KR20020033625A - Substituted imidazothiazoles as antidepressant agents - Google Patents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof include depression, anxiety, psychosis (e.g. schizophrenia), chronic impairment, obesity, drug addiction, drug abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, compulsive reactivity, Panic attacks, social phobias; Appetite disorders such as bulimia, anorexia, news and overeating, treatment of non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, and neurological diseases such as epileptic seizures, epilepsy, brain damage, cerebral ischemia, head injury and bleeding Useful for the treatment and / or prevention of conditions with the same nerve damage.

Formula I

In Formula I above,

A is S or O,

R ₁ is H, halo, C _1-3 alkyl group or C _1-3 alkylthio group,

R ₂ is H or fluoro,

R ₃ is methyl, ethyl or isopropyl.

Description

Substituted imidazothiazoles as antidepressant agents

The present invention provides a novel 3- (benzo [b] thiophen-3-yl) imidazo having affinity for the 5-HT _1A receptor and inhibiting neuronal reuptake of 5-hydroxytryptamine and / or noradrenaline. [2,1-b] thiazole, preparation method thereof, pharmaceutical composition containing the same and depression, anxiety, psychosis (eg schizophrenia), chronic impairment, obesity, drug addiction, drug abuse, cognitive impairment, Alzheimer's disease Illness, cerebral ischemia, obsessive-compulsive behavior, panic attacks, social phobias; Appetite disorders such as bulimia, anorexia, news and overeating, treatment of non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, and epileptic seizures, neurological diseases (e.g. epilepsy) and / or seizures, brain damage, cerebral ischemia, head injury and It relates to their use in the treatment and / or prophylaxis of conditions with nerve damage such as bleeding and as a smoking cessation aid.

WO 98/41528 discloses compounds of Formula A and pharmaceutically acceptable salts thereof in the form of respective enantiomers, racemates, or other mixtures of enantiomers, including depression, anxiety, Parkinson's disease, and obesity. It has been described as useful in the treatment of neurological diseases such as cognitive impairment, epileptic seizures, epilepsy and as a neuroprotective agent to protect against conditions such as seizures.

In Formula A above,

Ar is each a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted with one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted with one or more halo, d) one or more halo Phenyl optionally substituted with one or more substituents selected from optionally substituted alkylthio groups of 1 to 3 carbon atoms, e) phenoxy groups optionally substituted with one or more halo or f) phenyl optionally substituted with one or more halo. , Naphthyl or benzo [b] thiophenyl,

R ₁ and R ₂ may be the same or different and independently represent a) H, b) an alkyl group having 1 to 6 carbon atoms, c) an alkenyl group having 3 to 6 carbon atoms, d) a cycloalkyl group having 3 to 7 carbon atoms e) a cyclomethyl group having 3 to 7 carbon atoms in the ring, f) i) halo, ii) an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halo, iii) 1 carbon optionally substituted with one or more halo Aryl or heteroaryl groups optionally substituted with one or more substituents selected from an alkoxy group having from 3 to 3 and an alkylthio group optionally substituted with at least one halo or g) an alkyl chain having 1 to 3 carbon atoms and aryl or heteroaryl Optionally an alkyl group of 1 to 3 carbon atoms optionally substituted with one or more halo, iii) an alkoxy group optionally substituted with one or more halo, and iv) one or more halo optionally Substituted carbon 1 to 3 of a substituent at least one selected from alkylthio group optionally or arylalkyl or heteroarylalkyl group which may be substituted; R ₁ and R ₂ each form an alkylene chain optionally substituted with one or more alkyl groups having 1 to 3 carbon atoms to form a 5- or 6-membered ring together with the atoms to which they are attached;

R ₃ is a) H, b) i) halo, ii) an alkyl group of 1 to 3 carbon atoms optionally substituted with one or more halo, iii) an alkoxy group of 1 to 3 carbon atoms optionally substituted with one or more halo, iv Aryl or heteroaryl groups optionally substituted with one or more substituents selected from alkylthio groups of 1 to 3 carbon atoms optionally substituted with one or more halo, c) aryl optionally substituted with one or more halo, ii) one or more halo A substituent selected from an alkyl group of 1 to 3 carbon atoms, iii) an alkoxy group of 1 to 3 carbon atoms optionally substituted with one or more halo, and iv) an alkylthio group of 1 to 3 carbon atoms optionally substituted with one or more halo. Or an optionally substituted arylmethyl group or d) an alkoxyalkyl group having 3 to 6 carbon atoms,

R ₄ and R ₅ may be the same or different and are independently alkyl groups having 1 to 3 carbon atoms, or R ₄ and R ₅ together with the atoms to which they are attached form a cycloalkyl ring having 3 to 6 carbon atoms.

See Sharpe C.J and Shadbolt R.S; Journal of Medical Chemistry, 1971, Vol. 14 No. 10, p.977-982) describe certain dihydroimidazo [2,1-b] thiazole compounds with antidepressant activity. However, the document mentions that these compounds are generally less active and more toxic than the imidazolines also described in the document.

WO 97/02269 discloses that a compound of Formula B and a pharmaceutically acceptable salt thereof have affinity for the 5-HT _1A receptor and have a neuronal resorption of 5-hydroxytryptamine and / or noradrenaline. It is described as suppressing.

In Formula B above

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 is a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted with one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted with one or more halo, d) one or more halo Optionally substituted alkylthio group, alkylsulfinyl or alkylsulfonyl group having 1 to 3 carbon atoms, e) hydroxy, f) acyloxy group having 1 to 3 carbon atoms, g) hydroxyalkyl group having 1 to 3 carbon atoms, h) cyano, i) alkanoyl groups having 1 to 6 carbon atoms, j) alkoxycarbonyl groups having 2 to 6 carbon atoms, k) carbamoyl groups optionally N-substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms Or carbamoylmethyl groups, l) sulfamoyl or sulfamoylmethyl groups optionally N-substituted with one or two alkyl groups of 1 to 3 carbon atoms or m) optionally substituted with one or two alkyl groups of 1 to 3 carbon atoms Is an amino group and R ₁ is when g is 2, 3 or 4, Same or different,

R ₂ , R ₃ and R ₄ are independently H or an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halo,

R ₅ is a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted with one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted with one or more halo, d) one or more halo Optionally substituted alkylthio group, alkylsulfinyl or alkylsulfonyl group having 1 to 3 carbon atoms, e) hydroxy, f) acyloxy group having 1 to 3 carbon atoms, g) hydroxyalkyl group having 1 to 3 carbon atoms, h) cyano, i) alkanoyl groups having 1 to 6 carbon atoms, j) alkoxycarbonyl groups having 2 to 6 carbon atoms, k) carbamoyl groups optionally N-substituted with 1 or 2 alkyl groups having 1 to 3 carbon atoms Or a carbamoylmethyl group, l) sulfamoyl or sulfamoylmethyl group optionally N-substituted with one or two alkyl groups of 1 to 3 carbon atoms, m) optionally substituted with one or two alkyl groups of 1 to 3 carbon atoms Amino group or n) H.

These compounds are mentioned as useful in the treatment of CNS diseases. However, these compounds exhibit activity as monoamine oxidase inhibitors and / or exhibit affinity for other receptors, such as muscarinic receptors, and therefore are likely to cause unwanted side effects. Surprisingly, the present invention unexpectedly provides compounds with superior selectivity and efficacy. Compounds of the present invention are not specifically described or shown in WO 97/02269.

US Pat. No. 4,160,768 describes 3- (2-benzofuranyl) -5,6-dihydroimidazo [2,1-b] -thiazoles useful as anti-inflammatory agents. This document does not describe or present compounds of the invention.

The present invention provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof.

In formula I above

A is S or O,

R ₁ is H, halo, C _1-3 alkyl group or C _1-3 alkylthio group,

R ₂ is H or fluoro,

R ₃ is methyl, ethyl or isopropyl.

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

Preferred A is S.

Preferred A is O.

More preferably R ₃ is methyl.

Preferred groups of compounds of formula (I) are compounds of formula (Ia) and pharmaceutically acceptable salts thereof.

In Formula Ia above,

R is H or chloro.

In a preferred compound of the invention A is S, R ₁ is H, fluoro, or chloro, R ₂ is H or fluoro and R ₃ is methyl.

In a more preferred compound of the invention A is S, R ₁ is H or fluoro, R ₂ is H or fluoro and R ₃ is methyl.

In the most preferred compounds of the invention A is S, R ₁ is H, R ₂ is H and R ₃ is methyl.

The compounds of formula (I) may exist as salts with pharmaceutically acceptable acids. The present invention includes all such salts. Examples of such salts are hydrochloride, hydrogen bromide, sulfate, methanesulfonate, nitrate, maleate, formate, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (-)-tartrate Or mixtures thereof including racemic mixtures], and salts with amino acids such as succinate, benzoate, oxalate and glutamic acid. Such salts may be prepared by methods known to those skilled in the art.

Certain compounds of formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and / or geometric isomer of a compound of formula (I), and mixtures thereof.

Certain compounds of formula (I) may exist in different stable coordination forms that can be separated. For example, where bulky groups are present, steric hindrance can limit rotation around one or more single bonds. For example, due to steric hindrance or deformation of the ring, torsional asymmetry due to limited rotation around the asymmetric single bond can allow separation of different ligands. The present invention includes each of the configurational isomers of the compounds of formula (I) and mixtures thereof.

Certain compounds of formula (I) and salts thereof may exist in one or more crystal forms and the present invention includes each crystal form and mixtures thereof. Certain compounds of formula (I) and salts thereof may also be present in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof.

Certain compounds of formula (I) contain one or more chiral centers and exist in different optically active forms. When the compound of formula (I) contains one chiral center, the compound is present in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. The enantiomers form diastereomeric salts that can be separated by, for example, crystallization, for example, by crystallization, gas-liquid chromatography or liquid chromatography in a manner known to those skilled in the art. Or diastereomeric derivatives or complexes which can be separated by chiral environment, such as gas-liquid chromatography or liquid chromatography, on a chiral support such as silica having a bound chiral ligand or in the presence of a chiral solvent. Can be formed and divided. If the enantiomer of interest is converted to another chemical by one of the separation processes described above, it is known that additional steps are needed to liberate the desired enantiomer form. Alternatively, certain enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting enantiomers to other enantiomers by asymmetric conversion.

