GB2230779A

GB2230779A - Imidazo [2, 1-b] benzothiazoles

Info

Publication number: GB2230779A
Application number: GB9008661A
Authority: GB
Inventors: Charles John Robert Hedgecock; David Paul Kay
Original assignee: Roussel Laboratories Ltd
Current assignee: Roussel Laboratories Ltd
Priority date: 1989-04-19
Filing date: 1990-04-18
Publication date: 1990-10-31
Anticipated expiration: 2010-04-18
Also published as: FR2646159B1; GB2230779B; GB8908846D0; GB9008661D0; FR2646159A1

Abstract

Imidazo [2.1 -b] benzothiazoles of formula I <IMAGE> and acid addition salts thereof are prepared by (1) reaction of a compound of formula II <IMAGE> with a compound of formula III <IMAGE> to give a compound of formula IA which can in subsequent steps be converted to other compounds of formulae I R2 and R3 completing a ring, R1 being cyclopropyl optionally bearing certain defined substituents and R being hydrogen, C2-5 alkoxy carbonyl or cyano, or (2) reaction of a compound of formula II with a compound of formula VI <IMAGE> to give a compound of formula ID. <IMAGE> Precursors of compounds (II) are of the formula (VII> <IMAGE> Several new compounds of formula I possess inverse agonist and tranquillising properties.

Description

Chemical Compounds This invention relates to a new process for the preparation of imidazo[2,1-b]benzothiazoles and acid additions salts thereof, to new imidazo[2,l-b)- benzothiazoles, to their use as medicaments and to pharmaceutical compositions containing them.

In British Patent Application No. 8824492.6, the applicant described certain new imidazo[2,l-b)- benzothiazoles and salts thereof, as well as processes for the preparation of these compounds and their use as medicaments. The applicant has now found a new process for the preparation of these compounds.

According to one aspect of the invention there is provided a process for the preparation of a compound of formula I

[wherein 91 represents a group of formula A

wherein R4 represents a hydrogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms, a carboxyl group, a cyano group, an amido group, a monoor dialkylamido group in which the alkyl groups may be the same or different and each contains from 1 to 5 carbon atoms or a halogen atom; R2 and R3 together represent a group

wherein m represents an integer 1, 2 or 3;; X1 and X2, which may be the same or different, each represents a hydrogen atom, a straight-chain or branched alkyl group containing 1 to 5 carbon atoms, a straightchain or branched alkoxy group containing 1 to 5 carbon atoms, an aralkoxy group, an aryloxy group, a halogen atom, or a nitrile or azido group, or X1 and X2 together represent a methylenedioxy group) which comprises either a) reacting a compound of formula II

(wherein R2 and R3 are as defined above) with a compound of formula III (CH3)2S = CH R Hale (III) (wherein Hal represents a halogen atom and R represents a hydrogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms or a cyano group) to obtain a compound of formula 1A

(wherein R, R2 and R3 are as defined above) which is optionally isolated or, if desired, subsequently subjecting a compound of formula 1A in which R represents an alkoxycarbonyl group containing 2 to 5 carbon atoms to saponification to obtain a compound of formula IB

(wherein R2 and R3 are as defined above) which is optionally isolated or, if desired, subsequently reacting the compound of formula 1B with N,N'-carbonyldiimidazole to obtain a compound of formula IV

(wherein R2 and R3 are. as defined above) and subsequently reacting the compound of formula IV with a compound of formula V

(wherein R5 and R6, which may be the same or different, each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms) to obtain a compound of formula Ic

(wherein R2, R3, R5 and R6 are as defined above); or b) reacting a compound of formula II as defined above with the fluoroborate salt of a compound of formula VI

(wherein Hal represents a halogen atom and Alk represents an alkyl group containing 1 to 3 carbon atoms) in the presence of a suitable base to obtain a compound of formula ID

(wherein R2, R3 and Hal are as defined above).

The term "alkoxycarbonyl group containing 2 to 5 carbon atoms" as used herein includes, for example, a methoxycarbonyl, ethoxycarbonyl, or propoxy carbonyl group.

