, R4 and B5 are as hereinbefore defined), followed, if desired, by isolation of the compound of formula (I'), optionally in the form of an acid addition salt thereof.
The halogenation reaction may advantageously be carried out either
a) using N-bromosuccinimide when a compound of formula (I') in which Rí represents bromine is required.
b) using N-chiorosuccinimide when a compound of formula (I') in which B; represents chlorine is required.
Compounds of formula (I) wherein R2 represents a group of formula:
(wherein R6 is as hereinbefore defined), R1, R3 and R5 are as hereinbefore defined and R4 represents a
C1-6 alkoxy, C2-8 acyloxy or C1-8 alkyl group may be prepared by acylation of a compound of formula (V):
(wherein R1, R3, R4 and R5 are as hereinbefore defined with the exception of compounds wherein R4 represents a hydroxy group) to obtain a compound of formula (Ic)
(wherein R1, R3, R4, R5 and R6 are as hereinbefore defined, except that R4 is other than a hydroxy group) followed, if desired, by isolation of the compound of formula (Ic), optionally in the form of an acid
addition salt thereof.
The acylation of the compound of formula (V) may advantageously be carried out using an acyl
halide, of the formula R6CO-Hal, wherein R6 is as defined above and Hal represents a halogen, e.g.
chlorine or bromine atom, in the presence of an organic solvent e.g. pyridine.
Compounds of formula (V) may be prepared for example by reduction of a compound of formula
(wherein R1, R3, R4 and R5 are as hereinbefore defined), other than compounds in which R4 represents a hydroxy @roup. The reduction of the compound of formula (A) may advantageously be carried out using a reducing agent such as sodium borohydride in the presence of an organic solvent such as ethanol. @@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@
The formula (A) encompasses some compounds of formulae (IA) and (l') above and certain compounds described in the present applicants'British Patent Application No. 8110586 filed 3 April 1981.Compounds of formula (A) may all be prepared by the methods described above for compounds of formulae (IA) and (I') and as described in the above specification and outlined hereinafter, or by methods analogous to these methods.
Compounds of formula (I) wherein R2 represents a group of formula:
(wherein R7 is as hereinbefore defined), R,, R3 and R5 are as hereinbefore defined, and R4 represents a C18 alkoxy, hydroxy or C1-8 alkyl group and acid addition salts thereof may be prepared by reacting a compound of formula (A) above (with the exception in this instance of compounds of formula (A) wherein R4 represents a C28 acyloxy group), with an appropriate Grignard reagent formed from a compound of the formula R7-Y, wherein Y is as hereinbefore defined, or with a reagent of formula
R7-Li, to obtain a compound of formula (ID)
(wherein R1, R3, R4 and R6 are as hereinbefore defined, except that R4 is other than a C28 acyloxy group) followed, if desired, by isolation of the compound of formula (ID) optionally in the form of an acid addition salt thereof. The reaction is preferably carried out in the presence of an anhydrous ether, e.g.
diethyl ether.
Compounds of formula (I) wherein R2 represents a group of formula:
(wherein R8 is as hereinbefore defined), R1, R3 and R5 are as hereinbefore defined and R4 represents a C18 alkoxy, hydroxy or C18 alkyl group may be prepared by dehydration of a compound of formula (ID) above wherein R7 represents a group B8-CH2- wherein R8 is as hereinbefore defined to obtain a compound of formula (IE)
(wherein R1, R3, R4 and R5 are as hereinbefore defined, except that R4 is other than a C25 acyloxy group). The compounds of formula (ID) for this reaction may be obtained as described above and the dehydration reaction may be carried out with or without intermediate isolation of the compounds of formula (ID) The dehydration reaction is advantageously carried out using concentrated hydrochloric acid.
Compounds of formula (I) wherein R4 represents a hydroxy group, R2 represents a benzoyl group or a group of formula
and R1, R3 and R% are as hereinbefore defined, may be prepared by hydrolysis of the corresponding compound wherein R4 represents a C18 alkoxy group to obtain a compound of formula (IF)
(wherein R1, R3 and B5 are as hereinbefore defined and R2 represents a benzoyl group or a group of formula
followed, if desired, by isolation of the compound of formula (IF) optionally in the form of an acid addition salt thereof. The hydrolysis may advantageously be carried out using hydrobromic acid with heating at reflux temperature for about 30 hours in the presence of water.