If the compound of formula (I) contains one or more chiral centers, it may exist in diastereomeric form. Diastereomeric pairs can be separated by methods known to those skilled in the art, for example by chromatography or crystallization and each enantiomer in each pair can be separated as described above. The present invention includes each enantiomer of a compound of formula (I) and mixtures thereof.

Particular compounds of formula I are as follows:

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

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

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

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

As used hereinafter, the term "active compound" denotes a compound of formula (I) or a salt thereof. In therapeutic use, the active compounds can be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions of the invention may be ingested in the form of known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are known in the pharmaceutical art. The composition of the present invention may contain 0.1 to 99% by weight of the active compound. Compositions of the present invention are generally prepared in unit dosage form. Preferably, the unit dose of the active ingredient is 1 to 500 mg. Excipients used in the preparation of these compositions are excipients known in the pharmaceutical art.

Compositions for oral administration are preferred compositions of the present invention and they are in the form of pharmaceuticals known for oral administration, such as tablets, capsules, syrups and aqueous or oil suspensions. Excipients used in the preparation of these compositions are excipients known in the pharmaceutical 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 lubricant such as magnesium stearate and tableting the mixture in a known manner. . Tablets may be formulated to release the compounds of the present invention in a manner known to those skilled in the art. Such tablets may optionally be provided with an enteric coating by known methods, for example using cellulose acetate phthalate. Similarly, capsules containing active compounds and with or without excipients, such as hard or soft gelatin capsules, can be prepared by conventional methods and, if desired, enteric coatings can be prepared by known methods. Can provide. Tablets and capsules may conveniently contain 1 to 500 mg of the active compound, respectively. Examples of other compositions for oral administration include, but are not limited to, aqueous suspensions containing the active compounds in an aqueous medium in the presence of nontoxic suspending agents, such as sodium carboxymethylcellulose, and suitable vegetable oils such as peanut oil. There is an oily suspension containing a compound of.

Solid oral dosage forms can be formulated to release the active compound in a manner known to those skilled in the art. Solid oral dosage forms coated with an enteric coating comprising a composition of the present invention may be advantageous depending on the nature of the active compound. Various materials, such as shellac and / or sugars, may be present as coatings or may otherwise modify the physical form of the oral dosage form. For example, enteric coatings can be provided in tablets or pills, as the case may be, by known methods, for example using cellulose acetate phthalate and / or hydroxy propyl methylcellulose phthalate.

Capsules and / or caplets containing the active compound (eg hard or soft gelatin capsules) (with or without excipients such as fatty oils) may be prepared by conventional methods, and in some cases, known It is possible to provide an enteric coating in a conventional manner. The contents of the capsules and / or caplets may be formulated to release the active compound using known methods.

Liquid oral dosage forms comprising the compositions of the present invention include aqueous suspensions containing the active compound in an aqueous medium in the presence of elixirs, suspending agents and / or syrups (e.g., non-toxic suspending agents such as sodium carboxymethylcellulose) and And / or an oily suspending agent containing the active compound in a suitable vegetable oil such as peanut oil and / or sunflower seed oil. Liquid oral dosage forms may also include one or more sweetening, flavoring, preservatives and / or mixtures thereof.

The active compound can be formulated into granules with or without additional excipients. The granules can be taken directly by the patient or added to a suitable liquid carrier (eg water) prior to ingestion. The granules may contain disintegrants (eg, pharmaceutically acceptable effervescent couples formed from acids and carbonates or bicarbonates) to facilitate dispersion in the liquid medium.

Preferably each oral dosage form of each stomach comprises about 1 to about 1000 mg, more preferably about 5 to about 500 mg (e.g. 10 mg, 50 mg, 100 mg, 200 mg or 400 mg) of active compound. It may contain.

Compositions of the present invention suitable for rectal administration are suppositories having a pharmaceutical form known for rectal administration, such as hard fats, semisynthetic glycerides, cocoa butter and / or polyethylene glycol bases.

Pharmaceutical compositions are also known as pharmaceutical dosage forms (eg, aqueous) for parenteral administration, such as parenterally (eg, subcutaneously, intramuscularly, percutaneously and / or intravenously (eg by injection and / or infusion)). And / or as a sterile suspending agent in an oily medium and / or as a sterile solution in a suitable solvent, preferably a solvent isotonic with the blood of the subject patient). Parenteral dosage forms can be sterilized, for example, by microfiltration and / or using a suitable sterilizing agent such as ethylene oxide. Optionally, one or more of the following pharmaceutically acceptable adjuvants suitable for parenteral administration may be added to the parenteral dosage form: local anesthetics, preservatives, buffers and / or mixtures thereof. Parenteral dosage forms may be stored in suitable sterile sealed containers (eg, ampoules and / or vials) until use. The parenteral dosage form may be frozen after filling the container to improve stability during storage and the fluid (eg water) may be removed under reduced pressure.

Pharmaceutical compositions may be administered nasally in pharmaceutical forms known for nasal administration, such as sprays, aerosols, nebulizing liquids and / or powders. Metered dose systems (eg, aerosols and / or inhalants) known to those skilled in the art can be used.

The pharmaceutical composition may be administered into the lumen in a pharmaceutical form known for intranasal administration (e.g., sustained-release tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and / or powders). (Eg, sublingual).

The composition for topical administration may be kept in contact with the skin such that the compound is administered transdermally, including the matrix in which the pharmacologically active compound of the invention is dispersed. Suitable transdermal compositions are prepared by mixing a pharmaceutically active compound with a topical vehicle such as mineral oil, petrolatum and / or waxes such as paraffin wax or beeswax and potential transdermal accelerators such as dimethyl sulfoxide or propylene glycol. can do. Alternatively, the active compound may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical formulation should be such that a therapeutically effective amount of the compound is delivered during the time the topical formulation is applied to the skin.

The compounds of the present invention may also be administered from external sources, for example by sperm injection or by continuous infusion from a source of the compound in the body. Internal sources may be injected, for example, in the form of implanted reservoirs containing the compounds to be injected which are subsequently released by osmotic action, and (a) very poorly soluble compounds in water, for example dodecanoate. For liquids such as suspensions or solutions in pharmaceutically acceptable oils of the compounds or (b) for the compound to be injected, an implant, which may be a solid, for example in the form of an implanted support such as a synthetic resin or waxy material, have. The support may be a monolith containing all compounds or a series of several bodies each containing a portion of a compound to be delivered. The amount of active compound present in the internal source should be such that a therapeutically effective amount of the compound is transported over a long period of time.

In some formulations it may be beneficial to use the compounds of the invention in the form of very small sized particles, for example in the form of small particles such as obtained by fluid energy grinding.

In the compositions of the present invention, the active compound may optionally be mixed with other suitable pharmacologically active ingredients.

The invention also includes a compound of formula (I) for use as a drug.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) include, but are not limited to, depression, anxiety, psychosis (eg, schizophrenia), panic disorder, obesity, drug addiction, drug abuse, cognitive impairment, Alzheimer's disease in mammals, particularly humans. Cerebral ischemia, obsessive-responsive behavior, panic attacks, social phobias; It can be used to treat appetite disorders such as bulimia, anorexia, news and overeating, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and stress and can help people quit smoking. The compositions of the present invention can also be used for the treatment and / or prevention of conditions with neurological damage, such as epileptic seizures, neurological diseases (eg epilepsy) and / or seizures, brain damage, cerebral ischemia, head injury and bleeding. The exact amount of active compound administered in such a treatment depends on a number of factors, such as the age of the patient, the severity of the symptom and the past history, and always depends on the findings of the clinician administering it, but the active compound administered daily The amount of can be administered in 1 to 1000 mg, preferably 5 to 500 mg at a time or divided one or more times a day.

In another embodiment, the present invention is directed to depression, anxiety, psychosis (eg, schizophrenia), chronic impairment, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-responsive behavior, panic attacks, social phobias; Appetite disorders such as bulimia, anorexia, news and overeating, treatment of non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, and epileptic seizures, neurological diseases (e.g. epilepsy) and / or seizures, brain damage, cerebral ischemia, head injury and Provided is the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment of a condition with nerve damage, such as bleeding, and the use of the compound as a smoking cessation aid.

The present invention is also characterized by administering a therapeutically effective amount of a compound of formula (I) to a patient in need thereof, such as depression, anxiety, psychosis (e.g. schizophrenia), chronic impairment, obesity, drug addiction, drug abuse Cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-responsive behavior, panic attacks, social phobias; Treats appetite disorders such as bulimia, anorexia, news and overeating, non-insulin dependent diabetes, hyperglycemia, hyperlipidemia and stress, epileptic seizures, neurological diseases (e.g. epilepsy) and / or seizures, brain damage, cerebral ischemia, head injury and bleeding It provides a method for treating a condition such as nerve damage. The present invention also provides a method of assisting smoking cessation in humans, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I).

The present invention also provides a method of reducing the craving for smoking in humans, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I). The present invention also provides a method of reducing weight gain after smoking cessation in humans, characterized by administering to the patient a therapeutically effective amount of a compound of formula (I).

In addition, the compounds of the present invention may be useful in treating metabolic diseases and disorders resulting therefrom, such as non-motor active fever and increased metabolic rate, sexual dysfunction, sleep apnea, premenstrual syndrome, incontinence, hyperactive disease, resting hernias, and It may be useful for the treatment and prevention of reflux esophagitis, pain, especially neuralgia, weight gain associated with medication, chronic fatigue syndrome, osteoarthritis and gout, cancer associated with weight gain, menstrual abnormalities, gallstones, upright hypotension and pulmonary hypertension .

The compounds of the present invention may be useful for the prevention of cardiovascular disease and for assisting in reducing platelet adhesion, weight loss after pregnancy and weight loss after smoking.