The term "mono- or dialkylamido group in which the alkyl groups may be the same 6r different and each contains from 1 to 5 carbon atoms" as used herein includes, for example, a monomethylamido, dimethylamido, monoethylamido, diethylamido, monopropylamido or dipropylamido group.

The term "halogen atom" as used herein includes, for example, a fluorine, chlorine or bromine atom.

The reaction between the compound of formula II and the compound of formula III is preferably effected in the presence of an anhydrous organic solvent such as chloroform. In the compound of formula III, Hal preferably represents a bromine atom.

The saponification of the compound of formula 1A is preferably effected in the presence of a dilute solution of a base such as sodium or potassium hydroxide.

The reaction between the compound of formula IB and N, N-carbonyldiimidazole is preferably effected in the presence of an organic solvent such as dimethyl formamide.

The reaction of the compound of formula IV with the compound of formula V is advantageously effected in the presence of an organic solvent such as dichloromethane.

In the reaction between the compound of formula II and the fluoroborate salt of the compound of formula VI, a suitable base to use is, for example, sodium hydride.

The compounds of formula II may conveniently be prepared by oxidising a compound of formula VII

wherein R2 and R3 are as defined above.

The oxidation of the compound of formula VII is preferably effected by means of a weak oxidant such as manganese dioxide in the presence of an organic solvent such as dichloroethane.

The compounds of formula'VII may be conveniently prepared by reacting a compound of formula VIII

(wherein R2 and R3 are as defined above) with a magnesium vinyl halide.

The reaction between the compound of formula VIII and the magnesium vinyl halide is preferably effected in the presence of an anhydrous organic solvent such as tetrahydrofuran.

The compounds of formula VIII may, for example, be prepared by oxidising a compound of formula IX

(wherein R2 and R3 are as defined above).

The compounds of formula IX may, for example, be prepared by reacting a compound formula X:

(wherein R2 and R3 are as defined above) with 3-bromol-hydroxypropan-2-one.

The compounds of formula X can, for example, be prepared as described in J. Het. Chem. (1980), 17, 1325.

The compounds of formula IX can also be prepared, for example, by reducing a compound of formula XI

(wherein R' represents an alkyl group containing 1 to 3 carbon atoms, and R2 and R3 are as defined above). The compounds of formula XI can be prepared, for example, as described in Farmaco. Ed. Scc. (1977), 32, 735.

According to a further aspect of the invention there is provided a new process for the preparation of the compounds of formula Ic as defined above which comprises reacting a compound of formula IV as defined above with a compound of formula V as defined above. The compounds of formula IV may, for example, be prepared as described above, or by any other convenient method.

The compounds of formula I are basic in character.

The acid addition salts of the compounds of formula I can advantageously be prepared by reacting, in approximately stoichiometric proportions, an inorganic or organic acid with the compound of formula I. The salts can be prepared, for example, without intermediate isolation of the corresponding base.

The acid addition salts may be those of inorganic or organic acids and may be, for example, salts formed with hydrochloric, hydrobromic, hydriodic, nitric, sulphuric, phosphoric, propionic, formic, benzoic, maleic, fumaric, succinic, tartric, citric, oxalic, glyoxylic or aspartic acid or with alkanesulphonic acids such as methanesulphonic acid or arylsulphonic acids such as benzenesulphonic acid.

According to a still further aspect of the invention, there are provided the following new compounds which for convenience are referred to hereinafter as compounds of formula IE: -[imidazo[2,1-b]benzothiazol-2-yl] (2' -carbethoxy- cyclopropyl) methanone; -[imidazot2,1-b]benzothiazol-2-yl] (2'-cyanocyclopropyl) methanone; -[imidazo[2,1-b]benzothiazol-2-yl] (2'-carboxycyclopropyl) methanone; -timidazot2,1-b]benzothiazol-2-yl] (2 '-N,N-dimethyl- carboxamidocyclopropyl) methanone; -Eimidazo[2,1-b]benzothiazol-2-yl] (2'-carboxamidocyclopropyl) methanone; -[imidazo[2, l-b]benzothiazol-2-yl] (2'-chlorocyclopropyl) methanone; and acid addition salts thereof.

