KR20020033626A - Thiazoloderivatives and pharmaceutical compositions containing them - Google Patents

Abstract

A compound of formula (I), a method for preparing the same, a pharmaceutical composition containing the same, depression, anxiety, psychosis (eg, schizophrenia), panic dyskinesia, obesity, drug addiction, drug abuse, cognitive disease, Alzheimer's disease, Cerebral ischemia, compulsive behavior, panic stroke, social phobia; Treats anorexia nervosa, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress, such as pathological hunger, anorexia, snacks and late night syndromes, and nervous system diseases such as stroke, epilepsy and / or stroke, brain tumors, brain ischemia And the use of these as an adjuvant for smoking cessation, and for the treatment and / or prevention of conditions in which neurological damage, such as hair damage and bleeding, is present.

Formula I

Description

Thiazolo derivatives and pharmaceutical compositions containing them

The present invention provides certain novel substituted dihydroimidazos [2,1-b] that have affinity for the 5-HT _1A receptor and inhibit neuronal reuptake of 5-hydroxytryptamine and / or noradrenaline. Thiazole and dihydro-5H-thiazolo [3,2-a] pyrimidine compounds, methods for their preparation, pharmaceutical compositions containing them, and depression, anxiety, psychosis (eg, schizophrenia), chronic dyskinesia, Obesity, drug addiction, substance abuse, cognitive disorders, Alzheimer's disease, obsessive compulsive behavior, panic stroke, social phobia, anorexia nervosa (e.g. pathological starvation, anorexia, snack and late night syndrome), non-insulin dependent diabetes mellitus, hyperglycemia To treat hyperlipidemia, stress, and as a supplement for smoking cessation and to treat neurological disorders such as seizures, nervous system diseases (e.g. epilepsy) and / or stroke, brain tumors, cerebral ischemia, head damage and bleeding Or its use in prevention It relates.

WO 98/41528 discloses compounds of formula (A) comprising pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates or other mixtures of enantiomers such as depression, anxiety, Parkinson's syndrome, obesity, It is said to be useful for the treatment of cognitive diseases, seizures, and neurological diseases (eg epilepsy) and as a neuroprotective agent to protect against conditions such as stroke. The compounds of the present invention are not described or suggested in this document.

In Formula A,

Ar is each a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted by one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted by one or more halo, d) one or more halo Optionally substituted by one or more substituents selected from the group consisting of an alkylthio group having 1 to 3 carbon atoms optionally substituted by e) a phenoxy group optionally substituted by one or more halo and f) a phenyl optionally substituted by one or more halo. Phenyl, naphthyl or benzo [b] thiophenyl which may be substituted,

R ₁ and R ₂ may be the same or different and are independently 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 cycloalkylmethyl group having 3 to 7 carbon atoms in the ring, f) a halo (i), an alkyl group having 1 to 3 carbon atoms optionally substituted by one or more halo, and a carbon number optionally substituted by one or more halo Aryl or heteroaryl groups optionally substituted by one or more substituents selected from the group consisting of alkoxy groups (iii) of 1 to 3 and alkylthio groups (iv) of 1 to 3 carbon atoms, optionally substituted by one or more halo, g ) An alkyl chain having 1 to 3 carbon atoms and an aryl or heteroaryl group optionally substituted by halo (i), an alkyl group having 1 to 3 carbon atoms (ii) optionally substituted by one or more halo, by one or more halo Arylalkyl or hetero optionally substituted by one or more substituents selected from the group consisting of alkoxy groups (iii) having from 1 to 3 alkoxy and alkylthio groups (iv) having from 1 to 3 carbon atoms optionally substituted by one or more halo An arylalkyl group,

R ₁ and R ₂ form an alkylene chain optionally substituted by one or more alkyl groups each having 1 to 3 carbon atoms to form a 5 or 6 membered ring with the atoms to which they are attached,

R ₃ is a) H, b) halo (i), an alkyl group of 1 to 3 carbon atoms optionally substituted by one or more halo (ii), an alkoxy group of 1 to 3 carbon atoms optionally substituted by one or more halo (iii) Aryl or heteroaryl group optionally substituted with one or more substituents selected from the group consisting of alkylthio groups (iv) having 1 to 3 carbon atoms optionally substituted with one or more halo, c) aryl is halo (i), Alkyl groups of 1 to 3 carbon atoms optionally substituted by one or more halo, alkoxy groups of 1 to 3 carbon atoms optionally substituted by one or more halo, and 1 to 3 carbon atoms optionally substituted by one or more halo Arylmethyl group optionally substituted by one or more substituents selected from the group consisting of alkylthio groups (iv) of d) or alkoxyalkyl groups having 3 to 6 carbon atoms,

R ₄ and R ₅ may be the same or different, and are independently an alkyl group having 1 to 3 carbon atoms,

R ₄ and R ₅ together with the atoms to which they are attached form a cycloalkyl ring of 3 to 6 carbon atoms.

Mr. Sharp. Sharpe C.J and Shardbolt R. Shadbolt RS (Journal of Medicinal Chemistry, 1971, Vol. 14 No. 10, p977-982) describes certain dihydroimidazo [2,1-b] thiazole compounds with antidepressant activity. have. However, the literature also mentions that these compounds are generally less active and more toxic than imidazolines already described in the literature. The compounds of the present invention are not described or suggested in this document.

WO 97/02269 discloses that compounds of formula (B), including pharmaceutically acceptable salts thereof, have affinity for 5-HT _1A receptors and reabsorb neurons of 5-hydroxytrytamine and / or noradrenaline It is described as suppressing. These compounds are said to be useful for the treatment of CNS diseases. However, these compounds exhibit activity as monoamine oxidase inhibitors and / or have affinity for other receptors, such as muscarinic receptors, and are therefore likely to cause undesirable side effects. Surprisingly, the present invention provides compounds with unexpectedly good selectivity and efficacy. The compounds of the present invention are not described or suggested in WO 97/02269.

In Formula B,

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

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

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

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

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

In Formula I,

A is S or O,

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

R ₂ and R ₃ are each H,

R ₄ is hydroxyalkyl group having 1 to 6 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, 3 to 6 carbon atoms where hydroxy is not directly bonded to one of the carbons of the double bond A hydroxyalkenyl group having 3 to 6 carbon atoms, a hydroxy alkynyl group having 3 to 6 carbon atoms, a hydroxycycloalkyl group having no hydroxy attached directly to one of the triple bond carbons Alkenyl group, arylalkenyl group having 8 to 10 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, C _3-7 alkynylalkoxy C _1-3 alkyl group, C _4-7 cycloalkylalkoxy C _1-3 alkyl C _1-3 alkoxy C _1-3 alkyl group, C _1-3 alkylthio C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, arylthio group, C _1-6 Alkanoyl group, C _3-6 alkoxycarbonylalkyl group, cyano, halo, C _1-4 alkyliminomethyl group, C _1-4 alkylaminoalkyl group or hydroxyiminomethyl group,

R ₅ is H or halo.

In a preferred aspect, the present invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof.

Formula I

In Formula I,

A is S or O,

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

R ₂ and R ₃ are each H,

R ₄ is a hydroxyalkyl group of 1 to 6 carbon atoms, a hydroxyalkenyl group of 3 to 6 carbon atoms, in which hydroxy is not directly bonded to one of the carbons of a double bond, or hydroxy is to one of the carbons of a triple bond Hydroxyalkynyl groups having 3 to 6 carbon atoms, hydroxycycloalkyl groups having 3 to 6 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms, which are not directly bonded, C _1-3 Alkoxy C _1-3 alkyl group, C _1-3 alkylthio C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, C _1-6 alkanoyl group, halo, C _1-4 Alkyliminomethyl group or hydroxyiminomethyl group,

R ₅ is H or halo.

As used herein, the term halo can be seen to include fluoro, chloro, bromo and iodo. In alkyl groups, alkenyl groups, alkynyl groups, alkylthio groups and alkoxy groups containing two or more carbon atoms, it can be seen that the alkyl groups can be straight or branched. Aryl is used to denote phenyl optionally substituted by one or more of C _1-3 alkyl groups, C _1-3 alkoxy groups or halo.

In a first group of preferred compounds of the invention, A is S.

In a second group of preferred compounds of the invention, A is O.

Preferably, g is 0 or 1 and R ₁ is a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted by one or more halo or alkoxy of 1 to 3 carbon atoms optionally substituted by one or more halo Group. Preferably, R ₁ is at position 5 of the benzo [b] thiophene ring. More preferably, g is 0 or 1 and R ₁ is halo or an alkoxy group having 1 to 3 carbon atoms. Most preferably, g is 0 or 1 and R ₁ is chloro or methoxy.

Preferably, n is two.

Preferably, R ₂ and R ₃ are each H.

Preferably, R ₄ is a hydroxyalkyl group having 1 to 6 carbon atoms, a hydroxyalkenyl group having 3 to 6 carbon atoms, wherein the hydroxy is not directly bonded to one of the carbons of the double bond, and the hydroxy is a triple bond. A hydroxyalkynyl group having 3 to 6 carbon atoms, a C 2-4 alkenyl group optionally substituted by one or more C _1-2 alkyl groups, not directly bonded to one of the carbons, a C _1-4 alkyliminomethyl group Or hydroxyiminomethyl group. More preferably, R ₄ is a hydroxyalkyl group having 1 to 5 carbon atoms, a hydroxyalkenyl group having 3 to 5 carbon atoms, wherein the hydroxy is not directly bonded to one of the carbons of the double bond, and the hydroxy is a triple bond A hydroxyalkynyl group having 3 to 4 carbon atoms or an alkenyl group having 2 carbon atoms optionally substituted by one or more methyl groups, which is not directly bonded to one of the carbons of. Most preferably, R ₄ is hydroxymethyl or vinyl. Hydroxymethyl is particularly preferred for R ₄ .

Preferred groups of R ₄ are hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1- Hydroxy-3-methylbutyl, 1-hydroxypentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2-methyl But-3-enyl, 1-hydroxypent-4-enyl, 1-hydroxypropynyl, 1-hydroxybut-2-ynyl, methoxymethyl, ethoxymethyl, methylthio, bromo, chloro, vinyl , Allyl, 1-methylvinyl, formyl, acetyl, N- (1-methylethyl) iminomethyl and hydroxyiminomethyl. More preferably, R ₄ is hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, 1-hydroxypentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2 -Methylbut-3-enyl, 1-hydroxypent-4-enyl, 1-hydroxypropynyl, 1-hydroxybut-2-ynyl, vinyl, 1-methylvinyl, acetyl, N- (1-methyl Ethyl) iminomethyl and hydroxyiminomethyl. Most preferably, R ₄ is hydroxymethyl or vinyl. Hydroxymethyl is particularly preferred.

Preferably, R ₅ is H.

Preferably, n is two.

In a preferred group of compounds of formula (I), A is S, g is 0 or 1, n is 2, R ₁ is halo or an alkoxy group having 1 to 3 carbon atoms, R ₂ and R ₃ are each H, R ₄ is a hydroxyalkyl group having 1 to 5 carbon atoms, a hydroxyalkenyl group having 3 to 5 carbon atoms, wherein the hydroxy is not directly bonded to one of the carbons of the double bond, and the hydroxy is to one of the carbons of the triple bond A hydroxyalkynyl group having 3 to 4 carbon atoms or an alkenyl group having 2 carbon atoms optionally substituted by one or more methyl groups, which is not directly bonded, and R ₅ is H.

In a preferred group of compounds of formula (I), preferably g is 0 or 1 and R ₁ is chloro or methoxy. More preferably, R ₁ is at position 5 of the benzo [b] thiophene ring.

In a more preferred aspect, the present invention provides a compound of formula la and pharmaceutically acceptable salts thereof.

In Formula Ia,

A is S or O,

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

R ₄ is hydroxyalkyl group having 1 to 6 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, 3 to 6 carbon atoms where hydroxy is not directly bonded to one of the carbons of the double bond Hydroxyalkenyl group of hydroxy, hydroxyalkynyl group of 3 to 6 carbon atoms, hydroxyalkynyl group of 2 to 8 carbon atoms, arylal of 8 to 10 carbon atoms, wherein hydroxy is not directly bonded to one of the triple bond carbons Kenyl group, C3-C6 cycloalkyl group, C _3-7 alkynylalkoxyC _1-3 alkyl group, C _4-7 cycloalkylalkoxyC _1-3 alkyl group, C _1-3 alkoxyC _1-3 alkyl C _1-3 alkylthio, C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, arylthio group, C _1-6 alkanoyl group, C _3-6 alkoxycarbonylalkyl group, cyano, halo, C _1-4 alkyl butylimino methyl group, C _1-4 alkylamino methyl group or hydroxyimino A naphthyl group.

In a first group of preferred compounds of the invention, A is S. Preferably, n is 2 in the present compound group. Preferably, g is 0 or 1 in the present compound group. Preferably, R ₁ is halo, an alkoxy group having 1 to 3 carbon atoms or an alkylthio group having 1 to 3 carbon atoms.

In a second group of preferred compounds of the invention, A is O. Preferably, n is 2 in the present compound group. Preferably, g is 0 or 1 in the present compound group. Preferably, R ₁ is halo, an alkoxy group having 1 to 3 carbon atoms or an alkylthio group having 1 to 3 carbon atoms.

In the compounds of formula (I) and formula (Ia), the preferred R ₁ groups are methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, bromo, chloro, fluoro, iodo, trifluoro Methyl, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, hydroxy, formyloxy, acetoxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1- Hydroxypropyl, cyano, formyl, acetyl, methoxycarbonyl, ethoxycarbonyl, carbamoyl, carbamoylmethyl, sulfamoyl, sulfamoylmethyl, amino, methylamino, dimethylamino, ethylamino or diethylamino to be. More preferably, R ₁ is methoxy, chloro or methylthio.

In the compounds of formula (I) and formula (Ia), preferred R ₄ groups are cyclopropyl, methoxy, ethoxy, bromo, chloro, fluoro, iodo, trifluoromethyl, trifluoromethoxy, hydroxymethyl, 1- Hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydroxypropyl, 1-hydroxy-2-methylpropyl, 1-hydroxybutyl, 1-hydroxy-3-methylbutyl, 1-hydroxy Pentyl, 1-hydroxypropenyl, 1-hydroxybut-3-enyl, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2-methylbut-3-enyl, 1-hydroxypent- 4-enyl, 3-hydroxybut-1-enyl, 1-hydroxypropynyl, 1-hydroxybut-2-ynyl, α-hydroxy-2-methoxybenzyl, methoxymethyl, ethoxymethyl, Isopropoxymethyl, cyclopropylmethoxymethyl, cyclobutylmethoxymethyl, prop-2-ynyloxymethyl, methylthio, pentylthio, vinyl, allyl, prop-1-enyl , 2-methylprop-2-enyl, 1-methylvinyl, styryl, formyl, acetyl, cyano, ethoxycarbonylmethyl, N- (1-methylethyl) iminomethyl, N-methylaminomethyl And hydroxyiminomethyl. More preferably, R ₄ is hydroxymethyl, 1-hydroxyethyl or vinyl. Most preferably, R ₄ is hydroxymethyl or vinyl.

In a particularly preferred compound of formula (la), A is S or O, g is 0 or 1, n is 2, R ₁ is halo, an alkoxy group having 1 to 3 carbon atoms or an alkylthio group having 1 to 3 carbon atoms, R ₄ is hydroxyalkyl group having 1 to 4 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, 3 to 4 carbon atoms where hydroxy is not directly bonded to one of the carbons of the double bond Hydroxyalkenyl group of hydroxy, hydroxyalkynyl group having 3 to 4 carbon atoms, alkenyl group having 2 to 3 carbon atoms, C _1-3 alkylthio group, wherein hydroxy is not directly bonded to one of the triple bond carbons , C _1-2 alkanoyl group or hydroxyiminomethyl group.

In the remainder of the art, the term "compound of formula (I)" means a compound of formula (I) or formula (Ia). Similarly, the term “compound of formula (I)” means a compound of formula (I) or a compound of formula (Ia).

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, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, formate, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (-)-tart Or mixtures thereof including racemate mixtures], succinates, oxalates, benzoates and salts with amino acids such as glutamic acid. Such salts are prepared by methods known to those skilled in the art as described in the Examples.

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 structural forms that can be separated. For example, where bulky groups are present, it may limit the rotation of one or more single bonds or bonds due to steric hindrance. For example, torsional asymmetry due to limited rotation about asymmetric single bonds due to steric hindrance or ring deformation can allow separation of different structures. The present invention includes each of the structural isomers of the compounds of formula (I) and mixtures thereof.

Certain compounds of formula (I) and salts thereof may exist in one or more crystalline forms, and the present invention includes each crystalline form and mixtures thereof. Certain compounds of formula (I) and salts thereof may also exist in the form of solvates (eg hydrates), and the present invention includes solvates and mixtures thereof, respectively.