Compounds of formula (I) wherein R4 represents a C25 acyloxy group and R1, R2, R3 and B5 are as hereinbefore defined, may be prepared by reaction of the corresponding compound wherein R4 represents a hydroxy group with a compound of formula (VI)
Hal-R9 (Vl) (wherein B9 represents a C29 acyl group and Hal is as hereinbefore defined or with a compound of formula (VII)
(R9)2O (VII) (wherein B9 is as defined above) to obtain a compound of formula (IG)
(wherein R1, R2, R3, B5 and B9 are as hereinbefore defined) followed, if desired, by isolation of the compound of formula (IG), optionally in the form of an acid addition salt thereof.The reaction may if desired employ a compound of formula (IF) which may be obtained as described above and the reaction with the compound of formulae (VI) or (VII) may in that case be carried out with or without isolation of the compound of formula (IF), The reactions may advantageously be carried out in the presence of an organic solvent such as triethylamine.
Acid addition salts of the compounds of formula (I) may be prepared by conventional methods, e.g.
by reaction of the compound of formula (I) with a mineral or organic acid, advantageously in substantially equimolar proportions.
As mentioned above, the compounds of formula (I) and acid addition salts thereof possess interesting pharmacological activity, in particular a remarkable anxiolytic activity as well as a certain hypnotic activity. These properties are illustrated in more detail by experimental results given hereinafter.
These properties indicate that the compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof may be of use as medicaments.
The present invention accordingly further provides compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof for use as medicaments, for example in the treatment of anxiety, chronic anxiety accompanied by agitation, irritability and aggression, anxiety accompanied by insomnia and muscular tension and distress.
Preferred in this connection are the compounds of formula (I) falling within the definitions of preferred compounds already given above and the specific compounds already mentioned, and pharmaceutically acceptable acid addition salts thereof.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of formula I as hereinbefore defined or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient.
For pharmaceutical administration the compounds of general formula (I) and their pharmaceutically acceptable acid addition salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for digestive or parenteral administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, gelatin capsules, granules, suppositories and solutions e.g. for injection.
The active ingredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 0.1 mg to 100 mg preferably from 0.1 mg to 20 mg of active ingredient. The oral daily dosage, which may be varied according to the compound used, the subject treated and the complaint concerned, may, for example, be from 0.5 to 200 mg per day in adults.
In a further aspect the invention provides, as novel industrial products useful as intermediates in the preparation of compounds of formula (I), the compounds of formula (V):
(wherein R1, R3, R4 and P5 are as defined above with the exception of compounds wherein R4 represents a hydroxy group) and salts thereof.
Compounds of formula (II), where they are not known per se, may be prepared by methods analogous to the methods described in the present applicants' British Patent Specification No.
1596652 or in British Patent Specification No. 1542778. The compounds of formula (II) may also be prepared as described in J.C.S. 1958 page 614 or following the method described in "Synthesis" 1977 page 500.
The compounds of formula (A) described in British Patent Application 8110586 mentioned above may be prepared by a process comprising reacting a compound of formula
(wherein R3 represents a hydrogen atom, R4 represents a C19 alkoxy group, and P5 is as defined above) with a compound of formula
(wherein X is as defined above) to obtain a compound of formula
(wherein R3 represents a hydrogen atom, R4 represents a C19 alkoxy group and P5 and Xe are as defined above), followed by cyclisation of the compound thus formed to give a compound of formula (A) above.
The following non-limiting Examples illustrate the invention. Temperatures are given in OC.
EXAMPLE 1 (7-Ethyl-5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethyl acetate
Step A: (7-Ethyl-5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanol Sodium borohydride (1.51 g; 0.04 mol) was added in portions to a stirred suspension of (7-ethyl 5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanone (3.30 g; 0.01 mol) in ethanol (200 ml). After stirring at room temperature for 2h the excess borohydride was destroyed by a dropwise addition of water and then the solvent removed under reduced pressure. The residue was partitioned between dichloromethane-water mixture and after separating the organic layer the aqueous layer was further extracted with dichloromethane.The combined organic extract was washed with water, dried over anhydrous magnesium sulphate and evaporated under reduced pressure to give the title compound as a yellow gum (3.10 g; 93%).
