GB2232666A

GB2232666A - Imidazo [2,1-b] benzothiazoles

Info

Publication number: GB2232666A
Application number: GB9008662A
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: 1990-12-19
Anticipated expiration: 2010-04-18
Also published as: FR2646158B1; GB8908845D0; FR2646158A1; GB9008662D0; GB2232666B

Abstract

Imidazo [2,1 -b] benzothiazoles of formula I <IMAGE> and salts thereof are obtained by reacting a compound of formula IV <IMAGE> with a compound of formula V R1-Mg-Hal R1 being C3-6 cycloalkyl and R2 and R3 completing a ring. Several new compounds of formula I possess inverse agonist and tranquillising properties. Precursors of compounds of formula (IV) have the formula (III):- <IMAGE>

Description

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

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

wherein R1 represents a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, 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 reacting a compound of formula IV::

(wherein R2 and R3 are as defined above) with a compound of formula V Rl-Mg-Hal (V) (wherein R1 is as defined above; and Hal represents a halogen atom) The term "straight-chain or branched alkyl group containing 1 to 5 carbon atoms" as used herein includes, for example, a methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl or tertiary butyl group.

The term "straight-chain or branched alkoxy group containing 1 to 5 carbon atoms" as used herein includes, for example, a methoxy, ethoxy, propoxy, or isopropoxy group.

The term Aaralkoxy group" as used herein includes, for example, a benzyloxy, phenylethyloxy or thienylmethoxy group.

The term "aryloxy group" as used herein includes, for example, a phenyloxy or naphthyloxy group.

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

The reaction of the compound of formula IV with the Grignard reagent of formula V is conveniently effected in the presence of an organic solvent such as tetrahydrofuran.

The compound of formula IV is preferably prepared by reacting a compound of formula III:

(wherein R2 and R3 are as defined above) with O,Ndimethyl-hydroxylamine hydrochloride.

The reaction of the compound of formula III with O,N-dimethyl-hydroxylamine hydrochloride is conveniently effected in the presence of an anhydrous solvent such as dimethylformamide.

The compound of formula III can be prepared, for example, by reacting a compound of formula II:

(wherein R2 and R3 are as defined above) with N, N ' -carbonyldiimidazole.

The reaction of the compound of formula II with N, N'-carbonyldiimidazole is conveniently effected in the presence of an anhydrous organic solvent such as dimethylformamide.

Compounds of formula IV can most conveniently be prepared in a one-pot process from compounds of formula II, without isolating intermediate imidazolides of formula III.The compounds of formula II can be prepared, for example, as described in Farmaco. Ed.

Sci (1977), 32, 735.

The compounds of formula I are basic in character and can form acid addition salts.

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, tartaric, citric, oxalic, gyloxylic, and aspartic acid, and alkanesulphonic acids such as methanesulphonic acid and arylsulphonic acids such as benzenesulphonic acid.

The acid addition salts of the compounds of formula I can be advantageously prepared by reacting an inorganic or organic acid in approximately stoichiometric, proportions, with a compound of formula I.

The salts can be prepared, if desired, without first isolating the corresponding bases.

Some of the compounds of formula I are new and, according to a further aspect of the invention, there are provided compounds of formula IA

[wherein RA represents a cyclobutyl, cyclopentyl or cyclohexyl group; and R2 and R3 are as defined above] and acid addition salts thereof.

Preferred compounds of formula 1A are those wherein RA is as defined above; and R2 and R3 together represent a group

wherein X1 and X2, which may be the same or different, each represents a hydrogen atom, a methyl group or a methoxy group and acid addition salts thereof Particularly preferred are the following compounds: timidazo-[2,1-b]-benzo-thiazol-2-yl] cyclobutyl-methanone; [imidazo-[2,1-b]-benzo-thiazol-2-yl] cyclopentylmethanone; and timidazo (2,l-bi-benzo-thiazol-2-yl] cyclohexyl-methanone; and acid addition salts thereof.

The compounds of formula I possess very interesting pharmacological properties; of particular note are the benzodiazepine 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 IA and the pharmaceutically acceptable salts thereof are thus of use as medicaments.

Therefore, according to a further aspect of the invention there is provided the use of compounds of formula IA as defined above and pharmaceutically acceptable acid addition salts thereof as medicaments.

Preferred for use as medicaments are the compounds of formula IA as defined above wherein RA is as defined above; and R2 and R3 together represent a group

wherein X1 and X2, which may be the same or different, each represents a hydrogen atom, a methyl group or a methoxy group and acid addition salts thereof.

Particularly preferred for use as medicaments are the following compounds: limidazo-12,1-b benzo-thiazol-2-yl] cyclobutyl-methanone; [imidazo-[2,1-b]-benzo-thiazol-2-yl] cyclopentylmethanone; and timidazo [2,1-b]-benzo-thiazol-2-yl] cyclohexyl-methanone; and acid addition salts thereof.

