SK16842001A3 - Substituted imidazothiazoles as antidepressant agents - Google Patents

Abstract

Compounds of Formula (I) including pharmaceutically acceptable salts thereof, in which A is S or O; R1 is H, halo, a C1-3 alkyl group or a C1-3 alkylthio group; R2 is H or fluoro; and R3 is methyl, ethyl or isopropyl are useful in the treatment of depression, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, cerebral ischaemia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress and in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage.

Description

Substituted imidazothiazoles as antidepressants

Technical field

The invention relates to novel 3- (benzo [b] thiophen-3-yl) -imidazo [2,1-b] thiazoles having affinity for 5-HT 1A receptors that inhibit 5-hydroxy-tryptamine and / or noradrenaline neuronal reuptake, methods for their preparation, pharmaceutical compositions containing them and their use in the treatment of depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias, disorders such as bulimia, anorexia, overexpression and morbidity, non-insulin-dependent diabetes mellitus, hyperglycemia; hyperlipidemia, stress, and also as a smoking cessation aid and in the treatment and / or prevention of seizures, neurological diseases such as epilepsy and / or stays where neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and haemorrhage occur .

BACKGROUND OF THE INVENTION

WO 98/41528 discloses that compounds of formula A

(D including their pharmaceutically acceptable salts, in the form of their individual enantiomers, racemates or mixtures of enantiomers, wherein:

Ar is phenyl, naphthyl or benzo [b] thienyl, each of which is optionally substituted with one or more groups selected from a) halogen, b) alkyl of 1 to 3 carbon atoms, optionally substituted by one or more; (c) C 1 -C 3 alkoxy optionally substituted by one or more halogen atoms; (d) C 1 -C 3 alkylthio optionally substituted by one or more halogen atoms; (e) Phenoxy optionally substituted by one or more atoms; or f) phenyl optionally substituted by one or more halogen atoms;

R 1 and R ₂ may have the same or different meanings and each independently represents a group from a) H, b) alkyl of 1 to 6 carbon atoms, c) alkenyl of 3 to 6 carbon atoms, d) cycloalkyl of 3 to 7 atoms f) aryl or heteroaryl optionally substituted with one or more substituent groups selected from the group consisting of i) halogen, ii) alkyl of 1 to 3 carbon atoms optionally substituted by one or more carbon atoms, e) cycloalkylmethyl having 3 to 7 carbon atoms in the ring moiety; (iii) C 1 -C 3 alkoxy optionally substituted by one or more halogen atoms; (iv) C 1 -C 3 alkylthio optionally substituted by one or more halogen atoms; (g) Arylalkyl or heteroarylalkyl, wherein the alkyl chain comprises 1; up to 3 carbon atoms and the aryl or heteroaryl group may be optionally substituted once but or a plurality of i) halogen, ii) alkyl having 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, iii) alkoxy having 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, iv) alkylthio 1 to 3 carbon atoms optionally substituted by one or more halogen atoms; or R 1 and R ₂ form an alkylene chain optionally substituted with one or more alkyl groups each containing 1 to 3 carbon atoms, such that together with the atoms to which they are attached, they form a 5 or 6 membered ring.

“· R * p r r r r t- r r i i r f

R 3 represents a) H, b) an aryl or heteroaryl group optionally substituted by one or more groups selected from the group consisting of i) halogen, ii) alkyl having 1 to 3 carbon atoms, optionally substituted with one or more halogen atoms, iii) alkoxy having 1 to 3 (Iv) alkylthio of 1 to 3 carbon atoms with optional substitution by one or more halogen atoms; (c) an arylmethyl group wherein the aryl group is optionally substituted by one or more groups selected from the group consisting of i; (ii) alkyl having 1 to 3 carbon atoms optionally substituted by one or more halogen atoms; (iii) alkoxy having 1 to 3 carbon atoms optionally substituted by one or more halogen atoms; (iv) alkylthio having 1 to 3 carbon atoms optionally substituted; by substitution with one or more halogen atoms well, or d) an alkoxyalkyl group containing 3 to 6 carbon atoms; and

R 4 and R 5, which may have the same or different meanings, each independently represent an alkyl group having 1 to 3 carbon atoms, or R 4 and R 5 together with the carbon atom to which they are attached form a cycloalkyl ring containing 3 to 6 carbon atoms ;

are useful for the treatment of depression, anxiety, Parkinson's disease, obesity, cognitive diseases, seizures, neurological diseases such as epilepsy, and as neuroprotective agents for the prevention of conditions such as stroke. The compounds of the present invention are not included in the above specification, nor are they intended to be used.

Sharpe C.J and Shadbolt R.S. (Journal of Medicinal Chemistry, 1971, Vol.14, No.10, pp. 977-982) discloses certain dihydroimidazo [2,1-b] thiazole compounds having antidepressant activity. In addition, it is reported that these compounds are generally less potent and more toxic than the imidazolines also described in the above work. The compounds of the invention are not included or anticipated in this work.

WO 97/02269 discloses compounds of formula (B)

including pharmaceutically acceptable salts thereof, wherein

A is S (O) _P or O;

p is 0, 1 or 2;

g is 0, 1, 2, 3, or 4;

n is 2 or 3;

R 1 represents a group selected from a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted with one or more halogen atoms; (e) hydroxy; (f) acyloxy of 1 to 3 carbon atoms; optionally substituted with one or more halogen atoms; (g) hydroxyalkyl of 1 to 3 carbon atoms (h) cyano; (i) C 1 -C 6 alkanoyl; (j) C 2 -C 6 alkoxycarbonyl; (k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1; up to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms; m) or an amino group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings;

R 2, R 3 and R 4 each independently represent hydrogen or a C 1 -C 3 alkyl group optionally substituted by one or more halogen atoms; and

R 5 represents a group selected from a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted with one or more halogen atoms; (e) hydroxy; (f) acyloxy of 1 to 3 carbon atoms; optionally substituted with one or more halogen atoms; (g) hydroxyalkyl of 1 to 3 carbon atoms (h) cyano; (i) C 1 -C 6 alkanoyl; (j) C 2 -C 6 alkoxycarbonyl; (k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1; up to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) an amino group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, or n) H;

which have an affinity for 5-HT 1A receptors and inhibit 5-hydroxytryptamine and / or noradrenaline reuptake by neurons. These compounds are said to be useful in the treatment of CNS diseases. In addition, the compounds exhibit activity as monoamine oxidase inhibitors and / or have activity on other receptors, for example muscarinic receptors, and are likely to cause undesirable side effects.

Surprisingly, the compounds of the invention have unexpectedly improved selectivity and potency. In WO 97/02269, the compounds of the invention are not described or envisaged.

US 4,160,768 discloses that 3- (2-benzofuryl) -5,6-dihydroimidazo [2,1-b] thiazole is useful as an anti-inflammatory agent. The compounds of the invention are not described or envisaged herein.

I ľ

SUMMARY OF THE INVENTION

The invention provides novel compounds of formula I

including pharmaceutically acceptable salts thereof, wherein

A is S or O;

R 1 represents H, halogen, C 1-3 alkyl or C 1-6 alkyl. ₃ alkylthio;

R ₂ is H or fluoro; and

R 3 is methyl, ethyl and isopropyl.

Preferred substituents R 1 include H, fluoro, chloro, bromo, methyl and methylthio.

Preferably, A is S.

Preferably, A is O.

More preferably, R 3 is methyl.

A preferred group of compounds of formula I are those of formula Ia

wherein R is H or chloro, including pharmaceutically acceptable salts thereof.

Preferred compounds of the invention include those wherein A is S; R 1 is H, fluoro or chloro; R ₂ is H or fluoro; and R 3 represents a methyl group.

Even more preferred compounds of the invention include those wherein A is S; R 1 is H or fluoro; R ₂ is H or fluoro; and R3 represents a methyl group.

Most preferred compounds of the invention include those wherein A is S; R | represents H; R ₂ is H; and R3 represents a methyl group.

The compounds of formula I may form salts with pharmaceutically acceptable acids. The invention includes all such salts. Examples of said salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, formates, acetates, citrates, fumarates, tartrates (e.g. (+) - tartrates, (-) tartrates or mixtures thereof including racemic mixtures), succinates, benzoates, oxalates and salts with amino acids such as salts with glutamic acid. Said salts may be prepared by methods known in the art.

Certain compounds of formula I may form different tautomeric forms or different geometric isomers, and the invention includes each such tautomer and / or geometric isomer of the compounds of formula I and mixtures of these isomers.

Certain compounds of Formula I may exist in a variety of stable conformational forms that can be separated. For example, in the case of the presence of a bulky group, it is possible to limit rotation about one or more single bonds by steric hindrance. Torsional asymmetry due to limited rotation about an asymmetrically arranged single bond, for example due to steric hindrance or ring strain, may allow separation of different conformers. The invention includes each of the conformational isomers of the compounds of Formula I and mixtures thereof.

Certain compounds of Formula I and salts thereof may exist in more than one crystalline form, and the present invention includes each such crystalline form and mixtures thereof. Certain compounds of Formula I may also form solvates, for example hydrates, and the invention includes each such solvate and mixtures thereof.

Certain compounds of formula I contain one or more chiral centers and may form various optically active forms. When the compounds of formula I contain one chiral center, they may exist in two enantiomeric forms and the invention includes both these forms and mixtures thereof. Said enantiomers may be resolved by methods known in the art, for example by preparing diastereomeric salts which may be separated, for example, by crystallization; preparing diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas chromatography or liquid chromatography; or by gas or liquid chromatography using chiral phases, for example a chiral carrier such as silica with a bound chiral ligand or by means of a chiral solvent. It should be noted that when the desired enantiomer is converted to the next chemically defined component by the separation methods described above, an additional stage of treatment is required to release the desired enantiomer. Alternatively, specific enantiomers may be prepared by asymmetric syntheses using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

When a compound of formula I contains more than one chiral center, it may exist in diastereomeric forms. Said diastereomeric pairs may be separated by methods known in the art, for example by chromatography or crystallization, and the individual enantiomers of each pair may then be separated by the methods described above. The present invention includes each diastereomer of the compounds of Formula I and mixtures thereof.