The compounds of the invention are particularly useful for treating obesity and related concurrent lesion diseases such as diabetes, hyperglycemia and hyperlipidemia. Monoamine reuptake inhibitors used to treat obesity are commonly known to be associated with cardiovascular side effects such as increased heart rate and increased blood pressure. The compounds of the present invention reduce cardiovascular side effects that can be expected to arise from the administration of monoamine reuptake inhibitors, in particular noradrenaline reuptake inhibitors. While not wishing to be bound by theory, the combination of the 5-HT _1A agonism in the compounds of the present invention reduces cardiovascular side effects that may result from their monoamine reuptake inhibition, particularly their noradrenaline reuptake inhibition. same.

In another aspect, the invention provides a method for reducing cardiovascular side effects of a therapeutic drug for obesity, characterized by incorporation into a compound 5-HT _1A agonism.

In another aspect, the present invention provides the use of a compound which is a 5-HT _1A agonist and a monoamine reuptake inhibitor, in particular a noradrenaline reuptake inhibitor, in the treatment of obesity and related co-lesional disease without causing cardiovascular side effects.

The beneficial properties of particularly preferred compounds of the invention in reducing cardiovascular side effects can be demonstrated by rat telemetry studies that continuously record heart rate, blood pressure, body temperature and motor activity over time. Suitable methods are described in Brockway, BP, Mills, PA & Azar, SH (1991), A New method for continuous chronic measurement of blood pressure, heart rate and activity in the 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 present invention can be measured electrophysiologically by methods known to those skilled in the art.

Now, a method for preparing a compound of formula (I) will be described. The manufacturing process can be performed according to each criterion or by multiple parallel synthesis methods, also known as High Speed Analoguing. The process is preferably carried out at atmospheric pressure.

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

The compounds of formula (I) can be prepared by dehydrating the compounds of formula (II) at a temperature of 0 to 200 ° C., preferably 20 to 150 ° C., optionally in the presence of an acid such as acetic acid or sulfuric acid.

In Formula II above,

A, R ₁ , R ₂ and R ₃ are as defined above.

The compound of formula (II) is prepared by reacting the compound of formula (III) with the compound of formula (IV) at a temperature of from 0 to 200 ° C in the presence of a solvent, for example ethanol, optionally in the presence of an acid, for example acetic acid, preferably from 20 ° C. It can be prepared by heating and reacting at a temperature in the boiling point range of the solvent used.

In Formula IV above,

Z is a leaving group such as halo (e.g. bromo),

A, R ₁ , R ₂ and R ₃ are as defined above.

Compounds of formula (I) also directly convert compounds of formula (III) to compounds of formula (IV) at temperatures between 0 and 200 ° C., optionally in the presence of acids, for example acetic acid, optionally in the presence of a solvent, for example ethanol, Without separating the intermediate of II, it can be prepared by heating and reacting preferably at a temperature of 20 to 150 캜.

Compounds of formula (I) wherein R ₃ is methyl or ethyl are used as solvents in the presence of reducing agents, for example borane / t-butylamine complexes and optionally catalysts, for example Lewis acid catalysts such as aluminum chloride For example, it may be prepared by reacting in dichloromethane at a temperature in the boiling range of -20 ℃ to the solvent used.

In Formula V above,

R ₁ , R ₂ and A are as defined above,

R ₄ is H or methyl.

Compounds of formula (V) may be prepared by reacting a compound of formula (VI) with a metalizing agent such as ethylmagnesium chloride, followed by a formylating or acylating agent such as dimethylformamide or N-methoxy-N-methylacet It can be prepared by reacting an amide with a solvent such as tetrahydrofuran at a temperature ranging from -50 ° C to the boiling point of the solvent used.

In Formula VI above,

X is a leaving group such as bromo.

Compounds of formula (VI) wherein X is bromo are used at temperatures ranging from -50 ° C. in the presence of a compound of formula (VII) with a brominating agent such as bromine or phenyltrimethylammonium tribromide and a solvent such as dichloromethane or tetrahydrofuran It can be prepared by reacting at a temperature in the boiling range of the solvent.

Compounds of formula (VII) can be prepared by the methods described in WO 97/02269.

The ability of a compound of Formula (I) to interact with the 5-hydroxytryptamine (5-HT) receptor for the product of Examples 1-17 was found for the in vitro 5-HT receptor, in particular for the 5-HT _1A receptor. This is demonstrated by the following test, which measures the ability to inhibit triple ligand binding.

Male Sprague-Dawley rats (Charles River); Hippocampus tissue from the brain in the body weight range 150-250 g] is homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7, 1:40 (w / v) as measured at 25 ° C.) and centrifuged at 40,000 g for 10 minutes at 4 ° C. Isolate. The pellet is homogenized again in the same buffer, incubated at 37 ° C. for 10 minutes and centrifuged at 40,000 g for 10 minutes at 4 ° C. The final pellet was resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl ₂ , 0.1% L-ascorbic acid and 10 μM pargiline hydrochloride (equivalent to tissue wet weight 6.25 mg / ml) and immediately to the binding assay. use.

Membrane (400 μl; equivalent to tissue wet weight 2.5 mg / tube) was added to a single concentration of 1 nM of [ ³ H] 8-hydroxy-2- (dipropylamino) tetraline ([ ³ H] 8-OH-DPAT ) 50 μl and 50 μl of distilled water (total binding) or 50 μl of test compound (at a single concentration of 10 ⁻⁶ M or 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of 5-HT (10 μM, nonspecific) Incubate at 25 ° C. for 30 min. The culture is terminated by rapid filtration under vacuum through a Skatron 11734 filter using a Skatron Cell Harvester. The filter is washed with ice cold 50 mM Tris-HCl buffer at pH 7.7 (at 25 ° C., set to 9,9,0 and washed). Insert the labeled filter paper disc into the vial, add flash fluid and measure radioactivity by liquid scintillation counting.

The ability of the compound of Formula I to interact with the 5-hydroxytryptamine (5-HT) resorption site was determined from the standard ligand [ ³ H] from the in vitro 5-HT resorption site for the products of Examples 1-17. This was demonstrated by the following test, which measures the ability of a compound to replace a tallowram.

Whole cerebral cortex tissue from the brains of male Charles River rats weighing 150-250 g is homogenized in ice-cold 50 mM Tris-HCl at pH 7.4 (measured at 25 ° C) containing 120 mM sodium chloride and 5 mM potassium chloride and centrifuged at 40,000 g for 10 minutes. Isolate. The supernatant is decanted and the pellet is re-homogenized in Tris buffer at 1:60 (weight / volume) and then centrifuged at 40,000 g for 10 minutes. Repeat this step further. The final pellet is resuspended in 50 mM Tris-HCl at pH 7.4 containing 120 mM sodium chloride and 50 mM potassium chloride (equivalent to tissue wet weight 3.125 mg / ml) and immediately used for binding assays. All centrifugations are performed at 4 ° C.

Membrane (400 μl; equivalent to tissue wet weight 1.25 mg / tube) was added with 50 μl of [ ³ H] citalopram at a single concentration of 1.3 nM and 50 μl of distilled water (total binding) or 50 μl of test compound (10 ⁻⁶ M Single concentration or 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of paroxetine (0.5 μM; nonspecific binding) for 1 hour at 27 ° C. Membrane bound radioactivity is recovered by filtration under vacuum through a Skatron 11734 filter using a Skatron cell harvester. The filter is then washed with ice cold 50 mM Tris-HCl buffer at pH 7.4 (set at 9,9,0 at 25 ° C. and wash). Insert the labeled filter paper disc into the vial, add flash fluid and measure radioactivity by liquid scintillation counting.

The ability of the compound of Formula I to interact with the noradrenaline (NA) resorption site is the ability of the compound to replace the standard ligand [ ³ H] nisoxetine from the noradrenaline reuptake site in vitro for the products of Examples 1-17. It was proved by the following test to measure.

Whole cerebral cortex tissue from the brains of male Charles River rats, weighing 150-250 g, was treated with Kinematic polytron (rate set at 6 for 10 seconds) to pH 7.4 (25 ° C.) containing 120 mM sodium chloride and 5 mM potassium chloride. Homogenized in ice-cold 50 mM Tris-HCl (Tris buffer; 1:60 (weight / volume)) and centrifuged at 40,000 g for 10 minutes. The supernatant is decanted and the pellet is re-homogenized in Tris buffer at 1:60 (weight / volume) and then centrifuged at 40,000 g for 10 minutes. Repeat this step twice and centrifuge four times to homogenize the brain tissue as a whole. The final pellet is resuspended in 50 mM Tris-HCl at pH 7.4 containing 300 mM sodium chloride and 50 mM potassium chloride (equivalent to tissue wet weight 18.75 mg / ml) and used immediately for binding assays. All centrifugations are performed at 4 ° C.

Membrane (400 μl; equivalent to tissue wet weight 7.5 mg / tube) was added 50 μl of [ ³ H] nisocetin at a single concentration of 0.6 nM and 50 μl of distilled water (total binding) or 50 μl of test compound (10 ⁻⁶ M Concentration or 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of marginol (1 μM, nonspecific binding) for 4 hours at 4 ° C. Membrane bound radioactivity is recovered by filtration under vacuum through a Skatron 11734 filter using a Skatron cell harvester. The filter is washed with ice-cold 50 mM Tris-HCl buffer (set to 9,9,0 and washed) at pH 7.4 containing 120 mM sodium chloride and 5 mM potassium chloride. Insert the labeled filter paper disc into the vial, add flash fluid and measure radioactivity by liquid scintillation counting.

The ability of the compounds of formula (I) to interact with muscarinic receptors alters the ability of compounds to replace the standard ligand [ ³ H] N-methylscopolamine from in vitro muscarinic receptors for the products of Examples 1-17. The next test to measure was demonstrated.

Whole cerebral cortex tissue from the brains of male Charles River rats, weighing 150-250 g, was measured at 25 ° C. (pH 7.4) containing 100 mM sodium chloride and 10 mM magnesium chloride using polytron PT3100 (speed set at 21,700 rpm, 3 × 5 sec). Homogenize in ice-cold 20 mM HEPES buffer and centrifuge at 49,500 g for 30 minutes at 4 ° C. The supernatant is decanted and the pellet is re- homogenized in 20 mM HEPES buffer at pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride (equivalent to tissue wet weight 12.5 mg / ml). Store the membrane at -80 ° C until needed.