Compounds of formula IA are of use, for example, in the treatment of memory problems, particularly in geriatrics, and in cerebral senescence problems.

Some of the compounds can also be used in the treatment of obesity and as minor tranquillizers in the treatment of certain agitated or irritated states.

The usual dose, which varies according to 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 still further aspect of the invention there are provided pharmaceutical compositions comprising, as active ingredient, at least one compound or formula IA as defined above or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutical carrier and/or excipient.

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

These pharmaceutical compositions can 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 gelatine capsules, granules, suppositories, solutions e.g. for injection; they can be prepared by conventional methods. The active ingredient(s) can be used in conjunction with excipients conventionally used 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 and preservatives.

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

wherein in R2 and R3 are as defined above; the compounds of formula III:

wherein R2 and R3 are as defined above.

The following non-limiting Examples illustrate the invention in greater detail: Exampte 1 : [imidazo (2,1-b) benzo-thiazol-2-yl] cyclopropyl methanone Step (a) : O-N-dimethyl-imidazo 2,1-b benzo-thiazole-2-carboxamate Imidazo C2,1-b3 benzo-thiazole-2-carboxylic acid 1.8 g, 0,0083 mole) in dry dimethylformamide (25 ml) was stirred at room temperature under nitrogen with carbonyldiimidazole (2.25 g, 0.0138 mote). After 30 min a thick precipitate of the intermediate imidazolide was formed. This was diluted with dry d.m.f. (20 ml) and the mixture treated with O,N-dimethylhydroxylamine hydrochloride (1.35 g, 0.0138 mole) and stirred overnight.Further O,N dimethyl hydroxylamine hydrochloride (1.35 g, 0.0138 mole) and triethylamine (1.5 g, 0.149 mole) was added and the mixture stirred at 60=C for 2 hours to complete conversion. The mixture was poured onto water and extracted with ethyl acetate (5 x 200 mt). The extracts were dried over magnesium sulphate and evaporated giving [2,1-b] benzo-thiazole-2-carboxamate as pale yellow crystals (2.0 g, 95 X).

Step (b) : [imidazo (2,1-b) benzo-thiazol-2-yl] cyclopropyl methanone Cyclopropyl magnesium bromide was prepared by the addition of cyclopropylbromide (1.7 g, 0.019 mole) to a suspension of magnesium turnings (0.34 g, 0.019 mole) in dry tetrahydrofuran (35 ml). This solution was stirred during the additions of O,N dimethyl-imidazo [2,1-b] benzo-thiazole2-carboxamate (1 g, 0.0038 mole) in one portion and stirred for a further 3 hrs. The mixture was poured onto aqueous ammonium chloride and extracted with chloroform. The extracts were combined, dried over magnesium sulphate and evaporated to low bulk. On dilution with ether colourless crystals of Eimidazo (2,1-b) benzo-thiazol-2-yl cyclopropyl methanone were formed and collected (0.6 g, 65 %).

The obtained compound is identical to the compound of example 2 of GB Application N# 88.244926.

Example 2 : [i#idazo (2,1-b) benzo-thiazol-2-yl] cyclobutyl methanone Using a process similar to that used at Step b of example 1, but starting from cyclobutyl magnesium bromide the [imidazo (2,1-b) benzothiazol-2-yl] cyclobutyl methanone was obtained.

(Melting point, IR Spectrum, NMR Spectrum and analytical data are given in Table I).

Example 3 : [i#idazo C2,1-b) benzo-thiazol-2-yl] cyclopentyl methanone Using a process similar to that used at Step b of example 1, but starting from cyclopentyt magnesium bromide the ìmidazo (2,1-b) benzo-thiazol-2-yl] cyclopentyl-methanone was obtained.

Example 4 : [imidazo (2,1-b) benzothiazol-2-yl] cyclohexyl methanone Using a process similar to that used at Step b of example 1, but starting from cyclohexyl magnesium bromide the [imidazo (2,1-b) benzothiazol2-yl] cyclohexyl methanone was obtained.