Step B: (7-Ethyl-5-methoxyimidazo[l ,2-a]quinolin-2-yl)phenylmethyl acetate
A solution of (7-ethyl-5-methoxyimidazol[1 ,2-a]quinolin-2-yl)phenylmethanol (3.1 g; 9.3 mmol) in pyridine (50 ml) was stirred and cooled to 50C and acetyl chloride (1.10 g; 14 mmol) added dropwise while keeping the reaction temperature below 50C throughout. After the addition of the acid chloride was complete, the mixture was warmed to room temperature and then poured onto ice-water mixture.
The product precipitated out as a white solid and was filtered off, washed with water, dried and recrystallised from petroleum ether (60--800C)-ethyl acetate mixture to give the cream coloured acetate (2.23 g; 64%), mp 93-50C.
EXAMPLE 2 (1 -Bromo-7-ethyl-5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanone N-bromosuccinimide (1.0 g) was added to a stirred solution of (7-ethyl-5-methoxyimidazo[1 ,2- a]quinolin-2-yl)phenylmethanone (1.6 g) in chloroform (25 ml). 10 min later the solution was washed with water, evaporated to dryness and the residue triturated with ethanol to give the (1 -bromo-7-ethyl- 5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanone, (1.4 g; 71%) as a cream crystalline solid, mp 171--20.
EXAMPLE 3 (1 -chloro-7-ethyl-5-methoxyimidazo[l ,2-a]quinolin-2-yl)phenylmethanone Using a method similar to that used at Example 2, but using N-chlorosuccinimide (0.8 g) and refluxing the solution for 4 h, the (1 -chloro-7-ethyl-5-methoxyimidazo[1,2-a]quinolin-2- yl)phenylmethanone (1.4 g; 79%) was similarly prepared as a cream crystalline solid, mp 1768 .
EXAMPLE 4 2-benzoyl-7-ethylimidazo[1 ,2-a]quinolin-2-ol A suspension of (7-ethyl-5-methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanone (10 g) in hydrobromic acid (48%; 200 ml) was stirred under reflux for 30 h, diluted with water (200 ml), cooled in ice and filtered. The collected solid was washed with water and dissolved in hot methanol (100 ml). The solution was basified with aqueous ammonia (d 0.88) and diluted with water to give the 2-benzoyl-7 ethyl-imidazo[1 ,2-a]quinolin-5-ol (7.5 g, 78%) as a colourless, crystalline solid, mp 268-700C.
EXAMPLE 5 1-(7-ethyl-5-methoxyimidazol[1,2-a]quinolin-2-yl)phenylethanol
(7-ethyl-5-methoxyimidazo[1,2-a]quinolin-2-yl)phenylmethanone (6.6g) was added in portions to a stirred solution of methyl magnesium iodide (from magnesium (1.2 g) and iodomethane (7.1 g) in dry ether (250 ml). The mixture was stirred under reflux for 8h and poured into aqueous ammonium chloride. The mixture was extracted with ethyl acetate, the organic layer washed, dried and evaporated to dryness and the residue filtered from ether to give the 1 -(7-ethyl-5-methoxyimidazo[1 ,2-a]quinolin- 2-yl)phenylethanol (4.9 g; 71%) as colourless crystalline solid, mp 187-8 .
EXAMPLE 6 (2-benzoyl-7-ethylimidazo[1,2-a]quinolin-5-yl) acetate
A mixture of 2-benzoyl-7-ethylimidazo[1 ,2-a]quinolin-5-ol obtained at Example 4 (2 g), acetic anhydride (10 ml) and triethylamine (5 drops) was heated on a steam-bath for 1 h, stirred overnight at room temperature, diluted with ether and filtered to give (2-benzoyl-7-ethylimidazo[1 ,2-a]quinolin-5-yl) acetate (2 g, 88%) as a cream crystalline solid, mp 2023 .
EXAMPLE 7 7-ethyl-5-methoxy-2-(1-phenylvinyl)imidazo[1,2-a]quinoline hydrochloride
1-(7-ethyl-5-methoxyimidazo[1,2-a]quinolin-2-yl)-1-phenylethanol obtained at Example 5 (2.5 g) was added in portions to stirred concentrated hydrochloric acid (15 ml) at 80 to which ethanol (1 ml) had been added. After 1 h the mixture was diluted with water, filtered and the solid washed with water and acetone to give the 7-ethyl-5-methoxy-2-(1 -phenylvinyl)imidazo[1 ,2]quinoline hydrochloride (2.6 g, 99%) as colourless crystals, mp 188--910.