Specific compounds of formula I include:

3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2, l-b] thiazole;

3- (5-chloro-benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2, l-b] thiazole;

3- (4-fluoro-benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2, l-b] thiazole;

3- (benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydro-imidazo [2, l-b] thiazole;

2-methyl-3- (5-methylbenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole;

3- (benzo [b] thiophen-3-yl) -2-isopropyl-5,6-dihydroimidazo [2,1-b] thiazole;

2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydro-imidazo [2,1-b] thiazole;

3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole;

3- (5-chloro-benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydro-imidazo [2, l-b] thiazole;

3- (5-bromo-benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2, l-b] thiazole;

and

3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole and pharmaceutically acceptable salts thereof.

The invention also encompasses pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or a salt thereof with a pharmaceutically acceptable diluent or carrier.

The term active compound as used herein means a compound of formula (I) or a salt thereof. In therapy, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the compositions for therapy of the invention may be in any known form for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in said compositions are well known in the art. Said compositions may contain 0.1-99 wt. of the active compound. The compositions of the invention are generally prepared in unit dosage form. A preferred dosage unit of the active ingredient is 1-500 mg. Additives suitable for use in such compositions include those well known in the pharmaceutical technology art.

Preferred compositions for oral administration include the compositions of the invention in known forms for such administration, such as tablets, capsules, syrups and aqueous or oily suspensions. The ingredients used to prepare these compositions are ingredients known in the pharmaceutical technology art. Tablets may be prepared by mixing the active compound with an inert diluent, such as calcium phosphate, in the presence of a disintegrant, such as corn starch, and a glidant, such as magnesium stearate, and mixing the ingredients by known methods. Tablets may also be prepared in a manner providing controlled release of the compounds of the invention. Such tablets may, if desired, be provided with enteric coatings prepared by known methods, for example cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules containing the active compound with or without additives, can be prepared by conventional methods and, if necessary, can be provided with an enteric coating in a known manner. Tablets and capsules preferably contain 1 to 500 mg of active compound per dosage unit. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethylcellulose, and an oily suspension containing the compound of the invention in a suitable, vegetable oil such as peanut oil.

Solid dosage forms can be formulated according to methods known in the art for the preparation of sustained release compositions. Depending on the nature of the active compound, solid dosage forms for oral administration with enteric coatings may be preferred. Various coatings, for example shellac / or sugar, may be used as coatings, or the oral dosage form may be physically modified in another way. For example, tablets or pills may be provided with enteric coatings, if desired, by known methods, for example, using cellulose acetate phthalate and / or hydroxypropyl methylcellulose phthalate.

Capsules and / or encapsulated forms (e.g., hard or soft gelatin capsules) containing the active compound (with or without the addition of other ingredients such as a fatty oil) can be prepared if necessary with an enteric coating. The contents of the capsule / or encapsulated form can be formulated by known methods to provide a controlled release formulation.

Liquid oral dosage forms containing compositions of the invention such as tincture, suspensions and / or syrup (e.g., an aqueous suspension containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent [such as sodium carboxymethylcellulose] and / or an oil suspension containing the active compound vegetable oil [such as peanut oil and / or sunflower oil]). Liquid dosage forms may also contain one or more sweetening, flavoring, flavoring, preservative and / or mixtures thereof.

The active compound can also be formulated as granules with or without additional ingredients. The granules may be administered directly to the patient, or may be added to a suitable liquid carrier (e.g., water) prior to administration. The granules may contain disintegrants (for example, a pharmaceutically acceptable combination for preparing an effervescent mixture containing an acid and a carbonate or bicarbonate) to facilitate dispersion in the liquid medium.

r 12

The content of active compound in each of the above dosage forms is preferably from about 1 mg to about 1000 mg, more preferably from about 5 mg to about 500 mg (for example 10 mg, 50 mg, 100 mg, 200 mg or 400 mg).

Compositions of the invention suitable for rectal administration include forms known in the art for such administration, such as suppositories containing hardened fat, semi-synthetic glyceride, cocoa butter and / or polyethylene glycol as a base.

The pharmaceutical compositions may also be administered parenterally (e.g., subcutaneously, intramuscularly, intradermally and / or intravenously (as by injection and / or infusion) in dosage forms known in the art for parenteral administration (such as sterile suspensions in aqueous and / or oily medium and / or or sterile solutions in suitable solvents, preferably being isotonic with the blood of the intended patient) Parenteral dosage forms may be sterilized (for example, by microfiltration and / or using suitable sterilizing agents [such as ethylene oxide]). acceptable adjuvant compositions suitable for parenteral administration: topical anesthetics, preservatives, buffering agents and / or mixtures thereof The parenteral dosage forms are stored in suitable sterile, well-sealed containers (e.g., ampoules and / or vials). To increase storage stability, they can be prepared in the form obtained by freezing after filling into a container and removing the liquid (e.g. water) under reduced pressure.

The pharmaceutical compositions may be administered nasally in forms known in the art for such administration (for example, sprays, aerosols, nebulized solutions and / or powders). Dosage systems known in the art (e.g., for aerosols and / or inhalation means) may also be used.

The pharmaceutical compositions can also be administered to the buccal cavity (e.g., sublingually) in known dosage forms suitable for this type of administration (such as slow-dissolving tablets, chewing gums, tablets, pills, lozenges, gels, pastes, mouthwashes, rinses). and / or powders).

Compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the invention are dispersed so as to bring them into contact with the skin and transdermal administration. A suitable transdermal composition can be prepared by mixing the active compound with a vehicle for topical administration such as mineral oil, petrolatum and / or wax, for example paraffin wax or beeswax together with a transdermal delivery accelerator such as dimethylsulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical preparation should be such that a therapeutically effective amount of the compound is transferred over a period of time intended for contact of the topical preparation with the skin.

The compounds of the invention may also be administered by continuous infusion, either from an external source, for example by intravenous infusion, or from a source of the compound placed in the body. Internal sources include implanted containers containing a compound for infusion that is continuously released by, for example, osmosis and implants, which may be a) liquids such as a suspension or solution of a compound for infusion in a pharmaceutically acceptable oil, said compound being in the form of a very difficult a water soluble derivative such as its dodecanoate salt; or b) a solid form, wherein the implant is a compound for infusion on a carrier, for example a synthetic resin. The carrier may be a single unit containing all of the compound to be administered, or it may be a plurality of bodies each containing a proportion of the compound to be administered. The amount of the compound contained in the internal source should be such that a therapeutically effective amount thereof is administered over a usually long period.

In some formulations, it may be advantageous to use the compounds of the invention in the form of particles having a very small size, for example, particles obtained by fluid grinding.

In the compositions of the invention, the active compound of the invention may, if desired, be combined with other compatible pharmacologically active ingredients.

The invention also includes a compound of formula I for use as a medicament.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I can be used to treat depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias, eating disorders such as bulimia, anorexia, excessive killing and morbidity, insulin non-dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress in mammals, as well as aids to help stop smoking in humans. The compositions may also be used in the treatment and / or prevention of seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage occurs. Although the exact amount of active compound administered with said treatment depends on several factors such as the age of the patient, the severity of the condition, the medical history and, depending on the judgment of the attending physician, the daily dose of active compound is in the range 1 to 1000 mg. single dose or in divided doses one or more times a day.

In yet another aspect, the invention provides the use of a compound of Formula I for the manufacture of a medicament useful for the treatment of depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's, cerebral ischemia, obsessive compulsive behavior. , panic attacks, social phobias, eating disorders such as bulimia, anorexia, excessive appetite and morbidity, non-insulin-dependent diabetes mellitus, hyperglycaemia, hyperlipidemia and stress, as well as aids to facilitate smoking cessation, seizures, and neurological disorders such as / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage occurs.

r * r «· t

The invention also provides a method of treating depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobia, eating disorders bulimia, anorexia, excessive stamina and morbidity, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidaemia, stress, seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head trauma and hemorrhage, said method comprising administering to a patient in need thereof an effective amount of a compound of Formula I. The invention also provides a method of aiding smoking cessation in a human comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I.

The invention also provides a method of reducing the appetite for smoking in a human comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I. The invention also provides a method of reducing weight gain after smoking cessation in a human comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I.

In addition, the compounds of the invention may be useful in the treatment or prevention of metabolic diseases and conditions arising therefrom, such as non-thermogenesis, increased metabolic rate, sexual dysfunction, sleep apnotic syndrome, premenstrual syndrome, urinary incontinence, hyperactivity disorders, hiatal hernia and reflux esophagus, pain, particularly neuropathic pain, weight gain associated with drug therapy, chronic fatal syndrome, osteoarthritis and gout, weight gain associated with weight gain, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension.

The compounds of the invention may be useful in preventing cardiovascular disease, reducing platelet cohesiveness, as a weight loss support after pregnancy and as a weight loss support after the patient has stopped smoking.

The compounds of the invention are particularly useful for the treatment of obesity and associated disease states such as diabetes, hyperglycemia and hyperlipidemia. It is known that monoamine reuptake inhibitors, which are often used to treat obesity, often have cardiovascular side effects, such as increased heart rate and elevated blood pressure. The compounds of the invention reduce the cardiovascular side effects expected from the administration of monoamine reuptake inhibitors, particularly noradrenaline reuptake inhibitors. Without attempting to be bound by theory, it is believed that the combination of 5-HT 1A agonism of the compounds of the invention reduces the side effects that may arise from their inhibition of monoamine reuptake, particularly the inhibition of noradrenaline reuptake.

In another aspect, the invention provides a method of reducing cardiovascular side effects of an anti-obesity drug comprising incorporating into a 5-HT 1 agonist compound. Another aspect of the invention includes the use of a 5-HT 1A agonist compound which is a monoamine reuptake inhibitor, particularly a norepinephrine reuptake inhibitor. obesity and related disease states without inducing cardiovascular side effects.

The beneficial effects of particularly preferred compounds of the invention on reducing cardiovascular side effects can be demonstrated by telemetric studies in rats, with continuous recordings of heart rate, blood pressure, body temperature and physical activity. Suitable methods are described in: Brockway BP., Mills PA. & Azar SH. (1991) A new method for continuous chronic blood pressure measurement, heart rate and activity in rat via radio-telemetry, Clinical and Experimental Hypertension-Theory and Practice A13 (5), 885-895 and Guiol C., Ledoussal C. &. Surge J-M. (1992) A radiotelemetry system for chronic measurement of blood pressure and heart rate in the unrestrained rat. Validation of method. Journal of Pharmacological and Toxicological Methods 28: 99-105.