The membrane is thawed and diluted 1:10 in ice-cold 20 mM HEPES buffer at pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride and homogenized using polytron PT3100 as above. Diluted membrane (200㎕; equivalent to 0.25㎎ wet weight / tube of tissue) to 100mM sodium chloride and 10mM of a single concentration of 20mM HEPES buffer 200㎕, 0.15nM of pH 7.5 containing magnesium chloride ^[3 H] methyl-N- 50 μl of scopolamine and 50 μl of distilled water (total binding) or 50 μl of test compound (at a single concentration of 10 ⁻⁶ M or 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of atropine sulfate (1 μM , Nonspecific binding) for 30 minutes at 30 ° C. Membrane-bound radioactivity is recovered by filtration under vacuum through a Skatron 11734 filter using a Skatron cell harvester. The filter is washed with ice-cold 20 mM HEPES buffer (5,5 and washed) at pH 7.5. Insert the labeled filter paper disc into the vial, add flash fluid and measure radioactivity by liquid scintillation counting.

For each of these tests, the compounds of formula (I) replacing the standard ligands from the in vitro 5-HT _1A receptor and 5-hydroxytrytamine (5-HT) and noradrenaline (NA) resorption sites and muscarinic receptors Ability,% specific binding substitution of triple ligand by ^10-6 M test compound is calculated by the following method.

First, the specific binding of the triple ligand in the absence (A) and presence (B) of the test compound is measured.

In the absence of a compound:

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

In the presence of compound ( ^10-6 M):

B (dpm) = binding at 10 ^-6 M (dpm)-nonspecific binding (dpm)

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

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

% Replacement of specific binding of the triple ligand by the test compound is% specific binding in the presence of the compound from% specific binding in the absence of the compound (which is considered the maximum binding and therefore equals 100%) Get it by subtracting:

% Replacement at 10 ⁻⁶ M =% specific binding rate at 100 ^{−6 −6} M.

In some cases, a concentration range of compounds is used to create replacement curves for compounds that replace at least 50% of the specific binding of the triple ligand at ^10-6 M. K _{i is} then calculated by fitting nonlinear regression to the data from three simultaneous experiments by fitting the following simultaneous equations (derived from Feldman's equation):

Where B is the concentration of bound ligand-receptor complex. This is calculated for each observation as follows:

B =

L is the concentration of the compound.

[L] _Tot is the concentration of triple ligand used, calculated as follows:

[L] _Tot =

K _d is the equilibrium dissociation constant for the ligand.

F ₁ and F ₂ are the concentrations of the free ligand and the free compound, respectively.

r ₁ is the total concentration of the reactor in the first experiment. It must be a multiple of C _k for subsequent experiments (C ₁ = 1).

N _k is a nonspecific binding constant.

The results obtained in the above tests for 5-HT _1A binding and 5-HT and NA uptake, and muscarinic binding to the final products of Examples 1-17 thereafter are shown in Table 1 below. K _i is nM and is the average of three respective measurements. The% figure is the percent replacement at 10 ⁻⁶ M for a single measurement.

Example number 5-HT _1A 5-HT Absorption NA absorption Muscarinic One 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% 17 9.0 12% 15.1 231

The K _i value is the average of one measurement, two measurements, or the average of three measurements.

NT = not tested.

The ability of the compounds of the invention to inhibit monoamine oxidase A activity is demonstrated by the following test.

This assay is performed using the following general process, where the tissue source is the human placenta:

enzyme temperament culture Reaction product Detection method MAO-A (h) Kinuramin (0.15mM) 30 minutes / 30 degrees Celsius 4-OH Quinoline Spectroscopy

Compounds are tested in duplicates at 1 and 10 μM.

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.

Acute Breeding Research

Animals and environment

This experiment was performed on male Sprague Dawley rats (300-450 g at the start of the experiment), which was obtained from Charles Margate. The animals are each placed in polypropylene cages with metal grid floors with a temperature of 21 ± 1 ° C. and 55% humidity. Place a polypropylene tray under each cage. Animals are kept in the day and night cycle of conversion. Turn off the light from 09:30 to 17:30, then shine red light. Animals are always free to access the rat powder diet and tap water. The diet is in a glass feed can (10 cm in diameter; 8 cm in depth) with an aluminum lid. Each lid has a cut hole (3 cm in diameter) to allow access to the feed. Animals are allowed to acclimate to these environments for at least two weeks before testing.

Examination process

Prior to testing, animals are randomly placed into treatment groups comprising 6 to 8 rats, weighed and their feed intake is measured over 6 hours. These reference readings are taken to ensure that the weight and feed intake of each group of rats does not differ significantly from that prior to drug treatment. On test day, the animals are given a vehicle or three doses of the test drug. All drugs are administered orally at the onset of memorization since rats spend most of their feed on memorization. The medication is weighed (almost 0.1 g) at the time of drug administration and weighed 1, 2, 4, 6 and 24 hours after administration. At each reading, the tray below us is checked for scattered feed, and then the scattered feed is put back into the feeder. However, feeds scattered from the feed can generally be ignored.

All drug doses are expressed in free base. The drug is dissolved in deionized water or suspended in 0.4% cellosize using a sonic bath.

Data analysis

The variation in body weight is explained by displaying the results in g / kg of body weight kg (mean group ±± mean). ED ₅₀ values (dose of drug required to reduce feed intake to 50% of control value) are calculated from logarithmic S-shaped curves using published computer programs. Statistical comparisons between mean group intakes are made using the analysis of variance and Dunnett's two-tailed test.

The compounds of the present invention surprisingly have a higher affinity for the 5HT _1A receptor as compared to the compounds exemplified in WO 97/02269.

Preferred compounds of the present invention also surprisingly have a lower affinity for muscarinic receptors as compared to the examples of WO 97/02269. For example, K _i of Example 1 of WO 97/02269 is 130 nM. Muscarinic affinity can cause unwanted side effects, such as oral dryness, blurred vision, severe sweating, chest tremors, constipation, and exacerbation of narrowing glaucoma. Blackwell, B. Adverse effects of antidepressant drugs. Part 1 Monoamine oxidase inhibitors and tricyclics. Drugs 21, 202-219, 1981]. It is clear that it is desirable for the compound to have minimal affinity for the muscarinic receptor.

More preferred compounds of the present invention also have markedly reduced MAO _A inhibitory activity compared to the compounds exemplified in WO97 / 02269.

In the above test, the product of Example 1 of the present invention exhibited an IC ₅₀ of 1600 nM, while the product of Example 1 of WO 97/02269 exhibits an IC ₅₀ of 33 nM. These results demonstrate that the selectivity of the compounds of the present invention is surprisingly improved compared to the compounds described previously. The combination of inhibition of monoamine oxidase activity and inhibition of 5-HT reuptake has been described in Sertonin syndrome [Sternbach, H. Serotonin syndrome. Am. J. Psychiatry 148, 705-713, 1991, which is very undesirable.

The most preferred compounds of the invention also have improved activity in acute breeding studies compared to the compounds exemplified in WO 97/02269. In the acute breeding study, the product of Example 1 of the present invention had an ED ₅₀ of 1.1 mg / kg at 2 hours, whereas the ED ₅₀ at 2 hours of Example 1 of WO 97/02269 was 4.5 mg. / Kg.

These results demonstrate a surprising improvement in the effects of the compounds of the present invention compared to the compounds described in the prior art.

The invention is illustrated by the following examples, which are provided only as examples. The final product of each of these examples is characterized by one or more of the following processes: high performance liquid chromatography, elemental analysis, nuclear magnetic resonance spectra, mass spectra and infrared spectra.

Example

Example 1

a) Stirring of 3-acetyl-benzo [b] thiophene (10 g) in tetrahydrofuran (250 mL) at −70 ° C. with lithium bis (trimethylsilyl) amide (1M solution in tetrahydrofuran; 60 mL) at −70 ° C. under nitrogen After dropwise addition to the solution, the mixture is stirred at -70 ° C for 1 hour. A solution of iodomethane (3.54 mL) in tetrahydrofuran (20 mL) was added dropwise at -70 ° C. over 15 minutes, and the stirred mixture was allowed to warm to ambient temperature over 18 hours, then saturated aqueous ammonium chloride solution (300 mL) ) The product is extracted with ethyl acetate (3x100 mL) and the combined extracts are washed with water (2x50 mL) and saturated aqueous sodium chloride solution (50 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R instrument using a 99: 1 mixture of petroleum ether (boiling point: 40-60 ° C.) and ethyl acetate as eluent. The appropriate fractions are combined to remove the solvent in vacuo to afford 3-propionylbenzo [b] thiophene (2.7 g) as a colorless solid which is used without further purification.

b) Phenyltrimethylammonium tribromide (13.35 g) 3-propionyl-benzo [b] thiophene (6.75 g) in tetrahydrofuran (100 mL) over 30 minutes at 0-5 ° C. under nitrogen; method described above To a stirred solution), and the mixture is stirred at 0 ° C. for 20 minutes and at ambient temperature for 4 hours. The resulting solid is collected by filtration and washed with tetrahydrofuran (30 mL), and then the filtrate and the tax solution are combined to remove the solvent under vacuum. The residue was dissolved in dichloromethane (200 mL), and then the solution was washed with water (3x30 mL) and saturated aqueous sodium chloride solution (30 mL), dried (Na ₂ SO ₄ ), and the solvent removed to remove 1- as a brown oil. (Benzo [b] thiophen-3-yl) -2-bromopropan-1-one (9.2 g) is obtained, which solidifies slowly at ambient temperature and is used without further purification.

c) crude 1- (benzo [b] thiophen-3-yl) -2-bromopropane-1-one (9.2 g), 2-imidazolidinthione (3.5 g), ethanol (200 mL) and The mixture of acetic acid (100 mL) is heated under reflux for 17 h under nitrogen and then the solvent is removed in vacuo. The residue was triturated with ether (100 mL), and then the resulting solid was collected by filtration and crystallized from ethanol to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo. [2,1-b] thiazole hydrobromide (4.9 g) is obtained as a white solid. Melting point 277-278 ° C.