EXAMPLE 8 (7-ethyl-5-methoxy-4-methylimidazo[1,2-a]quinolin-2-yl)phenylmethanone
To 2-amino-6-ethyl-4-methoxy-3-methylquinoline dissolved in dimethoxymethane was added 3bromo-phenyl-propan-1 ,2-dione and the mixture obtained was stirred at room temperature for 2.5 hr.
The precipitated salt 6-ethyl-4-methoxy-3-methyl-1-(3-phenyl-2,3-dioxopropyl)-2-quinolinium bromide was filtered off, washed with ether, suspended in ethanol and heated under reflux until a clear solution was obtained. After cooling to room temperature the crystallised salt was filtered off. The mother liquors were concentrated under reduced pressure and diluted with ether to precipitate a second crop. The combined crops were shaken with a mixture of chloroform and aqueous potassium carbonate. The organic layer was washed, dried (MgSO4), concentrated under reduced pressure and diluted with ethanol to crystallise in two crops (7-ethyl-5-methoxy-4-methylimidazo[l ,2-a]quinolin-2- yl)phenylmethanone (yield 22%, mp 1 41--2 0).
EXAMPLE 9 (7-ethyl-5-methylimidazo[1,2-a]quinolin-2-yl) phenylmethanone
Using a method similar to that used at Example 8 but starting from 2-amino-6-ethyl-4methylquinoline and from 3-bromo-1 -phenylpropane-1 ,2-dione, the (7-ethyl-5-methylimidazo[1 2- a]quinolin-2-yl)phenylmethanone was obtained (yield: 22%) mp 1 87-90C. (see Table 1 below).
EXAMPLE 10 (4,7-diethyl-5-methoxyimidazo[1,2-a]quinolin-2-yl)phenylmethanone
Using a method similar to that used at Example 8 but starting from 2-amino-3,6-diethyl-4methoxyquinoline and from 3-bromo-l -phenylpropan-l ,2-dione, the (4,7-diethyl-5 methoxyimidazo[1 ,2-a]quinolin-2-yl)phenylmethanone was obtained (yield 18%) mp 1 45-60C. (See
Table 1 below).
TABLE 1
Theory/Found Example R1 R2 R3 R4 R5 Yield Mp IR (KBr disc) Formula M.Wt. C H N X 1 H CH(OAc)Ph H OCH3 7-C2H5 60 93-5 3140, 1630 C23H22N2O3 374.45 73.78 5.92 7.48 78.9 6.0 7.5 2 Br COPh H OCH3 " 71 171-2 1662, 1638 C21H17BrN2O2 409.29 61.63 4.19 6.84 19.52 (Br) 61.7 4.2 6.9 19.6 3 Cl COPh H OCH3 " 79 176-8 164 C21H17CIN2O2 364.83 69.14 4.70 7.68 9.72 (Cl) 69.0 4.8 7.7 10.1 4 H COPh H OH " 71 268-70 3130, 1638 C20H16N2O2 316.36 75.93 5.10 8.85 75.65 5.15 8.9 5 H C(OH)MePh H OCH3 " 78 187-8 1741, 1630 C22H22N2O2 346.44 76.28 6.40 8.09 76.0 6.5 8.0 6 H COPh H OAc " 71 202-3 3115, 1771, 1645 C22H18N2O3 358.40 73.73 5.06 7.82 73.7 5.1 7.8 7 H CPh=CH2 H OCH3 " 99 188-91 1641, 1630infl., 1620 infl.C22H20N2O.HCl 364.9 67.43 6.91 7.15 9.05 (Cl) 67.4 6.2 7.2 9.2 8 H COPh CH3 OCH3 " 22 141-2 3120, 1635, 1595 C22H20N2O2 344.4 76.72 5.85 8.13 76.7 5.9 8.2 9 H COPh H CH3 " 22 187-9 3100, 1625, 1595 C21H18N2O 314.4 80.23 5.77 8.91 80.4 5.8 8.9 10 H COPh C2H5 OCH3 " 18 145-6 3120, 1630, 1570 C23H22N2O2 358.4 77.07 6.19 7.81 77.1 6.2 7.8 The activity of the compounds according to the invention may be illustrated as follows:
Biochemical and Pharmacological Activity
Biochemical Pharmacology:
The affinity of the compounds for the benzodiazepine receptor was assessed using the radioligand [3H]flunitrazepam and modifications of the original radioreceptor binding method of Squires and
Braestrup (Nature, 1 977, 266, 732). The values below are nanomolar concentrations of test drug which inhibited the specific binding of 0.6nM[3H]flunitrazepam to rat forebrain membrane preparations by 50% (IC50nM).