As indicated in British Patent Application No.

8824492.6, the compounds of formula I as defined above possess very interesting pharmacological properties; of particular note are the inverse agonist properties of variable strength depending on substitution. Some of the compounds also possess tranquillizing properties.

These properties are further illustrated in the experimental section.

The compounds of formula 1E are thus of use as medicaments. Therefore, according to a further aspect of the invention there is provided the use of compounds of formula 1E as defined above and pharma- ceutically acceptable acid addition salts thereof as medicaments These medicaments are of use, for example, in the treatment of memory problems, particularly in geriatrics, and in cerebral senescence problems. Some of the compounds are also useful in the treatment of obesity and also as minor tranquillizers in the treatment of certain agitated or irritated states.

The usual dose, which varies depending on the compound used, the patient treated and the illness concerned, can be, for example, from 0.1 mg to 200 mg per day by the oral route.

According to a yet further aspect of the invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound of formula IE as defined above or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier and/or excipient.

The compounds of formula IE and the pharmaceutically acceptable acid addition salts thereof can be incorporated into pharmaceutical compositions for the digestive or parenteral route.

These pharmaceutical compositions may be, for example, solid or liquid and may be in conventional pharmaceutical forms used in human medicine, for example, plain or coated tablets, capsules including gelatin capsules, granules, suppositories, solutions e.g. for injection; these may be prepared according to conventional methods. The active ingredient(s) may be used in conjunction with excipients customarily employed in pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, various wetting, dispersing or emulsifying agents or preservatives.

The following intermediates, useful in the preparation of compounds of formula I are new and comprise a further aspect of the invention: The compounds of formula VII

wherein R2 and R3 are as defined above.

The compounds of formula II

wherein R2 and R3 are as defined above.

The compounds of formula IV

wherein R2 and R3 are as defined above.

The following non-limiting examples further illustrate the invention: Example 1 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-carboethoxy cyclopropyl) methanone Step (A) : (imidazo [2,1-b] benzo-thiazol-2-yl) vinyl methanol Imidazo [2,1-b] benzo-thiazol-2-carboxaldehyde (20 g, 0.1 mole) in dry THF (1L) was stirred under nitrogen during the addition of 1M vinyl magnesium bromide (149 ml, 0.14 mole). The mixture was stirred for 1 hour at room temperature then poured onto aqueous ammonium chloride solution and extracted with ethylacetate. The extracts were dried over magnesium sulphate and evaporated under reduced pressure. Trituration of the residue with diethylether gave 1-(imidazo E2,13 benzo-thiazol-2-yl)-1-vinyl methanol as cream coloured crystals (23.0 g, 92 X).

Step (B) : (imidazo C2,1-b3 benzo-thiazol-2-yl) vinyl methanone (Imidazo EZ,I-b3 benzo-thiazol-2-yl) vinylmethanol (100 mg, 0.43 mmol) in dichloromethane (20 ml) was stirred at room temperature with manganese dioxide (400 mg, 0.46 mmol) for 3 hrs and filtered through elite. The filtrate was evaporated to dryness under reduced pressure and triturated with ether giving (imidazo C2,1-b3 benzo-thiazol-2-yl) vinyl methanone as colourless crystals (61 mg, 61.5 X).

Step (C) : (imidazo E2,I-b3 benzo-thiazol-2-yl) (2'-carboethoxycyclopropyl) methanone Carbethoxymethyldimethylsulphonium bromide (J. OC. (1967) 32 (11) 3351) (9.0 g, 0.039 mole) in chloroform (31 ml) was stirred vigorously at 0n, during the addition in one portion of a mixture of saturated potassium carbonate solution (23.5 ml) and 12.5 N sodium hydroxide solution (3.1 ml, 0.039 mole). The mixture was warmed to 15n and stirred for 15 minutes. The top chloroform layer was collected, dried over potassium carbonate and added to a solution of (imidazo C2,1-b3 benzo-thiazol-2-yl) vinyl methanone (4.5 9, 0.0197 mole) in chloroform (39 ml). The mixture was stirred overnight at room temperature, washed with aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica gel eluting with 2 X ethylacetate/dichloromethane to give (imidazo [2,1-b] benzo-thiazol-2-yl) (2'-carboethoxycyclopropyl) methanone (3.7 g, 60 X) as colourless crystals.