The 5-HT 1A agonism of particularly preferred compounds of the invention can be ascertained by electrophysiological assays known in the art.

The following is a description of the processes for the preparation of the compounds of formula I. The processes can be carried out by the individual preparation process or by means of parallel syntheses referred to as High Speed Analoguing. Preferably, said processes are carried out at atmospheric pressure.

Compounds of formula I may be prepared by the methods described in WO 97/02269. In addition, compounds of Formula I may be prepared by the methods described below.

Compounds of formula (I) may be prepared by dehydrating a compound of formula (II)

wherein A, R 1, R ₂ , R 3g and g are as defined above, optionally in the presence of an acid such as acetic acid or sulfuric acid at a temperature in the range of 0 to 200 ° C; preferably in the range of 20-150 ° C.

Compounds of formula II may be prepared by reacting a compound of formula III

with a compound of formula IV

wherein Z is a leaving group such as halogen such as bromine, and A, R 1, R ₂ and R 3 are as defined above, at a temperature in the range of 0-200 ° C, in the presence of a solvent such as ethanol and optionally in the presence of an acid such as acid acid; preferably by heating at a temperature between 20 ° C and the boiling point of the solvent used.

Compounds of formula I can also be prepared by directly reacting a compound of formula III with a compound of formula IV at a temperature in the range of 0-200 ° C, optionally in the presence of an acid such as acetic acid and optionally in the presence of a solvent such as ethanol without isolation of the intermediate. of formula II; preferably by heating at a temperature in the range of 20-150 ° C.

Compounds of formula I wherein R 3 is methyl or ethyl may be prepared by reaction of a compound of formula V

P P · ·

wherein R 1, R 2 and A are as defined above and R 4 is H or a methyl group with a reducing agent, for example borane / tert-butylamine complex, optionally in the presence of an acid such as a Lewis acid catalyst such as aluminum chloride in a solvent such as in dichloromethane, at a temperature ranging from -20 ° C to the boiling point of the solvent used.

Compounds of formula V may be prepared by reaction of a compound of formula VI

wherein X is a leaving group such as bromine with a methylating agent such as ethylmagnesium chloride and subsequent treatment with a formulating or acylating agent such as dimethylformamide or with N-methoxy-N-methylacetamide in the presence of a solvent such as tetrahydrofuran, at a temperature ranging from -50 ° C to the boiling point of the solvent used.

Compounds of formula VI wherein X is bromo may be prepared by reaction of a compound of formula VII

F f

with a brominating agent such as bromine or phenyltrimethylammonium tribromide in the presence of a solvent such as dichloromethane or tetrahydrofuran at a temperature ranging from -50 ° C to the boiling point of the solvent used.

Compounds of formula VII can be prepared by the methods described in WO97 / 02269.

The ability of the compounds of formula I to interact with 5-hydroxytryptamine (5-HT) receptors has been demonstrated in the products prepared according to Examples 1 to 17 by the following assay, which determines the ability of the compounds to inhibit tritiated ligand binding in vitro to 5-HT receptors, in particular for 5-HT1A-Hippokampal brain receptors of male Sprague-Dawley rats (Charles River, weighing 150-250 g) are homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7 at 25 ° C, 1:40 wt. and then centrifuged at 40,000 g and a spin time of 10 minutes. The pellet is rehomogenised in the same buffer, incubated at 37 ° C for 10 minutes and then centrifuged at 40,000 g for 10 minutes. The final pellet is resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl 2, 0.1% L-ascorbic acid and 10 μΜ pargyline hydrochloride (equivalent to 6.25 mg wet tissue weight / ml) and the product used. immediately before detention.

Membranes (400 μΐ: 2.5 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] 8-hydroxy-2- (dipropylamino) tetralin ([ ³ H] 8-OH-DPAT) at a single concentration of 1 nM and with 50 μΐ of distilled water (total binding) or with 50 μΐ of test compound (at a single concentration of 10 ^-6 M or at 10 concentrators in the range of 10-10 ³ M) or with 50 μΐ of 5-HT (10 μΜ, non-specific binding) ) at 25 ° C for 30 minutes. The incubation is terminated by rapid filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester. The filters are then washed with ice-cold 50 mM tris-HCl, pH 7.7 (at 25 ° C, and wash values set at 9.9.0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and scintillation is measured with a liquid scintillator.

The ability of the compounds of formula I to interact with 5-hydroxytryptamine (5-HT) reuptake sites has been demonstrated in the products prepared according to Examples 1-17 by the following assay, which determines the ability of the compounds to replace the standard ligand, [ ³ H] citalopram from uptake of 5-HT in vitro.

Frontal cortical tissue of the brain of male Charles River rats, weighing 150-250 g, is homogenized in ice cold 50 mM trisHCl buffer pH 7.4 (measured at 25 ° C) containing 120 mM sodium chloride and 5 mM potassium chloride (tris 1:30 w / v) and then centrifuged at 40,000 g and a spin time of 10 minutes. The superantant is removed and the pellet rehomogenised in 1:60 w / v tris buffer. and then centrifuged at 40,000 g for 10 minutes. This step is repeated. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.4) containing 120 mM sodium chloride and 5 mM potassium chloride (equivalent to 3.125 mg wet tissue weight / ml) and the product used immediately prior to binding determination. All centrifugations were performed at 4 ° C.

Membranes (400 μΐ; equivalent to 1.25 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] citalopram at a single concentration of 1.3 nM and with 50 μΐ of distilled water (total binding) or with 50 μΐ of test compound (at one concentration). a concentration of 10 ⁶ M or 10 concentrations in the range of 10 ¹¹ - 10 ^-3 M or with 50 μΐ of paroxetine (0,5 μΜ, non-specific binding) for 1 h at 27 ° C. The membrane-bound radioactivity was determined after filtration under vacuum through Skatron 11734 filters pre-saturated in 0.5% PEI using a Skatron Cell Harvester. The filters are then washed with ice-cold 50 mM tris-HCl, pH 7.4 (at ° C, and set wash values of 9.9.0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and scintillation is measured with a liquid scintillator.

The ability of the compounds of formula I to interact with noradrenaline reuptake sites (NAs) has been demonstrated in the products prepared according to Examples 1-17 by the following assay, which determines the ability of the compounds to replace the standard [ ³ H] nizoxetine ligand from noradrenaline reuptake sites in vitro.

Frontal cortical brain tissue of male Charles River rats, weighing 150-250 g, is homogenized in ice cold 50 mM trisHCl buffer pH 7.4 (at 25 ° C) containing 120 mM sodium chloride and 5 mM potassium chloride (tris-buffer) (1:60 w / v) using Kinematic Polytron (at a speed set to 6 for 10 minutes) and then centrifuged at 40,000 g and a spin time of 10 minutes. The superantant is removed and the pellet rehomogenised in 1:60 w / v tris buffer. and then centrifuged at 40,000 g for 10 minutes. This step is repeated two more times, so that homogenization of the brain tissue by centrifugation is performed four times. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.4) containing 300 mM sodium chloride and 5 mM potassium chloride (equivalent to 18.75 mg wet weight tissue / ml) and the product used immediately prior to the binding assay. All centrifugations were performed at 4 ° C.

Membranes (400 μΙ; equivalent to 7.5 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] nizoxetine at a single concentration of 0.6 nM and 50 μΐ of distilled water (total binding) or 50 μΐ of the test compound (at one concentration). a concentration of 10 ^-6 M or at 10 concentrations ranging from 10 '-10 ^{Q' 3} M) or 50 μΐ mazindol (1 μΜ, non-specific binding) for 4 h at 4 ° C. The membrane-bound radioactivity was determined after filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester. The filters are then washed rapidly with ice-cold 50 mM tris-HCl, pH 7.4 containing 120 mM sodium chloride and 5 mM potassium chloride (at set wash values).

9,9,0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and scintillation is measured with a liquid scintillator.

The ability of the compounds of formula I to interact with muscarinic receptor sites was determined for the products prepared according to Examples 1-17 by the assay below, which determined the ability of the compounds to replace the standard ligand, [ ³ H] -N-methylscopolamine from muscarinic receptors in vitro.

Frontal cortical brain tissue of male Charles River rats, weighing 150-250 g, is homogenized in ice-cold 20 mM HEPES buffer pH 7.5 (value determined at 25 ° C) containing 100 mM sodium chloride and 10 mM magnesium chloride (1). (10 w / v) using a Polytron PT3100 (at a speed set at 21,700 rpm) and then centrifuged at 49,500 g and a spin time of 30 minutes at 4 ° C. The superantant was removed and the pellet rehomogenized in 20 mM HEPES buffer, pH 7.5, containing 100 mM sodium chloride and 10 mM potassium chloride (equivalent to 12.5 mg wet tissue / ml). The membranes are stored at -80 ° C until use.

The membranes are thawed, diluted 1: 10 in ice-cold 20 mM HEPES buffer pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride, homogenized using a Polytron 3100 as described above. Diluted membranes (200 μΐ; equivalent to 0.25 mg wet tissue / tube) are incubated with 200 μΐ 20 mM HEPES buffer pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride and 5 mM potassium chloride and 50 μΐ [ ³ H] N-methylscopolamine at a single concentration of 10 ⁶ M and with 50 μΐ distilled water (total binding) or with 50 μΐ of the test compound (at a single concentration of 10 ⁶ M or at 10 concentrations in the range 10 ' ^1! -10 ^{3 3} M) or with 50 μΐ atropine sulphate (1 μΜ, non-specific binding) for 30 minutes at 30 ° C. The membrane-bound radioactivity was determined after filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester. The filters are then rapidly washed with ice-cold 20 mM HEPES buffer, pH 7.5 (wash 1.2 at 5.5 setting). The filter discs thus treated are then placed in vials on the outside, scintillation liquid is added, and scintillation is measured with a liquid scintillator.

In each of the above assays to determine the ability of compounds of Formula I to replace standard ligands from 5-HT 1A receptors, 5-hydroxytriptamine (5-HT) and noradrenaline (NA) reuptake sites, and muscarinic receptors in vitro, the percent displacement of specifically bound of tritiated ligand by a compound of the invention at a concentration of 10 ^-6 M as follows.