Product of Example IC, nM 1 5000 2 3200 3 975 4 430 5 8000 6 395 7 120 8 7 9 250 10 135 EXAMPLE A:
Tablets were prepared corresponding to the formula: - (7-ethyl-5-methoxy-4-methylimidazo[i ,2-a]quinolin- 2-yl)phenylmethanone 20 mg - Excipient q.s. for one tablet up to 150 mg
(details of the excipient: lactose, starch, talc, magnesium stearate).
EXAMPLE B
Tablets were prepared according to the formula: - (4,7-diethyl-5-methoxyimidazo[l ,2-a]quinolin-2-yl)phenylmethanone 20 mg - Excipient q.s. for one tablet up to 150 mg
(details of the excipient: lactose, starch, talc, magnesium stearate).
Claims (54)
1. Compounds of formula I
[wherein
R1 represents a hydrogen atom or a chlorine or bromine atom;
R2 represents a benzoyl group, a group of formula
(wherein R6 represents a C15 alkyl group), a group of formula
(wherein R, represents an alkyl group) or a group of formula:
(wherein R8 represents a hydrogen atom or an alkyl group), the symbol Ph representing a phenyl group;
R3 represents a hydrogen atom or a C1-5 alkyl group;
R4 represents a C15 alkoxy group, a hydroxy group, a C25 acyloxy group or a C18 alkyl group, and
R5 represents a C15 alkyl group; provided that R, and R3 do not both represent hydrogen atoms when R2 represents a benzoyl group and R4 represents a C1-8 alkoxy group] and salts thereof.
2. Compounds as claimed in claim 1 wherein R1, R3, R4 and R5 are as defined in claim 1 and R2 represents a benzoyl group, a group of formula
(wherein Fl6 represents a C1-5 alkyl group), a group of formula
(wherein R7 represents a C15 alkyl group) or a group of formula
(wherein R8 represents a hydrogen atom or a C14 alkyl group), the symbol Ph representing a phenyl group.
3. Compounds as claimed in claim 1 or claim 2 wherein R3 represents a hydrogen atom or a methyl or ethyl group, R4 represents a methoxy, hydroxy, acetoxy or methyl group and R5 represents a methyl or ethyl group.
4. Compounds as claimed in claim 1, wherein R, represents a hydrogen atom, R2 represents a benzoyl group or a 1 -phenyl-vinyl group, R3 represents a hydrogen atom or a methyl or ethyl group, R4 represents a methoxy, hydroxy, acetoxy or methyl group and R5 represents an ethyl group.
5. Compounds as claimed in claim 1, wherein R, represents a hydrogen atom, R2 represents a benzoyl group, R3 represents a methyl or ethyl group, R4 represents a methoxy group and R5 represents an ethyl group.
6. (7-Ethyl-5-methoxy-4-methylimidazo[1,2-a]quinolin-2-yl)phenylmethanone and salts thereof.
7. 4,7-Diethyl-5-methoxyimidazo[1,2-a]quinolin-2-yl)phenylmethanone and salts thereof.
8. Salts of compounds as claimed in any preceding claim formed with hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic acid or an alkanesulphonic or arylsulphonic acid.
9. Pharmaceutically acceptable acid addition salts of compounds as claimed in any one of claims 1 to 7.
10. Compounds as claimed in any preceding claim as herein specifically described.
11. Compounds as claimed in any preceding claim as herein specifically described in any of
Examples 1 to 10.
12. Compounds of formula I as defined in claim 1 and pharmaceutically acceptable acid addition salts thereof for use as medicaments.
13. Compounds of formula I as defined in claim 1 and pharmaceutically acceptable acid addition salts thereof for use in the treatment of anxiety, chronic anxiety accompanied by agitation, irritability and aggression, anxiety accompanied by insomnia and muscuiar tension and distress.
14. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a hydroxygen atom, R2 represents a benzoyl group, R4 represents a C1-8 alkyl group and R3 and R5 are as defined in claim 1, which comprises cyclising a compound of formula IV
(wherein R3 and R5 are as defined in claim 1, R4 represents a C15 alkoxy or C19 alkyl group and Xe represents an anion).