Example 2 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-cyanocyclopropyl) methane Using a method similar to that used at Step C of Example 1 but starting from cyanomethyldimethylsulphonium bromide (Wellcome Foundation Ltd Brit GB 1597309) imidazo CCZ,1-b3 benzo-thiazol-2-yl3 (2'-cyanocyclopropyl) methane was prepared.

Example 3 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-cyrboxycyclopropyl) methanone (Imidazo [2,1-b] benzo-thiazol-2-yl) (2'-carboethoxycyclopropyl) methanone (2.38 g, 0.00758 mole) in acetone (100 ml) was treated with 0.25 M potassium hydroxide solution (41 ml, 0.0103 mole) and stirred overnight at room temperature. The mixture was neutralised by the addition of dilute sulphuric acid (0.5 g in 10 ml water, 0.OQ51 mole), filtered and the residue washed with water and dried under vacuum to give (imidazo E2,1-b3 benzothiazol-2-yl) (2'-carboxycyclopropyl) methanone as a colourless solid (1.95 g, 90 X).

Example 4 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-N,N-dimethylcarboxa midocyclopropyL) methanone (Imidazo C2,1-b3 benzo-thiazol-2-yl) (2'-carboxycyclopropyl) methanone (0.975 g, 0.00341 mole) in dry dimethylformamide (6.0 ml) was stirred at room temperature under dry nitrogen with carbonyldiimidazole (0.78 g, 0.0048 mole) for three hours and filtered. The intermediate imidazolide was used directly by dissolving in dichloromethane and treating with an excess of 33 % dimethylamine/ethanol (10 ml). The mixture was stirred 2hrs at room temperature, washed with water and dried over magnesium sulphate.Evaporation under reduced pressure gave (imidazo C2,1-b3 benzo-thiazol-2-yl) (2'-N,N dimethylcarboxamidocyctopropyl) methanone (1.02 g, 96 X) as colourless crystals.

Example 5 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-carboxamidocyclopropyl) ethanone Using a method similar to that used at example 4, but starting from ammoniac/ethanol, (imidazo C2,1-bn benzo-thiazol-2-yl) (2'-carboxamido cyclopropyl) methanone was prepared.

Example 6 : (imidazo [2,1-b] benzo-thiazo(-2-yl) (2'-chlorocyclopropyl) methanone (Imidazo L2,1-b) benzo-thiazol-2-yl) vinyl methanone (238 mg, 0.001 mole) and (dimethylamino) chloromethylphenyloxosulphonium fluoroborate (prepared by the method of C. Johnson & E. Janiga - J American Chem Soc (1973) 45, 7692) (460 mg, 0.0015 mole) were stirred in dry dimethyl formamide (3.0 ml) under nitrogen at On during the addition of sodium hydride (50 mg of 50 X oil dispersion, 0.0016 mole). The mixture was warmed at room temperature, stirred for 2 hours and further ylid added (100 mg BF4 salt, 12 mg NaH ; 0.0003 mole).After a further lhr at room temperature the mixture was diluted with ice/water and extracted with ethyl acetate. The extracts were dried over magnesium sulphate, evaporated under reduced pressure and the residue chromatographed on silica gel eluting with 2 X ethylacetate/dichloromethane to give (imidazo C2,1-b3 benzo-thiazol-2-yl) (2'-chlorocyclopropyl) methanone as colourless crystals (169 mg, 60 X).

Yield, melting point, IR and NMR Spectrum and analytical data are given in Table I.