Certain compounds of formula (I) contain one or more chiral centers and exist in different optically active forms. If the compound of formula (I) comprises one chiral center, the compound is present in two enantiomeric forms, and the present invention includes a mixture of two enantiomers and enantiomers. Enantiomers can be prepared by methods known to those skilled in the art, for example, by the formation of diastereomeric salts which can be separated by crystallization; By formation of diastereomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; Or by, for example, gas-liquid or liquid chromatography with bound chiral ligands or in the presence of a chiral solvent, for example under a chiral environment on a chiral support for silica. In the case of converting the desired enantiomer to another chemical group by one of the separation methods described above, it can be seen that additional steps are required to release the desired enantiomer form. In addition, certain enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents or by converting one enantiomer to another by asymmetric modification.

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 the individual enantiomers in each pair can be separated as described above. The present invention includes each diastereomer of a compound of formula (I) and mixtures thereof.

Certain compounds of formula (I) and pharmaceutically acceptable salts thereof and other mixtures of the respective enantiomers, racemates or enantiomers are as follows:

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

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

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

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

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

3- (benzo [b] thiophen-3-yl) -2-bromo-6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine;

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

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] propan-1-ol;

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

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

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

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-en-1-ol ;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-2-yn-1-ol;

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

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

[3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol;

N- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-ylmethylidene] -1-methylethylamine;

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

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

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

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

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

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylpropan-1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] butan-1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-ene- 1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -3-methylbutan-1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pentan-1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-yn-1-ol ;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-ene -1-ol;

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4-en-1-ol;

[3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] (2-methoxyphenyl) methanol;

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

[3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidin-2-yl] methanol;

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

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

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

[3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol;

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

[3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -N-methylmethylamine;

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

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

4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-3-ol;

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

Ethyl [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] acetate;

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

{3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazol-2-yl} methanol;

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

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

2-bromo-3- (7-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole;

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

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

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. For therapeutic use, the active compounds can be administered orally, rectally, parenterally or topically, preferably orally. Accordingly, the therapeutic compositions of the present invention may take certain forms of pharmaceutical compositions known for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the pharmaceutical art. The composition of the present invention may contain 0.1 to 99% by weight of 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 invention and they are present in known pharmaceutical formulations, such as tablets, capsules, syrups and aqueous or oily suspensions for such administration. 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 by known methods. . Tablets may be formulated by methods known to those skilled in the art to provide sustained release of the compounds of the present invention. Such tablets can optionally provide enteric skin by known methods, for example using cellulose acetate phthalate. Similarly, hard or soft gelatin capsules containing the active compound with or without the addition of capsules, for example excipients, can be prepared by conventional methods and, if desired, by providing known enteric skin by known methods. can do. Tablets and capsules may conveniently contain 1 to 500 mg of the active compound, respectively. Other oral compositions include, for example, an aqueous suspending agent containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent (such as sodium carboxymethylcellulose) and an appropriate vegetable oil (such as peanut oil). Oily suspensions containing the compound are included.

Preferably, the compositions of the present invention are administered orally in a pharmaceutical formulation known for oral administration. Suitable dosage forms for oral administration include tablets, pills, capsules, caplets; Multiparticulates including granules, beads, pellets and microencapsulated particles; Powders, elixirs, syrups, suspensions and solutions.

Solid oral dosage forms, such as tablets, may be prepared by mixing the pharmaceutical composition of the present invention with one or more of the following ingredients or mixtures thereof:

Inert diluents (e.g. calcium carbonate, calcium sulfate, compressed sugar, powdered sugar, dexrate, dextrin, dextrose, dibasic calcium phosphate dihydrate, glyceryl palmitostearate, vegetable hardened oil, kaolin, lactose, magnesium carbonate , Magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylate, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc and tribasic calcium phosphate);

Disintegrants (e.g. alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polyacrylic potassium, Starch and agar including powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, corn starch);

Lubricants such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, castor hardened oil, vegetable hardened oil, light metal oil, magnesium stearate, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearate Aryl fumarate, stearic acid, talc and zinc stearate);

Binders [e.g. acacia, alginic acid, carbomer, carboxymethylcellulose sodium, dextrin, ethylcellulose, gelatin, guar gum, vegetable hardening oil, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, liquid glucose, magnesium silicate Starch, aluminium, sugars such as sucrose, molasses and lactose, including aluminum, maltodextrin, methylcellulose, polymethacrylate, povidone, pregelatinized starch, sodium alginate, corn starch and natural and synthetic rubbers ( Eg Irish Moss, Polyethylene Glycol, Wax, Microcrystalline Cellulose and Polyvinylpyrrolidone)];

Colorants (eg, conventional pharmaceutically acceptable dyes);

Sweetening and flavoring agents;

antiseptic;

One or more pharmaceutically acceptable couples or couples (e.g., compounds containing acid and carbonate or bicarbonate salts) foamed to aid dissolution when a solid dosage form is added to water and

Any other ingredient known in the art that can make oral dosage forms by known methods such as tableting and the like.

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

Capsules and / or caplets (eg, hard or soft gelatin capsules) containing the active compound (with or without the addition of excipients such as fatty oils) can be prepared by conventional methods and, if desired, Enteric skin can be provided by a method. The components of the capsules and / or caplets may be formulated using known methods to provide sustained release of the active compound.

Liquid oral dosage forms comprising a composition of the present invention comprise an aqueous suspension 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 suspension containing the active compound in a suitable vegetable oil such as peanut oil and / or sunflower oil. Liquid oral dosage forms may also include one or more sweetening, flavoring, preservatives and / or mixtures thereof.

The active compound may be formulated into granules in the presence or absence of additional excipients. The granules can be taken directly by the patient or they can be added to a suitable liquid carrier (eg water) prior to ingestion. The granules may contain disintegrants, such as pharmaceutically acceptable effervescent couples formed from acids and carbonate or bicarbonate salts, to facilitate dispersion in the liquid medium.

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

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

The pharmaceutical composition may also contain a sterile suspension and / or appropriate in aqueous and / or oily media, preferably isotonic with the blood of the intended patient (e.g., a pharmaceutical dosage form known for parenteral administration, for example parenteral administration). Sterile solution in a solvent), subcutaneously, intramuscularly, intradermal and / or intravenously (eg by injection and / or infusion)). Parenteral dosage formulations may be sterilized (eg by microfiltration and / or using an appropriate sterilant [eg ethylene oxide]). Optionally, one or more of the following pharmaceutically acceptable adjuvants may be added to the parenteral dosage form for parenteral administration: 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. To enhance stability during storage, parenteral dosage forms can be frozen after filling the container and fluid (eg water) can be removed under reduced pressure.

Pharmaceutical compositions may be administered intranasally in pharmaceutical formulations known for intranasal administration, such as sprays, aerosols, sprays and / or powders. Metered dose systems (eg, aerosols and / or inhalers) known to those skilled in the art can be used.

The pharmaceutical composition may be administered orally (eg, in a pharmaceutical formulation known for oral administration, such as sustained release tablets, chewing gum, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and / or powders). : Sublingually).

The composition for topical administration may comprise a matrix in which the pharmacologically active compound of the invention is dispersed such that the compound remains in contact with the skin for transdermal administration of the compound. Suitable transdermal compositions include pharmaceutically active compounds in combination with potential transdermal accelerators such as dimethyl sulfoxide or propylene glycol, and topical vehicles such as mineral oil, waseline and / or waxes such as paraffin wax or beeswax. It can be prepared by mixing with. 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 delivers the topical formulation over the skin for the intended period of time.

The compounds of the present invention can also be administered from external sources, for example by intravenous infusion or by continuous infusion from a source of compound located in the body. Internal sources are implanted, for example, in the form of implantable reservoirs containing the compound to be released continuously by osmotic events and (a) in the form of, for example, a derivative that is rarely water soluble, such as the dodecanoate salt. Implants, which may be solid, in the form of a liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound or (b) an implantable support (eg, a synthetic resin or wax material) for the compound to be infused. The support may be a single object containing all compounds or a series of several objects each containing a portion of the 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 delivered for a long time.

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

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

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

Pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) include, but are not limited to, depression, anxiety, psychosis (e.g. schizophrenia), chronic dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases in mammals, especially humans, Alzheimer's disease, obsessive compulsive behavior, panic stroke, social phobia, anorexia nervosa (e.g. pathological hunger, anorexia, snack and late night syndromes), non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, treatment of stress, It can be used as a smoking cessation aid. In addition, the compositions can be used to treat and / or prevent stroke, neurological diseases (eg, epilepsy) and / or conditions in which neurological damage is present, such as stroke, brain tumors, cerebral ischemia, head injury and bleeding. The precise amount of active compound administered in the treatment depends on a number of factors, such as the age of the patient, the severity of the condition and past medical history and should always be followed by the careful instructions of the administering physician, but the active compound administered per day The amount of is provided in a range of 1 to 1000 mg, preferably 5 to 500 mg, in a single dose per day or in one or more divided doses.

In another aspect, the invention provides depression, anxiety, psychosis (e.g., schizophrenia), panic dyskinesia, obesity, drug addiction, drug abuse, cognitive disease, Alzheimer's disease, obsessive behavior, panic stroke, social phobia, Treats anorexia nervosa (e.g., pathological starvation, anorexia, snack and late-night syndromes), non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress, used as an adjuvant for smoking cessation, strokes, neurological disorders (e.g. Epilepsy) and / or the use of a compound of formula (I) in the manufacture of a medicament for use in the treatment and / or prevention of conditions in which neurological damage, such as stroke, brain tumor, cerebral ischemia, head injury and bleeding is present. .

The invention also includes the administration of a therapeutically effective amount of a compound of formula (I) to a patient in need thereof, including depression, anxiety, psychosis (eg, schizophrenia), panic dyskinesia, obesity, drug addiction, drug abuse, awareness Sexual disorders, Alzheimer's disease, obsessive compulsive behavior, panic stroke, social phobias, anorexia nervosa (e.g. pathological hunger, anorexia, snack and late night syndrome), non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress and stroke, Methods of treating neurological diseases (eg, epilepsy) and / or conditions in which neurological damage exists, such as stroke, brain tumors, cerebral ischemia, head injury and bleeding, are provided.

The present invention also provides a method of reducing the desire for human smoking, comprising administering to a patient in need thereof 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 a human, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula (I).

In addition, the compounds of the present invention may be used for metabolic diseases and conditions caused therefrom, such as non-motor fever and increased metabolic rate, sexual disorders, sleep apnea, premenstrual syndrome, urinary incontinence, hyperactivity disorders, hiatus hernia and esophagus Reflux, pain, especially neuropathic pain, weight gain associated with medication, chronic fatigue syndrome, osteoarthritis and gout, cancer associated with weight gain, menstrual abnormalities, gallstones, orthostatic hypotension and pulmonary hypertension .

The compounds of the present invention may be useful for the prevention of cardiovascular disease and for the reduction of platelet adhesion, in helping to lose weight after pregnancy and in helping to lose weight after smoking.

The compounds of the present invention are particularly useful in the treatment of obesity and related co-morbidities such as diabetes, hyperglycemia and hyperlipidemia. Monoamine reuptake inhibitors used to treat obesity are often 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 are expected to result from the administration of monoamine reuptake inhibitors, in particular noradrenaline reuptake inhibitors. Without wishing to be bound by theory, the combination of 5-HT _1A agonistic actions in the compounds of the present invention can reduce cardiovascular side effects that are expected to result from monoamine reuptake inhibition, particularly their noradrenaline reuptake inhibition. .

In another aspect, the present invention provides a method for reducing the cardiovascular side effects of an anti-obesity agent, including incorporating a 5-HT _1A agonistic action into a compound.

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

Useful properties of particularly preferred compounds of the invention that reduce cardiovascular side effects can be explained by telemetry studies in rats in which heart rate, blood pressure, body temperature and motor activity are recorded over time. Suitable methods are as follows: Brockway, BP, Mills, PA & Azar, SH (1991); New continuous long-term measurement of blood pressure, heart rate and activity in rats via radiometric telemetry. Clinical and Experimental Hypertension. Theory and Practice A 13 (5), 885-895 and Guiol, C. Ledoussal, C & Surge, J-M (1992); Radiation telemetry system for long-term measurement of blood pressure and heart rate in unrestricted rats. Validation of method. Journal of Pharmacological and Toxicological Methods, 28, 99-105.

5-HT of particularly preferred compounds of the invention_1A Agonistic action can be measured electrophysiologically by methods known to those skilled in the art.

The process for preparing the compound of formula (I) will be described below. The method can be carried out on an individual basis or by a multi-parallel synthesis method also known as High Speed Analoguing. The method is preferably carried out at atmospheric pressure.

Compounds of formula (I) can be prepared by the process 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 in the range of 0 to 200 ° C., preferably 20 to 150 ° C., optionally in the presence of an acid (eg acetic acid or sulfuric acid).

In Chemical Formula II,

A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , g and n are as defined above.

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

Where

A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , g and n are as defined above,

Z is a leaving group, for example halo (eg bromo).

Compounds of formula (I) also contain compounds of formula (IV) at a temperature ranging from 0 to 200 ° C., without separation of intermediates of formula (II), optionally in the presence of an acid (eg acetic acid), optionally in the presence of a solvent (eg ethanol) By reacting with the compound, it can be prepared directly by heating at a temperature in the range of preferably 20 to 150 ° C.

Compounds of formula (I), wherein R ₄ is halo, react compounds of formula (V) at temperatures ranging from -50 to 200 ° C, optionally in the presence of a solvent (e.g. dichloromethane, tetrahydrofuran or acetone) Trimethylammonium tribromide, iodine monochloride or benzyltrimethylammonium tetrachloroiodate).

Where

A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above.

R ₄ is a group of the formula -CH (OH) R _x wherein R _x is a C _1-5 alkyl group, a C 2-5 alkenyl group, a C 2-5 alkynyl group or (2-C _{1- 3} alkoxyphenyl)] is a compound of formula (I) wherein the compound of formula (VI) is selected from an organometallic reagent (e.g., in the presence of a solvent (e.g. tetrahydrofuran or ether) at temperatures ranging from -50 deg. And R _x MgX or a compound of R _x Li, wherein R _x is as defined above and X is halo, for example bromo.

Where

A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above,

R _y is H.

R ₄ is a group of the formula -CH (OH) R _y , wherein R _y is a C _1-5 alkyl group, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, or (2-C _{1- 3} alkoxyphenyl)] is a compound of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is C _1-5 alkyl , An alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, or (2-C _1-3 alkoxyphenyl)] is used in the presence of a solvent (eg ethanol) from 0 ° C. to the boiling point range of the solvent used. It can be prepared by reacting with a reducing agent such as sodium borohydride at a temperature of.

Compounds of formula I, wherein R ₄ is hydroxymethyl, are compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , g and n are as defined above and R _y is H ) May be prepared by reacting with a reducing agent (e.g. sodium borohydride) in a solvent (e.g. methanol) at a temperature in the range of -50 deg. C to the boiling point of the solvent used.

Compounds of formula (I) wherein R ₄ is hydroxyiminomethyl refer to compounds of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is H It may be prepared by reacting with hydroxylamine or a salt thereof at a temperature in the range of 0 to 250 ° C., optionally in the presence of a solvent such as an alcohol such as ethanol.

Compounds of formula (I) wherein R ₄ is cyano include compounds of formula (VI), wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is H, the presence of formic acid Can be prepared by reacting with hydroxylamine or a salt thereof at a temperature in the range from 0 to 250 ° C.

Compounds of formula (I) wherein R ₄ is a C _1-4 alkyliminomethylene group include compounds of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y Is H) an amine of the formula R _a NH ₂ , wherein R _a is C ₁ , optionally in the presence of a solvent (eg ethanol), optionally in the presence of an acid catalyst (eg acetic acid) at a temperature ranging from 0 to 250 ° C. _-4 alkyl group).

A compound of formula I R ₄ is C _1-4 alkylamino-methylene group is a compound of Formula I (wherein, R ₄ is a C _1-4 alkyl diamino methylene _{group, A, R 1, R 2} , R 3, R ₅ , g and n are as defined above) by reacting with a reducing agent (e.g. sodium borohydride) in the presence of a solvent (e.g. alcohol, e.g. ethanol) at a temperature in the boiling range of 0 ° C to the solvent used. It can manufacture.

Compounds of formula I, wherein R ₄ is a C _1-4 alkylaminomethylene group, are compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is Is an amine of the formula R _a NH ₂ , wherein R _a is a C _1-4 alkyl group and a reducing agent in the presence of a solvent such as tetrahydrofuran at temperatures ranging from 0 ° C. to the boiling point of the solvent used. For example, by reacting with sodium triacetoxyborohydride.

Compounds of formula I, wherein R ₄ is a group of formula -C (OH) R _x R _y , wherein R _x and R _y are each independently a C _1-5 alkyl group, are compounds of formula VI, wherein A , R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is a C _1-5 alkyl group) in the presence of a solvent (eg tetrahydrofuran or ether) at −50 ° C. Organometallic reagents [eg, compounds of the formula R _x MgX or R _x Li (e.g., where R _x is as defined above and X is halo, for example bromo) at temperatures ranging from the boiling point of the solvent used. It can be prepared by reacting with].