1 5. A process as claimed in claim 14 wherein Xe in the compound of formula IV is a halogen anion.
16. A process as claimed in claim 14 or claim 15 wherein the cyclisation is effected by heating the compound of formula IV in the presence of an organic solvent.
17. A process as claimed in any of claims 14 to 1 6 wherein a compound of formula IV used in the process is prepared by reacting a compound of formula II
(wherein R3, R4 and R5, are as defined in claim 14) with a compound of formula Ill
(wherein X represents a group capable of elimination to form the anion Xe).
1 8. A process as claimed in claim 17 wherein the cyclisation of the compound of formula IV is effected without isolation thereof from the reaction mixture.
19. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a hydrogen atom, R2 represents a benzoyl group, R4 represents a C19 alkoxy group or a C19 alkyl group and R3 and R5 are as defined in claim 1, which comprises oxidising a compound of formula VIII
(wherein R1, R3 and R5 are as defined in claim 1 and R4 represents a C19 alkoxy or C18 alkyl group).
20. A process as claimed in claim 19, wherein oxidation is effected using manganese dioxide, nitric acid, ferric chloride or chromic oxide/pyridine or by an Oppenauer oxidation or by dehydrogenation over a copper catalyst.
21. A process as claimed in claim 19 or claim 20, wherein a compound of formula VIII used in the process is prepared by reacting a compound of formula (IX)
(wherein R1, R3, R4, and R5 are as defined in claim 19) with a Grignard reagent formed from a compound of formula X
(wherein Y represents a chlorine, bromine or iodine atom) or with phenyllithium.
22. A process as claimed in claim 21 wherein the group Y in the compound of formula X represents a bromine atom.
23. A process as claimed in claim 21 or claim 22, wherein the compound of formula IX used in the process is prepared by oxidising a compound of formula Xl
(wherein R1, R3, R4 and R5 are as defined in claim 19).
24. A process as claimed in claim 23, wherein the compound of formula Xl used in the process is prepared by reducing a compound of formula XII
(wherein R1, R3, R4 and R8 are as defined in claim 19 and Q represents an esterified carboxy group).
25. A process as claimed in claim 24, wherein the group Q in the compound of formula XII represents an alkoxycarbonyl or aralkoxycarbonyl group.
26. A process as claimed in claim 25 wherein the alkyl portion of the group 0 in the compound of formula XII contains 1 to 3 carbon atoms.
27. A process as claimed in any of claims 24 to 26, wherein the reduction is effected using lithium aluminium hydride, sodium borohydride/aluminium chloride or lithium borohydride as a reducing agent.
28. A process for the preparation of compounds as claimed in claim 1 wherein R1 represents a chlorine or bromine atom and R2, R3, R4 and R5 are as defined in claim 1, which comprises halogenating a corresponding compound of formula I wherein R1 represents a hydrogen atom.
29. A process as claimed in claim 28 wherein the halogenating agent used is N-bromosuccinimide (when a compound of formula I in which R1 represents a bromine atom is required) or Nchlorosuccinimide (when a compound of formula I in which R1 represents a chlorine atom is required).
30. A process for the preparation of compounds as claimed in claim 1 wherein R2 represents a group of formula
(wherein R5 is as defined in claim 1), R1, R3 and R5 are as defined in claim 1 and R4 represents a C1-8 alkoxy, C28 acyloxy or C19 alkyl group, which comprises acylating a compound of formula V
(wherein R1, R3 and R5 are as defined in claim 1 and R4 represents a C1a alkoxy C29 acyloxy or C18 alkyl group).
31. A process as claimed in claim 30 wherein the acylation is effected using a compound of formula
(wherein R6 is as defined in claim 1 and Hal represents a halogen atom) in the presence of an organic solvent.
32. A process as claimed in claim 31 wherein the acylating agent used is a compound of formula
wherein R5 is as defined in claim 1 and Hal represents a chlorine or bromine atom.
33. A process as claimed in any of claims 30 to 32, wherein a compound of formula V used in the process is prepared by reducing a compound of formula A
(wherein R1, R3 and R5 are as defined in claim 1 and R4 represents a C15 alkoxy, C2s acyloxy or C1-8 alkoxy group).