First, the specific binding of the tritiated ligand is calculated in the absence (A) and in the presence (B) of the test compound:

In the absence of compound:

A (dpm) = total binding (dpm) - nonspecific binding (dpm)

In the presence of compound (10 ⁶ M):

B (dpm) = binding in the presence of 10 ^-6 M (dpm) - non-specific binding

The specific binding of the tritiated ligand in the presence of compound (B) is then recalculated to the percentage of specific binding of the tritiated ligand in the absence of compound (A):

% specific binding at 10 ^-6 M = B (dpm) / A (dpm) x 100

The percent expressed displacement of the specifically binding tritiated ligand by the test compound (10 ^-6 M) is then obtained by subtracting the percentage of specific binding in the presence of the compound from the percentage of specific binding in the absence of the compound considered to be maximal binding and thus 100%:

% displacement at 10 ' ⁶ M = 100% special. bonds at 10 ^-6 M

In some cases, where compounds displaced > 50% specifically binding tritiated ligand at a compound concentration of 10 ^-6 M, the concentration range of the test compound and the plotted dependence curves were used in the frrr assay. The K i values were then calculated as satisfying the following simultaneous equations (which are derived from the Feldman equations) of the robust non-linear regression of the values obtained from three parallel determinations;

k: = k, and b =

J + -ic -L + K *

F, = -ab + ^ ab ² + Κ / Ί.

C / LO _t + N F,

K ,, + F, +

K.

Non - specific data.

Alternatively, where B is the concentration of bound ligand-receptor complex. This value is calculated for each experiment from:

DPM

B = (specific activity) x (volume per incubation)

L means compound concentration, [L] iot = concentration of tritiated ligand used, calculated as = (mean DPM for DPM of total samples added) x dilution (specific activity) x (volume per incubation)

K d represents the equilibrium dissociation constant of the ligand.

F ₁ and F ₂ are the concentrations of the corresponding free ligand and free compound. The term r 1 refers to the total concentration of the receptor in the first experiment. This expression needs to be multiplied by Ck (Ci = 1) in subsequent attempts.

Nk means a non-specific binding constant.

The results obtained in the above assays for binding to 5-HT 1A and uptake of 5-HT 1A and binding to muscarinic receptors using the end products of Examples 1-17 below are shown in Table 1 below. o the average of three independent determinations. Values in% represent% displacement at a concentration of 10 ^-6 in one assay.

Table 1

Example # 5-HT, and uptake 5HT capture NA muscarinic receptor 1 5.6 266 3.1 352 2 2.3 292 13.2 268 3 98% 48% 102% 62 4 3.4 212 2.8 274 5 3.6 217 1.4 342 6 2.8 113 1.1 530 7 13.6 194 1.4 49 8 0.6 183 89 157 9 39 0.28 3.03 179 10 1.4 177 16.6 147 11 11.5 238 7.3 342 12 NT NT NT 67% 13 1.0 123 7.5 194 14 2.0 47 3.3 8.7 15 1.8 86 2.8 230 16 8.8 33% 4.6 39%

'R *> r

17 9.0 12% 15.1 231

Kj values are for n = 1, mean n = 2 or mean n = 3,

NT = not rated

The ability of the compounds of the invention to inhibit the monoamine oxidase activity can be demonstrated by the following assay.

The determination is carried out using the following general procedure, using human placenta as the tissue source:

enzyme substrate incubation reaction product detection method MAO-A (h) Kynuramine (0.015 mM) 30 min / 30 ° C 4-OH quinoline spectrometer photometry

Compounds were evaluated at 1 and 10 micromolar concentrations in duplicate.

See Weyler W. and Salach J.I. (1985) Purification and properties of mitochondrial monoamine oxidase type A from human placenta. J. Biol. Chem., 260: 13199-13207.

Study of acute food intake

Test animals and environment

The experiments were performed on male Sprague-Dawley rats (300-450 g at the start of the experiment) obtained from Charles River (Margate). The animals are housed one by one in polypropylene cages with a metal grid floor at a temperature of 21 ± 1 ° C and 55% humidity. Polypropylene trays are placed under each cage. Animals are housed in a reverse light-dark cycle. The light turns off from 9.30 to 17.30 during which time the red light is on. The animals

- They have free access to powdered food for rats and have plenty of drinking water at all times. Food is placed in glass bowls (10 cm in diameter; 8 cm deep) with aluminum lids. Each cap has a cut hole (3 cm diameter) for access to food. Animals are housed under these conditions for at least two weeks prior to the start of the experiment.

e e

Test procedure

The day before the experiment, the animals are randomly assigned to treatment groups containing 6-8 rats, weighed and their food intake is determined for 6 hours. These baseline values are read to confirm that body weight and food intake of the different groups of rats do not differ significantly prior to drug administration. On the day of the start of the experiment, the animals are administered vehicle or one of three doses of the test drug. The drug is always administered orally at the onset of the dark phase of the cycle, as rats consume most of the food during that phase. The dishes with the food are weighed (to the nearest 0.1 g) at the time of drug administration and at 1, 2, 4, 6 and 24 hours after drug administration. At each reading, the amount of food seized onto the pans is determined and then returned to the food pans. However, the amount of food scattered from the dishes is generally negligible.

All drug doses are expressed in the form of their free bases. Drugs are dissolved in deionized water or suspended in 0.4% cellulose using an ultrasonic bath.

Analysis of results

Body weight variations were included in the results as g / kg rat weight (mean rat group values ± mean standard deviation). ED 50 values (drug dose needed to reduce food intake to 50% of control value) were calculated from the logistic sigmoid curve using the appropriate computer program. Statistical comparisons of mean income values in each group were performed by dispersion analysis and Dunnett's two-tailed test.

The compounds of the invention have a surprisingly high affinity for the 5HT 1A receptors as compared to the compounds exemplified in WO 97/02269.

In addition, the preferred compounds of the invention surprisingly have a lower affinity for muscarinic receptors compared to the compounds disclosed in the examples in WO97 / 02269. For example, the compound of Example 1 of WO97 / 02269 has a K i value of 130 nM. Muscarinic affinity can cause undesirable side effects, such as dry mouth, blue-red vision, sweating, palpitations, constipation, and narrow glaucoma with narrow ventricular vision (Blackwell, B. Adverse effects of antidepressant drugs.). -219.1981). Obviously, the compounds need to have minimal affinity for muscarinic receptors.

Even more preferably, the compounds of the invention have significantly reduced MAO inhibitory activity _and compared to the compounds disclosed in WO 97/02269.

In the above test, the compound of Example 1 of the invention has an IC 50 of 1600 nM, while the compound of Example 1 of WO97 / 02269 has an IC 50 of 33 nM. These results demonstrate a surprising improvement in selectivity for the compound of the invention over the compounds already described. The combination of inhibition of monoamine oxidase activity and inhibition of 5-HT reuptake can induce serotonin syndrome (Sternbach H. Serotonin syndrome. Am.J.Psychiatry 148,705-713,1991), which is highly undesirable.

In addition, the most preferred compounds of the invention show improved efficacy in acute food intake studies as compared to the compounds exemplified in WO97 / 02269. In the above acute feeding studies the product of Example 1 of the present invention have an ED 50 for 2 h 1.1 mg / kg whereas the compound of Example 1 WO97 / 02269 has an ED ₅₀ for 2 h 4.5 mg / kg.

The above results demonstrate a surprising improvement in the efficacy of the compounds of the invention as compared to those previously described in the art.

The invention is further illustrated by the following examples, which, however, are for the purpose of illustration only. The end products prepared by the method of the following examples were characterized by one or more of the following methods: high performance liquid chromatography, elemental analysis r * e * r * r * r * r * r f r.

• nuclear magnetic resonance spectrometry, mass spectrometry and infrared spectroscopy.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

a) Lithium bis (trimethylsilyl) amide (1 mol / L solution in tetrahydrofuran; 60 ml) was added dropwise at -70 ° C under a nitrogen atmosphere to a stirred solution of 3-acetylbenzo [b] thiophene (10 g) in tetrahydrofuran (250 mL) and the mixture was then stirred at -70 ° C for 1 hour. Iodomethane solution was added dropwise over 15 minutes at -70 ° C, the stirred mixture was allowed to warm to room temperature over 18 hours and then added to a saturated aqueous ammonium chloride solution (300 mL). The product was extracted with ethyl acetate (3 x 100 mL) and the combined extracts were washed with water (2 x 50 mL) and saturated aqueous sodium chloride solution (50 mL), dried (Na ₂ SO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica in a Biotage Flash 40i®, eluting with petroleum ether (t 40-60 ° C) and ethyl acetate (99: 1). Appropriate fractions were combined and evaporated to give 3-propionyl-benzo [b] thiophene as a colorless solid (2.7 g) which was used without further purification.

b) To a stirred solution of 3-propionylbenzo [b] thiophene (6.75 g; prepared in the previous step) in tetrahydrofuran (100 mL) was added phenyltrimethylammonium tribromide (13.35) portionwise at 0 ° C under nitrogen. g), and then the mixture is stirred at 0 ° C for 20 minutes and at room temperature for 4 hours. The resulting solid was collected by filtration and washed with tetrahydrofuran (30 mL), then the filtrate and washings were combined and the solvent removed in vacuo. The residue was dissolved in dichloromethane and then washed with water (3 x 30 mL) and saturated aqueous sodium chloride solution (30 mL), dried (Na ₂ SO 4), and evaporated to afford 1- (benzo [b] thiophene-3). (yl) -232 bromopropan-1-one as a brown oil which solidified on standing at room temperature and used without further purification.

c) A mixture of crude 1- (benzo [b] thiophen-3-yl) -2-bromopropan-1-one (9.2 g), 2-imidazolidinethion (3.5 g), ethanol (200 mL) and acetic acid (100 g). ml) was refluxed under a nitrogen atmosphere for 17 hours and then the solvent was removed in vacuo. The residue was triturated with ether (100 mL), the solid obtained was then filtered off and crystallized with ethanol to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole. hydrobromide as a white solid (4.9 g), m.p. Mp 277-278 ° C.