Example 7 : Tablets were prepared according to the following formulation Compound of Example 1 ..................................... 20 mg - Excipient for one tablet up to ....................... 150 mg (details of the excipient : lactose, starch, talc, magnesium stearate).

Example 8 Tablets were prepared according to the following formulation : Compound of Example 4 .................................. 20 mg - Excipient for one tablet up to ....................... 150 mg (details of the excipient : Lactose, starch, talc, magnesium stearate).

TABLE I

Example R1 R2R3 Yield Mpt C IR cm-1 Nmr # Analysis % C% H% N% S% 1A # 92 143.5 3200 (OH), 1500, 1469 CDCl3 7.69 (dd, 1H); 7.63 (s, 1H): Found 1431, 1332, 1044 7.57 (dd, 1H); 7.42 (dt, 1H); 7.32 (dt,1H); 6.20 (m, 1H); 5.50 (dd, 1H); 5.34 (br.s,1H); 5.32 (dd, 1H) 1B # 62 182.4 3120(CH) 1661 (C=O) CDCl3 8.43 (s, 1H); 7.72 (m, 2H); Found 63.14 3.63 12.15 13.91 1596, 1512, 1497, 1389 7.48 (m, 3H); 6.65 (dd, 1H), C12H8N2OS 63.14 3.58 12.27 14.05 5.93 (dd, 1H) 1C # 60 161.3 3135 (CH), 1728, 1663, CDCl3 8.36 (s, 1H); 7.76 (d, 2H); Found 64.94 4.53 14.16 1520, 1331 7.70 (d, 1H); 7.50 (dt, 1H); 7.42 C16H14N2O3S 65.07 4.44 14.23 (dt, 1H); 4.18 (q, 2H); 3.51 (m, 1H); 2.42 (m, 1H); 1.64 (t, 2H); 1.28 (t, 3H) 2 # 51 203.5 3120, 2235(CH), 1661 CDCl3 8.38 (s, 1H); 7.77 (dd, 1H); Flound 62.82 3.31 15.65 12.00 1512, 1494, 1318 7.71 (dd, 1H); 7.50 (m, 2H); 3.75 C14H9N3OS 62.91 3.39 15.72 11.99 (m, 1H); 2.18 (m, 1H); 1.66 (m, 2H) 3 # 90 305(d) 3140, 2900, 2500 (COOH) DMSOd6 12.60 (brs, 1H); 9.19 (s, 1H); Found 58.72 3.64 9.70 1710, 1658, 1520 8.18 (dd, 1H); 8.09 (dd, 1H); 7.60 C14H10N2O3S 58.73 3.52 9.78 (dt, 1H); 7.50 (dt, 1H); 3.37 (m, 1H); 2.09 (m, 1H); 1.48 (m, 2H) 5 # 95 300(d) 3260, 3180 (NH2), DMSOd6 9.16 (s, 1H); 8.17 (d, 1H); Found 58.43 3.94 14.60 11.19 3120, 1660, 1512, 1494 8.07 (d, 1H); 7.75 (brs), 1H); 7.59 C14H11N3O2S 58.13 3.99 14.6 11.03 (t, 1H); 7.48 (t, 1H); 7.07 (s, 1H); 1/4H2O 3.25 (m, 1H); 2.22 (m, 1H); 1.36 (t, 2H) 4 # 96 193.5 3135, 1650, 1420, 1378 CDCl3 8.41 (s, 1H); 7.75 (dd, 1H); Found 60.82 4.87 13.36 10.03 1319, 1217, 1152 7.68 (dd, 1H); 7.50 (2xdt, 2H); C16H15N3O2S 60.46 4.91 13.22 10.09 3.43 (m, 1H); 3.16 (s, 3H); 3.00 1/4H2O (s, 3H); 2.61 (m, 1H); 1.64 (m, 2H) 6 # 60 187.90 3132, 1657, 1513, 1497, CDCl3 8.35 (s, 1H); 7.7S (dd, 1H); Found 56.36 3.39 10.12 11.59 1366, 1274, 1053 7.69 (dd, 1H); 7.51 (dt, 1H); 7.44 C13H9N2OSCl 56.42 3.28 10.12 11.59 (dt, 1H); 3.60 (m, 1H); 3.45 (m, 1H); 1.80 (m, 1H); 1.58 (m, 1H) Biochemical Activity Test 1 The affinity of the active ingredients for the benzodiazepine receptors was measured using a radioactively labelled (3H) compound flunitrazepam, and a modified version of the method of Squires and Braestrup (Nature, 1977, 266, 732).