34. A process for the preparation of compounds as claimed in claim 1 wherein R1, R3 and R5 are as defined in claim 1, R2 represents a group of formula
(wherein R7 is as defined in claim 1) and R4 represents a C19 alkoxy, hydroxy or C19 alkyl group, which comprises reacting a compound of formula A
(wherein R@ @ and R are as defined in claim 1 and @ @@@@@@@@@@ @@@@ @@@@@ @@@@@@@@ group) with a Grignard reagent formed from a compound of formula
R7-Y wherein R7 is as defined in claim 1 and Y represents a chlorine, bromine or iodine atom, or with a reagent of formula R7-Li.
35. A process for the preparation of compounds as claimed in claim 1 wherein R1, R3 and R5 are as defined in claim 1, R2 represents a group of formula
(wherein R8 is as defined in claim 1) and R4 represents a C1-8 alkoxy, hydroxy or C1-8 alkyl group, which comprises dehydrating a compound of formula 1D
wherein R, R and B are as defined in claim 1 @ represents @@@ @@@@@@ @@@@@@@@@ @@@ @@@ and R7 represents a group of formula
R8-CH2wherein R8 is as defined in claim 1).
36. A process for the preparation of compounds as claimed in claim 1 wherein R1, R3 and R5 are as defined in claim 1, R2 represents a benzoyl group or a group of formula
and R4 represents a hydroxy group, which comprises hydrolysing a corresponding compound of formula
I wherein R4 represents a C14 alkoxy group.
37. A process for the preparation of compounds as claimed in claim 1 wherein R1, R2, R3 and R5 are as defined in claim 1 and R4 represents a C29 acyloxy group, which comprises reacting a corresponding compound of formula I, wherein R4 represents a hydroxy group, with a compound of formula (VI) Hal-R9 (Vl) (wherein R9 represents a C29 acyl group and Hal represents a halogen atom) or with a compound of formula (VII)
(R9)20 (Vll) (wherein R9 represents a C25 acyl group).
38. A process as claimed in claim 37 wherein the starting material of formula I wherein R4 represents a hydroxy group is prepared by a process as claimed in claim 36, optionally with or without isolation of said starting material from the reaction mixture.
39. A process as claimed in any of claims 14 to 38, wherein a compound of formula I, initially obtained, is subsequently converted into a salt thereof, or a salt of a compound of formula I, initially obtained, is subsequently converted into another salt thereof or into a compound of formula
40. A process as claimed in any one of claims 14 to 39, wherein a compound of formula I as defined in claim 1 or an acid addition salt thereof, initially obtained, is subsequently converted without isolation from the reaction mixture into an acid addition salt thereof or into another compound of formula I or an acid addition salt thereof.
41. A process as claimed in any one of claims 14 to 40 substantially as herein described.
42. A process as claimed in any one of claims 14 to 41 substantiallay as herein described in any of
Examples 1 to 10.
43. Compounds of formula I as claimed in claim 1 and salts thereof when prepared by a process as claimed in any one of claims 14 to 42.
44. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as claimed in claim 1 or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient.
45. Composition as claimed in claim 44 in a form suitable for digestive or parenteral administration.
46. Composition as claimed in claim 44 or claim 45 in the form of plain tablets, coated tablets, capsules, gelatin capsules, granules, suppositories and solutions.
47. Compositions as claimed in any one of claims 44 to 46 in the form of dosage units.
48. Compositions as claimed in claim 47 wherein each dosage unit contains from 0.1 mg to 100 mg of active ingredient.
49. Compositions as claimed in claim 47 or claim 48 wherein each dosage unit contains from 0.1 mg to 20 mg of active ingredient.
50. Pharmaceutical compositions as claimed in claim 44 substantially as herein described.
51. Pharmaceutical compositions as claimed in claim 44 substantially as herein described in either of Examples A and B.
52. Compounds of formula V
(wherein R1, R3 and R5 are as defined in claim 1 and R4 represents a C19 alkoxy group, a C29 acyloxy group or a C19 alkyl group) and salts thereof.