Compounds of Formula I, wherein R ₄ is a group of Formula -C (OH) R _x R _y , wherein R _x and R _y are the same C _1-2 alkyl group, are defined as compounds of Formula VI, Wherein R _y is OR _z and R _z is a C _1-6 alkyl group) at a temperature ranging from -50 ° C. to the boiling point of the solvent used in the presence of a solvent (eg tetrahydrofuran or ether). Example: a compound of formula R _x MgX or R _x Li, wherein R _x is as defined above and X is halo, eg bromo).

Compounds of formula I wherein R ₄ is a C _2-6 alkenyl group in which the double bond is bonded to the α carbon to the thiazole ring or styryl group are compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is hydrogen or a C _1-4 alkyl group) in the presence of a base (eg n-butyllithium) in a solvent (eg ether, for example , Phosphonium salt of the formula R _z Ph ₃ P ⁺ Br ^- at temperatures ranging from -78 ° C to the boiling point of the solvent used, in tetrahydrofuran, wherein R _z is a C _1-5 alkyl group or benzyl group It can manufacture by reacting with.

Compounds of formula (I) wherein R ₄ is a C _2-6 alkanoyl group include compounds of formula (I) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R ₄ is halo , For example bromo or chloro) or a compound of formula V in the presence of a solvent (eg ether, such as diethyl ether or tetrahydrofuran), ranging from -78 ° C to the boiling point of the solvent used In which a compound of formula R _b MgX or R _b Li (e.g., wherein R _b is a C _1-6 alkyl group and X is halo, for example bromo or chloro), Acylating agents, for example compounds of the formula R _c CON (CH ₃ ) OCH ₃ , wherein the temperature is in the range of from 0 ° C. to the boiling point of the solvent used in a solvent such as ether, for example tetrahydrofuran. R _c is a C _1-5 alkyl group). Compounds of formula VI can be prepared in a similar manner.

A compound of formula (I) wherein R ₄ is a C _1-3 alkoxyC _1-3 alkyl group is a compound of formula (I) wherein R ₄ is a hydroxy C _1-3 alkyl group and A, R ₁ , R ₂ , R ₃ , R _5, g and n are as defined above) with a base (e.g., solvent in the presence of sodium hydride) (e.g., n, N- dimethylformamide) at a temperature of -50 to 150 C _1- ℃ range in ₃ alkylating agents, for example C _1-3 alkyl halides, such as C _1-3 alkyl iodide.

A compound of formula (I) wherein R ₄ is a C _4-7 cycloalkoxyC _1-3 alkyl group is a compound of formula (I) wherein R ₄ is a hydroxy C _1-3 alkyl group, and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above) in the presence of a base (e.g. sodium hydride) in a solvent (e.g. N, N-dimethylformamide) at a temperature ranging from -50 to 150 ° C. It can be prepared by reacting with a _4-7 cycloalkylalkylating agent, for example C _4-7 cycloalkylalkyl halide (eg C _4-7 cycloalkylalkyl iodide).

A compound of formula I wherein R ₄ is a C _3-7 alkynylalkoxyC _1-3 alkyl group is a compound of formula I wherein R ₄ is a hydroxy C _1-3 alkyl group, and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above, in the presence of a base (eg sodium hydride) at a temperature ranging from -50 to 150 ° C. in a solvent (eg N, N-dimethylformamide). It may be prepared by reacting with a C _3-7 alkynylalkylating agent such as C _3-7 alkynylalkyl halide (eg C _3-7 alkynylalkyl iodide).

A compound of formula (I) wherein R ₄ is a C _1-3 alkylthioC _1-3 alkyl group is a compound of formula (I) wherein R ₄ is a mercapto C _1-3 alkyl group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above in the presence of a base (e.g. sodium hydride or sodium hydroxide), in a solvent (e.g. N, N-dimethylformamide) in the range of -50 to 150 ° C. It can be prepared by reaction with a C _1-3 alkylating agent, for example C _1-3 alkyl halide (eg C _1-3 alkyl iodide) at temperature.

A compound of formula (I) wherein R ₄ is a C _1-3 alkylthio group or an arylthio group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above is a compound of formula (I) R ₄ is halo) or a metal at a temperature in the range of −100 ° C. to the boiling point of the solvent used, in a compound of Formula V and a solvent such as ether or a mixture of ethers such as tetrahydrofuran or diethyl ether Reacting with an agent, for example a compound of formula RMgX or RLi, where R is a C _1-6 alkyl group and X is halo, for example chloro, bromo or iodo, to obtain an intermediate complex. It can then be prepared by reacting with a disulfide of formula R _d S-SR _d , wherein R _d is a C _1-3 alkyl group or aryl group, at a temperature in the boiling range of the solvent used -100 ° C.

A compound of formula (I) wherein R ₄ is a C _1-3 alkoxy group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above is a compound of formula (I) wherein R ₄ is halo, Bromo or iodo), for example, in the presence of a solvent (eg C _1-3 alcohol or dimethylformamide), optionally in the presence of a catalyst (eg copper (I) salt) in the range of 0 to 350 ° C. It can be prepared by reacting with a C _1-3 alkoxide salt, for example sodium or potassium salt at temperature.

Compounds of formula I wherein R ₄ is a C _3-6 alkenyl group in which the double bond is not bonded to the α carbon to the thiazole ring are compounds of formula I wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R ₄ is halo, e.g. bromo or chloro, or a compound of formula V is used as a solvent (e.g. ether, e.g. diethyl ether or tetrahydrofuran). Compounds of the formula R _b MgX or R _b Li in the presence of) at temperatures ranging from -78 ° C. to the boiling point of the solvent used, wherein R _b is a C _1-6 alkyl group and X is halo, for example bro Parent or chloro), and the resulting product is then subjected to an alkenylating agent, for example, at a temperature in the solvent (eg ether, for example tetrahydrofuran) at a temperature in the range of 0 ° C. to the boiling point of the solvent used. C _3-6 alkenyl-methyl halide (for example: C _3-6 alkenyl, methyl iodide) and reaction sikimeu Writing can be prepared.

Compounds of formula I, wherein R ₄ is a C _3-6 alkoxycarbonylalkyl group, are compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is hydrogen a) a base (such as a solvent in the presence of sodium hydride) (for example, ethers, for example, in formula 1, 4-dioxane) the temperature of the boiling point range of -78 ℃ to the solvent to be used in the Me ₂ Reacted with a phosphonate of NCH [PO (OR _z ) ₂ ] ₂ , where R _z is a C _1-4 alkyl group, and then the resulting intermediate product is partially hydrolyzed in the presence of an acid, such as hydrochloric acid. It can manufacture by making it.

Compounds of formula I wherein R ₄ is a C _4-6 hydroxyalkenyl group in which the double bond is bonded to the α carbon to the thiazole ring are compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined above and R _y is hydrogen) in the presence of a base (e.g. sodium hydride) in a solvent (e.g. ether, e.g. tetrahydrofuran) To a compound of the formula (R _z O) ₂ POCH ₂ COR _c , wherein R _z is a C _1-2 alkyl group and R _c is a C _1-3 alkyl group at a temperature in the boiling range of the solvent used. The resulting intermediate product can then be prepared by reacting with a reducing agent (eg sodium borohydride) in a solvent (eg ethanol) at a temperature in the boiling range of the solvent used -20 ° C.

Compounds of formula III are either commercially available or can be prepared by methods known to those skilled in the art. Compounds of formula IV can be prepared by methods known to those skilled in the art, as specified in the individual examples described herein.

The ability of a compound of formula (I) to interact with a 5-hydroxytryptamine (5-HT) receptor has been shown to improve the ability of compounds to inhibit the binding of tritiated ligands to 5-HT receptors and, in particular, 5-HT _1A receptors in vitro. It was demonstrated as the product of Examples 1-56 by the following test to determine the ability.

Hippocampal tissue obtained from the brains of male Sprague-Dawley rats (Charles River; weight range 150-250 g) is homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7, 1:40 w / v measured at 25 ° C) And centrifuge at 40,000 g for 10 minutes at 4 ° C. The pellet is re-homogenized in the same buffer, incubated at 37 ° C. for 10 minutes and then 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 (corresponding to 6.25 mg / ml of wet weight of tissue). Use immediately for assay.

Membrane (400 μl; corresponding to wet weight of 2.5 mg / tube of tissue) was added to [ ³ H] 8-hydroxy-2- (dipropylamino) tetraline ([ ³ H] 8-OH at a single concentration of 1 nM). 50 μl of DPAT) and 50 μl of distilled water (total binding) or 50 μl of test compound (at a single concentration of 10 ⁻⁶ M or at 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 5-HT (10 μM Incubate for 30 minutes at 25 ° C. The culture is terminated by rapid filtration in vacuo through a Skrtron 11734 filter using a Skatron Cell Harvester. The filter is washed with ice cold 50 mM Tris-HCl buffer, pH 7.7 (25 ° C., wash setting 9,9,0). The graded filter paper discs are punctured into vials, scintillation fluid is added, and radioactivity is measured by liquid scintillation coefficients.

The ability of a compound of formula (I) to interact with a 5-hydroxytryptamine (5-HT) resorption site is such that it replaces the standard ligand [ ³ H] citaloprem, from the 5-HT resorption site in vitro. The product of Examples 1-56 was demonstrated by the following test to determine the ability of.

Frontal cortex tissue obtained from the brains of male Charles River rats weighing 150-250 g was ice-cold 50 mM Tris-HCl buffer (pH 7.4 measured at 25 ° C.) containing 120 mM sodium chloride and 5 mM potassium chloride. Homogenize in Tris buffer; 1:30 w / v) and centrifuge at 40,000 g for 10 minutes. Discard the supernatant and re-homogenize the pellet in Tris buffer (1:60 w / v), then centrifuge at 40,000 g for 10 minutes. Repeat this step several times. The final pellet is resuspended in 50 mM Tris-HCl buffer (pH 7.4) (corresponding to wet weight 3.125 mg / ml of tissue) containing 120 mM sodium chloride and 5 mM potassium chloride and used immediately in the binding assay. All centrifugations are performed at 4 ° C.

Membrane (400 μl; corresponding to a wet weight of 1.25 mg / tube of tissue) was 50 μl of [ ³ H] citaloprem and 50 μl of distilled water (total binding) at a single concentration of 1.3 nM or 50 μl of test compound ( ^10-6 Incubate at 27 ° C. for 1 hour at a single concentration of M or at 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of paroxetine (0.5 μm, nonspecific binding). Membrane binding radioactivity is recovered by filtration under vacuum through a Scrone 11734 filter pre-soaked in 0.5% PEI using a Scrone cell harvester. The filter is then washed with ice cold 50 mM Tris-HCl buffer, pH 7.4 (25 ° C., wash setting 9,9,0). Graded filter paper discs are punched into vials, scintillation fluid is added, and radioactivity is measured by liquid scintillation coefficients.

The ability of a compound of formula (I) to interact with a noradrenaline (NA) resorption site is determined in the following test, which measures the ability of a compound to substitute the standard ligand [ ³ H] nisoxetine from the noradrenaline reuptake site in vitro. By the products of Examples 1 to 33.

Frontal cortex tissue obtained from the brains of male Higgs River rats weighing 150-250 g was ice-cold 50 mM Tris-HCl buffer (pH 7.4 measured at 25 ° C.) containing 120 mM sodium chloride and 5 mM potassium chloride (Tris buffer; 1 : 60 w / v) and centrifuge at 40,000 g for 10 minutes. Discard the supernatant and re-homogenize the pellet in Tris buffer (1:60 w / v), then centrifuge at 40,000 g for 10 minutes. Repeat this step two more times, in total, homogenizing brain tissue and centrifuging four times. The final pellet is resuspended in 50 mM Tris-HCl buffer (pH 7.4) (corresponding to wet weight of tissue 18.75 mg / ml) containing 300 mM sodium chloride and 5 mM potassium chloride and used immediately for binding assays. All centrifugations are performed at 4 ° C.

Membrane (400 μl; corresponding to wet weight 7.5 mg / tissue of tissue) 50 μl of [ ³ H] nisoxetine and 50 μl of distilled water (total binding) at a single concentration of 0.6 nM or 50 μl of test compound (10 ⁻⁶ M At a single concentration of 10 or at 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or 50 μl of marginal (1 μM, nonspecific binding) at 4 ° C. for 4 hours. Membrane bound radioactivity is recovered by filtration under vacuum through a Scrone 11734 filter using a Scrone cell harvester. The filter is then washed with ice cold 50 mM Tris-HCl buffer, pH 7.4 (wash settings 9,9,0) containing 120 mM sodium chloride and 5 mM potassium chloride. Graded filter paper discs are punched into vials, scintillation fluid is added, and radioactivity is measured by liquid scintillation coefficients.

The ability of a compound of formula (I) to interact with a muscarinic receptor is determined by the following test, which measures the ability of a compound to substitute the standard ligand [ ³ H] N-methylscopolamine from the muscarinic receptor in vitro. Proven by 1 to 56 product.

The frontal cortical tissue obtained from the brains of male Higgs River rats weighing 150-250 g contains 100 mM sodium chloride and 10 mM magnesium chloride using Polytron PT3100 (speed setting; 21,700 rpm, 3 x 5 seconds). Homogenized in ice cold 20 mM HEPES buffer (pH 7.5 measured at 25 ° C.) (1:10 w / v) and centrifuged at 49,500 g at 4 ° C. for 30 minutes. Discard the supernatant and re-homogenize the pellet in 20 mM HEPES buffer (pH 7.5; corresponding to wet weight of tissue 12.5 mg / ml) containing 100 mM sodium chloride and 10 mM magnesium chloride. The membrane is stored at -80 ° C until needed.

The membrane is dissolved and diluted 1:10 with ice cold 20 mM HEPES buffer (pH 7.5) containing 100 mM sodium chloride and 10 mM magnesium chloride and homogenized using the polytron PT3100 as described above. The diluted membrane (200 μl; corresponding to wet weight 0.25 mg / tube of tissue) was added to 200 μl of 20 mM HEPES buffer (pH 7.5) containing 100 mM sodium chloride and 10 mM magnesium chloride at a single concentration of [ ³ H] N 50 μl of methylscopolamine and 50 μl of distilled water (total binding) or 50 μl of test compound (at a single concentration of 10 ⁻⁶ M or at 10 concentrations ranging from 10 ⁻¹¹ to 10 ⁻³ M) or atropine sulfate ( 1 μm, nonspecific binding) and incubate at 30 ° C. for 30 minutes. Membrane bound radioactivity is recovered by filtration under vacuum through a Scrone 11734 filter using a Scrone cell harvester. The filter is then quickly washed with ice cold 20 mM HEPES buffer (pH 7.5) (wash 1,2 at 5,5 settings). Graded filter paper discs are punched into vials, scintillation fluid is added, and radioactivity is measured by liquid scintillation coefficients.

In vitro, these measure the ability of compounds of formula (I) to substitute standard ligands from 5-HT _1A receptor and 5-hydroxytrytamine (5-HT) and noradrenaline (NA) resorption sites and muscarinic receptors For each test, the substitution rate of the specific binding of the tritiated ligand by the ^10-6 M test compound is calculated by the following method.

First, the specific binding of tritiated ligands in the absence (A) and presence (N) of the test compound is determined:

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

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

Subsequently, the substitution rate of the specific binding of the tritiated ligand by the test compound ( ^10-6 M) is obtained by subtracting the% of specific binding in the presence of the compound from the% of specific binding in the absence of the compound, which is referred to as the maximum binding. Consider, 100%:

% Substitution at 10 ⁻⁶ M =% specific binding at 100 −10 ⁻⁶ M

In some cases, substitution curves are drawn for compounds that substitute for at least 50% of the specific binding of tritiated ligands at 10 ⁻⁶ M using the concentration range of the compound. Ki is then calculated by adjusting the following simultaneous equation (derived from the Feldman equations) by strong nonlinear regression on the data obtained from three experiments simultaneously:

Where

B is the concentration of bound ligand-receptor complex, which for each observation Is calculated by

L is the concentration of the compound,

[L] _tot is the concentration of tritiated ligand used Is calculated by

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 receptors in the first experiment, which should be multiplied by C _k (C ₁ = 1) for subsequent experiments,

N _k is a nonspecific binding constant.

The results obtained in the above tests for 5-HT _1A binding and 5-HT and NA resorption and muscarinic binding to the final products of Examples 1 to 56 are shown in Table 1 below. K _i is in nM and is the average of three independent measurements. The% number is the percent substitution at 10 ⁻⁶ M in a single measurement.