Alternative preparation

a) To a stirred mixture of benzo [b] thiophene (50 g) and anhydrous sodium acetate (46 g) in dichloromethane (500 mL) at about 5 ° C was added a solution of bromine (20 mL) in dichloromethane (100 mL), and After stirring at room temperature for 72 hours, it is filtered and the solvent is removed in vacuo. Distillation of the residue gave 3-bromobenzo [b] thiophene as a pale yellow oil (51.3 g), b.p. 93-104 ° C at 53 Pa.

b) A stirred solution of N, O-dimethylhydroxylamine hydrochloride (50 g) in water (500 ml) was cooled with ice and potassium carbonate (125 g) was added portionwise over 10 minutes. Toluene (500 mL) was then added and the stirred mixture was cooled to 0 ° C and propionyl chloride (43 mL) was added dropwise at 0-5 ° C. After complete addition, the mixture was stirred at 0 ° C for 5 minutes, then the cooling bath was removed and stirring was continued for an additional hour. The aqueous phase was separated and washed with toluene (2 x 100 mL), then the combined toluene fractions were washed with water (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried (Na 2 SO 2), and evaporated in vacuo to give a solvent. N-methoxy-N-methylpropionamide as a colorless oil (19.9 g), which was used without further purification. Additional product was isolated from the combined aqueous phase by extraction with ether (2 x 100 mL) and then extraction with dichloromethane (2 x 100 mL). The combined extracts were dried (Na ₂ SO 4) and evaporated in vacuo to give N-methoxy-N-methyl-33-propionamide as a colorless oil (14.2 g) which was used without further purification.

c) To a mixture of magnesium turnings (5.05 g) and tetrahydrofuran (25 mL) was added several iodine crystals followed by 10 mL of a solution of 3-bromobenzo [b] thiophene (42.1 g) in tetrahydrofuran (200 mL). The mixture is heated under a nitrogen atmosphere to initiate the formation of the Grignard reagent, then the heat source is removed and the remaining 3-bromobenzo [b] -thiophene solution is added with stirring and at a rate to maintain a slight reflux. After the addition was complete (about 35 minutes), the mixture was stirred without heating for an additional 35 minutes, then heated at reflux for 10 minutes and then allowed to cool to room temperature. A solution of N-methoxy-N-methylpropionamide (23.1 g) in tetrahydrofuran (100 mL) was then added over 2 minutes and the mixture was stirred at room temperature for 20 minutes and then refluxed for 5 hours, then cooled in ice and mol / L hydrochloric acid (125 mL) was added dropwise. The mixture was stirred for 30 minutes, filtered (Celite), and the filtrate was concentrated in vacuo to remove tetrahydrofuran. The product was extracted into ethyl acetate (2 x 300 ml), then the combined extracts were washed with water (2 x 200 ml) and saturated aqueous sodium chloride solution (2 x 200 ml), dried (Na ₂ SO 4) and the solvent. is removed in vacuo. The residue was triturated with petroleum ether (60-80 ° C) (100 mL) and the resulting solid was filtered and dried under vacuum at 45 ° C for 6 hours to give 3-propionylbenzo [b] thiophene as a red-brown solid (23.3). g), mp 73 75 ° C.

d) To a stirred solution of 3-propionylbenzo [b] thiophene (4.34 g) in tetrahydrofuran (80 ml) was added phenyltrimethylammonium tribromide (8.6 g) portionwise at 0-5 ° C, under nitrogen atmosphere, and then the mixture is stirred at room temperature for 4 hours. The resulting solid was collected by filtration and washed with tetrahydrofuran (30 mL), then the filtrate and washings were combined and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -2-bromopropane as a residue. Ion as a brown oil, which was used without further purification.

e) A mixture of crude 1- (benzo [b] thiophen-3-yl) -2-bromopropan-1-one, 2-imidazolidinethion (2.33 g), and ethanol (120 mL) was heated to reflux for 1 min. nitrogen, then acetic acid (60 mL) was added, the mixture was heated at reflux for 24 hours, and then the solvents were removed in vacuo. Crystallization of the residue from ethanol (125 mL) gave 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide as a white solid (4.4). g), tt Mp 272-274 ° C.

Alternative preparation

a) A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo- [2,1b] thiazole hydrobromide (200 g; prepared by a method similar to that described in WO 97/02269), saturated aqueous sodium carbonate solution (1000 ml) and dichloromethane (2000 ml) was stirred vigorously at room temperature for 1.5 hours, then the organic layer separated, washed with water (500 mL), dried _(MgSO4) and the solvent removed in vacuo . This procedure was repeated on the same scale and the two products were combined to give 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole as a pale yellow solid (264). , 3 g), which was used without further purification.

b) To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (264.3 g) in dichloromethane was added dropwise at 0-5 ° C over 1, Bromine (55.5 mL) was added over 75 hours, then the mixture was stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. The resulting solid was filtered, washed with dichloromethane (300 mL) and dried in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide as a pale yellow solid (431 g) which was used without further purification.

c) 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (170 g) is added portionwise under nitrogen atmosphere at 0-8 ° C for 1 hour to a stirred solution of ethylmagnesium chloride [2.0 M in ether (620 mL)] in tetrahydrofuran (1700 mL), and the resulting mixture was then stirred at 3 ° C for 1.5 hours. Dimethylformamide (136 ml) was then added over 30 minutes at 3-8 ° C, and the mixture was stirred at room temperature for 2 hours, cooled to 8 ° C and carefully quenched with saturated aqueous ammonium chloride solution (600 ml) and water ( 350 ml). Ethyl acetate (1500 ml) was then added, the mixture was stirred at room temperature for 18 hours, and the solid obtained (fraction 1) was filtered off. The organic layer of the filtrate was separated, washed with saturated aqueous sodium chloride solution (500 mL), dried (MgSO 4 and the solvents removed in vacuo. The residue was dissolved in hot propanol-2-ol (1000 mL) and filtered while hot, After standing at room temperature for 20 hours, the resulting solid was filtered, washed with propanol-2-ol (100 mL) and dried in vacuo at 70 ° C to give 3- (benzo [b] thiophen-3-yl). -5,6-dihydroimidazo [2,1b] thiazole-2-carboaldehyde as a yellow solid (19.4 g), mp 206 [deg.] C. A mixture of solid fraction 1, dichloromethane (2100 mL), 2 mol / l hydrochloric acid (250 mL). ) and water (1000 ml) was stirred at room temperature for 15 minutes, then triethylamine (80 ml) was added, the dichloromethane layer was separated and another portion of the product was isolated by extraction from the aqueous layer into dichloromethane (500 ml). (MgSO4 and removal of the solvent in vacuo yielded an additional 3- (ben from [b] -thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde as a yellow solid (63.0 g), m.p. 208 ° C.

d) Borane / tert-butylamine complex (18.3 g) was added portionwise to an ice-cooled stirred suspension of finely-dusted aluminum chloride (14 g) in dichloromethane (330 mL) and then stirred at 0 ° C for 55 minutes. A solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (10g) in dichloromethane (70 ml) was added dropwise at 0 ° C and the mixture was stirred 15 minutes at 0 ° C and then 21 hours at room temperature. The mixture was then cautiously quenched with water (1000 mL) followed by 2.5 mol / L hydrochloric acid (175 mL), then basified to pH 10 by the addition of aqueous 5 M sodium hydroxide. The aqueous phase was separated and washed with dichloromethane (300 mL), then the combined dichloromethane solutions were dried (MgSO 4) and the solvent was removed in vacuo. Half (5 g) of the residue was dissolved in ethanol (12 mL) and 48% hydrobromic acid (3.5 mL) was added. The mixture was diluted with ether (100 mL) and the resulting solid was filtered off and then suspended in ethanol (46 mL). The mixture was then heated to reflux for 15 minutes, then cooled with ice, and the resulting solid was filtered, washed with ether (40 mL) and dried in vacuo to give 3- (benzo [b] thiophen-3-yl) - 2-methyl-5,6-dihydroimidazo [2,1b] thiazole hydrobromide as a white solid (3.54 g), m.p. Mp 273-276 ° C.

Example 2

a) A solution of 3-bromo-5-chlorobenzo [b] thiophene (2g) in ether (20 mL) was added dropwise at -70 ° C under nitrogen atmosphere to a stirred solution of butyllithium (2.5 mol / L solution in hexanes; 4). , 14 mL) in ether (46 mL), and then stirred at -70 ° C for 30 min. Then, 2-bromopropionyl chloride (1.67 g) was added in one portion, the mixture was stirred at -70 ° C for 4 hours and then allowed to warm to 0 ° C. The mixture was then stirred at 0 ° C for an additional 30 minutes and then quenched with saturated aqueous ammonium chloride solution (50 mL). The aqueous layer was separated and washed with ether (2 x 30 mL) and the combined ethereal solutions were washed with saturated aqueous sodium chloride solution (2 x 30 mL) and dried (Na 2 SO 4). The solvent was then removed in vacuo and the residue purified by flash chromatography on silica using petroleum ether (b.p. 60-80 ° C) and ethyl acetate 9: 1 as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 1- (5-chlorobenzo [b] thiophen-3-yl) 2-bromopropan-1-one (0.32 g) as a white solid which was used without further purification. cleaning.

b) A mixture of 1- (5-chlorobenzo [b] thiophen-3-yl) -2-bromopropan-1-one (0.3 g),

Of 2-imidazolidinethion (0.12 g), and ethanol (10 mL) was heated to reflux under nitrogen for 15 min, then acetic acid (4 mL) was added and the mixture was heated at reflux for 24 h. the solvents are removed in vacuo. The residue was dissolved in a minimum amount of water, the solution was basified to pH 12 by the addition of aqueous 5 M potassium hydroxide solution and the product was extracted into dichloromethane (3 x 30 ml). The extracts were dried (Na 2 SO 4) and the solvent removed in vacuo. The residue is then purified by flash chromatography on silica using a Biotage Flash 40i® mobile phase, which is dichloromethane and then a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined and evaporated in vacuo to give 3- (5-chlorobenzo- [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1b] thiazole as a yellow solid (m.p. 0.1 g), m.p. Mp 264-267 ° C.