53. Compounds as claimed in claim 52 as herein specifically described.
54. Compounds as claimed in claim 53 as herein specifically described in any of Examples 1 to 10.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8228069 | 1982-10-01 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8326230D0 GB8326230D0 (en) | 1983-11-02 |
| GB2127824A true GB2127824A (en) | 1984-04-18 |
| GB2127824B GB2127824B (en) | 1986-02-12 |
Family
ID=10533302
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08326230A Expired GB2127824B (en) | 1982-10-01 | 1983-09-30 | Imidazo(1,2-a)quinolines |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0107988B1 (en) |
| JP (1) | JPS5978188A (en) |
| AT (1) | ATE28646T1 (en) |
| AU (1) | AU564997B2 (en) |
| CA (1) | CA1206475A (en) |
| DE (1) | DE3372771D1 (en) |
| DK (1) | DK454783A (en) |
| ES (1) | ES8704944A1 (en) |
| FI (1) | FI76335C (en) |
| GB (1) | GB2127824B (en) |
| GR (1) | GR79396B (en) |
| HU (1) | HU189750B (en) |
| IE (1) | IE56052B1 (en) |
| IL (1) | IL69721A (en) |
| PT (1) | PT77436B (en) |
| ZA (1) | ZA836701B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0700395A2 (en) * | 2007-06-07 | 2009-03-02 | Sanofi Aventis | Substituted [1,2,4] triazolo [1,5-a] quinolines, process for their preparation, pharmaceutical compositions thereof, and intermediates |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2096143A (en) * | 1981-04-03 | 1982-10-13 | Roussel Lab Ltd | Imidazo(1,2-a)quinoline derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1596652A (en) * | 1977-01-20 | 1981-08-26 | Roussel Lab Ltd | Imidazo (1,2-a) quinoline-2-carboxylic acid and derivatives |
-
1983
- 1983-09-09 ZA ZA836701A patent/ZA836701B/en unknown
- 1983-09-14 IL IL69721A patent/IL69721A/en unknown
- 1983-09-26 JP JP58176548A patent/JPS5978188A/en active Pending
- 1983-09-29 HU HU833389A patent/HU189750B/en not_active IP Right Cessation
- 1983-09-29 GR GR72585A patent/GR79396B/el unknown
- 1983-09-29 EP EP83401914A patent/EP0107988B1/en not_active Expired
- 1983-09-29 AT AT83401914T patent/ATE28646T1/en not_active IP Right Cessation
- 1983-09-29 DE DE8383401914T patent/DE3372771D1/en not_active Expired
- 1983-09-30 ES ES526143A patent/ES8704944A1/en not_active Expired
- 1983-09-30 FI FI833553A patent/FI76335C/en not_active IP Right Cessation
- 1983-09-30 AU AU19823/83A patent/AU564997B2/en not_active Ceased
- 1983-09-30 CA CA000438135A patent/CA1206475A/en not_active Expired
- 1983-09-30 GB GB08326230A patent/GB2127824B/en not_active Expired
- 1983-09-30 IE IE2321/83A patent/IE56052B1/en unknown
- 1983-09-30 PT PT77436A patent/PT77436B/en not_active IP Right Cessation
- 1983-10-03 DK DK454783A patent/DK454783A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2096143A (en) * | 1981-04-03 | 1982-10-13 | Roussel Lab Ltd | Imidazo(1,2-a)quinoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| PT77436A (en) | 1983-10-01 |
| ZA836701B (en) | 1984-10-31 |
| IL69721A0 (en) | 1983-12-30 |
| FI76335C (en) | 1988-10-10 |
| IL69721A (en) | 1987-03-31 |
| HU189750B (en) | 1986-07-28 |
| EP0107988A3 (en) | 1985-05-22 |
| FI833553A0 (en) | 1983-09-30 |
| JPS5978188A (en) | 1984-05-04 |
| IE56052B1 (en) | 1991-03-27 |
| CA1206475A (en) | 1986-06-24 |
| PT77436B (en) | 1986-04-17 |
| GR79396B (en) | 1984-10-22 |
| AU564997B2 (en) | 1987-09-03 |
| DK454783D0 (en) | 1983-10-03 |
| EP0107988A2 (en) | 1984-05-09 |
| FI833553A (en) | 1984-04-02 |
| DK454783A (en) | 1984-04-02 |
| ES8704944A1 (en) | 1987-04-16 |
| EP0107988B1 (en) | 1987-07-29 |
| AU1982383A (en) | 1984-04-05 |
| ES526143A0 (en) | 1987-04-16 |
| DE3372771D1 (en) | 1987-09-03 |
| FI76335B (en) | 1988-06-30 |
| GB8326230D0 (en) | 1983-11-02 |
| IE832321L (en) | 1984-04-01 |
| GB2127824B (en) | 1986-02-12 |
| ATE28646T1 (en) | 1987-08-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19930930 |