Alternative Method A

a) a solution of bromine (20 mL) in dichloromethane (100 mL) is added dropwise to a stirred mixture of benzo [b] thiophene (50 g) and anhydrous sodium acetate (46 g) in dichloromethane (500 mL) at approximately 5 ° C., The mixture is stirred at ambient temperature for 72 hours, then filtered and the solvent is removed in vacuo. The residue is distilled to give 3-bromobenzo [b] thiophene (51.3 g) as a pale yellow oil. Boiling Point: 93-104 ° C. at 53 Pa.

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

c) Some iodine crystals were added to a mixture of magnesium metal (5.05 g) and tetrahydrofuran (25 mL), followed by a solution of 3-bromobenzo [b] thiophene (42.1 g) in tetrahydrofuran (200 mL). Add. The mixture is heated under nitrogen to initiate the formation of the Grignard reagent, then the heat source is removed and the remaining amount of 3-bromobenzo [b] thiophene solution is stirred while maintaining the rate at which gentle reflux is maintained. Upon completion of the addition (approximately 35 minutes), the mixture is stirred for an additional 35 minutes without heating, then heated under reflux for 10 minutes and cooled to ambient temperature. A solution of N-methoxy-N-methylpropionamide (23.1 g) in tetrahydrofuran (100 mL) was added over 2 minutes, the mixture was stirred at ambient temperature for 20 minutes, stirred at reflux for 5 hours, Cool in ice and add 2M hydrochloric acid (125 mL) dropwise. The mixture is stirred for 30 minutes, filtered (celite), and the filtrate is concentrated in vacuo to remove tetrahydrofuran. The product is extracted with ethyl acetate (2x300 mL) and the combined extracts are washed with water (2x200 mL) and saturated aqueous sodium chloride solution (2x200 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. The residue was triturated with petroleum ether (boiling point 60-80 ° C.) (100 mL) and the resulting solid was collected by filtration and then dried under vacuum at 45 ° C. for 6 hours to afford 3-propionylbenzo [b] ti as a pale yellow solid. Obtain offpen (23.3 g). Melting point 73-75 ° C.

d) Phenyltrimethylammonium tribromide (8.6 g) was added to a stirred solution of 3-propionylbenzo [b] thiophene (4.34 g) in tetrahydrofuran (80 mL) over 10 minutes at 0-5 ° C. under nitrogen. The mixture is then stirred at ambient temperature for 4 hours. The resulting solid was collected by filtration, washed with tetrahydrofuran (30 mL), then the filtrate and wash were combined and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -2 as a brown oil. Obtain bromopropan-1-one, which is used without further purification.

e) a mixture of crude 1- (benzo [b] thiophen-3-yl) -2-bromopropane-1-one, 2-imidazolidinethione (2.33 g) and ethanol (120 mL) under reflux After heating for 15 minutes under nitrogen, acetic acid (60 ml) is added and the mixture is heated at reflux for 24 hours and then the solvent is removed in vacuo. The residue was crystallized from ethanol (125 mL) to give 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydro as a white solid. Obtain bromide (4.4 g). Melting point 272-274 ° C.

Alternative Method B

a) 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (200 g; described in WO 97/02269); Prepared in a similar manner to the above), a mixture of saturated aqueous sodium carbonate solution (1000 ml) and dichloromethane (2000 ml) was vigorously stirred at ambient temperature for 1.5 hours, then the organic layer was separated and water (500 ml) After washing, it is dried (MgSO ₄ ) and the solvent is removed in vacuo. The process was repeated on the same scale and the two products combined to form 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (264.3) as a pale yellow solid. g) is obtained, which is used without further purification.

b) Bromine (55.5 mL) was added 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] in dichloromethane over 1.75 h at 0-5 ° C. To the stirred solution of thiazole (264.3 g) is added dropwise, then the mixture is stirred at 0 ° C. for 30 minutes and at ambient temperature for 1 hour. The resulting solid was collected by filtration, washed with dichloromethane (300 mL) and dried at 70 ° C. under vacuum to yield 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6 as a pale yellow solid. -Dihydroimidazo [2,1-b] thiazole hydrobromide (431 g) is obtained, which is used without further purification.

c) 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (170 g) under 0 to 8 To a stirred solution of ethylmagnesium chloride [2.0 M solution in ether (620 mL)] in tetrahydrofuran (1700 mL) at 占 폚 was added over a period of 1 hour, and the mixture was stirred at 3 占 폚 for 1.5 hours. Dimethylformamide (136 mL) was added over 30 minutes at 3-8 ° C., then the mixture was stirred at ambient temperature for 2 hours, cooled to 8 ° C., saturated aqueous ammonium chloride solution (600 mL) and water (350 mL ) With caution and stop. Ethyl acetate (1500 mL) is added, the mixture is stirred at ambient temperature for 18 hours and the resulting solid (fraction 1) is collected by filtration. The organic layer of the filtrate is separated, washed with saturated aqueous sodium chloride solution (500 mL) and dried (MgSO ₄ ) to remove the solvent under vacuum. The residue is dissolved in hot propan-2-ol (1000 mL) and the solution is filtered while hot and then left to stand at ambient temperature for 20 hours. The resulting solid was collected by filtration, washed with propan-2-ol (100 mL) and dried at 70 ° C. under vacuum to afford 3- (benzo [b] thiophen-3-yl) -5,6- as a yellow solid. Dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (19.4 g) is obtained. Melting point 206 캜. A mixture of solid fraction 1, dichloromethane (2100 mL), 2M hydrochloric acid (250 mL) and water (1000 mL) was stirred at ambient temperature for 15 minutes, then triethylamine (80 mL) was added. The dichloromethane layer is separated and further product is isolated from the aqueous layer by extraction with dichloromethane (500 mL). The combined dichloromethane solutions were dried (MgSO ₄ ) and the solvent was removed in vacuo to further 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1 as yellow solid. -b] thiazole-2-carboxaldehyde (63.0 g) is obtained. Melting point 208 캜.

d) Borane / t-butylamine complex (18.3 g) is added to an ice-cold, stirred suspension of finely divided aluminum chloride (14 g) in dichloromethane (330 ml), and the mixture is 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 (10 g) in dichloromethane (70 mL) was prepared. After dropwise addition at 0 ° C., the mixture is stirred at 0 ° C. for 15 minutes and at ambient temperature for 21 hours. The mixture is carefully added water (1000 mL), then quenched carefully with 2.5M hydrochloric acid (175 mL), and then basified to pH 10 by addition of 5M aqueous sodium hydroxide solution. The aqueous phase is separated and washed with dichloromethane (300 mL), then the dichloromethane solutions are combined and dried (MgSO ₄ ) and the solvent is removed in vacuo. Half of the residue (5 g) is dissolved in ethanol (12 mL) and 48% hydrobromic acid (3.5 mL) is added. The mixture is diluted with ether (100 mL) and the resulting solid is collected by filtration and then suspended in ethanol (46 mL). The mixture was heated at reflux for 15 minutes, ice-cooled, the resulting solid was collected by filtration, washed with ether (40 mL) and dried under vacuum to yield 3- (benzo [b] thiophen-3-yl)-as a white solid. 2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (3.54 g) is obtained. Melting point 273-276 ° C.

Example 2

a) a solution of 3-bromo-5-chlorobenzo [b] thiophene (2 g) in ether (20 mL) at -70 ° C. under nitrogen at n-butyllithium (2.5 M solution in hexane) in ether (46 mL); 4.14 ml) is added dropwise to the stirred solution, and then the mixture is stirred at −70 ° C. for 30 minutes. 2-Bromopropionyl chloride (1.67 g) is added in one portion and the mixture is stirred at -70 ° C for 4 hours and then warmed to 0 ° C. The mixture was stirred for an additional 30 minutes at 0 ° C. and then quenched by addition of saturated aqueous ammonium chloride solution (50 mL). The aqueous layer is separated, washed with ether (2 × 30 mL), then the combined etheric solutions are washed with saturated aqueous sodium chloride solution (2 × 30 mL) and dried (Na ₂ SO ₄ ). The solvent is removed in vacuo and the residue is purified by flash chromatography on silica using a 9: 1 mixture of petroleum ether (boiling point 60-80 ° C.) and ethyl acetate as eluent. The appropriate fractions were combined and the solvent removed in vacuo to yield 1- (5-chlorobenzo [b] thiophen-3-yl) -2-bromopropan-1-one (0.32 g) as a white solid, which was Use without further purification.

b) 1- (5-chlorobenzo [b] thiophen-3-yl) -2-bromopropane-1-one (0.3 g), 2-imidazolidinthione (0.12 g) and ethanol (10 mL) ) Is heated under reflux for 15 minutes under nitrogen, then acetic acid (4 ml) is added and the mixture is heated under reflux for 24 h and then the solvent is removed in vacuo. The residue is dissolved in a minimum volume of water, the solution is basified to pH 12 by addition of 5M aqueous sodium hydroxide solution and the product is extracted with dichloromethane (3x30 mL). The extract is dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica in the apparatus using Biotage Flash 40i ^R using dichloromethane as a eluent followed by a 20: 1 mixture of dichloromethane and methanol. The appropriate fractions were combined and the solvent removed under vacuum to yield 3- (5-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2.1-b] thiazole as a yellow solid. (0.1 g) is obtained. Melting point 264-267 ° C.