Example 3

a) To a stirred solution of triethylamine (244.85 ml) in dimethylformamide (400 ml) was added dropwise under nitrogen atmosphere at 110 ° C methyl thioglycolate (62.87 ml) and the mixture was stirred at 110 ° C for 30 minutes. The solution is then added rapidly

Of 2,6-difluorobenzaldehyde (100 g) in dimethylformamide (100 ml) and the mixture was heated at reflux for 4 hours. The mixture was cooled to room temperature and added to ice / water (4000 mL). The product was filtered off and dried in vacuo to give methyl 4-fluorobenzo [b] thiophene-2-carboxylate as a white solid (110 g) which was used without further purification.

b) To a stirred suspension of methyl 4-fluorobenzo [b] thiophene-2-carboxylate (110 g) in methanol (1500 mL) at room temperature under a nitrogen atmosphere was added aqueous 2 M sodium hydroxide solution. The resulting mixture was stirred at room temperature for 4 hours, then the dissolved phase was separated from the unreacted methyl 4-fluorobenzo [b] thiophene-2-carboxylate by decanting into 2 mol / L hydrochloric acid (3,000 ml). The resulting solid was filtered from the acidic mixture and dried in vacuo at 60 ° C to give 4-fluorobenzo [b] thiophene-2-carboxylic acid as a white solid (77 g) and used without further purification. The remaining unreacted methyl 4-fluorobenzo [b] thiophene-2-carboxylate was dissolved in hot methanol (500 mL), then aqueous 2 M sodium hydroxide solution (250 mL) was added at room temperature. The mixture was stirred at room temperature for 8 hours and then added to 2 mol / L hydrochloric acid (1000 mL). The resulting solid was filtered and dried in vacuo to give 4-fluorobenzo [b] thiophene-2-carboxylic acid as a white solid (33 g).

c) To a stirred solution of 4-fluorobenzo [b] thiophene-2-carboxylic acid (77 g) in quinoline (500 ml) was added copper powder (40 g) and the mixture was heated with stirring at 180-200 ° C for 2 hours. The mixture was then allowed to cool to room temperature and added to 2 mol / L hydrochloric acid (1500 mL). Ethyl acetate (1000 mL) was then added, the mixture was filtered through Celite®, which was then washed with ethyl acetate (500 mL), then the combined organic layers were dried (MgSO ₄ ) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica using petroleum ether (bp 40-60 ° C) followed by petroleum ether (bp 40-60 ° C) / ethyl acetate (25: 1) as eluent. Appropriate fractions were combined and solvent removed to give 4-fluorobenzo- [b] thiophene (50.46 g) as a colorless oil.

d) To a stirred mixture of 4-fluorobenzo [b] thiophene (50.46 g) and anhydrous sodium acetate (40 g) in dichloromethane (400 mL) under a nitrogen atmosphere at -25 ° C was added dropwise a solution of bromine (18, 7 ml) in dichloromethane (200 ml, stirred at room temperature for 18 hours, then filtered and the solvent removed in vacuo. The residue was dissolved in dichloromethane (about 50 ml) and then water (300 ml) was added under a nitrogen atmosphere. and zinc powder (about 40 g) .The resulting mixture was heated at reflux for 4 hours and then allowed to stand at room temperature for 20 hours, then ethyl acetate (300 mL) was added, heating was continued for 15 minutes at room temperature. The mixture was filtered (Celite®) and the filter cake was washed with ethyl acetate (3 x 100 mL). The aqueous phase was separated and washed with ethyl acetate (200 mL) then the combined organic solutions are dried (MgSO ₄ ) and the solvents are removed TLC in vacuo afforded 3-bromo-4-fluorobenzo [b] thiophene as a light brown solid (59.4 g) which was used without further purification.

e) A solution of 3-bromo-4-fluorobenzo [b] thiophene (59.4 g) in tetrahydrofuran (250 mL) was added to a stirred solution of ethylmagnesium bromide [2.0 mol / L in ether (190 mL)] in tetrahydrofuran (800 mL) at 0 ° C under a nitrogen atmosphere, then the mixture was refluxed for 1.5 h and then allowed to cool to room temperature. N-Methoxy-N-methylpropionamide (33.5 g) was then added and the mixture was heated at reflux for 2 hours. The mixture was then allowed to cool to room temperature and added to a saturated aqueous ammonium chloride solution (1000 mL). The product was extracted into ethyl acetate (2 x 500 mL), the combined organic layers were then dried (MgSO ₄ ) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica using eluting with petroleum ether (t 40-60 ° C) followed by dichloromethane. The appropriate fractions were combined and solvent removed to give 4-fluoro-3-propionylbenzo [b] thiophene (22 g) as a brown solid ·

f) Phenyltrimethylammonium tribromide (39.5 g) was added to a stirred solution of 4-fluoro-3-propionylbenzo [b] -thiophene (22 g) in tetrahydrofuran (300 mL) at 0 ° C under nitrogen and stirred for 3 hours at room temperature. The formed solid was collected by filtration on silica, washing with dichloromethane, then the filtrate and washings were combined and the solvents removed to give 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) propan-1-one in as a brown oil (about 40 g), which was used without further purification.

g) A mixture of crude 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) propan-1-one (about 40 g), 2-imidazolidinethion (10.71 g), ethanol (150 mL) and of acetic acid (75 mL) was heated at reflux under nitrogen for 2 hours, then an additional portion of 2-imidazolidinethion (2.2 g) was added and heating at reflux continued for a further 2 hours. The mixture was then cooled to 0 ° C, the solid formed was filtered off and washed with ethanol (2 x 100 mL) and then basified by stirring with a mixture of saturated aqueous sodium bicarbonate (500 mL) and dichloromethane (500 mL) for 30 minutes. The organic layer was separated, the aqueous layer was shaken with dichloromethane (2 x 100 mL) and the combined dichloromethane solutions were dried (MgSO 4) and the solvent was removed in vacuo. The residue was dissolved in ethanol (200 mL) and then concentrated hydrochloric acid (6 mL) was added at 0 ° C. The solvents were then removed in vacuo and crystallization of the residue from ethanol (about 100 mL) afforded 3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride as a white solid (17.5 g), m.p. 259-262 [deg.] C.

Example 4

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (5 g of a product prepared in a similar manner to that described in Example 1: alternative preparation B A solution of fumaric acid (2.13 g) in ethanol (40 ml) was added at 0 ° C at 40 ° in ethanol (10 ml). The resulting mixture was stirred at 0 ° C for 15 minutes, the resulting solid was filtered off and dried in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-a]. bthiazole fumarate as a white solid (4.71 g), m.p. Mp 179-181 ° C.

Example 5

To a solution of 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (4.27 g of product prepared in a similar manner to that described in Example 1: alternative preparation) B) Concentrated hydrochloric acid (4 ml) was added in ethanol (45 ml), then the resulting mixture was added to ether (250 ml) and stirred for 15 minutes. The resulting solid was filtered, washed with ether (50 mL) and dried in vacuo at 70 ° C to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole -hydrochloride as a white solid (3.50 g), m.p. Mp 254-256 ° C.

Example 6

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (2.66 g of product prepared in a similar manner to that described in Example 1: alternative) Preparation B) in ethanol (28 mL) was added a solution of D, L-tartaric acid (1.43 g) in ethanol (30 mL). The resulting suspension was stirred for 5 minutes and then ether (80 mL) was added. The solid was filtered, washed with ether (50 mL) and dried in vacuo at 70 ° C to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole- D, L-tartrate as a white solid (4.00 g), m.p. Mp 204-205 ° C.

Example 7

In a manner similar to that described in Example 1: Alternative Preparation A, using the bromination of benzo [b] thiophene as the starting reaction followed by reaction with magnesium and then with N-methoxy-N-methylbutyramide, was prepared as a colorless solid 3- ( benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1b] thiazole hydrobromide, mp Mp 219-221 ° C.

Example 8

a) A solution of 3-bromo-5-methylbenzo [b] thiophene (2.5 g; prepared by bromination of 5-methylbenzo [b] thiophene in a manner similar to that described in Example 1: alternative preparation A) in ether (5 ml) was added dropwise at -70 ° C under a nitrogen atmosphere to a stirred solution of butyllithium (1.6 M in hexanes; 7 mL) in ether (20 mL) and then stirred at -70 ° C for 30 min. A solution of N-methoxy-N-methylpropionamide (1.3 g) in ether (5 mL) was then added dropwise over 20 minutes, the mixture was stirred at -70 ° C for 3 hours, allowed to warm to room temperature over 20 hours. then quench with 2 M hydrochloric acid (25 mL). The ether layer was separated, washed with water (25 mL) and saturated aqueous sodium chloride solution (25 mL), dried (MgSO ₄ ) and the solvents evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with petroleum ether (60-80 ° C) and ethyl acetate (40: 1). The appropriate fractions were combined and evaporated in vacuo to give a mixture of 5-methyl-3-propionylbenzo [b] thiophene and 5-methyl-2-propionylbenzo [b] thiophene (20: 1) (1.2 g) as an off-white solid, which was used without further purification.

b) To a stirred solution of 5-methyl-3-propionylbenzo [b] -thiophene (1.2 g; prepared as described above) in tetrahydrofuran (20 mL) was added phenyltrimethylammonium tribromide (2.25) portionwise at 0 ° C. g), and the mixture is then stirred for 1 hour at 0 ° C and then for 20 hours at room temperature. The mixture was then filtered and the solvent removed in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with water (2 x 50 mL), dried (MgSO ₄ ) and evaporated in vacuo to give a dark brown solid which was triturated with petroleum ether (t 60-80 ° C). ). Removal of the solvent in vacuo afforded 2-bromo-1- (5-methylbenzo [b] thiophen-3-yl) propan-1-one (0.75 g) which was heated to reflux with a mixture of 2-imidazolidine thion ( 0.27 g), ethanol (30 ml), and acetic acid (15 ml) for 24 hours. Then the solvents are removed in vacuo, the residue is triturated with ether (20 ml) and the solid obtained is filtered off and dried in vacuo to give 2-methyl-3- (5-methylbenzo- [b] thiophen-3-yl) - 5,6dihydroimidazo [2,1b] -thiazole hydrobromide as a white solid (0.52 g), mp 266-269 ° C.

Example 9

In a manner similar to that described in Example 1: Alternative Preparation A, using the bromination of benzo [b] thiophene as the starting reaction followed by reaction with magnesium and then with N-methoxy-3, N-dimethylbutyramide is prepared as a light brown solid 3 - (benzo [b] thiophen-3-yl) -2-isopropyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide, mp 208-210 ’C.