Example number 5-HT _1A 5-HT Absorption NA absorption Muscarin One 51% One% 58% 0% 2 13 398 3.7 19% 3 201 200 12 28% 4 26 72% 6.2 0% 5 11 162 3.1 16% 6 7.7 378 3.5 9% 7 18 492 8.9 338 8 79% 48% 85% 87% 9 114 119 17 17% 10 73% 19% 94% 16% 11 97% 8% 61% 39% 12 93% 18% 87% 54% 13 101 89 2.0 15 14 82% 39% 3.1% 16% 15 60 269 8.1 4% 16 27 510 3.8 418 17 16 162 2.7 10.4 18 2.0 14% 46 11% 19 59% 8% 57% 19% 20 5.0 623 9.3 420 21 62% 13% 93% 22% 22 93 283 2.2 49 23 27 71 1.1 63 24 98 245 5.6 353 25 74% 34% 99% 51% 26 61% 57% 99% 33% 27 64% 43% 99% 49% 28 73% 48% 97% 48% 29 55% 42% 99% 35% 30 58% 42% 99% -5% 31 53% 62% 101% 28% 32 69% 54% 100% 36% 33 55% 48% 101% 28% 34 76 234 61 23% 35 36.5 347 2.2 245 36 62% 68% 104% 95% 37 189 30% 146 20% 38 50% 5% 84% 16% 39 73% 64% 64% 64% 40 75% 62% 44% 16% 41 2.9 110 7.5 28% 42 100% 65% 101% 31% 43 57% 60% 102% 99% 44 53% 4% 86% 32% 45 8.8 28 1.6 7.9 46 94% 92% 100% 88% 47 53% 65% 97% 39% 48 23 24.3 4.1 3.9

Example number 5-HT _1A 5-HT Absorption NA absorption Muscarin 49 77% 61% 102% 73% 50 98% 46% 82% 81% 51 2.1 251 17 39% 52 66% 86% 103% 97% 53 64% 71% 101% 100% 54 54% 97% 101% 2% 55 60% 85% 101% NT 56 61% 81% 101% 96% Ki value is the average when n is 1 or the average when n is 3. NT: Not tested.

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

The assay is performed using the following general method in which the tissue is the human placenta:

enzyme temperament culture Reaction product Detection method MAO-A (h) Kynuramine (0.15 mM) 30 minutes / 30 degrees Celsius 4-OHquinoline Spectrophotometry

Compounds are tested twice at 1 and 10 μm.

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

Combination of inhibition of monoamine oxidase activity and inhibition of 5-HT reuptake can lead to significantly undesirable serotonin syndrome (Sternbach, H. Serotonin syndrome, Am. J. Psychiatry 148, 705-713, 1991).

Acute Breeding Research

Animals and environment

Experiments are performed on male Sprague-Dawley rats (weight 300-450 g at the start of the experiment) obtained from Charles River (Margate). Animals are individually housed 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 reverse day and night cycles. The light is blocked from 09.30 to 17.30 when the room is illuminated with red light. Animals are always free to access the rat powder diet and tap water. The diet is contained in a glass feed can (10 cm in diameter; 8 cm deep) 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

The day before the test, animals are randomly placed into treatment groups containing 6 to 8 rats, weighed and their feed intake measured over 6 hours. These reference readings are taken to ensure that the body weight and feed intake of the rats of the different groups do not differ significantly from that prior to drug treatment. On the day of testing, animals are given a vehicle or three doses of test drug. All drugs are administered orally at the onset of memorization since rats spend most of their feed on memorization. The feed bottle is weighed (up to approximately 0.1 g) upon 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 change in body weight can be seen by expressing the results as g / kg rat weight (treatment group mean ± standard error mean). The ED ₅₀ value (drug dose required to reduce feed intake to 50% of control) is calculated from the logarithmic sigmoid curve using a specific computer program. Statistical comparisons between mean group intakes are performed using variable analysis and Dunnett's test (two-tailed).

Particularly preferred compounds of formula (Ia) have surprisingly lower affinity for muscarinic receptors than the examples of WO 97/02269 and / or significantly reduced MAO compared to the compounds exemplified in WO 97/02269. _A has inhibitory activity. For example, Example 1 of WO 97/02269 has a muscarinic receptor binding K _i of 130 nM. Muscarinic affinity can lead to undesirable side effects, such as exacerbation of dry mouth, dreaming, sweating, palpitations, constipation, and narrow angle glaucoma (Blackwell, B. Adverse effects of antidepressant drugs.Part 1 Monoamine oxidase inhibitors) and tricyclics.Drugs 21, 202-219, 1981). Clearly, compounds with minimal affinity for muscarinic receptors are preferred.

Particularly preferred compounds of the invention have good activity in acute breeding studies compared to the compounds exemplified in WO 97/02269.

The invention is illustrated by the following examples which are presented by way of example only. The final product of each of these examples is characterized by one or more of high performance liquid chromatography, elemental analysis, nuclear magnetic resonance spectroscopy, mass spectroscopy and infrared spectroscopy.

Example

Example 1

Triethylamine (75 mL) was diluted 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thia in dichloromethane (400 mL) at less than 10 ° C. To the stirred suspension of sol hydrobromide (50 g, prepared in a manner similar to that described in WO 97/02269) is added dropwise, and then the mixture is stirred at ambient temperature for 1 hour. Water (300 mL) was added, then the organic phase was separated, washed twice with 100 mL of water and with saturated aqueous sodium chloride solution (100 mL) and dried (Na ₂ SO ₄ ) to remove the solvent under vacuum, 3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole is obtained as a pale yellow solid (34 g) used without further purification.

n-butyllithium (2.5M solution in hexanes; 17.5 mL) in 3- (benzo [b] thiophen-3-yl) -5,6-dihydro in tetrahydrofuran (260 mL) at −70 ° C. under nitrogen. To the stirred solution of imidazo [2,1-b] thiazole (10.14 g) was added dropwise, then the mixture was stirred at −70 ° C. for 20 minutes, warmed to 0 ° C. and then stirred at 0 ° C. for 30 minutes do. Dimethylformamide (2.86 mL) is added and the mixture is stirred at ambient temperature for 20 minutes. Saturated aqueous sodium chloride solution (200 mL) and ether (400 mL) were added, then the organic phase was separated, washed with water (100 mL) and saturated aqueous sodium chloride solution (100 mL), dried (Na ₂ SO ₄ ), and then solvent Is removed under vacuum. The residue is purified by flash chromatography on silica using a 10: 1 mixture of dichloromethane and methanol as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue is heated to reflux with propan-2-ol (100 mL) for 5 minutes, then the mixture is filtered hot and cooled to ambient temperature. The resulting solid was collected by filtration and dried under vacuum at 60 ° C. to give 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] -2-car Voxaldehyde is obtained as a yellow solid (1.4 g). Melting point 206 캜.

Example 2

3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.198 g), sodium borohydride (0.026 g) And a mixture of methanol (20 mL) under nitrogen at ambient temperature for 1 hour, then water (2 mL) is added and the mixture is concentrated in vacuo to remove methanol. The residue was partitioned between water (30 mL) and ethyl acetate (50 mL), then the organic phase was separated, washed with saturated aqueous sodium chloride solution (20 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo. To give [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol as a yellow solid (0.077 g) do. Melting point 168-170 ° C.

Example 3

3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.44 g), hydroxylamine hydrochloride (0.118 g) and a mixture of ethanol (30 mL) are heated under reflux for 2.75 h and then cooled to ambient temperature. The resulting solid is collected by filtration and suspended in dichloromethane (50 mL). Triethylamine (3 mL) was added, and the resulting solution was washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried (MgSO ₄ ), and then the solvent was removed under vacuum to obtain 3- ( Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde oxime is obtained as a white solid (0.07 g). Melting point 226 to 228 ° C.

Example 4

Methylmagnesium bromide (3M solution in ether, 1.2 mL) was added to 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo in tetrahydrofuran (30 mL) at 0 ° C. under nitrogen. To the stirred solution of 2,1-b] thiazole-2-carboxaldehyde (0.286 g) is added drop wise, and then the mixture is stirred at ambient temperature for 15 minutes. Water (5 mL) and ethyl acetate (70 mL) were added, then the organic phase was separated, washed with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), dried (Na ₂ SO ₄ ), and the solvent Remove under vacuum. The residue was triturated with ether (30 mL), the resulting solid was collected by filtration and then dried under vacuum at 100 ° C. to give 1- [3- (benzo [b] thiophen-3-yl) -5,6- Dihydroimidazo [2,1-b] thiazol-2-yl] -ethanol is obtained as off-white solid (0.213 g). Melting point 174-176 ° C.

Example 5

Of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (0.5 g) in ethanol (25 mL) The suspension is heated under reflux until all solids are dissolved. Ethereal hydrogen chloride solution (1M; 2 mL) is added, then the mixture is heated to reflux for 3 minutes and cooled to ambient temperature. The resulting solid was collected by filtration, washed with ether (20 mL) and dried under vacuum at 60 ° C. to give 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [ 2,1-b] thiazole-2-methanol hydrochloride is obtained as a white solid (0.32 g). Melting point 240-250 ° C. (decomposition). An ethereal hydrogen chloride solution (1M; 2 mL) is added to the remaining filtrate from the separation of the solid and the mixture is stirred at ambient temperature for 18 hours. The resulting solid was collected by filtration, washed with ether (20 mL) and dried under vacuum at 60 ° C. to yield [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo A second crop of [2,1-b] thiazol-2-yl] methanol hydrochloride is obtained as a white solid (0.1 g). Melting point 240-250 ° C. (decomposition).

Example 6

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

Bromine (55.5 mL) was added 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (264.3 g) in dichloromethane at 0-5 ° C. To the stirred solution of was added dropwise for 1.75 hours, then the mixture was 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 then dried in vacuo at 70 ° C. to be used without further purification 3- (benzo [b] thiophen-3-yl) -2- Bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide is obtained as a pale yellow solid (431 g).

3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (170 g) was dissolved in nitrogen with tetrahydrofuran (1700). ML) was added to a stirred solution of ethylmagnesium chloride (2.0M solution in ether (620 mL)) in portions at 0-8 ° C. for 1 h, then the mixture was stirred at 3 ° C. for 1.5 h. Dimethylformamide (136 mL) was added at 3-8 ° C. for 30 minutes, 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) Quench by carefully adding Ethyl acetate (1500 mL) is added and the mixture is stirred at ambient temperature for 18 hours, then 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), dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is dissolved in hot propan-2-ol (1000 mL), the solution is filtered hot and left at ambient temperature for 20 hours. The resulting solids were collected by filtration, washed with propan-2-ol (100 mL) and dried under vacuum at 70 ° C. to give 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimime. Dazo [2,1-b] thiazole-2-carboxaldehyde is obtained as a yellow solid (19.4 g). 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 separated from the aqueous layer into dichloromethane (500 mL) by extraction. The combined dichloromethane solution was dried (MgSO ₄ ) and the solvent removed in vacuo to further add 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b ] Thiazole-2-carboxaldehyde is obtained as a yellow solid (63.0 g). Melting point 208 캜.

Sodium borohydride (12.5 g) was added to 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole- in methanol (1200 mL) for 10 minutes. To the ice cold stirred suspension of 2-carboxaldehyde (63 g) is added in portions, then the mixture is stirred at 5 ° C. for 30 minutes, at ambient temperature for 4 hours and at reflux for 20 minutes. The mixture is cooled to ambient temperature for 1 hour, then water (200 mL) is added and stirring is continued at ambient temperature for 1 hour. The resulting solid was collected by filtration, washed with water (200 mL), ethanol (200 mL) and ether (200 mL) and then dried in vacuo at 60 ° C., which was used without further purification [3- (benzo [ b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol is obtained as an off-white solid (52.1 g).

Of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (52.1 g) in methanol (2200 mL) The stirred suspension is heated under reflux until virtually all solids are dissolved. The heat source is removed and a solution of fumaric acid (21 g) in methanol (250 mL) is added for 1 minute. The mixture is stirred for 10 minutes, then left at ambient temperature for 1 hour and ice cooled for 3 hours. The resulting solids were collected by filtration, washed with ice cold methanol (200 mL), dried under vacuum at 60 ° C. for 3 hours and at 80 ° C. for 2 hours, and found to be solvated with 1 equivalent of methanol by nMr spectroscopy. Obtain a white solid. This solid is combined with a second sample (5.2 g; also solvated by methanol) of the product prepared in a similar manner as described above, and the combined material is ground using a pestle and mortar and then at 90 ° C. and 133 kPa. Dry for 15 hours in vacuo to give [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol fumarate ( Solvated with 0.05 equivalents of methanol) is obtained as a white solid (53.4 g). Melting point 258-262 DEG C (decomposition).

Example 7

Phenyltrimethylammonium tribromide (3.0 g) in 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1 in tetrahydrofuran (50 mL) at 0 ° C. under nitrogen. -b] to a stirred suspension of thiazole (2.0 g) is added in portions and the mixture is stirred at 0 ° C. for 1 hour and at ambient temperature for 18 hours. Water (50 mL) and triethylamine (50 mL) are added, the organic phase is separated, washed with saturated aqueous sodium chloride solution (50 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is purified by flash chromatography on silica using a 9: 1 mixture of ethyl acetate and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to afford 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole. Obtained as a yellow solid (1.0 g). Melting point 196 to 200 ° C.

Example 8

Phenyltrimethylammonium tribromide (0.75 g) was added to 3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [] in tetrahydrofuran (15 mL) at 0 ° C. under nitrogen. To the stirred suspension of 3,2-a] pyrimidine (0.5 g; prepared in a similar manner as described in WO 97/02269) in portions, the mixture is stirred at 0 ° C. for 4 hours, Warm to temperature. Water (50 mL) and triethylamine (50 mL) are added, the organic phase is separated, washed with saturated aqueous sodium chloride solution (50 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is purified by flash chromatography on silica using a 9: 1 mixture of ethyl acetate and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to afford 3- (benzo [b] thiophen-3-yl) -2-bromo-6,7-dihydro-5H-thiazolo [3,2-a] Pyrimidine is obtained as a pale yellow solid (0.2 g). Melting point 200 to 202 캜.

Example 9

Sodium hydride (60% dispersion in mineral oil; 1.35 g) was added in portions to a stirred solution of 3-acetyl-benzo [b] thiophene (2.9 g) in diethyl carbonate (50 mL) at ambient temperature under nitrogen, and then The mixture is stirred at 80 ° C. for 1.5 h and then poured into a mixture of water (300 mL) and acetic acid (5 mL). The product is extracted three times with 150 ml of ether, then the combined extracts are washed twice with 50 ml of water and with saturated aqueous sodium chloride solution (50 ml) and dried (MgSO ₄ ) to remove the solvent in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R apparatus using a 9: 1 mixture of hexane and ethyl acetate as eluent. The appropriate fractions are combined and the solvent is removed in vacuo to give ethyl 3- (benzo [b] thiophen-3-yl) -3-oxopropanoate as a brown oil (1.5 g) which is used without further purification. .

Phenyltrimethylammonium tribromide (2.15 g) in ethyl 3- (benzo [b] thiophen-3-yl) -3-oxo-propanoate (1.5 g) in tetrahydrofuran (30 mL) at 0 ° C. under nitrogen. To the stirred solution is added in portions, then the mixture is stirred at 0 ° C. for 30 minutes and at ambient temperature for 1.5 hours. The resulting solid is filtered off and washed with tetrahydrofuran (30 mL). The filtrate and washings are combined and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R apparatus using a mixture of 9: 1 of petroleum ether (boiling point: 60-80 ° C.) and ethyl acetate as eluent. The appropriate fractions are combined and the solvent is removed in vacuo to give ethyl 3- (benzo [b] thiophen-3-yl) -2-bromo-3-oxopropanoate as a brown solid (1.7 g). Melting point 81-83 ° C.

Of ethyl 3- (benzo [b] thiophen-3-yl) -2-bromo-3-oxopropanoate (1.7 g), 2-imidazolidinethione (0.53 g) and ethanol (30 mL) The mixture is heated at reflux for 10 minutes and then the mixture is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is triturated with ethanol (20 mL). The resulting solid was collected by filtration, washed with ethanol (10 mL) and ether (20 mL), dried at 60 ° C. in vacuo, ethyl 3- (benzo [b] thiophen-3-yl) -5,6 -Dihydroimidazo [2,1-b] thiazole-2-carboxylate is obtained as an off-white solid (1.15 g). Melting point 209 to 211 ° C.

Ethyl 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxylate (0.4 g), triethylamine (2 mL) And a mixture of dichloromethane (15 ml) was stirred at ambient temperature for 20 minutes, then diluted with dichloromethane (40 ml), washed twice with 20 ml of water and washed with saturated aqueous sodium chloride solution (20 ml) and dried ( Na ₂ SO ₄ ), and then the solvent is removed in vacuo. The residue (0.22 g) was dissolved in tetrahydrofuran (7 mL) and methylmagnesium bromide (3M solution in ether; 0.66 mL) was added under nitrogen. The mixture is stirred at ambient temperature for 2 hours, followed by further addition of methylmagnesium bromide (3M solution in ether; 0.42 ml) and toluene (5 ml). The mixture is stirred at ambient temperature for 5 minutes and at 90-95 ° C. for 5 hours, then cooled to ambient temperature and diluted with water (30 mL). The product is extracted twice with 30 ml of ethyl acetate and the combined extracts are washed with water (30 ml) and saturated aqueous sodium chloride solution (30 ml), dried (MgSO ₄ ) and the solvent is removed in vacuo. The mixture of residue, fumaric acid (0.037 g) and ethanol (5 mL) is heated under reflux for 5 minutes, then the hot solution is discarded from a small amount of undissolved solid and cooled to ambient temperature. The resulting solids were collected by filtration, washed with ether (10 mL) and dried at 60 ° C. in vacuo to give 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimime Dazo [2,1-b] thiazol-2-yl] -1-methyl-ethanol fumarate is obtained as off-white solid (0.057 g). Melting point 180 to 182 ° C.