Example 3

a) Methyl thioglycolate (62.87 mL) is added dropwise to a stirred solution of triethylamine (244.85 mL) in dimethylformamide (400 mL) at 110 ° C. under nitrogen, and then the mixture is stirred at 110 ° C. for 30 minutes. A 2,6-difluorobenzaldehyde (100 g) solution in dimethylformamide (100 mL) is added quickly, then the mixture is heated at reflux for 4 h. The mixture is cooled to ambient temperature and then added to a mixture of ice and water (4000 mL). The product was collected by filtration and dried under vacuum to afford methyl 4-fluorobenzo [b] thiophene-2-carboxylate (110 g) as a white solid, which was used without further purification.

b) 2M aqueous sodium hydroxide solution (1000 ml) is added to a stirred suspension of methyl 4-fluorobenzo [b] thiophene-2-carboxylate (110 g) in methanol (1500 ml) at ambient temperature under nitrogen. The mixture is stirred at ambient temperature for 4 hours and then the solution phase is separated by decanting from unreacted methyl 4-fluorobenzo [b] thiophene-2-carboxylate with 2M hydrochloric acid (3000 mL). The resulting solid was collected by filtration from the acidic mixture and dried at 60 ° C. in vacuo to yield 4-fluorobenzo [b] thiophene-2-carboxylic acid (77 g) as a white solid, which was used without further purification. The remaining unreacted methyl 4-fluorobenzo [b] thiophene-2-carboxylate is dissolved in hot methanol (500 mL), then 2M aqueous sodium hydroxide solution (250 mL) is added at ambient temperature. The mixture is stirred at ambient temperature for 8 hours and then added to 2M hydrochloric acid (1000 mL). The resulting solid is collected by filtration and dried in vacuo to yield 4-fluorobenzo [b] thiophene-2-carboxylic acid (33 g) as a white solid.

c) Copper powder (40 g) was added to a stirred solution of 4-fluorobenzo [b] thiophene-2-carboxylic acid (77 g) in quinoline (500 mL), and then the mixture was stirred and stirred at 180 to 220 ° C. for 2 hours. Heat. The mixture is cooled to ambient temperature and then added to 2M hydrochloric acid (1500 mL). Ethyl acetate (1000 mL) is added and the mixture is filtered through celite, which is washed with ethyl acetate (500 mL), the combined organic layers are dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using petroleum ether (boiling point 40-60 ° C.) as eluent followed by a 25: 1 mixture of petroleum ether (boiling point 40-60 ° C.) and ethyl acetate. The appropriate fractions are combined and the solvent is removed in vacuo to afford 4-fluorobenzo [b] thiophene (50.46 g) as a colorless oil.

d) A solution of bromine (18.7 mL) in dichloromethane (200 mL) was stirred with 4-fluorobenzo [b] thiophene (50.46 g) and anhydrous sodium acetate (40 g) in dichloromethane (400 mL) at -25 ° C. To the mixture is added dropwise under nitrogen, the mixture is stirred at ambient temperature for 18 hours, then filtered and the solvent is removed in vacuo. The residue is dissolved in dichloromethane (approximately 50 mL) and then dissolved in water (300 mL), then zinc powder (approximately 40 g) is added under nitrogen. The mixture is heated at reflux for 4 hours and then left at ambient temperature for 20 hours. Ethyl acetate (300 mL) is added and heating is continued for 15 minutes under reflux, then the mixture is cooled to ambient temperature. The mixture is filtered (celite) and the filter cake is washed with ethyl acetate (3x100 mL). The aqueous phase was separated and washed with ethyl acetate (200 mL), then the combined organic solutions were dried (MgSO ₄ ) and the solvent removed in vacuo to afford 3-bromo-4-fluorobenzo [b] ti as a pale brown solid. Offen (59.4 g) is obtained, which is used without further purification.

e) A solution of 3-bromo-4-fluorobenzo [b] thiophene (59.4 g) in tetrahydrofuran (250 mL) was dissolved in ethyl magnesium bromide [ether (190 mL) in tetrahydrofuran (800 mL). M solution] was added under 0 ° C. nitrogen, and the mixture was heated at reflux for 1.5 hours and cooled to ambient temperature. N-methoxy-N-methylpropionamide (33.5 g) is added and the mixture is heated at reflux for 2 hours. The mixture is cooled to ambient temperature and then added to saturated aqueous ammonium chloride solution (1000 mL). The product is extracted with ethyl acetate (2x500 mL), then the extracts are combined and dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using petroleum ether (boiling point 40 to 60 ° C.) as eluent, followed by dichloromethane. The appropriate fractions are combined and the solvent is removed in vacuo to yield 4-fluoro-3-propionylbenzo [b] thiophene (22 g) as a reddish 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) under 0 ° C. nitrogen, and then the mixture Stir at ambient temperature for 3 hours. The resulting solid was filtered off through silica, washed with dichloromethane, the filtrate and wash were combined and the solvent removed in vacuo to afford 2-bromo-1- (4-fluorobenzo [b] thiophene- as brown oil. 3-yl) propan-1-one (approx. 40 g) is obtained, which is used without further purification.

g) crude 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) propan-1-one (approx. 40 g), 2-imidazolidinethione (10.71 g), ethanol ( 150 mL) and acetic acid (75 mL) are heated under reflux for 2 hours under nitrogen, then additional 2-imidazolidinethione (2.2 g) is added and heating is continued under reflux for 2 hours. The mixture was cooled to 0 ° C., the resulting solid was collected by filtration, washed with ethanol (2 × 100 mL), and then stirred in a mixture of saturated aqueous sodium hydrogen carbonate solution (500 mL) and dichloromethane (500 mL) for 30 minutes to give basic. Make it angry. The organic layer is separated and the aqueous layer is shaken with dichloromethane (2x250 mL), then the dichloromethane solution is combined and dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue was dissolved in ethanol (200 mL) and then concentrated hydrochloric acid (6 mL) was added at 0 ° C. The solvent was removed in vacuo, then the residue was crystallized from ethanol (approximately 100 mL) to give 3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro as a white solid. Obtain imidazo [2,1-b] thiazole hydrochloride (17.5 g). Melting point 259-262 ° C.

Example 4

A solution of fumaric acid (2.13 g) in ethanol (40 mL) was added to 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1 in ethanol (10 mL). -b] to a stirred solution of thiazole (5 g; prepared by a method analogous to that described in Alternative Method B of Example 1) at 0 ° C. The mixture was stirred at 0 ° C. for 15 min, then the resulting solid was collected by filtration and dried under vacuum to afford 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-di as a white solid. Hydroimidazo [2,1-b] thiazole fumarate (4.71 g) is obtained. Melting point 179-181 ° C .;

Example 5

Concentrated hydrochloric acid (4 mL) was added to 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole in ethanol (45 mL). 4.27 g; to a stirred solution of a) prepared in a similar manner to the method described in Alternative Method B of Example 1 at 0 ° C., then the mixture is added to ether (250 mL) and stirred for 15 minutes. The resulting solid was collected by filtration and dried at 70 ° C. under vacuum to yield 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1- as a white solid. b] thiazole hydrochloride (3.50 g) is obtained. Melting point 254-256 ° C.

Example 6

A solution of D, L-tartaric acid (1.43 g) in ethanol (30 mL) was added to 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimime in ethanol (28 mL). To a stirred solution of polyzo [2,1-b] thiazole (2.66 g; prepared in a similar manner to that described in Alternative Method B of Example 1). The resulting suspension is stirred for 5 minutes, then ether (80 ml) is added. The solid was collected by filtration, washed with ether (50 mL) and dried at 70 ° C. under vacuum to afford 3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-di as a white solid. Hydroimidazo [2,1-b] thiazole D, L-tartrate (4.00 g) is obtained. Melting point 204-205 캜.

Example 7

In a method analogous to that described in Alternative Method A of Example 1, initiation of bromination of benzo [b] thiophene followed by reaction with magnesium followed by reaction with N-methoxy-N-methylbutyramid 3- (Benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide is prepared as a colorless solid. Melting point 219-221 ° C.

Example 8

a) 3-bromo-5-methylbenzo [b] thiophene (2.5 g in ether (5 mL); 5-methylbenzo [b] thiophene in a similar manner to that described in Alternative Method A of Example 1 Bromide) was added to a stirred solution of n-butyllithium (1.6M solution in hexane; 7 mL) in ether (20 mL) under -70 ° C nitrogen, and the mixture was stirred at -70 ° C for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.3 g) in ether (5 mL) was added dropwise over 20 minutes, and the mixture was stirred at -70 ° C. for 3 hours and warmed to ambient temperature over 20 hours. Next, 2M hydrochloric acid (25 ml) was added to quench the mixture. The ether layer is separated, washed with water (25 mL) and saturated aqueous sodium chloride solution (25 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is purified by flash chromatography on silica using 40: 1 mixture of petroleum ether (boiling point 60-80 ° C.) and ethyl acetate as eluent. 20: 1 of 5-methyl-3-propionylbenzo [b] thiophene and 5-methyl-2-propionylbenzo [b] thiophene (1.2 g) as an off-white solid by combining the appropriate fractions and removing the solvent under vacuum. A mixture is obtained, which is used without further purification.

b) Stirring of phenyltrimethylammonium tribromide (2.25 g) in 5-methyl-3-propionylbenzo [b] thiophene (1.2 g; prepared as described above) in tetrahydrofuran (20 mL) at 0 ° C. After addition to the solution, the mixture is stirred at 0 ° C. for 1 hour at ambient temperature for 20 hours. The mixture is filtered and the solvent is removed in vacuo. The residue was dissolved in dichloromethane (50 mL) and then the solution was washed with water (2x50 mL) and dried (MgSO ₄ ) to remove the solvent under vacuum to give a dark brown solid which was petroleum ether (boiling point 60 to 60). 80 ° C.) (50 mL). The solvent was removed in vacuo to yield 2-bromo-1- (5-methylbenzo [b] thiophen-3-yl) propan-1-one (0.75 g), which was 2-imidazolidinethione ( 0.27 g), and a mixture of ethanol (30 mL) and acetic acid (15 mL) are heated under reflux for 24 hours under nitrogen. The solvent was removed in vacuo, the residue was triturated with ether (20 mL), and the resulting solid was collected by filtration and dried under vacuum to yield 2-methyl-3- (5-methylbenzo [b] thiophen-3- as a white solid. Il) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (0.52 g) is obtained. Melting point 266-269 ° C.

Example 9

Initiating by bromination of benzo [b] thiophene in a similar manner as described in Alternative Method A of Example 1, followed by reaction with magnesium and then with N-methoxy-3, N-dimethylbutyramide, 3- (benzo [b] thiophen-3-yl) -2-isopropyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide is prepared as a light brown solid. Melting point 208-210 ° C.