Example 10

To a stirred solution of 4-fluorophenylmethylsulfide (22.0 g) in tetrahydrofuran was added dropwise at -70 ° C under nitrogen atmosphere secbutyllithium (1.25 mol / L solution in cyclohexane: hexane 92: 8) and then the mixture was stirred 65 minutes at -70 ° C. Dimethylformamide (13.2 ml) was then added dropwise at -68 ° C to -70 ° C and the stirred mixture was allowed to warm slowly to room temperature over 20 minutes and then added to a solution of acetic acid (10 ml) in water ( 500 ml). The product was extracted into ether (3 x 150 ml) and the combined extracts washed with 2M hydrochloric acid (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried (Na ₂ SO 4) and the solvents removed under vacuum. The residue (25 g), which was used without further purification, contained approximately 2: 3 of 4-fluorophenylmethylsulfide and 2-fluoro-5- (methylthio) benzaldehyde, approximately according to nuclear magnetic resonance results.

b) A stirred mixture of methylthioglycolate (8.9 ml), crude 2-fluoro-5- (methylthio) benzaldehyde (25 g; prepared as above), dimethylaceramide (250 ml) and ethyldiisopropylamine (42 ml) was heated for 3, 5 hours at 140-150 ° C and then the solvent is removed in vacuo. Water (650 mL) was added to the residue, and the product was then extracted into dichloromethane (3 x 150 mL). The combined extracts were washed with water (3 x 150 mL), dried (Na _e SO4) and the solvent removed in vacuo. The residue was purified by trituration with ether (250 mL), the resulting solid was filtered, washed with ether (2 x 50 mL), and dried in vacuo to give methyl 5- (methylthio) benzo [b] thiophene-2-carboxylate. (13.3 g) as a pale, yellow solid, mp 89.7-90.4 ° C.

c) Sodium hydroxide (8 g) was dissolved in water (100 ml) and the solution was added to a stirred solution of methyl 5- (methylthio) benzo [b] thiophene-2-carboxylate (23.8 g; prepared as described above). supra) in methanol (300 mL). The resulting mixture was heated at reflux for 10 minutes and then allowed to stand at room temperature for 3 days. The suspension is then concentrated to a total volume of about 250 ml by heating, then water (100 ml) is added and the mixture is filtered hot to remove insoluble matter. A solution of concentrated hydrochloric acid (40 ml) in water (20 ml) was added to the filtrate, and the resulting solid was collected by filtration and washed with water, followed by drying in vacuo at 80 ° C to give 5- (methylthio) benzo [ b] thiophene-2-carboxylic acid in the form of a pale yellow solid (21 g), m.p. 186-186.5 ° C.

d) A mixture of powdered copper (5.3 g), 5- (methylthio) benzo [b] thiophene-2-carboxylic acid (20 g) and quinoline (100 ml) was heated under stirring to reflux under a nitrogen atmosphere. minutes and then hot filtered. The filtrate was added to a mixture of concentrated hydrochloric acid (100 mL), ice (500 g) and ether (200 mL), then the solid formed was filtered off and washed with ether. The aqueous phase was separated and a further portion of the product was obtained by extraction from the aqueous phase into ether (2 x 150 mL). The combined ether layers were washed with 2M hydrochloric acid (200 mL) and water (200 mL) and removal of the solvent in vacuo gave 5- (methylthio) benzo [b] thiophene as a light brown solid (14.7 g), which was used without further purification.

e) A solution of 5- (methylthio) benzo [b] thiophene (14.7 g) in dichloromethane (180 mL) was added to a stirred solution of aluminum bromide (26.2 g), bromoacetyl bromide (7.12 mL) and dichloromethane (120 mL). ml) at <0 ° C under a nitrogen atmosphere, and the dark red-brown obtained is then stirred at <0 ° C for 30 minutes and at room temperature for 20 hours. Then the solution was poured into a mixture of ice (600 g) and concentrated hydrochloric acid (50 ml), then dichloromethane (300 ml) was added and the insoluble components were removed by filtration (Celite®). The aqueous phase was separated and a further portion of the product was obtained by extraction from the aqueous phase into dichloromethane (300 mL). The combined dichloromethane solutions were then dried (MgSO 4) and the solvent removed in vacuo. To the residue was added acetic acid (200 mL) and dichloromethane (200 mL), followed by a solution of 2-imidazolidinethion (5.29 g) in acetic acid (200 mL), and then dichloromethane was removed by distillation. The remaining mixture was heated at reflux for two hours, then the total volume of the mixture was reduced to about 200 ml by heating under vacuum. The hot solution is separated by decantation from the undissolved components and then allowed to cool. Further undissolved components were removed in the same manner as above and then the solvents were removed in vacuo at 50 ° C. The residue was treated with water (300 mL) and aqueous 5 M sodium hydroxide solution (300 mL), and the product was then extracted into dichloromethane (300 mL). The extract was dried (Na ₂ SO 4) and the solvent removed in vacuo. The residue was partially purified by flash chromatography on silica using ethyl acetate followed by 8: 1: 1 ethyl acetate: methanol: triethylamine. The appropriate fractions were combined and the solvents removed in vacuo to give 3- [5 (methylthio) benzo [b] thiophen-3-yl] 5,6-dihydroimidazo [2,1b] thiazole as a yellowish brown gum (3.6 g) , which was used without further purification.

f) To a stirred solution of 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1b] thiazole (3.55 g; prepared as described above) in dichloromethane (80 mL) was added a solution of bromine (1.87 g) in dichloromethane (10 mL) while maintaining the internal temperature of the reaction mixture below 20 ° C, then the dichloromethane phase was separated by decantation from the insoluble components and concentrated in vacuo. The residue was triturated with dichloromethane (10 mL) and the resulting solid collected by filtration to give 2-bromo-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [ 2,1b] Thiazole hydrobromide in the form of a yellow-brown solid (2.97 g), m.p. Mp 260-265 ° C.

r

g) A solution of ethylmagnesium chloride (2.8 mol / L in tetrahydrofuran (8.76 mL)) was added at -10 ° C to a stirred suspension of 2-bromo-3- [5- (methylthio) benzo [b] under nitrogen. thiophen-3-yl] -5,6-dihydroimidazo- [2,1b] thiazole hydrobromide (2.90 g) in tetrahydrofuran (40 mL), and the mixture is then stirred at room temperature for 90 minutes and then cooled to - Low: 14 ° C. Dimethylformamide (5 ml) was then added and the resulting suspension was stirred at room temperature for 2 hours, then ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml) were added. The ethyl acetate layer was separated, dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 3- [5- (methylthio) -benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde as a solid (1.4 g), mp 157-158.5 ° C, which was used without further purification.

h) To a stirred suspension of dusted aluminum chloride (0.80 g) in dichloromethane (20 mL) at 0 ° C under a nitrogen atmosphere was added borane / tert-butylamine complex (1.04 g) and the mixture was then stirred at 0 ° C for 1 hour. . Then add 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.66 g; prepared as above) , the mixture is stirred for 15 minutes at 0 ° C and then left to stand at room temperature for 20 hours. The mixture was then carefully quenched with water (25 mL) followed by 2 mol / L hydrochloric acid (25 mL), then heated to decompose any borane complexes present. The suspension is then filtered, and the filtrate is made alkaline (pH 14) by the addition of aqueous 5 M sodium hydroxide solution. The product was extracted into dichloromethane (2 x 50 mL), the combined extracts were dried (Na ₂ SO ₄ ), and the solvents were then removed in vacuo. To a solution of the orange-yellow residue (0.39 g) in a mixture of dichloromethane (25 mL) and ethyl acetate (50 mL) was then added anhydrous oxalic acid (0.12 g) in ethyl acetate (10 mL) and then the dichloromethane was removed by distillation. The solid obtained is then filtered off, washed with ethyl acetate (2 x 10 ml) and dried in vacuo to give 2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydro -imidazo [2,1b] thiazole oxalate as a white solid (0.36 g), mp 197 ° C.

Example 11

a) A solution of 5-fluorobenzo [b] thiophene (2.8 g; prepared from 2,5-difluorobenzaldehyde in a manner similar to that described in Examples 3 and 10) in dichloromethane (27 ml) was added dropwise under a nitrogen atmosphere to the stirred mixture. aluminum chloride (7.34 g) 2-bromopropionyl chloride (4.73 g) in dichloromethane (70 ml), stirred at room temperature for 2.5 hours, then added to ice-cold water (250 ml) and stirred for 1 hour. hour. The aqueous phase was separated and another portion of the product was extracted into dichloromethane (100 mL), the combined dichloromethane solutions were washed with water (2 x 100 mL) and saturated aqueous sodium chloride solution (2 x 100 mL), dried (Na ₂ SO 4) and the solvent is removed in vacuo. The residue was purified twice by flash chromatography on silica using a Biotage Flash 40i ® system and using a mixture of petroleum ether (t 60-80 ° C) and ether as the eluent. The appropriate fractions were combined and the solvents removed in vacuo to give a 2-bromo- 1- (5-fluorobenzo [b] thiophen-3-yl) propan-1-one and 2-bromo-1- (5-fluorobenzo [b] thiophen-2-yl) propan-1 (2.1 g) 9: 1, which was used without further purification.

b) A mixture of crude 2-bromo-1- (5-fluorobenzo [b] thiophen-3-yl) propan-1-one (2.1 g; prepared as above), 2-imidazolidinethion (0.75 g) and ethanol (60 mL) was heated at reflux for 10 min and then acetic acid (30 mL) was added. The resulting mixture was heated at reflux for 20 hours, then allowed to stand at room temperature for 60 hours and then the solvents were removed in vacuo. The residue was triturated with ethanol (100 mL), and the resulting solid was dissolved in hot ethanol (100 mL). The total volume is then reduced to about 60 ml by distillation and the mixture is allowed to cool to room temperature. The resulting solid was collected by filtration, dried in vacuo and recrystallized from ethanol (75 mL) to give 3- (5-fluoro-benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2,1b] 1-Thiazole hydrobromide as a white solid (0.45 g), m.p. M.p. 268-271 ° C.

r r f | · • r r r r

Example 12

a) 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole is prepared by alkalizing a mixture of 3- (5-fluorobenzo [b] thiophene- 3-yl) -2-methyl-5,6-dihydroimidazo [2,1b] thiazole hydrobromide and 3- (5-fluorobenzo [b] thiophen-2-yl) -2-methyl-5,6-dihydroimidazo [2,1b] ] thiazole hydrobromide (prepared in a manner similar to that described in Example 11). The pure free base is obtained by flash chromatography on silica using a Biotage Flash 40i® system using either 9: 1 then 1: 1 dichloromethane: methanol or 97: 3 then 9: 1 dichloromethane / methanol. as eluents.

b) To a solution of 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (4.6 g) in ethanol (250 mL) is added acid hydrochloric acid 5.5 mol / L, and the resulting mixture was added dropwise with stirring to ether (400 mL) and then additional ether (2000 mL) was added. The suspension is allowed to stand at room temperature for 3 days and the resulting solid is collected by filtration, washed with ether (200 mL) and dried in vacuo to give 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl- 5,6-dihydroimidazo [2,1b] thiazole hydrochloride as a white solid (3.6 g), m.p. Mp 243-244 ° C.