Example 10

Ethylmagnesium chloride (2M solution in ether; 1.4 mL) was added to 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2, in tetrahydrofuran (30 mL) at ambient temperature. To the stirred solution of 1-b] thiazole-2-carboxaldehyde (0.52 g) is added drop wise, and the mixture is then stirred at ambient temperature for 30 minutes. In addition, ethylmagnesium chloride (2M in ether; 0.5 ml) is added and the mixture is stirred at ambient temperature for 1 hour and then quenched by addition of water (30 ml). The product was extracted with ether (50 mL), then extracted twice with 50 mL of ethyl acetate and the combined extracts washed twice with 30 mL of saturated aqueous sodium chloride solution, 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 apparatus using a 99: 1 mixture of dichloromethane and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2- Il] propan-1-ol is obtained as an orange solid (0.24 g). Melting point 92 to 94 ° C.

Example 11

Triethylamine (50 mL) was added 3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1- in dichloromethane (25 mL) at ambient temperature. b] dropwise to a stirred suspension of thiazole hydrobromide (1 g; prepared in a similar manner as described in WO 97/02269), and then the mixture is stirred at ambient temperature for 10 minutes. Water (25 mL) was added followed by separation of the organic phase, washing with water (25 mL) and then drying (Na ₂ SO ₄ ) to remove the solvent in vacuo to give 3- (5) which was used without further purification. -Methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole is obtained as a brown solid (0.65 g).

Phenyltrimethylammonium tribromide (1.5 g) in 3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo in tetrahydrofuran (25 mL) at 0 ° C. under nitrogen. To a stirred solution of [2,1-b] thiazole (0.65 g) is added in portions and the mixture is stirred at 0 ° C. for 16 h and then warmed to ambient temperature. Triethylamine (50 mL) and water (50 mL) were added, then the organic phase was separated and dried (Na ₂ SO ₄ ) to remove the solvent in vacuo. The residue is purified by flash chromatography on silica using a mixture of 99: 1: 0.1 of ethyl acetate, methanol and triethylamine as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue was crystallized from methanol, the resulting solid was collected by filtration and then dried under vacuum at ambient temperature to give 2-bromo-3- (5-methoxybenzo [b] thiophen-3-yl) -5, 6-Dihydroimidazo [2,1-b] thiazole is obtained as off-white solid (0.05 g). Melting point 210 ° C. (decomposition).

Example 12

Phenyltrimethylammonium tribromide (1.0 g) in 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimime in tetrahydrofuran (20 mL) at 0-5 ° C. under nitrogen. To a stirred solution of multizo [2,1-b] thiazole (0.8 g; prepared in a similar manner as described in WO 97/02269) is added in portions and the mixture is stirred at ambient temperature for 18 hours. Water (30 mL) and triethylamine (5 mL) were added, then the product was extracted twice with 20 mL of dichloromethane, and the combined extracts were washed four times with 20 mL of water, dried (MgSO ₄ ), and then solvent Under vacuum to remove 2-bromo-3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole as a yellow solid ( 0.72 g). Melting point 205-208 degreeC (decomposition).

Example 13

A mixture of 3-acetylbenzo [b] thiophene (25 g), dimethylamine hydrochloride (15.05 g), paraformaldehyde (5.7 g), concentrated hydrochloric acid (1 mL) and ethanol (75 mL) was refluxed for 18 hours. After heating, it is cooled to ambient temperature. The resulting solid was collected by filtration and dried under vacuum at ambient temperature to give 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) propan-1-one hydrochloride as a pink solid (15.7 g). Obtained as Melting point 169 to 171 ° C. The solvent is removed from the filtrate under vacuum and the residue is triturated with ether (100 mL). The resulting solid was collected by filtration and dried under vacuum at ambient temperature to remove the second crop of 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) -propan-1-one hydrochloride. Obtained as a pink solid (13.8 g).

A mixture of 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) -propan-1-one hydrochloride (29.4 g) and water (600 mL) was added to a saturated sodium carbonate solution to pH 9.0 After basification, the mixture is stirred at ambient temperature for 1 hour, and then the free base is extracted three times with 100 ml of ether. The combined extracts are dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is dissolved in methanol (50 mL), then the solution is ice cooled and iodomethane (15.7 mL) is added dropwise. The mixture was stirred at ambient temperature for 1 hour, then the resulting solid was collected by filtration, washed well with ether, dried at ambient temperature under vacuum, [3- (benzo [b] thiophen-3-yl)- 3-oxopropyl] trimethylammonium iodide is obtained as a pink solid (28.7 g). Melting point 165 to 167 ° C.

[3- (benzo [b] thiophen-3-yl) -3-oxopropyl] trimethylammonium iodide (5.0 g), sodium bicarbonate (5.0 g), ether (150 mL) and water (130 mL) The mixture of was stirred at ambient temperature for 4 hours and then the product was extracted with ether (3x150 mL). The combined extracts are dried (MgSO ₄ ) and the solvent is removed in vacuo to give 1- (benzo [b] thiophen-3-yl) propenone (2.1 g) as a pink solid, which is used without further purification. .

A solution of 1- (benzo [b] thiophen-3-yl) propenone (0.75 g) and benzyl alcohol (0.41 mL) in dichloromethane (2 mL) was cooled to 0 ° C. and concentrated sulfuric acid (2 drops) Add. The mixture is stirred at 0 ° C. for 3 hours and then left at 4 ° C. for 18 hours. An additional amount of benzyl alcohol (0.82 mL) was added and the mixture was stirred at 0 ° C. for 7 hours, then diluted with dichloromethane (20 mL), twice with 10 mL of saturated aqueous sodium hydrogen carbonate solution and water (10 mL). Washed with and dried (MgSO ₄ ). The solvent is removed in vacuo and the residue is purified by pre-scale thin layer chromatography on silica-coated glass plates using dichloromethane as eluent. The appropriate fraction of silica is separated from the developed plate and the product is extracted by grinding with dichloromethane (30 mL). The extract is filtered and the solvent is removed in vacuo to yield 1- (benzo [b] thiophen-3-yl) -3-benzyloxypropan-1-one (0.49 g) as an orange oil, which is further purified. Use without

Stirring of phenyltrimethylammonium tribromide (0.4 g) in 1- (benzo [b] thiophen-3-yl) -3-benzyloxypropan-1-ol (0.43 g) in tetrahydrofuran (5 mL) under nitrogen To the solution was added in portions, the mixture was stirred at ambient temperature for 18 hours, then filtered and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -3-benzyloxy- as a yellow oil. Obtain 2-bromopropan-1-one (0.56 g), which is used without further purification.

1- (benzo [b] thiophen-3-yl) -3-benzyloxy-2-bromopropane-1-one (0.54 g), 2-imidazolidinthione (0.15 g), ethanol (3 mL ) And acetic acid (1 mL) are heated to reflux under nitrogen for 18 h, then the solvent is removed in vacuo. The residue was triturated with ice cold ethanol (5 mL) and the resulting solid collected by filtration, washed with ethanol (5 mL) and dried under vacuum at 60 ° C. to give 3- (benzo [b] thiophene as a cream solid. -3-yl) -2-ethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (0.19 g) is obtained. Melting point> 250 ° C.

Example 14

Vinylmagnesium chloride (1M solution in tetrahydrofuran; 6.7 mL) was added 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimime in tetrahydrofuran (30 mL) under nitrogen at 0 ° C. To the stirred suspension of polyzo [2,1-b] thiazole-2-carboxaldehyde (0.64 g) is added dropwise, then the mixture is stirred at 0 ° C. for 10 minutes and at ambient temperature for 30 minutes. Water (50 mL) is added and the mixture is concentrated in vacuo to remove tetrahydrofuran and then the product is extracted with ethyl acetate (3 x 30 mL). The combined extracts are washed twice with 25 ml each of saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R apparatus using a 1-5% mixture of methanol in dichloromethane as eluent. The appropriate fractions are combined and the solvent removed in vacuo to yield 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole as a pale yellow foam. -2-yl] prop-2-en-1-ol (0.12 g) is obtained. Melting point 60-65 ° C.

Example 15

1-propynylmagnesium bromide (0.5M solution in ether; 10.5 mL) was added 3- (benzo [b] thiophen-3-yl) -5,6-di in tetrahydrofuran (30 mL) at 0 ° C. under nitrogen. To the stirred suspension of hydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g) is added dropwise, then the mixture is stirred at 0 ° C. for 10 minutes and at ambient temperature for 30 minutes. Water (60 mL) and ethyl acetate (100 mL) were added, then the organic phase was separated, washed twice with 25 mL each saturated aqueous sodium chloride solution, dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R apparatus using a 1-5% mixture of methanol in dichloromethane as eluent. The appropriate fractions are combined and the solvent removed in vacuo to give 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole as a white solid. -2-yl] but-2-yn-1-ol (0.11 g) is obtained. Melting point 190-200 ° C. (decomposition).

Example 16

n-butyllithium (2.5M solution in hexane; 4.7 mL) was added dropwise to a stirred solution of methyltriphenylphosphonium bromide (4.2 g) in tetrahydrofuran (30 mL) at 0 ° C. under nitrogen, and then the mixture was brought to 0 ° C. Stir for 5 minutes at 30 minutes at ambient temperature. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (3.05 g) was added in portions, and then the mixture was Heat under reflux for 3 hours and cool to ambient temperature. Water (50 mL) and ethyl acetate (75 mL) were added, then the organic phase was separated, washed with saturated aqueous sodium chloride solution (50 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is diluted with 2.5 M hydrochloric acid (75 mL) and the mixture is stirred at ambient temperature for 3 hours and then filtered to remove the rubbery semisolid. The filtrate was stirred with ethyl acetate (25 mL), then the organic phase was separated and dried (MgSO ₄ ) and the solvent removed in vacuo to afford slightly impure 3- (benzo [b] thiophen-3-yl) as a white solid. 2-vinyl-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride (0.85 g) is obtained. The additional product was extracted with dichloromethane (2 × 50 mL), separated and dried (MgSO 4), then the solvent was removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-vinyl-5 , 6-Dihydroimidazo [2,1-b] thiazole hydrochloride (0.49 g) is obtained as a white solid. Melting point 221-223 캜;

Example 17

3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (2 g) under nitrogen at 0-5 ° C. To a stirred solution of ethylmagnesium chloride (2M solution in ether; 7.2 ml) in tetrahydrofuran (20 ml) for 10 minutes is added in portions, and the mixture is stirred at 0-5 ° C. for 30 minutes. Allyl bromide (0.87 mL) is added dropwise and the mixture is stirred at ambient temperature for 18 hours, then quenched by addition of saturated aqueous ammonium chloride solution (15 mL) followed by water (10 mL). The product is extracted with ethyl acetate (50 mL), then the extract is washed with water (25 mL) and saturated aqueous sodium chloride solution (25 mL), dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 5-7% mixture of methanol in dichloromethane as eluent. The appropriate fractions are combined and the solvent removed in vacuo to give a brown rubber (0.36 g). The rubber is dissolved in ethanol (2 mL) and a solution of fumaric acid (0.13 g) in ethanol (2 mL) is added. The resulting solid was collected by filtration, washed with ethanol (10 mL) and dried under vacuum at 75 ° C. to yield 2-allyl-3- (benzo [b] thiophen-3-yl) -5,6- as an off-white solid. Dihydroimidazo [2,1-b] thiazole fumarate (0.22 g) is obtained. Melting point 163 to 164 ° C.

Example 18

n-butyllithium (2.5M solution in hexane; 1 mL) was added 3- (benzo [b] furan-3-yl) -5,6-dihydroimide in tetrahydrofuran (6 mL) under nitrogen at −70 ° C. To a stirred solution of dazo [2,1-b] thiazole (0.5 g; prepared in a similar manner as described in WO 97/02269) for 10 minutes, the mixture was then stirred at -70 ° C for 30 minutes. Stir. Dimethylformamide (0.2 mL) is added and the mixture is stirred at −70 ° C. for 5 minutes and then warmed to ambient temperature. Saturated aqueous ammonium chloride solution (30 mL) is added and the product is extracted with dichloromethane (3 x 30 mL). The combined extracts are washed with water (30 mL) and dried (Na ₂ SO ₄ ), then the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 9: 1 mixture of dichloromethane and methanol as eluent. 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-carboxaldehyde ( 0.24 g) is obtained as a brown solid. Melting point 192-195 ° C.

Methanol (6 mL) while gently warming 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.17 g) Sodium borohydride (0.035 g) is added and the mixture is stirred at ambient temperature for 30 minutes. Water (50 mL) was added and the mixture was stirred at ambient temperature for 1 h, then the resulting solids were collected by filtration, washed with water (10 mL), dried at 60 ° C. in vacuo, [3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (0.08 g) is obtained as a white solid. Melting point 184-187 캜.

Example 19

3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g), isopropylamine (1 mL) The stirred mixture of ethanol (50 mL) and acetic acid (1 drop) was heated to reflux for 4 hours, then the solvent was removed in vacuo. The residue was triturated with ether (30 mL) and the resulting solid was collected by filtration, washed with ether (10 mL) and dried under vacuum at ambient temperature to give N- [3- (benzo [b] ti as a light brown solid. Offfen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-ylmethylidene] -1-methylethylamine (0.38 g) is obtained. Melting point 180 to 182 ° C.

Example 20

Benzyltrimethylammonium chloride (8 g) is added in portions to a stirred solution of iodine trichloride (10 g) in dichloromethane (120 mL) at ambient temperature, then the mixture is stirred at ambient temperature for 2.5 hours. The resulting solid is collected by filtration and dried under vacuum at ambient temperature to yield benzyltrimethylammonium tetrachloroiodate (16.2 g) as a yellow solid, which is used without further purification.

Benzyltrimethylammonium tetrachloroiodate (5 g) was added to 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole in acetone (125 mL). 3 g) of the stirred solution is added in portions at 0 ° C. for 10 minutes, and then the mixture is stirred at 0 ° C. for 1 hour. The resulting solids were collected by filtration and ground with hot propan-2-ol (150 mL) and crystallized from ethanol (150 mL) to yield an off-white solid (0.74 g). The mother liquor is concentrated to 75 ml to give a second crop of 0.41 g. The two crops of solids were combined and ground with hot ethanol (40 mL), the resulting solids were collected by filtration, washed with ethanol (10 mL) and dried under vacuum at 60 ° C. to yield 3- (benzo as a off-white solid. [b] thiophen-3-yl) -2-chloro-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride 0.5 hydrate (0.91 g) is obtained. Melting point 255 to 257 ° C.

Example 21

3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (6 g) at 0-5 ° C. under nitrogen. To a stirred solution of ethylmagnesium chloride (2M solution in ether; 21.6 ml) in tetrahydrofuran (100 ml) for 10 minutes is added in portions, and the mixture is stirred at 0-5 ° C. for 1 hour. This mixture is added to a stirred solution of N-methoxy-N-methylacetamide (5 g) in tetrahydrofuran (50 mL) at 50-70 ° C. for 10 minutes, followed by further stirring at 70 ° C. for 2.5 hours. . The mixture was ice cooled, then saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and ethyl acetate (150 mL) were added. The organic layer is separated, washed with a mixture of saturated aqueous sodium chloride solution (100 mL) and water (100 mL), dried (MgSO ₄ ) and the solvent removed in vacuo. The residue is triturated with ether (3 × 50 mL) and the resulting solid is collected by filtration, washed with ether (30 mL) and dried under vacuum to give a yellow solid (1.84 g). Solid sample (0.25 g) was crystallized from ethanol (3.5 mL), the resulting solid was collected by filtration, washed with ethanol (5 mL) and dried under vacuum at 75 ° C. to give 2-acetyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (0.043 g) is obtained as a yellow solid. Melting point 203-205 캜.