The values given in Table 2 below are the concentration (mol x 10-9 of the compound under test which inhibits 50 X of the specific binding of 0.6 x 10-9 mol of 3H-labelled flunitrazepam in preparations of membranes from the rear portion of the brain in rats (IC50 values).

Test 2 : Measurement of in vivo binding to benzodiazepine receptors was carried out according to the method described by Goeders N E and Kuhar M J, Life Sciences (1985) 37 345.

TABLE II

Claims

Claims: 1. A process for the preparation of a compound of formula I

[wherein R1 represents a group of formula A

wherein R4 represents a hydrogen atom, an alkoxycarbonyl group containing
2 to 5 carbon atoms, a carboxyl group, a cyano group, an amido group, a mono- or dialkylamido group in which the alkyl groups may be the same or different and each contains from 1 to 5 carbon atoms or a halogen atom; R2 and R3 together represent a group

wherein m represents an integer 1, 2 or 3;X1 and X2, which may be the same or different, each represents a hydrogen atom, a straight-chain or branched alkyl group containing 1 to 5 carbon atoms, a straight-chain or branched alkoxy group containing 1 to 5 carbon atoms, an aralkoxy group, an aryloxy group, a halogen atom, or a nitrile or azido group, or X1 and X2 together represent a methylenedioxy group) which comprises either a) reacting a compound of formula II

(wherein R2 and R3 are as defined above) with a compound of formula III (CH3)62S - CH R Halo (III) (wherein Hal represents a halogen atom and R represents a hydrogen atom, an alkoxycarbonyl group containing 2 to 5 carbon atoms or a cyano group) to obtain a compound of formula 1A

(wherein R, R2 and R3 are as defined above) which is optionally isolated or, if desired, subsequently subjecting a compound of formula 1A in which R represents an alkoxycarbonyl group containing 2 to 5 carbon atoms to saponification to obtain a compound of formula IB

(wherein R2 and R3 are as defined above) which is optionally isolated or, if desired, subsequently reacting the compound of formula IB with N,N'carbonyldiimidazole to obtain a compound of formula IV

(wherein R2 and R3 are as defined above) and subsequently reacting the compound of formula IV with a compound of formula V

(wherein R5 and R5, which may be the same or different, each represents a hydrogen atom or an alkyl group containing 1 to 5 carbon atoms) to obtain a compound of formula Ic

(wherein R2, R3, R5 and R6 are as defined above); or b) reacting a compound of formula II as defined above with the fluoroborate salt of a compound of formula VI

(wherein Hal represents a halogen atom and Alk represents an alkyl group containing 1 to 3 carbon atoms) in the presence of a suitable base to obtain a compound of formula

(wherein R2, R3 and Hal are as defined above); and if desired subsequently converting a compound of formula IAT 13, IC or 1D thereby obtained into an acid addition salt thereof; 2. A process as claimed in claim 1 wherein the reaction of the compound of formula II with the compound of formula III is effected in the presence of chloroform.
3. A process as claimed in claim 1 or claim 2 wherein a compound of formula III in which Hal represents a bromine atom is used.
4. A process as claimed in any one of the preceding claims wherein the saponification of the compound of formula 1A is effected in the presence of a dilute solution of sodium or potassium hydroxide.
5. A process as claimed in claim 1 wherein the reaction of the compound of formula 13 with N,N'carbonyldiimidazole is effected in the presence of dimethyl formamide.
6. A process as claimed in claim 1 wherein in the reaction of the compound of formula II with the fluoroborate salt of the compound of formula VI, the base used is sodium hydride.
7. A process as claimed in any one of the preceding claims, wherein the compound of formula II is prepared by oxidation of a compound of formula VII

wherein R2 and R3 are as defined above.
8. A process as claimed in claim 7 wherein the oxidation of the compound of formula VII is effected by means of manganese dioxide.
9. A process as claimed in claim 7 or claim 8 wherein the oxidation is effected in the presence of dichloroethane.
10. A process as claimed in any one of claims 7 to 9 wherein the compound of formula VII is prepared by reacting a compound of formula VIII