Example 13

To a solution of 5-chloro-3-propionylbenzo [b] thiophene (5.8 g; prepared from 3-bromo-5-chlorobenzo [b] thiophene by reaction with butyllithium and then with N-methoxy-N-methylpropionamide in a manner similar to that described above in Example 2) in tetrahydrofuran (100 ml), phenyltrimethylammonium bromide (9.7 g) was added portionwise at 0-5 ° C over 2 minutes, and the mixture was then stirred at room temperature for 2.5 hours. The solid present is collected by filtration and the solvent is removed in vacuo. A mixture of the residue, 2-imidazolidinethion (2.65 g) and ethanol (120 mL) was heated to reflux for 15 minutes and then acetic acid (60 mL) was added. The resulting mixture was heated at reflux for 24 hours and then the solvents were removed in vacuo. Ethanol (50 ml) was added to the residue, then the solvent was removed in vacuo and the residual solid was recrystallized from hot ethanol (250 ml) and dried in vacuo at 50 ° C to give 3- (5-chlorobenzo [b] -thiophene). -3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide as a pink colored solid (6.25 g), m.p. Mp 283-286 ° C.

Example 14

In a similar manner to that described in Example 11 and starting from 5-chlorobenzo [b] thiophene (prepared in a manner similar to that described in J. Heterocycl. Chem (1988), 25 (4), 1271) and using 3-bromobutyryl chloride, 3- (5-chlorobenzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide as an off-white solid, m.p. 285-289 ° C (volume change at 240 ° C)

Example 15

Using a method similar to that described in Example 11 and using starting 5-bromobenzo [b] thiophene (prepared from 5-bromo-2-fluorobenzaldehyde in a manner similar to that described in Example 3) and using 2-bromo-propionyl chloride, 3- (5) was prepared. -bromobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2,1-b] thiazole hydrobromide as a brown solid, m.p. Mp 272-275 ° C.

Example 16

A mixture of crude 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) -propan-1-one (54 g; prepared by a method similar to that described in Example 3), 2-imidazolidinethion (19.4 g) of ethanol (200 ml) and acetic acid (100 ml) was refluxed under nitrogen for 2 hours, then a further portion of 2-imidazolidinethion (2 g) was added and heating at reflux was continued for 30 minutes. The mixture was cooled to 0 ° C and the resulting solid (49 parts) was filtered off and dried in vacuo to give 3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6- dihydroimidazo [2,1-b] thiazole hydrobromide (52.1 g), 1.1. Mp 264-266 ° C.

Example 17

To a suspension of 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo- [2,1b] thiazole (6.7 g; prepared according to Example 3 of WO 97/02269) in tetrahydrofuran (80 ml) butyllithium (2.5 mol / L in hexane; 14 mL) was added dropwise over 20 minutes at -70 ° C, and the mixture was then stirred at -70 ° C for 30 minutes. Dimethylformamide (2.7 ml) was then added and the mixture was allowed to warm to room temperature and quenched with saturated aqueous ammonium chloride solution (200 ml). The product was then extracted into dichloromethane (3 x 200 mL), then the extracts were washed with saturated aqueous sodium chloride solution (100 mL), dried (Na ₂ SO ₄ ) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (9: 1). Appropriate fractions were combined and evaporated to give a residue (4.3 g) which was purified by flash chromatography on silica using a Biotage Flash 40i ® system, eluting with dichloromethane: methanol (20: 1). The appropriate fractions were collected and the solvents removed in vacuo to give 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (3.3 g) as a brown solid, which was used without further purification.

From 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (3.0 g; prepared in a manner similar to that described above) and borane // tert -butylamine was prepared in a manner similar to that described in Example 1: Alternative Preparation A to prepare crude 3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (1.6 g) ). The crude product was dissolved in dichloromethane (50 mL) and then ether (50 mL) was added. The resulting solid was collected by filtration and then the solvents were removed from the filtrate in vacuo. The residue was purified by flash chromatography on a Jones Flashmaster II® system using dichloromethane and then 9: 1 dichloromethane: methanol as eluents. Appropriate fractions were collected and the solvents removed in vacuo to give a residue (4.3 g) which was purified by flash chromatography on a Biotage Flash 40i® system and dichloromethane / methanol (19: 1) as eluent. Appropriate fractions were combined and the solvents removed in vacuo to give a residue (0.28 g) which was dissolved in methanol (5 mL). Water (5 ml) was added and the mixture was acidified to pH 1 by addition of 2 mol / L hydrochloric acid. Methanol is removed from the turbid solution in vacuo and the insolubles removed by filtration. The filtrate was basified to pH 12 by the addition of aqueous 2M sodium hydroxide solution, then the resulting solids were filtered off, washed with water (10 ml) and dried in vacuo to give 3- (benzo [b] furan- 3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (0.18 g), m.p. Mp 119-122 ° C.

Example A

The use of the compounds of the invention for the preparation of pharmaceutical compositions is illustrated below. As used herein, the term "active compound" means any compound of the invention, but particularly a compound of the group of compounds representing the end products of the preceding examples.

(a) Capsules

To prepare the capsules, 10 parts by weight of the active compound and 240 parts by weight after deagregation of the individual components are mixed. The resulting mixture is placed in hard gelatin capsules such that it contains a unit dose or part of a unit dose of the active compound.

Γ Γ

(b) Tablets

Tablets are prepared with the following ingredients.

parts by weight active compound 10 lactose 190 corn starch 22 polyvinylpyrrolidone 10 magnesium stearate 3

The active compound, lactose and a portion of the starch are deagregated, mixed and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with magnesium stearate and the rest of the starch. The mixture is then compressed in a tablet press into tablets, each tablet containing a dosage unit or part of a dosage unit of the active compound.

c) Tablets with an enteric coating

Tablets are prepared as described in (b) above. The tablets were coated with an enteric coating in a conventional manner using 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Lace

In the preparation of suppositories, 100 parts by weight of the active compound is incorporated into 1300 parts by weight of the triglyceride lace base and the mixture is formulated into a suppository into suppositories, each suppository containing a therapeutically effective amount of the active ingredient.

Claims (20)

PATENT CLAIMS A compound of formula I and pharmaceutically acceptable salts thereof, wherein A is S or O; R1 is H, halogen, C1-3alkyl or C1-4alkylthio R ₂ is H or fluoro; and R 3 is methyl, ethyl and isopropyl. A compound according to claim 1, wherein A is S. A compound according to claim 1, wherein A is O. A compound according to any one of the preceding claims wherein R 1 represents a group selected from H, fluoro, chloro, bromo, methyl and methylthio. A compound according to any one of the preceding claims wherein R 3 is a methyl group. A compound of formula I according to claim 1 represented by formula (Ia) R 1a and pharmaceutically acceptable salts thereof, wherein R is H or chloro. I The compound of claim 1, wherein A is S; R 1 is H, fluoro or chloro; R ₂ is H or fluoro; and R3 represents a methyl group. The compound of claim 1, wherein A is S; R | H or fluoro; R ₂ is H or fluoro; and R3 represents a methyl group. The compound of claim 1, wherein A is S; R 1 is H; R ₂ is H; and R3 represents a methyl group. The compound of claim 1, which is a compound selected from the group consisting of: 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (4-Fluoro-benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro-imidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-methyl-3- (5-methylbenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (Benzo [b] thio-phen-3-yl) -2-isopropyl-5,6-dihydro-imidazo [2,1-b] thiazole; 2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-Chloro-benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydro-imidazo [2,1-b] thiazole; 3- (5-Bromobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; and 3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 10 together with a pharmaceutically acceptable diluent or carrier. A compound of formula I for use as a medicament. A compound of formula I for use in the treatment of depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobia , eating disorders such as bulimia, anorexia, excessive stamina and morbidity, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke occurs brain trauma, cerebral ischemia, head trauma and hemorrhage, and as a means to ease smoking. 14. The use of a compound of formula I in the preparation of a medicament for the treatment of depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic and panic , social phobias, eating disorders such as bulimia, anorexia, excessive knockout and morbidity, non-insulin-dependent diabetes mellitus, hyperglycemia; hyperlipidemia, stress, seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head trauma and hemorrhage occurs and as a means to facilitate smoking cessation. 15. A method of treating depression, anxiety, psychoses (e.g. schizophrenia), late dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias, eating disorders bulimia, anorexia, excessive squash and morbidity, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I. 16. A method of reducing the appetite for smoking in a human comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 10. 17. A method of reducing weight loss occurring in a human being as a result of quitting smoking, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 10. A compound of formula I according to any one of claims 1 to 10 for use in the treatment or prevention of metabolic diseases and conditions arising therefrom, such as in particular thermogenesis not resulting from muscle activity and increased metabolic rate, sexual dysfunction, sleep apnotic syndrome, premenstrual syndrome, urinary incontinence, hyperactivity disorders, hiatal hernia and reflux esophagus, pain, especially neuropathic pain, weight gain associated with drug therapy, chronic fatal syndrome, osteoarthritis and gout, weight gain associated with weight gain, menstrual dysfunction, ileum hypotension, bile stone hypertension, gallstones and bile stones . A compound of formula I according to any one of claims 1 to 10 for use in the prevention of cardiovascular disease, for reducing platelet retention, as a weight loss support after pregnancy and as a weight loss support after the patient has stopped smoking. 20. Processes for the preparation of a compound of formula I as described herein.