TABLE I

Analysis Example R RR Mpt C IR cm-1 Nmr# C% H% N% S% 2 # # 175-77 3120, 2980, 1660, CDCl3 8.32(1H, s) ; 7.69 (2H, 2xdd) Found 65.50 4.82 11.04 12.50 1515, 1495, 1270, 7.44(2H, 2xdt) ; 4.17(1H, p) ; C13H12N2OS 65 4.72 10.93 12.51 748 2.36(4H, m) ; 2.04(2H, m) 3 # " 178-80 3120, 2960, 1657, CDCl3 8.35(1H, s) ; 7.73(2H, 2xdd) ; Found 66.49 5.28 10.32 11.80 1510, 1495, 1320, 7.45(2H, 2xdt) ; 3.93(1H, p) ; C15H14NOS 66.64 5.22 10.36 11.86 1294, 1210, 1140, 1.98(4H, m) ; 1.73 (4H, m) 744 4 # " 155-57 3120, 2920, 1660, CDCl3 8.33(1H, s) ; 7.72(2H, 2xdd) ; Found 65.53 6.18 9.27 10.70 1510, 1493, 1206, 7.45(2H, 2xdt) ; 3.48(1H, m) ; C16H16N20S. 65.50 5.84 9.55 10.92 1143, 1745 1.99(2H, m) ; 1.78(3H, m) ; 1/2H2O 1.46(6H, m) Exanple 5 : Tablets were prepared according to the following formulation Compound of Example 2-------------------------------- 20 mg - Excipient for one tablet up to . 150 mg (details of the excipient : lactose, starch, talc, magnesium stearate).

Example 6 : TabLets were prepared according to the following formulation Compound of Example 3-------------------------------- 20 mg - Excipient for one tablet up to -------------------- 150 mg (details of the excipient : lactose, starch, talc, magnesium stearate).

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 af the method of Squires and Braestrup (Nature, 1977, 266, 732).

The values given in Table 2 be tow are the concentration (mol x 10-9) of the compound under test which inhibits 50 % of the specific binding of 0.6 x 10-9 mot 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 2

I I I I Example Test 1 Test 2 nM ED 50 mg/kg IP I I I I 2 2 | 303 1 37 I ~~~~~~~ I ~~~~~~~~~~ I I I | I I 3 124

Claims

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

(wherein R1 represents a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, 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 reacting a compound of formula IV

(wherein R2 and R3 are as defined above) with a compound of formula V R1-Mg-Hal (V) (wherein R1 is as defined above; and Hal represents a halogen atom); and if desired subsequently converting a compound of formula I thereby obtained into an acid addition salt thereof.
2. A process as claimed in claim 1 wherein the reaction of the compound of formula IV with the compound of formula V is effected in the presence of tetrahydrofuran.
3. A process as claimed in claims 1 or 2 wherein the compound of formula IV is prepared by reacting a compound of formula III

(wherein R2 and R3 are as defined in claim 1) with O,Ndimethyl-hydroxylamine hydrochloride.
4. A process as claimed in claim 3 wherein the reaction of the compound of formula III with O,Ndimethyl-hydroxylamine hydrochloride is effected in the presence of anhydrous dimethyl formamide.
5. A process as claimed in claim 3 or claim 4 wherein the compound of formula III is prepared by reacting a compound of formula II

(wherein R2 and R3 are as defined in claim 1) with N, N'carbonyldiimidazole.
6. A process as claimed in claim 5 wherein the reaction of the compound of formula II with N,N'carbonyldiimidazole is effected in the presence of anhydrous dimethyl formamide.
7. A process for the preparation of compounds of formula I as defined in claim 1 substantially as herein described.
8. A process for the preparation of compounds of formula I as defined in claim 1 substantially as herein described in any one of the Examples.
9. compounds of formula I as defined in claim 1 and acid addition salts thereof whenever prepared by a process as defined in any one of the preceding claims.
10. Compounds of formula 1A

[wherein RA represents a cyclobutyl, cyclopentyl or cyclohexyl group; and R2 and R3 are as defined in claim 1) and acid addition salts thereof.
11. Compounds of formula 1A as claimed in claim 10 wherein RA is as defined in claim 10; and R2 and R3 together represent a group

(wherein X1 and X2, which may be the same or different, each represents a hydrogen atom, a methyl group or a methoxy group) and acid addition salts thereof.
12. (Imidazo[2, 1-b)benzothiazol-2-yl) cyclobutylmethanone and acid addition salts thereof.
13. [Imidazo[2,1-b]benzothiazol-2-yl] cyclopentylmethanone acid addition salts thereof.
14. (Imidazo[2, l-b]benzothiazol-2-yl] cyclohexylmethanone and acid addition salts thereof.
15. Compounds of formula 1A as claimed in any one of claims 10 to 14 and physiologically acceptable salts thereof for use as medicaments.
16. The use of a compound of formula 1A as claimed in any one of claims 10 to 14 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.
17. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula 1A as claimed in any one of claims 10 to 14 or a physiologically acceptable salt thereof in association with a pharmaceutically acceptable carrier and/or excipient.
18. Compositions as claimed in claim 17 in the form of dosage units.
19. Pharmaceutical compositions as claimed in claim 17 substantially as herein described.
20. Pharmaceutical compositions as claimed in claim 17 substantially as herein described in Examples 5 and 6.
21. A compound of formula IV

(wherein R2 and R3 are as defined in claim 1).
22. A compound of formula III:

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