Example 10

a) a stirred solution of 4-fluorophenyl methyl sulfide (22.0 g) in tetrahydrofuran under -70 ° C nitrogen under secondary-butyllithium (1.25M solution in a 92: 8 mixture of cyclohexane: hexanes; 100 mL) After the addition, the mixture is stirred at -70 ° C for 65 minutes. Dimethylformamide (13.2 mL) is added dropwise at -68 to -70 ° C, and the stirred mixture is slowly warmed to ambient temperature over 20 hours, then added to a solution of acetic acid (10 mL) in water (500 mL). The product is extracted with ether (3x150 mL) and the combined extracts are washed with 2M hydrochloric acid (200 mL) and saturated aqueous sodium chloride solution (200 mL) and dried (Na ₂ SO ₄ ) to remove the solvent in vacuo. The residue (25 g) used without further purification was presumed to consist mainly of a 2: 3 mixture of 4-fluorophenyl methyl sulfide and 2-fluoro-5- (methylthio) benzaldehyde, respectively, by nuclear magnetic resonance spectra. do.

b) methyl thioglycolate (8.9 mL), crude 2-fluoro-5- (methylthio) benzaldehyde (25 g; prepared as above), dimethyl acetamide (250 mL) and ethyl diisopropylamine (42 mL) ) Is stirred for 3.5 h under 140-150 ° C. nitrogen and then the solvent is removed in vacuo. Water (650 mL) is added to the residue, then the product is extracted with dichloromethane (3x150 mL). The combined extracts are washed with water (3 × 150 mL) and dried (Na ₂ SO ₄ ) to remove the solvent under vacuum. The residue was purified by trituration with ether (250 mL), then the resulting solid was collected by filtration, washed with ether (2 × 50 mL) and dried under vacuum to yield methyl 5- (methylthio) benzo [b] as a pale yellow solid. Obtain thiophene-2-carboxylate (13.3 g). Melting point 89.7-90.4 ° C.

c) Sodium hydroxide (8 g) was dissolved in water (100 mL) and the solution was then methyl 5- (methylthio) benzo [b] thiophene-2-carboxylate (23.8 g; described above in methanol (300 mL)). To a stirred solution of (prepared in a similar manner to one). The mixture is heated at reflux for 10 minutes and then left to stand at ambient temperature for 3 days. The suspension is heated to concentrate to a total volume of approximately 250 ml, then water (100 ml) is added and the mixture is heat filtered to remove insoluble matter. A concentrated hydrochloric acid (40 mL) solution in water (20 mL) was added to the filtrate, and the resulting solid was collected by filtration, washed with water and dried under vacuum at 80 ° C. to give 5- (methylthio) -benzo [b] as a pale yellow solid. Obtain thiophene-2-carboxylic acid (21 g). Melting point 186-186.5 ° C.

d) A mixture of copper powder (5.3 g), 5- (methylthio) benzo [b] thiophene-2-carboxylic acid (20 g) and quinoline (100 mL) is stirred and heated under reflux for 30 minutes under nitrogen, Heat filtration The filtrate is added to a mixture of concentrated hydrochloric acid (100 mL), ice (500 g) and ether (200 mL), and the resulting solid is collected by filtration and washed with ether. The aqueous phase is separated off and the additional product is extracted from it with ether (2x150 mL). The combined ether layers were washed with 2M hydrochloric acid (200 mL) and water (200 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to afford 5- (methylthio) -benzo [b] ti as a pale brown solid. Offen (14.7 g) is obtained, which is used without further purification.

e) A solution of 5- (methylthio) benzo [b] thiophene (14.7 g) in dichloromethane (180 mL) was diluted with aluminum bromide (26.2 g), bromoacetyl bromide (7.12 mL) and dichloromethane (120 mL). The stirred mixture is added under nitrogen at 0 ° C., then the resulting dark red brown solution is stirred at below 0 ° C. for 30 minutes and at ambient temperature for 20 hours. The solution is added to a mixture of ice (600 g) and concentrated hydrochloric acid (50 mL), then dichloromethane (300 mL) is added and the insoluble material is filtered off (Celite). The aqueous phase is separated and additional product is extracted with dichloromethane (300 mL), then the dichloromethane solutions are combined and dried (MgSO ₄ ) and the solvent is removed in vacuo. Acetic acid (200 mL) and dichloromethane (200 mL) are added to the residue, followed by addition of a solution of 2-imidazolidinethione (5.29 g) in acetic acid (200 mL), followed by distillation of dichloromethane. The remaining mixture is heated under reflux for 2 hours and then under vacuum to reduce the total volume to approximately 200 ml. The hot solution is decanted from the insoluble material and then cooled. The additional insoluble material is removed as before and then the solvent is removed at 50 ° C. under vacuum. The residue is mixed with water (300 mL) and 5M aqueous sodium hydroxide solution (300 mL), and then the product is extracted with dichloromethane (300 mL). The extract is dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. The residue is partially purified by flash chromatography on silica using ethyl acetate as eluent, followed by an 8: 1: 1 mixture of ethyl acetate, methanol and triethylamine. The appropriate fractions were combined and the solvent removed under vacuum to afford 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thia as a light brown rubber. A sol (3.6 g) is obtained, which is used without further purification.

f) A solution of bromine (1.87 g) in dichloromethane (10 mL) was added to 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-di in dichloromethane (80 mL). To a stirred solution of hydroimidazo [2,1-b] thiazole (3.55 g; prepared as above) was added while maintaining an internal temperature below 20 ° C., the dichloromethane phase was decanted from the insoluble material and vacuumed Concentrate under. The residue was triturated with dichloromethane (10 mL), and the resulting solid was collected by filtration to give 2-bromo-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5 as a tan solid. , 6-dihydroimidazo [2,1-b] thiazole hydrobromide (2.97 g) is obtained. Melting point 260-265 ° C.

g) Ethyl magnesium chloride solution [2.8 M solution in tetrahydrofuran (8.76 mL)] was added 2-bromo-3- [5- (methylthio) benzo [] in tetrahydrofuran (40 mL) at -10 ° C. under nitrogen. b] To a stirred suspension of thiophen-3-yl] -5,6-dihydroimidazo [2.1-b] thiazole hydrobromide (2.90 g), the mixture is stirred for 90 minutes at ambient temperature and -5 ° C. Cool to Dimethylformamide (5 mL) is added and the resulting suspension is stirred at ambient temperature for 2 hours, then ethyl acetate (200 mL) and saturated aqueous ammonium chloride solution (200 mL) are added. The ethyl acetate layer was separated and dried (Na ₂ SO ₄ ), and the solvent was removed in vacuo to yield 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-di as a solid. Hydroimidazo [2,1-b] thiazole-2-carboxaldehyde (1.4 g) is obtained, which is used without further purification. Melting point 157-158.5 ° C.

h) Borane / t-butylamine complex (1.04 g) is added to a stirred suspension of aluminum chloride powder (0.80 g) in dichloromethane (20 mL) under 0 ° C. nitrogen, and then the mixture is stirred at 0 ° C. for 1 hour. . 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.66 g; above and And the mixture is stirred at 0 ° C. for 15 minutes and allowed to stand at ambient temperature for 20 hours. Water (25 mL) is added followed by 2M hydrochloric acid (25 mL) to quench the mixture, which is then warmed to decompose the borane complex. The suspension is filtered and then 5M aqueous sodium hydroxide solution is added to make the filtrate basic (pH 14). The product is extracted with dichloromethane (2x50 mL), then the extracts are combined and dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. Anhydrous oxalic acid (0.12 g) solution in ethyl acetate (10 mL) is added to an orange-yellow residue (0.39 g) solution in a mixture of dichloromethane (25 mL) and ethyl acetate (50 mL), and then dichloromethane is distilled off. . The resulting solid was collected by filtration, washed with ethyl acetate (2x10 mL) and dried under vacuum to yield 2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-yl] as a white solid. -5,6-dihydroimidazo [2,1-b] thiazole oxalate (0.36 g) is obtained. Melting point 197 ° C.

Example 11

a) A solution of 5-fluorobenzo [b] thiophene (2.8 g; prepared from 2,5-difluorobenzaldehyde in a similar manner as described in Examples 3 and 10) in dichloromethane (27 mL) was purged with nitrogen. To a stirred mixture of aluminum chloride (7.34 g) and 2-bromopropionyl chloride (4.73 g) in dichloromethane (70 mL) was added dropwise, and the mixture was stirred at ambient temperature for 2.5 hours, followed by ice cold water (250 mL ) And stir for 1 hour. The aqueous phase was separated and the additional product was extracted with dichloromethane (100 mL), then the dichloromethane solution was combined and washed with water (2x100 mL) and saturated aqueous sodium chloride solution (2x100 mL) and dried (Na ₂ SO ₄ ). The solvent is removed under vacuum. The residue is purified twice by flash chromatography on silica in a Biotage Flash 40i apparatus using a 9: 1 mixture of petroleum ether (boiling point 60-80 ° C.) and ether as eluent. Appropriate fractions were combined and the solvents removed under vacuum to remove 2-bromo-1- (5-fluorobenzo [b] thiophen-3-yl) propan-1-one and 2-bromo-1- (5-fluoro A 9: 1 mixture (2.1 g) of robenzo [b] thiophen-2-yl) propan-1-one is obtained, which is used without further purification.

b) crude 2-bromo-1- (5-fluorobenzo [b] thiophen-3-yl) propan-1-one (2.1 g; prepared as above), 2-imidazolidinethione (0.75 g) and a mixture of ethanol (60 mL) are heated under reflux for 10 min, then acetic acid (30 mL) is added. The mixture is heated at reflux for 20 hours, left at ambient temperature for 60 hours and then the solvent is removed in vacuo. The residue is triturated with ethanol (100 mL) and the resulting solid is dissolved in hot ethanol (100 mL). Distillation reduces the total volume to approximately 60 ml, then the mixture is cooled to ambient temperature. The resulting solid was collected by filtration, dried in vacuo and then recrystallized from ethanol (75 mL) to give 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5 as a white solid. , 6-dihydroimidazo [2,1-b] thiazole hydrobromide (0.45 g) is obtained. Melting point 268-271 ° C.