(wherein R2 and R3 are as defined in claim 1) with a magnesium vinyl halide.
11. A process as claimed in claim 10 wherein the reaction of the compound of formula VIII with the magnesium vinyl halide is effected in the presence of tetrahydrofuran.
12. A process as claimed in claim 10 or claim 11 wherein the compound of formula VIII is prepared by oxidation of a compound of formula IX

(wherein R2 and R3 are as defined in claim 1).
13. A process as claimed in claim 12 wherein the compound of formula IX is prepared by reacting a compound of formula X

(wherein R2 and R3 are as defined in claim 1) with 3bromo-1-hydroxypropan-2-one.
14. A process as claimed in claim 13 wherein the compound of formula X is prepared by reduction of a compound of formula XI

(wherein R' represents an alkyl group containing 1 to 3 carbon atoms, and R2 and R3 are as defined in claim 1).
15. A process for the preparation of a compound of formula Ic as defined in claim 1 which comprises reacting a compound of formula IV as defined in claim 1 with a compound of formula V as defined in claim 1.
16. A process as claimed in any one of claims 1 to 5 and 15 wherein the reaction of the compound of formula IV with the compound of formula V is effected in the presence of dichloromethane.
17. A process for the preparation of a compound of formula I as defined in claim 1 or an acid addition salt thereof substantially as herein described.
18. A process for the preparation of a compound of formula I as defined in claim 1 or an acid addition salt thereof substantially as herein described in any one of the Examples.
19. Compounds of formula I as defined in claim 1 and acid addition salts thereof whenever prepared by a process as claimed in any one of the preceding claims.
20. tImidazo[2,1-b]benzothiazol-2-yl] (2' -carbethoxy- cyclopropyl) methanone; timidazot2,1-b]benzothiazol-2-yl] (2 '-cyanocyclopropyl) methanone; [imidazoC2,1-bbenzothiazol-2-yl (2 'carboxycyclo- propyl) methanone; [imidazo [2, 1-b] benzothiazol-2-yl] (2'-N,N-dimethylcarboxamidocyclopropyl) methanone; [imidazo [2, 1-b] benzothiazol-2-yl] (2'-carboxamidocyclopropyl) methanone; [imidazo[2, l-b)benzothiazol-2-yl] (2' -chlorocyclopropyl) methanone; and acid addition salts thereof.
21. Compounds of formula I as claimed in claim 20 and physiologically acceptable salts thereof for use as medicaments.
22. The use of a compound of formula I as claimed in claim 20 or a physiologically acceptable salt thereof for the manufacture of a medicament for the treatment of memory or cerebral senescence disorders, obesity or agitated or irritable conditions.
23. Pharmaceutical compositions comprising, as an active ingredient, at least one compound of formula I as claimed in claim 20 or a physiologically acceptable salt thereof in association with a pharmaceutically acceptable carrier and/or excipient.
24. Compositions as claimed in claim 23 in the form of dosage units.
25. Pharmaceutical compositions as claimed in claim 23 substantially as herein described.
26. Pharmaceutical compositions as claimed in claim 23 substantially as herein described in Examples 7 or 8.
27. A compound of formula VII

wherein R2 and R3 are as defined in claim 1.
28. A compound of formula II

(wherein R2 and R3 are as defined in claim 1).
29. A compound of formula IV

(wherein R2 and R3 are as defined in claim 1).
30. Each and every novel method, process, compound and composition herein disclosed.