Example 22

Sodium hydride (60% dispersion in mineral oil; 0.15 g) was added to [3-benzo [b] thiophen-3-yl) -5,6-dihydroimidazo in dimethylformamide (20 mL) for 10 minutes at ambient temperature. To the stirred suspension of [2,1-b] thiazol-2-yl] methanol (1 g) is added in portions, and the mixture is stirred at ambient temperature for 45 minutes. Iodomethane (240 μL) is added and stirring is continued for an additional 2 hours at ambient temperature. Water (25 mL) and ethyl acetate (50 mL) were added, then the organic phase was separated, washed four times with 25 mL of water and washed with saturated aqueous sodium chloride solution (25 mL), dried (MgSO ₄ ) and the solvent under vacuum. Remove The residue is purified by flash chromatography on silica using a 5-8% mixture of methanol in dichloromethane as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue is dissolved in warm ethanol (3 mL) and added to a solution of fumaric acid (0.085 g) in warm ethanol (2 mL), then the mixture is cooled to ambient temperature. The resulting solid was collected by filtration, washed with ethanol (3 mL) and dried at 75 ° C. under vacuum to yield 3- (benzo [b] thiophen-3-yl) -2- (methoxymethyl)-as a white solid. 5,6-dihydroimidazo [2,1-b] thiazolefumarate (0.23 g) is obtained. Melting point 175 to 176 ° C.

Example 23

3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (5 g) at 0-5 [deg.] C. under nitrogen. To a stirred solution of ethylmagnesium chloride (2M solution in ether; 15 ml) in tetrahydrofuran (75 ml) for 30 minutes is added in portions, and the mixture is stirred at ambient temperature for 1 hour. The mixture is cooled to 0 ° C., dimethyl disulfide (1.8 mL) is added, then the mixture is stirred at ambient temperature for 24 hours and quenched by careful addition of saturated aqueous ammonium chloride solution (50 mL). The product is extracted with ethyl acetate (150 mL), then the extract is washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica in a Biotage Flash 40i ^R apparatus using a 19: 1 mixture of ethyl acetate and methanol as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue was triturated with ether (20 mL), the resulting solid was collected by filtration and dried in vacuo, then 3- (benzo [b] thiophen-3-yl) -2- (methylthio) -5 as an off-white solid. , 6-dihydroimidazo [2,1-b] thiazole (1.9 g) is obtained. Melting point 129-131 ° C.

Example 24

n-butyllithium (2.5M solution in hexanes; 1.7 mL) was added to an ice cold stirred suspension of methyltriphenylphosphonium bromide (1.5 g) in tetrahydrofuran (25 mL) under nitrogen, and then the mixture was stirred at ambient temperature for 30 minutes. Stir while. Solution of 2-acetyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (1.6 g) in tetrahydrofuran (15 mL) Was added and the mixture was heated at reflux for 4 hours, left at ambient temperature for 18 hours and then quenched by addition of water (50 mL). The product is extracted with ethyl acetate (50 mL), then the extract is washed with saturated aqueous sodium chloride solution (50 mL) and dried (MgSO ₄ ) to remove the solvent in vacuo. The residue is purified by flash chromatography on silica using a 5-6% mixture of methanol in dichloromethane as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2- (1-methylvinyl) -5,6-dihydroimidazo [2,1-b ] Thiazole (0.14 g) is obtained as a brown solid. Melting point 76 ° C.

Examples 25-33

Examples 25-33 are prepared as part of a High Speed Analogue library using the following general method:

A suitably commercially available Grignard reagent (3 molar equivalents) was added with 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b in tetrahydrofuran (4 mL). ] To a solution of thiazole-2-carboxaldehyde (about 50 mg), the mixture is stirred at ambient temperature for 1 hour, then water (1 ml) is added and the mixture is left to stand for 18 hours in the air. Evaporate the solvent. Dichloromethane (4 mL) was added, the solution was pipetted onto a ChemElute (CE 1103; pH 9) cartridge, then left for 15 minutes to allow the product to cartridge using dichloromethane (3 x 4 mL). Elutes from. The solvent is removed in vacuo to give the desired product, which is a Hypersil BDS C18 column (100 x 4.6 mm) using a gradient elution with a mixture of acetonitrile and 0.1 M ammonium acetate buffer according to the following time schedule Analyze by high performance liquid chromatography.

Minutes Acetonitrile (%) Ammonium Acetate (%) 0 10 90 8-9 100 0 11 10 90

All products of the examples below provide satisfactory mass spectra, and Hplc residence time and% purity are reported for each example.

Example 25

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylpropan-1-ol ( Retention time: 3.28 minutes-Purity: 80%).

Example 26

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] butan-1-ol (ret. Time: 3.29 Min-purity: 100%).

Example 27

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-ene- 1-ol (ret. Time: 3.42 min-purity: 100%).

Example 28

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -3-methylbutan-1-ol ( Retention time: 3.61 minutes-Purity: 90%).

Example 29

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pentan-1-ol (ret. Time: 3.68 Min-purity: 100%).

Example 30

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-yn-1-ol (residence Time: 2.71 min-purity: 100%).

Example 31

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-1-ol ( Retention time: 3.12 minutes-purity: 96%).

Example 32

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-ene -1-ol (ret. Time: 3.13 min-purity: 97%).

Example 33

1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4-en-1-ol ( Retention time: 3.44 minutes-purity: 85%).

Example 34

In a similar manner to Example 4, 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (Example 6 Prepared according to the process described in) and reacted with 2-methoxyphenylmagnesium bromide and the product is recrystallized from a mixture of methanol and propan-2-ol to give [3- (benzo [b] thiophen-3- Il) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] (2-methoxyphenyl) -methanol is obtained as a white solid. Melting point 195-197 ° C.

Example 35

n-butyllithium (2.5M solution in hexane; 73.8 ml) was added dropwise to a stirred mixture of tetrahydrofuran (680 ml) and methyltriphenylphosphonium bromide (65.7 g) under nitrogen at 0-4 ° C. for 45 minutes. The mixture is stirred at 4 ° C. for 10 minutes and at ambient temperature for 30 minutes. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (48 g; similar method as described in Example 6 , In portions at ambient temperature, then the mixture is heated to reflux for 3 hours, cooled to ambient temperature and added to water (500 mL). The product is extracted with ethyl acetate (3 x 400 mL), then the combined extracts are washed with water (400 mL) and dried (MgSO ₄ ) to remove the solvent in vacuo. The residue was triturated with ethyl acetate (300 mL) and the resulting solid collected by filtration and then recrystallized from ethyl acetate to give an off-white solid. The mother liquors obtained from the polishing and recrystallization are combined and concentrated to give an additional crop of solids. This is repeated until no more solid can be separated. The solids of all crops were combined and recrystallized from ethyl acetate repeatedly until it was at least 99% pure (by hplc), giving 3- (benzo [b] thiophen-3-yl) -2-vinyl-5, 6-Dihydroimidazo [2,1-b] thiazole (43.5 g) is obtained as off-white solid. Most of the solid (41 g) is dissolved in hot methanol (500 mL) and added to a saturated solution of fumaric acid in methanol (16.7 g), then the solvent is removed in vacuo. The residue was stirred with ether (500 mL) for 3 hours, the resulting solid was collected by filtration and then dried under vacuum at ambient temperature for 24 hours, 3- (benzo [b] thiophen-3-yl) -2 -Vinyl-5,6-dihydroimidazo [2,1-b] thiazole fumarate (56.8 g) is obtained as a white solid. Melting point 161-162 캜.

Example 36

In a manner similar to that described in Example 35, 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde Reaction with ethyltriphenylphosphonium bromide and n-butyllithium yields a crude product, which is purified by flash chromatography on silica using a 19: 1 mixture of dichloromethane and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give E- and Z-3- (benzo [b] thiophen-3-yl) -2-prop-1-enyl-5,6-dihydroimidazo [ A mixture of 3.7: 1 of 2,1-b] thiazole is obtained as a yellow solid. Melting point 62 to 68 ° C.

Example 37

In a manner similar to that described in Example 6, 3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyridinine (WO-97) / 02269), followed by reaction with ethylmagnesium chloride followed by dimethylformamide to give 3- (benzo [b] thiophen-3-yl) -6,7- Dihydro-5H-thiazolo [3,2-a] pyrimidine-2-carboxaldehyde is obtained. This was reduced to sodium borohydride in a similar manner to that described in Example 2, giving [3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2- a] pyrimidin-2-yl] methanol is obtained as off-white solid. Melting point 174-176 ° C.

Example 38

3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g; similar to that described in Example 6 Method), a mixture of hydroxylamine hydrochloride (0.16 g) and formic acid (1.3 mL) are heated at 90-95 ° C. for 25 h and then diluted with ether (50 mL). The resulting solid is collected by filtration, washed with water (30 mL) and then purified by flash chromatography on silica using a mixture of 95: 5 of dichloromethane and methanol as eluent followed by 85:15. The appropriate fractions were combined and the solvent removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carbonitrile 0.3 Formate (0.12 g) is obtained as a white solid. Melting point 195-196 ° C.

Example 39

A solution of diethyl benzylphosphonate (1.5 mL) in tetrahydrofuran (10 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.26 g) in tetrahydrofuran (15 mL) under nitrogen at ambient temperature. After the dropwise addition, the mixture is stirred at ambient temperature for 20 minutes. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.83 g; similar to that described in Example 6 Method), and the mixture is stirred at ambient temperature for 72 hours and then quenched by addition of water (30 mL). The product is extracted with dichloromethane (3 x 30 mL) and the combined extracts are dried (MgSO ₄ ) to remove the solvent in vacuo. The residue is triturated with ether (20 mL) and the resulting solid is collected by filtration. The ethereal mother liquor is concentrated in vacuo and the residue is triturated with ether (10 mL) to give a second crop of solids. The combined solids were dried under vacuum to afford 3- (benzo [b] thiophen-3-yl) -2-styryl-5,6-dihydroimidazo [2,1-b] thiazole (0.49 g). Obtained as a yellow solid. Melting point 153 to 155 ° C.

Example 40

In a manner similar to that described in Example 6, 3- (5-chloro-benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (WO agent) Prepared by basicization of the hydrobromide salt obtained in a similar manner as described in 97/02269), followed by reaction with ethylmagnesium chloride followed by dimethylformamide to give 3- (5-chlorobenzo [b ] Thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde as a yellow solid. Melting point 258-260 ° C.

Example 41

Sodium borohydride (0.06 g) was added to 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole- in ethanol (15 mL). To a stirred suspension of 2-carboxaldehyde (0.31 g) is added, the mixture is stirred at ambient temperature for 4 hours and then water (15 mL) is added. The resulting solid was collected by filtration, washed with ether (15 mL) and then dried under vacuum at 60 ° C. to [3- (5-chlorobenzo [b] thiophen-3-yl) -5,6- Dihydroimidazo [2,1-b] thiazol-2-yl] methane (0.14 g) is obtained as a white solid. Melting point 204-206 캜.

Example 42

[3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (0.6 g) is shown in Example 40. And similar to those described in 41. In this case, however, the product is of low purity. As a result, it is purified by pre-scale hplc using a mixture of acetonitrile and aqueous triethylammonium formate buffer as eluent. The appropriate fractions are combined and the solvent is removed in vacuo. The residue was triturated with water (2 x 3 mL) and the resulting solid was collected by filtration and dried at 60 ° C. in vacuo to give [3- (5-chlorobenzo [b] thiophen-3-yl) -5, 6-Dihydroimidazo [2,1-b] thiazol-2-yl] methanol formate (0.19 g) is obtained as off-white solid. Melting point 171-173 ° C.

Example 43

In a manner similar to that described in Example 23, 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (5 g) is reacted with ethylmagnesium chloride followed by diphenyl disulfide to give 3- (benzo [b] thiophen-3-yl) -2- (phenylthio) -5,6-dihydroimidazo [2, 1-b] thiazole (0.6 g) is obtained as a yellow solid. Melting point 123-125 ° C.

Example 44

Methylamine (2M solution in tetrahydrofuran; 8.7 mL) and sodium triacetoxyborohydride (0.56 g) in 3- (benzo [b] thiophen-3-yl) in tetrahydrofuran (20 mL) under nitrogen To a stirred solution of -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g; prepared in a similar manner as described in Example 6), the mixture was then added. Stir at ambient temperature for 72 hours. Additional methylamine solution (4.3 mL) is added and the mixture is stirred at ambient temperature for 48 hours, then quenched by addition of saturated aqueous sodium hydrogen carbonate solution (50 mL). The product is extracted with ethyl acetate (3 x 30 mL) and the combined extracts are washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL) and then dried (MgSO 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 were combined and the solvent removed in vacuo to give [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -N-methylmethylamine (0.19 g) is obtained as a waxy solid. Melting point 102-104 ° C.

Example 45

A solution of oxalyl chloride (13 mL) in dichloromethane (20 mL) was stirred a solution of cyclopropylacetic acid (5 g) and dimethylformamide (2 drops) in dichloromethane (20 mL) under nitrogen at −10 to 0 ° C. After dropwise addition, the mixture is stirred at ambient temperature for 24 hours and the solvent is removed in vacuo to give cyclopropylacetyl chloride as a brown oil, which is used without further purification.

Potassium carbonate (9.2 g) was added to the stirred solution of N, O-dimethylhydroxylamine hydrochloride (5.1 g) in a small amount of water at 0-5 ° C. for 10 minutes, then dichloromethane (30 mL) was added. Add. The cyclopropylacetyl chloride is dissolved in dichloromethane (20 mL) and the solution is added dropwise to the dimethylhydroxylamine solution at -5 to 0 ° C. The mixture is stirred at 0 ° C. for 30 minutes and at ambient temperature for 2 hours, then the product is extracted with dichloromethane (3 × 50 mL). The combined extracts are dried (Na ₂ SO ₄ ) and the solvent is removed in vacuo to give cyclopropyl-N-methoxy-N-methylacetamide (6.2 g) as a light brown oil, which is used without further purification. .

A few drops of a solution of 3-bromobenzo [b] thiophene (8.7 g) in tetrahydrofuran (35 mL) were added to a mixture of magnesium conversion (1.05 g), iodine dicrystals and tetrahydrofuran (5 mL) under nitrogen. Is added and the mixture is gently warmed to initiate the reaction. The remainder of the solution is then added at a rate sufficient to maintain moderate reflux. After the addition is terminated, the mixture is stirred at reflux for 1.5 h and then cooled to ambient temperature. A solution of cyclopropyl-N-methoxy-N-methylacetamide (6 g) in tetrahydrofuran (35 mL) was added at ambient temperature and the mixture was stirred at reflux for 5 hours and then at ambient temperature for 18 hours It is left to stand, quenched by addition of 2M hydrochloric acid (50 mL), and stirred at ambient temperature for 1 hour. The product was extracted with ethyl acetate (2 x 100 mL) and the combined extracts were washed with water (2 x 30 mL) and saturated aqueous sodium chloride solution (2 x 30 mL), then dried (MgSO ₄ ) to give the solvent under vacuum. Remove The residue is purified by flash chromatography on silica using a 1: 3 mixture of dichloromethane and petroleum ether (boiling point: 60-80 ° C.) as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -2-cyclopropyl-ethan-1-one (4.15 g) as an orange oil, which was further Use without purification.

Stirred solution of 1- (benzo [b] thiophen-3-yl) -2-cyclopropylethan-1-one (1 g) in tetrahydrofuran (15 mL) under phenyltrimethylammonium tribromide (1.74 g) 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 ethanol (12 mL) and 2-imidazolidinethione (0.47 g) and acetic acid (4 mL) are added, the mixture is heated to reflux under nitrogen for 18 hours and then the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 1: 3 mixture of dichloromethane and ether as eluent. The appropriate fractions were combined and the solvent removed in vacuo to afford 3- (benzo [b] thiophen-3-yl) -2-cyclopropyl-5,6-dihydroimidazo [2,1-b] thiazole hydro Bromide (0.72 g) is obtained as off-white solid. Melting point 181-183 ° C.

Example 46

A solution of iodine monochloride (1.83 g) in dichloromethane (5 mL) was added to 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo in dichloromethane (200 mL) at ambient temperature. To a stirred solution of [2,1-b] thiazole (3.8 g; prepared in a similar manner as described in Example 6) is added dropwise and the mixture is stirred at ambient temperature for 15 minutes. The resulting solid was collected by filtration, washed with dichloromethane (50 mL) and then air dried to afford 3- (benzo [b] thiophen-3-yl) -2-iodo-5,6-dihydroimime. Multizo [2,1-b] thiazole hydrochloride (1.3 g) is obtained as a pale yellow solid. Melting point 194.7 to 195.2 ° C.

Example 47

A solution of dimethyl 2-oxopropylphosphonate (1.28 g) in tetrahydrofuran (10 mL) was stirred with sodium hydride (60% dispersion in mineral oil; 0.46 g) in tetrahydrofuran (15 mL) at ambient temperature under nitrogen. After dropwise addition to the suspension, the mixture is stirred at ambient temperature for 20 minutes. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (2 g; similar method as described in Example 6 In an aliquot, and the mixture is stirred at ambient temperature for 18 hours and at reflux for 7 hours and then left at ambient temperature for 18 hours. The solvent is removed in vacuo, the residue is diluted with water (200 mL) and the product is extracted with dichloromethane (200 mL). The extract is dried (Na ₂ SO ₄ ), the solvent is removed in vacuo, and the residue is purified by flash chromatography on silica using a 19: 1 mixture of dichloromethane and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to afford 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2- Il] but-3-en-2-one (1.15 g) is obtained as a yellow solid. Melting point 164-166 캜.