Example 12

a) 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide and 3- (5- 58:42 mixture of fluorobenzo [b] thiophen-2-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (similar to that described in Example 11) Prepared by the process) to give 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole. do. Flash on silica in a Biotage Flash 40i device using a 1: 1 mixture of dichloromethane and methanol as eluent followed by a 9: 1 mixture or a 9: 1 mixture using a 97: 3 mixture of dichloromethane and methanol Purification by chromatography gives pure free base.

b) 5.5 M hydrochloric acid (4.3 mL) was added 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,] in ethanol (250 mL). 1-b] thiazole (4.6 g) solution was added and the mixture was added dropwise to ether (400 mL) with stirring, followed by ether (2000 mL). The suspension was left to stand at ambient temperature for 3 days, then the resulting solid was collected by filtration, washed with ether (200 mL) and dried at 40 ° C. under vacuum to afford 3- (5-fluorobenzo [b] ti as a white solid. Offfen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride (3.6 g) is obtained. Melting point 243-244 ° C.

Example 13

Phenyltrimethylammonium tribromide (9.7 g) in 5-chloro-3-propionylbenzo [b] thiophene (5.8 g; 3-bromine) in tetrahydrofuran (100 mL) over 2 minutes at 0-5 ° C. under nitrogen. Prepared by reacting n-butyllithium, followed by N-methoxy-N-methylpropionamide in a manner similar to that described in Example 2, from the parent-5-chlorobenzo [b] thiophene) Is stirred at ambient temperature for 2.5 hours. The resulting solid is filtered off and then the solvent is removed from the filtrate under vacuum. The mixture of residue, 2-imidazolidinethione (2.65 g) and ethanol (120 mL) was heated under reflux for 15 minutes, then acetic acid (60 mL) was added. The mixture is heated at reflux for 24 h and then the solvent is removed in vacuo. After ethanol (50 mL) was added to the residue, the solvent was removed in vacuo to give a solid which was recrystallized from hot ethanol (250 mL) and then dried under vacuum at 50 ° C. to give 3- (5- Chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (6.25 g) is obtained. Melting point 283-286 ° C.

Example 14

In a manner analogous to that described in Example 11, prepared by a method analogous to that described in 5-chlorobenzo [b] thiophene (J Heterocycl Chem (1988), 25 (4), 1271). ] And 3- (5-chlorobenzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] starting with 2-bromobutyryl chloride Thiazole hydrobromide is prepared as off-white solid. Melting Point 285-289 ° C. (Shrink at 240 ° C.).

Example 15

In a similar manner as described in Example 11, 5-bromobenzo [b] thiophene (prepared from 5-bromo-2-fluorobenzaldehyde in a similar manner as described in Example 3) and 2-bro 3- (5-bromobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide starting with morphopionyl chloride Is prepared as a brown solid. Melting point 272-275 ° C.

Example 16

Crude 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) propan-1-one (54 g; prepared by a similar method as described in Example 3), 2-imidazoli A mixture of dithione (19.4 g), ethanol (200 mL) and acetic acid (100 mL) was heated under reflux for 2 hours under nitrogen, followed by addition of additional 2-imidazolidinethione (2 g) for 30 minutes under reflux. Continue heating. The mixture was cooled to 0 ° C., the resulting solid was collected by filtration and then dried under vacuum to afford 3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro Imidazo [2,1-b] thiazole hydrobromide is obtained as a pale yellow solid (52.1 g). Melting point 264-266 ° C.

Example 17

n-butyllithium (2.5M solution in hexane; 14 mL) was added 3- (benzo [b] furan-3-yl) -5,6- in tetrahydrofuran (80 mL) under nitrogen at -70 ° C. over 20 minutes. Dihydroimidazo [2,1-b] thiazole (6.7 g; prepared using the process described in Example 3 of WO 97/02269) was added dropwise to the suspension, and then the mixture was added to -70 ° C. Stir for 30 minutes. Dimethylformamide (2.7 mL) is added and the mixture is allowed to warm to ambient temperature and then quenched by addition of saturated aqueous ammonium chloride solution (200 mL). The product is extracted with dichloromethane (3x200 mL), then the extract is washed with saturated aqueous sodium chloride solution (100 mL) and dried (Na ₂ SO ₄ ) to remove the solvent in vacuo. The residue is purified by flash chromatography on silica using a 9: 1 mixture of dichloromethane and methanol as eluent. The appropriate fractions are combined and the solvent is removed in vacuo to yield a residue (4.3 g), which is dichloro as eluent. Purification by flash chromatography on silica in a Biotage Flash 40i device using a 20: 1 mixture of methane and methanol. The appropriate fractions were combined and the solvent removed in vacuo to afford 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carbox as a brown solid. Aldehyde (3.3 g) is obtained, which is used without further purification.

Crude sample (1.6 g) of 3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole was replaced with 3- (benzo [b] Furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (3.0 g; prepared in a similar manner as described above) and borane / t-butylamine Prepared from the complex compound by a method similar to that described in Alternative Method B of Example 1. The crude product is dissolved in dichloromethane (50 mL), then ether (50 mL) is added. The resulting solid is filtered off and then the solvent is removed from the filtrate under vacuum. The residue is purified by flash chromatography on silica in a Jones Flashmaster II ^R apparatus using dichloromethane as eluent, followed by a 9: 1 mixture of dichloromethane and methanol. The appropriate fractions are combined and the solvent removed in vacuo to yield a residue (4.3 g) which is purified by flash chromatography on silica in a Biotage Flash 40i apparatus using a 19: 1 mixture of dichloromethane and methanol as eluent. . The appropriate fractions are combined and the solvent is removed in vacuo to give a residue (0.28 g) which is dissolved in methanol (5 mL). Water (5 mL) is added and the mixture is acidified to pH 1 by addition of 2M hydrochloric acid. Methanol is removed from the turbid solution under vacuum and then the insoluble material is filtered off. 2 M aqueous sodium hydroxide solution was added to basify the filtrate to pH 12, and the resulting solid was collected by filtration, washed with water (10 mL) and dried under vacuum to afford 3- (benzo [b] furan-- as a white solid. 3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole (0.18 g) is obtained. Melting point 119-122 ° C.

Example A

The use of the compounds of the present invention in the preparation of pharmaceutical compositions is described below. The term "active compound" in this description refers to a compound of the invention but in particular a compound which is the final product of the preceding examples.

a) capsules

In the preparation of capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are deaggregated and blended. The mixture is filled into hard gelatin capsules, each capsule containing the active compound in unit dose or as part of a unit dose.

b) tablets

Tablets are prepared from the following ingredients.

Parts by weight

Active compound 10

Lactose 190

Corn Starch 22

Polyvinylpyrrolidone 10

Magnesium Stearate 3

Some of the active compound, lactose and starch are deagglomerated and blended to granulate the resulting mixture into a polyvinyl pyrrolidone solution in ethanol. Anhydrous granules are blended with magnesium stearate and residual starch. The mixture is then compressed in a tablet press to obtain tablets each containing the active compound in unit dose or as part of a unit dose.

c) enteric retreat

Tablets are prepared by the method described above (b). The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) suppositories

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

Claims (20)

Compounds of formula (I) and pharmaceutically acceptable salts thereof. Formula I In Formula I above, A is S or O, R ₁ is H, halo, C _1-3 alkyl group or C _1-3 alkylthio group, R ₂ is H or fluoro, R ₃ is methyl, ethyl or isopropyl. The compound of claim 1, wherein A is S. 7. The compound of claim 1, wherein A is O. 7. The compound of any one of claims 1-3, wherein R ₁ is H, fluoro, chloro, bromo, methyl or methylthio. The compound of any one of claims 1-4, wherein R ₃ is methyl. The compound of formula Ia and a pharmaceutically acceptable salt thereof. Formula Ia In Formula Ia above, R is H or chloro. The compound of claim 1, wherein A is S, R ₁ is H, fluoro or chloro, R ₂ is H or fluoro and R ₃ is methyl. The compound of claim 1, wherein A is S, R ₁ is H or fluoro, R ₂ is H or fluoro and R ₃ is methyl. The compound of claim 1, wherein A is S, R ₁ is H, R ₂ is H and R ₃ is methyl. The method of claim 1, 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-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [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] thiophen-3-yl) -2-isopropyl-5,6-dihydroimidazo [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-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-bromobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole; 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) as claimed in claim 1 together with a pharmaceutically acceptable diluent or carrier. Compound of formula (I) for use as a drug. Depression, anxiety, psychosis (eg, schizophrenia), panic disorder, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias; Appetite disorders such as bulimia, anorexia, news and overeating, non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, stress, epileptic seizures, neurological diseases such as epilepsy and / or nerve damage such as seizures, brain damage, cerebral ischemia, head injury and bleeding A compound of formula (I) for use in the treatment of conditions with and for use as a smoking cessation aid. Depression, anxiety, psychosis (eg, schizophrenia), panic disorder, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias; Appetite disorders such as bulimia, anorexia, news and overeating, non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, stress, epileptic seizures, neurological diseases such as epilepsy and / or nerve damage such as seizures, brain damage, cerebral ischemia, head injury and bleeding Use of a compound of formula (I) for the manufacture of a medicament for use in the treatment of a condition and as a smoking cessation aid. Depression, anxiety, psychosis (eg schizophrenia), chronic impairment, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive, including administering to a patient a therapeutically effective amount of a compound of formula (I) Reactive behavior, panic attacks, social phobias; How to treat appetite disorders such as bulimia, anorexia, news and overeating, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress. A method of reducing a person's desire to smoke, comprising administering to a patient a therapeutically effective amount of a compound as claimed in claim 1. A method for reducing weight gain after smoking cessation in a human, comprising administering to the patient a therapeutically effective amount of the compound as claimed in claim 1. Metabolic disorders and diseases resulting therefrom, in particular non-motor active fever and increased metabolic rate, sexual dysfunction, sleep apnea, premenstrual syndrome, incontinence, hyperactive diseases, resting hernia and reflux esophagitis, pain, especially neuralgia, medication Any one of claims 1 to 10 for use in the treatment and prevention of weight gain associated with, chronic fatigue syndrome, osteoarthritis and gout, cancer associated with weight gain, dysmenorrhea, gallstones, upright hypotension and pulmonary hypertension A compound of formula I as claimed in claim. A compound of formula (I) as claimed in claim 1 for use in the prevention of cardiovascular disease, reduced platelet adhesion, weight loss after pregnancy or weight loss after smoking. A process for preparing a compound of formula (I), as described in the specification.