Sodium borohydride (36 mg) was added to 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole- in ethanol (10 mL). To a stirred solution of 2-yl] but-3-en-2-one (0.28 g) is added, the mixture is stirred at ambient temperature for 3 hours and then the solvent is removed in vacuo. The residue is diluted with water (100 mL) and the product is extracted with dichloromethane (100 mL) and the extract is dried (Na ₂ SO ₄ ) to remove the solvent in vacuo. The residue was triturated with ether (20 mL) and the resulting solid was collected by filtration and dried under vacuum to afford 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimime Dazo [2,1-b] thiazol-2-yl] but-3-en-2-ol (0.16 g) is obtained as off-white solid. Melting point 161-162 캜.

Example 48

In a similar manner as described in Example 17, 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide was Reaction with ethylmagnesium chloride followed by 3-bromo-2-methylpropene and fumaric acid to yield 3- (benzo [b] thiophen-3-yl) -2- (2-methylprop-2 as an off-white solid. -Enyl) -5,6-dihydroimidazo [2,1-b] -thiazole fumarate is obtained. Melting point 54 to 64 ° C.

Example 49

A solution of tetraethyl (dimethylamino) methylenediphosphonate (2.32 g) in 1,4-dioxane (5 mL) was dissolved in hydride (60 in mineral oil) in 1,4-dioxane (5 mL) under nitrogen at ambient temperature. % Dispersion; 0.28 g) is added dropwise to the stirred suspension and the mixture is stirred at ambient temperature until hydrogen evolution ceases. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (2 g; in a similar manner as described in Example 6 Preparative) and the mixture is stirred at 60 ° C. for 1.3 h, 18 h at ambient temperature and then poured into water (50 mL). The product is extracted with ethyl acetate (3x30 mL), the combined extracts are dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 93: 7 mixture of dichloromethane and methanol as eluent. Appropriate fractions are combined and the solvent is removed in vacuo to give 2- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole as a red oil. 2-yl] -1- (dimethylamino) ethenylphosphonate (1.78 g) is obtained, which is used without further purification.

2- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -1- (dimethylamino) ethenylforce A mixture of ponate (1.7 g) and concentrated hydrochloric acid (12 mL) is heated under reflux for 1 h and then ice-cooled. The product is extracted with dichloromethane (3x30 mL), the combined extracts are dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is dissolved in water (30 mL), the solution is neutralized by addition of excess saturated aqueous sodium hydrogen carbonate solution, and then the product is extracted with dichloromethane (3x30 mL). The combined extracts are dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is dissolved in ethanol (2 mL), oxalic acid (15 mg) is added, and the solvent is removed in vacuo. The residue was triturated with ether (10 mL) and the resulting solid was collected by filtration and dried under vacuum to yield ethyl [3- (benzo [b] thiophen-3-yl) -5,6-di as an off-white solid. Hydroimidazo [2,1-b] thiazol-2-yl] acetate oxalate (40 mg) is obtained. Melting point 102-104 ° C.

Example 50

Secondary butyllithium (1.25M solution in a 92: 8 mixture of cyclohexane and hexane; 100 mL) was added dropwise to a stirred solution of 4-fluorophenyl methyl sulfide (22.0 g) in tetrahydrofuran under nitrogen at -70 ° C. The mixture is then stirred at −70 ° C. for 65 minutes. Dimethylformamide (13.2 mL) was added dropwise at -68 ° C to -70 ° C, and the stirred mixture was slowly warmed to ambient temperature over 20 hours, then added to a solution of acetic acid (10 mL) in water (500 mL). do. The product is extracted with ether (3x150 mL), then 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 evaluated by nuclear magnetic resonance spectroscopy to consist mainly of a 2: 3 mixture of 4-fluorophenyl methyl sulfide and 2-fluoro-5- (methylthio) benzaldehyde, respectively.

Stirring of methyl thioglycolate (8.9 mL), crude 2-fluoro-5- (methylthio) benzaldehyde (25 g), dimethyl acetamide (250 mL) and N, N-diisopropyl-ethylamine (42 mL) The mixture is heated at 140-150 ° C. under nitrogen for 3.5 h 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 in vacuo. The residue was purified by grinding with ether (250 mL), then the resulting solid was collected by filtration, washed with ether (2 × 50 mL) and dried under vacuum to afford methyl 5- (methylthio) benzo [b] ti as a pale yellow solid. Obtain opene-2-carboxylate (13.3 g). Melting point 89.7 to 90.4 ° C.

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

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 to reflux under nitrogen for 30 minutes and then filtered hot. The filtrate is added to a mixture of concentrated hydrochloric acid (100 mL), ice (500 g) and ether (200 mL), and then the resulting solid is collected by filtration and washed with ether (200 mL). The aqueous phase is separated off and additional product is extracted therefrom using ether (2x150 mL). The combined ethereal solutions were combined and washed with 2M hydrochloric acid (200 mL) and water (200 mL), dried (Na ₂ SO ₄ ) and the solvent removed in vacuo to give 5- (methylthio) benzo [b as a light brown solid. ] Thiophene (14.7 g) is obtained, which is used without further purification.

A solution of 5- (methylthio) benzo [b] thiophene (14.7 g) in dichloromethane (180 mL) was treated with aluminum bromide (26.2 g), bromoacetyl bromide (7.12 mL) and dichloromethane under nitrogen at <0 ° C. (120 mL) was added to the stirred mixture, and the resulting dark reddish brown solution was stirred for 30 min at &lt; RTI ID = 0.0 &gt; C &lt; / RTI &gt; . Dichloromethane (300 mL) is added and the insoluble material is filtered off (Celite ^R ). The aqueous phase is separated and additional product is extracted therefrom with dichloromethane (300 mL), then the combined dichloromethane solutions are combined and dried (MgSO ₄ ) and the solvent is removed in vacuo. The residue is dissolved in a mixture of acetic acid (200 mL) and dichloromethane (200 mL), a solution of 2-imidazolidinethione (5.29 g) in acetic acid (200 mL) is added, and then dichloromethane is distilled off. 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. A further solid precipitates out 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 in vacuo to yield 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] as a tan rubber. Thiazole (3.6 g) is obtained, which is used without further purification.

A solution of bromine (1.87 g) in dichloromethane (10 mL) was washed at 15-20 [deg.] C. in 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5, in dichloromethane (80 mL), To the stirred solution of 6-dihydroimidazo [2,1-b] thiazole (3.55 g) was added dropwise, the mixture was stirred at ambient temperature for 10 minutes, and then the dichloromethane solution was decanted from the insoluble material and under vacuum Concentrate. The residue was triturated with dichloromethane (10 mL) and the resulting solid collected by filtration and dried under vacuum to yield 2-bromo-3- [5- (methylthio) benzo [b] thiophene- as a tan solid. 3-yl] -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (2.97 g) is obtained. Melting point 260 to 265 ° C.

Example 51

Ethylmagnesium chloride (2.8M solution in tetrahydrofuran; 8.76 mL) was added to 2-bromo-3- [5- (methylthio) benzo [b] thiophene in tetrahydrofuran (40 mL) at −10 ° C. under nitrogen. -3-yl] -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (2.9 g) was added to a stirred suspension, and then the mixture was stirred at ambient temperature for 90 minutes and brought to -5 ° C. Cool. 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- as a solid. Dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (1.4 g) is obtained, which is used without further purification. Melting point 157-158.5 ° C.

Sodium borohydride (0.114 g) was added to 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] in ethanol (40 mL). To a stirred solution of thiazole-2-carboxaldehyde (0.664 g) is added, the mixture is then stirred at ambient temperature for 24 hours and quenched by addition of 5M hydrochloric acid (10 mL). Excess 1 M aqueous sodium hydroxide solution is added to basify the mixture, concentrated in vacuo to remove ethanol, and the product is extracted with dichloromethane (3x30 mL). The combined extracts were dried (MgSO ₄ ) and the solvent was removed in vacuo and the residue was biotage flash chromatography on silica using a 34: 3: 3 mixture of ethyl acetate, industrial methylated spirit and triethylamine as eluent. Purify with. Appropriate fractions are combined, the solvent is removed in vacuo, and the residue is triturated with ether (10 mL). The resulting solid was collected by filtration and air dried to afford {3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1] as a beige solid. -b] thiazol-2-yl} -methanol (0.13 g) is obtained. Melting point 164 to 167 ° C.

Example 52

In a similar manner as described in Example 22, [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol ( 0.5 g) is reacted with sodium hydride and bromomethylcyclopropane followed by fumaric acid. In this case salt formation is carried out in methanol solution and no solid product precipitates. As a result, the solvent is removed in vacuo and the residue is triturated with ether (10 mL). The resulting solids were collected by filtration and dried in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-cyclopropylmethoxymethyl-5,6- as a pale brown solid with a melting point of 82 to 98 ° C. Dihydroimidazo [2,1-b] thiazole fumarate (40 mg) is obtained.

Example 53

Sodium hydride (60% dispersion in mineral oil; 0.153 g) was added to [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1- in dimethylformamide (50 mL). b] To a stirred suspension of thiazol-2-yl] methanol (1 g) is added in portions over 10 minutes at ambient temperature, and then the mixture is stirred at ambient temperature for 2 hours. 1-chloroprop-2-yne (276 μL) is added and stirring is continued for an additional 2 hours at ambient temperature. An additional amount of 1-chloroprop-2-yne (27 μl) is added and the mixture is stirred at ambient temperature for 18 hours. Water (500 mL) was added and the product was extracted with ethyl acetate (3 × 50 mL), then the combined extracts were washed with water (4 × 25 mL) and saturated aqueous sodium chloride solution (25 mL) and dried (MgSO ₄ ), and the solvent was vacuumed. Remove under The residue is purified by flash chromatography on silica using 5-8% methanol mixture in dichloromethane as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue is dissolved in methanol (15 mL) and fumaric acid (0.185 g) is added and the mixture is stirred at ambient temperature for 5 hours, then warmed to dissolve the product and filtered to remove a small amount of insoluble matter. The solvent was removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-prop-2-ynyloxymethyl-5,6-dihydroimidazo [2,1-b as a brown solid. ] Thiazole fumarate (0.67 g) is obtained. Melting point 120 ° C. (softening at 80-90 ° C.).

Example 54

A solution of potassium hydroxide (4.87 g) in a mixture of ethanol (140 mL) and water (35 mL) was added to 2-methoxybenzenethiol (10.6) in a mixture of ethanol (125 mL) and water (7.5 mL) under nitrogen at ambient temperature. ML) was added to the stirred solution at a time, and then the mixture was stirred at ambient temperature for 3.5 hours. A solution of 1-chloro-4-phenoxybut-2-yne (15.7 g) in a mixture of ethanol (125 mL) and water (7.5 mL) was added dropwise over 1.5 hours, and then the mixture was stirred at ambient temperature for 18 hours. Stir and remove the solvent under vacuum. The residue was diluted with water (75 mL) and the product extracted with ethyl acetate (2x115 mL), then the combined extracts were washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL) and dried (MgSO ₄ ), The solvent is removed in vacuo to give 1- (2-methoxyphenylthio) -4-phenoxybut-2-yne (24.7 g) as a yellow oil, which is used without further purification.

A solution of 3-chloroperoxybenzoic acid (70% purity; 9.1 g) in chloroform (210 mL) was added 1- (2-methoxyphenylthio) -4 in chloroform (95 mL) over 1.5 h at 0-5 ° C. Add dropwise to a stirred solution of phenoxybut-2-yne (10.5 g) and stir the mixture at ambient temperature for 18 hours, then wash it with 5% aqueous sodium carbonate solution (3x120 mL) and water (3x80 mL), Dry (MgSO ₄ ). The chloroform solution is stirred and heated under reflux for 7 hours, left at ambient temperature for 18 hours, then dried by washing with 5M aqueous sodium hydroxide solution (115ml), water (4x110ml) and saturated aqueous sodium chloride solution (100ml). (MgSO ₄ ). The solvent was removed in vacuo to give 1- (7-methoxy-2,3-dihydrobenzo [b] thiophen-3-yl) -2-phenoxyethan-1-one (10.7 g) as a brown rubber. Which is used without further purification.

1- (7-methoxy-2,3-dihydrobenzo [b] thiophen-3-yl) -2-phenoxyethan-1-one (10.7 g), acetic acid (100 mL) and concentrated sulfuric acid (12 Drop) is heated at 90-95 ° C. for 3 hours, then cooled to ambient temperature and poured into water (800 mL). The product was extracted with dichloromethane (2x250 mL) and the combined extracts were washed with 2M aqueous sodium hydroxide solution (2 x 200 mL) and water (3 x 200 mL), then dried (MgSO ₄ ) and the solvent removed in vacuo. do. The residue is purified by flash chromatography on silica using a 1: 1 mixture of dichloromethane and petroleum ether (boiling point 60-80 ° C.) as eluent. The appropriate fractions are combined and the solvent removed in vacuo to yield 1- (7-methoxybenzo [b] thiophen-3-yl) ethan-1-one (2 g) as a brown oil, which is used without further purification. do.

Phenyltrimethylammonium tribromide (2.55 g) was added to 1- (7-methoxybenzo [b] thiophen-3-yl) ethan-1-one in tetrahydrofuran (40 mL) over 20 minutes at ambient temperature and nitrogen. To a stirred solution of (1.4 g) is added in portions, the mixture is stirred at ambient temperature for 1 hour, then it is filtered and the solvent is removed in vacuo. The residue is dissolved in ethanol (30 mL) and 2-imidazolidinethione (0.69 g) and acetic acid (20 mL) are added and the mixture is heated at reflux for 18 h and then cooled to ambient temperature. The resulting solid was collected by filtration, washed with ether (20 mL) and dried under vacuum at 60 ° C. to give 3- (7-methoxybenzo [b] thiophen-3-yl) -5, as a gray solid. 6-dihydroimidazo [2,1-b] thiazole hydrobromide (1.48 g) is obtained. Melting point 277-279 ° C.

2M aqueous sodium hydroxide solution (110ml) was added to 3- (7-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (1.48 g) is basified and the free base is extracted with dichloromethane (150 mL). The extract is washed with water (2x70 mL) and dried (MgSO ₄ ) to remove the solvent in vacuo. The residue was dissolved in dichloromethane (23 mL), then the stirred solution was cooled to 0-5 ° C. and a solution of bromine (0.68 g) in dichloromethane (4.7 mL) was added dropwise over 45 minutes. The mixture was stirred at 0-5 [deg.] C. for 30 minutes, left at ambient temperature for 18 hours, then the resulting solid was collected by filtration, washed with dichloromethane (20 mL) and dried under vacuum to give 2-bro as a white solid. Mother-3- (7-methoxy-benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (1.22 g) is obtained. Melting point 240 to 242 ° C.

Example 55

Sodium hydride (60% dispersion in mineral oil; 0.38 g) in [3- (benzo [b] thiophen-3-yl) -5,6-dihydro in dimethylformamide (50 mL) over 10 minutes at ambient temperature To a stirred suspension of imidazo [2,1-b] thiazol-2-yl] methanol (2.5 g) is added in portions, and the mixture is stirred at ambient temperature for 2 hours. 2-bromopropane (0.9 mL) was added and stirring continued at ambient temperature for 2 hours. Additional 2-bromopropane (0.4 mL) is added and the mixture is stirred at ambient temperature for 72 hours. Sodium hydride (60% dispersion in mineral oil; 0.07 g) is added, the mixture is stirred for 10 minutes, then 2-bromopropane (0.16 mL) is added and the mixture is stirred at ambient temperature for 18 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (100 + 2 × 75 mL), then the combined extracts were washed with water (3 × 100 mL) and saturated aqueous sodium chloride solution (100 mL), dried (MgSO ₄ ), and solvent Is removed under vacuum. The residue is purified by flash chromatography on silica using a 1:19 mixture of methanol and dichloromethane as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 9: 1 mixture of ethyl acetate and methanol as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-isopropoxymethyl-5,6-dihydroimidazo [2,1- as a yellow solid. b] thiazole (0.12 g) is obtained. Melting point 64 to 66 ° C.

Example 56

Sodium hydride (60% dispersion in mineral oil; 0.46 g) was added to [3- (benzo [b] thiophen-3-yl) -5,6-dihydro in dimethylformamide (80 mL) over 10 minutes at ambient temperature. To a stirred suspension of imidazo [2,1-b] thiazol-2-yl] methanol (3 g) is added in portions, and the mixture is stirred at ambient temperature for 2 hours. Bromomethylcyclobutane (1.7 g) is added dropwise and the mixture is stirred at ambient temperature for 2.5 hours. Additional bromomethylcyclobutane (0.16 g) is added dropwise and the mixture is stirred at ambient temperature for 1 hour. Additional bromomethylcyclobutane (0.16 g) is added dropwise and the mixture is stirred at ambient temperature for 18 hours. Tlc indicates that the starting material still remains, therefore bromomethylcyclobutane (0.32 g) is added and the mixture is stirred for 2 hours at ambient temperature and 1 hour at 55 ° C. Additional sodium hydride (0.042 g) and bromomethylcyclobutane (0.8 g) are added and the mixture is stirred at 55 ° C. for 1 hour and ambient temperature for 18 hours. Water (100 mL) was added and the product was extracted with ethyl acetate (100 + 3 × 75 mL), then the combined extracts were washed with water (4 × 75 mL) and saturated aqueous sodium chloride solution (75 mL), dried (MgSO ₄ ), and solvent Is removed under vacuum. The residue is purified by flash chromatography on silica using a 1:19 mixture of methanol and dichloromethane as eluent. Appropriate fractions are combined and the solvent is removed in vacuo. The residue is purified by flash chromatography on silica using a 3: 1 mixture of petroleum ether (boiling point 60-80 ° C.) and ethyl acetate as eluent, followed by a 19: 1 mixture of dichloromethane and methanol. Appropriate fractions are combined and the solvent is removed in vacuo. Samples of the residue (30-70 mg) were further purified by preliminary scale hplc on a C8 symmetric shield column using a 2: 3 mixture of acetonitrile and triethylammonium formate buffer as eluent. The appropriate fractions were combined and the solvent removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-cyclobutylmethoxymethyl-5,6-dihydroimidazo [2,1 as brown rubber. -b] thiazole (12 mg) is obtained. ¹ H-nmr (DMSO-d ₆ ): δ _H 1.61-1.84 (6H, m, 3x cyclobutane CH ₂ ), 2.36-2.41 (1H, m, cyclobutane CH), 3.22 (2H, d, CH ₂ O ), 3.49-3.61 (2H, m, CH ₂ N), 3.98-4.05 (2H, m, CH ₂ O), 4.11-4.15 (2H, m, CH ₂ N), 7.45-7.49 (2H, m, 2xArH) ), 7.77-7.81 (1H, m, ArH), 8.01 (1H, s, ArH), 8.08-8.11 (1H, m, ArH).

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 refers to a particular compound which is the end product of one of the preceding examples.

a) capsule

In preparing the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are de-aggregated and blended. The mixture is filled into hard gelatin capsules, each containing the active compound as a 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 blended by deagglomeration and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. Anhydrous granules are blended with magnesium stearate and the remaining starch. The mixture is then compressed in a tablet press to obtain tablets containing the active compound as a unit dose or as part of a unit dose, respectively.

c) enteric tablets

A tablet is prepared by the method described in (b) above. The tablets are enteric coated by conventional methods 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 formed of suppositories, each containing a therapeutically effective amount of the active ingredient.

Claims (33)

A compound of formula I and a pharmaceutically acceptable salt thereof. Formula I In Formula I, A is S or O, 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 by one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted by one or more halo, d) each of one or more halo An alkylthio group, alkylsulfinyl group or alkylsulfonyl group, optionally substituted with 1 to 3 carbon atoms, e) hydroxy, f) an acyloxy group with 1 to 3 carbon atoms, g) a hydroxyalkyl group with 1 to 3 carbon atoms h) cyano, i) an alkanoyl group having 1 to 6 carbon atoms, j) an alkoxycarbonyl group having 2 to 6 carbon atoms, k) one or two alkyl groups each having 1 to 3 carbon atoms, optionally N- Substituted carbamoyl groups or carbamoylmethyl groups, l) sulfamoyl or sulfamoylmethyl groups optionally N-substituted by one or two alkyl groups each having 1 to 3 carbon atoms or m) each having 1 to 3 carbon atoms One with three or Is an amino group optionally substituted by two alkyl groups, R ₁ is the same or different when g is 2, 3 or 4, R ₂ and R ₃ are each H, R ₄ is hydroxyalkyl group having 1 to 6 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, 3 to 6 carbon atoms where hydroxy is not directly bonded to one of the carbons of the double bond A hydroxyalkenyl group having 3 to 6 carbon atoms, a hydroxy alkynyl group having 3 to 6 carbon atoms, a hydroxycycloalkyl group having no hydroxy attached directly to one of the triple bond carbons, Alkenyl group, arylalkenyl group having 8 to 10 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, C _3-7 alkynylalkoxyC _1-3 alkyl group, C _4-7 cycloalkylalkoxyC _1-3 alkyl group , C _1-3 alkoxyC _1-3 alkyl group, C _1-3 alkylthioC _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, arylthio group, C _1-6 alka Noyl group, C _3-6 alkoxycarbonylalkyl group, cyano, halo, C _1-4 alkyliminomethyl group, C _1-4 alkylaminoalkyl group or hydroxyiminomethyl group, R ₅ is H or halo. The method of claim 1, A is S or O, 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 by one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted by one or more halo, d) each of one or more halo An alkylthio group, alkylsulfinyl group or alkylsulfonyl group, optionally substituted with 1 to 3 carbon atoms, e) hydroxy, f) an acyloxy group with 1 to 3 carbon atoms, g) a hydroxyalkyl group with 1 to 3 carbon atoms h) cyano, i) an alkanoyl group having 1 to 6 carbon atoms, j) an alkoxycarbonyl group having 2 to 6 carbon atoms, k) one or two alkyl groups each having 1 to 3 carbon atoms, optionally N- Substituted carbamoyl groups or carbamoylmethyl groups, l) sulfamoyl or sulfamoylmethyl groups optionally N-substituted by one or two alkyl groups each having 1 to 3 carbon atoms or m) each having 1 to 3 carbon atoms One with three or Is an amino group optionally substituted by two alkyl groups, R ₁ is the same or different when g is 2, 3 or 4, R ₂ and R ₃ are each H, R ₄ is a hydroxyalkyl group of 1 to 6 carbon atoms, a hydroxyalkenyl group of 3 to 6 carbon atoms, wherein hydroxy is not directly bonded to one of the carbons of a double bond, hydroxy is one of the carbons of a triple bond Hydroxyalkynyl groups having 3 to 6 carbon atoms, hydroxycycloalkyl groups having 3 to 6 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms, which are not directly bonded, C _1-3 Alkoxy C _1-3 alkyl group, C _1-3 alkylthio C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, C _1-6 alkanoyl group, halo, C _1-4 Alkyliminomethyl group or hydroxyiminomethyl group, A compound of formula (I) and pharmaceutically acceptable salts thereof, wherein R ₅ is H or halo. The compound of claim 1 or 2, wherein A is S. 4. The compound of claim 1 or 2, wherein A is O. 4. The hydroxy alkyl group according to any one of claims 1 to ₄ , wherein R ₄ is a hydroxyalkyl group having 1 to 6 carbon atoms, and the hydroxy is not directly bonded to one of the carbons of the double bond. Alkenyl groups, hydroxyalkynyl groups of 3 to 6 carbon atoms, hydroxy not directly attached to one of the triple bond carbons, alkenyl groups of 2 carbon atoms optionally substituted by one or more C _1-2 alkyl groups , C _1-4 alkyliminomethyl group or hydroxyiminomethyl group. The hydroxy having 3 to 5 carbon atoms according to any one of claims 1 to 5, wherein R ₄ is a hydroxyalkyl group having 1 to 5 carbon atoms, and the hydroxy is not directly bonded to one of the carbons of the double bond. Alkenyl group, wherein hydroxy is a C3-4 hydroxyalkynyl group or a C2 alkenyl group optionally substituted by one or more methyl groups, which is not directly bonded to one of the triple bond carbons. 7. The compound of claim 1, wherein R ₄ is hydroxymethyl or vinyl. 8. A compound according to any one of claims 1 to 7, wherein n is 2. The alkyl group of any one of claims 1 to 8 wherein g is 0 or 1 and R ₁ is a) halo, b) an alkyl group of 1 to 3 carbon atoms optionally substituted by one or more halo or c) one or more A compound having 1 to 3 carbon atoms, optionally substituted by halo. The compound of claim 1, wherein R ₅ is H. 11. The compound of formula (Ia) and a pharmaceutically acceptable salt thereof, according to claim 1. Formula Ia In Formula Ia, A is S or O, 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 by one or more halo, c) an alkoxy group of 1 to 3 carbon atoms optionally substituted by one or more halo, d) each of one or more halo An alkylthio group, alkylsulfinyl group or alkylsulfonyl group, optionally substituted with 1 to 3 carbon atoms, e) hydroxy, f) an acyloxy group with 1 to 3 carbon atoms, g) a hydroxyalkyl group with 1 to 3 carbon atoms h) cyano, i) an alkanoyl group having 1 to 6 carbon atoms, j) an alkoxycarbonyl group having 2 to 6 carbon atoms, k) one or two alkyl groups each having 1 to 3 carbon atoms, optionally N- Substituted carbamoyl groups or carbamoylmethyl groups, l) sulfamoyl or sulfamoylmethyl groups optionally N-substituted by one or two alkyl groups each having 1 to 3 carbon atoms or m) each having 1 to 3 carbon atoms One with three or Is an amino group optionally substituted by two alkyl groups, R ₁ is the same or different when g is 2, 3 or 4, R ₄ is hydroxyalkyl group having 1 to 6 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, 3 to 6 carbon atoms where hydroxy is not directly bonded to one of the carbons of the double bond Hydroxyalkenyl group of hydroxy, hydroxyalkynyl group of 3 to 6 carbon atoms, hydroxyalkynyl group of 2 to 8 carbon atoms, arylal of 8 to 10 carbon atoms, wherein hydroxy is not directly bonded to one of the triple bond carbons Kenyl group, C3-C6 cycloalkyl group, C _3-7 alkynylalkoxyC _1-3 alkyl group, C _4-7 cycloalkylalkoxyC _1-3 alkyl group, C _1-3 alkoxyC _1-3 alkyl C _1-3 alkylthio, C _1-3 alkyl group, C _1-3 alkoxy group, C _1-3 alkylthio group, arylthio group, C _1-6 alkanoyl group, C _3-6 alkoxycarbonylalkyl group, cyano, halo, C _1-4 alkyl butylimino methyl group, C _1-4 alkylamino methyl group or hydroxyimino A naphthyl group. 12. The compound of claim 11, wherein A is S. 13. The compound of claim 11 or 12, wherein n is 2. The compound of any one of claims 11-13, wherein g is 0 or 1. The compound according to any one of claims 11 to 14, wherein R ₁ is halo, an alkoxy group having 1 to 3 carbon atoms or an alkylthio group having 1 to 3 carbon atoms. The compound of any one of claims 11-15, wherein A is O. 17. 17. The compound of any one of claims 11 to 16, wherein R ₄ is a hydroxyalkyl group having 1 to 4 carbon atoms, an α-hydroxy (2-C _1-3 alkoxyphenyl) methyl group, and hydroxy is a double bond. A hydroxyalkenyl group having 3 to 4 carbon atoms, not directly bonded to one of the carbons, a hydroxyalkynyl group having 3 to 4 carbon atoms, wherein the hydroxy is not directly bonded to one of the carbons of the triple bond, 2 To alkenyl group, C _1-3 alkylthio group, C _1-2 alkanoyl group or hydroxyiminomethyl group. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde; [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol; 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde oxime; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] ethanol; 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-bromo-6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -1-methylethanol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] propan-1-ol; 2-bromo-3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 2-bromo-3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-ethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-en-1-ol ; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-2-yn-1-ol; 3- (benzo [b] thiophen-3-yl) -2-vinyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-allyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; [3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol; N- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-ylmethylidene] -1-methylethylamine; 3- (benzo [b] thiophen-3-yl) -2-chloro-5,6-dihydroimidazo [2,1-b] thiazole; 2-acetyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (methoxymethyl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (methylthio) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (1-methylvinyl) -5,6-dihydroimidazo [2,1-b] thiazole; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylpropan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] butan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-ene- 1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -3-methylbutan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pentan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-yn-1-ol ; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-ene -1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4-en-1-ol; [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] (2-methoxyphenyl) methanol; 3- (benzo [b] thiophen-3-yl) -2-prop-1-enyl-5,6-dihydroimidazo [2,1-b] thiazole; [3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidin-2-yl] methanol; 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carbonitrile; 3- (benzo [b] thiophen-3-yl) -2-styryl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde; [3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol; 3- (benzo [b] thiophen-3-yl)-(2-phenylthio) -5,6-dihydroimidazo [2,1-b] thiazole; [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -N-methylmethylamine; 3- (benzo [b] thiophen-3-yl) -2-cyclopropyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-iodo-5,6-dihydroimidazo [2,1-b] thiazole; 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-3-ol; 3- (benzo [b] thiophen-3-yl) -2- (2-methylprop-2-enyl) -5,6-dihydroimidazo [2,1-b] thiazole; Ethyl [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] acetate; 2-bromo-3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole; {3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazol-2-yl} methanol; 3- (benzo [b] thiophen-3-yl) -2-cyclopropylmethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-prop-2-ynyloxymethyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-bromo-3- (7-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-isopropoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole and 3- (benzo [b] thiophen-3-yl) -2-cyclobutylmethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole and pharmaceutically acceptable Salts thereof and other mixtures of the respective enantiomers, racemates or enantiomers. 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde; [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol; 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde oxime; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] ethanol; 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-bromo-6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -1-methylethanol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] propan-1-ol; 2-bromo-3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 2-bromo-3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-ethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-en-1-ol ; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-2-yn-1-ol; 3- (benzo [b] thiophen-3-yl) -2-vinyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-allyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; [3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol; N- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-ylmethylidene] -1-methylethylamine; 3- (benzo [b] thiophen-3-yl) -2-chloro-5,6-dihydroimidazo [2,1-b] thiazole; 2-acetyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (methoxymethyl) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (methylthio) -5,6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (1-methylvinyl) -5,6-dihydroimidazo [2,1-b] thiazole; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylpropan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] butan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-ene- 1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -3-methylbutan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pentan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] prop-2-yn-1-ol ; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-ene -1-ol and From 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4-en-1-ol Selected compounds 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. A compound of formula (I) as claimed in claim 1 for use as a medicament. Depression, anxiety, psychosis, schizophrenia, full dyskinesia, obesity, drug addiction, substance abuse, cognitive disease, Alzheimer's disease, cerebral ischemia, obsessive behavior, panic stroke, social phobia, morbid hunger, anorexia, snacks and snacks The chemical formula as claimed in any one of claims 1 to 19 for the treatment of abnormal anorexia, such as syndrome, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, and as an adjuvant for smoking cessation. Compound of I. The method of claim 1, for use in the treatment and / or prevention of stroke, neurological diseases (e.g. epilepsy) and / or neurological damage such as stroke, brain tumors, cerebral ischemia, head injury and bleeding. A compound of formula (I) as claimed in any one of claims. Depression, anxiety, psychosis, schizophrenia, chronic dyskinesia, obesity, drug addiction, substance abuse, cognitive disease, Alzheimer's disease, cerebral ischemia, obsessive behavior, panic stroke, social phobia; Treats anorexia nervosa, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress, such as pathological hunger, anorexia, snack and night-time syndrome, used as a supplement for smoking cessation, neurological diseases such as stroke, epilepsy and / or Or claim 1 in the manufacture of a medicament for use in the treatment and / or prevention of conditions in which neurological damage, such as stroke, brain tumor, cerebral ischemia, head injury and bleeding is present. Use of a compound of formula (I) as one. 20. Depression, anxiety, psychosis, schizophrenia, chronic dyskinesia, including administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as claimed in claim 1, Obesity, drug addiction, substance abuse, cognitive disease, Alzheimer's disease, cerebral ischemia, obsessive behavior, panic stroke, social phobia; Neurological diseases and / or strokes, brain tumors, cerebral ischemia, head injuries, such as anorexia nervosa, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress and stroke, epilepsy, such as pathological hunger, anorexia, snack and late night syndrome And a condition in which nervous system damage such as bleeding is present. 20. A method of reducing the desire for human smoking, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1-19. 20. A method of reducing weight gain after smoking in a human, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1-19. Metabolic diseases and conditions caused therefrom, in particular non-motor fever and increased metabolic rate, sexual disorders, sleep apnea, premenstrual syndrome, incontinence, hyperactivity disorder, hiatus hernia and esophageal reflux, pain, in particular neuropathic pain, drugs Any one of claims 1 to 19 for use in the treatment or prevention of weight gain associated with therapy, chronic fatigue syndrome, osteoarthritis and pain, cancer associated with weight gain, menstrual abnormalities, gallstones, orthostatic hypotension and pulmonary hypertension. A compound of formula (I) as claimed in the claims. 20. A compound of formula I as claimed in any one of claims 1 to 19 for use in the prevention of cardiovascular diseases, in reducing platelet adhesion, in helping to lose weight after pregnancy or in helping to lose weight after smoking. The use of a compound which is a 5-HT _1A agonist and also a monoamine reuptake inhibitor, in particular noradrenaline reuptake inhibitor, in the treatment of obesity and related co-morbidity conditions without causing cardiovascular side effects. A method of treating obesity that does not cause cardiovascular side effects, comprising administering to a patient in need thereof a compound that is a 5-HT _1A agonist and is also a monoamine reuptake inhibitor, in particular a noradrenaline reuptake inhibitor. 20. A compound of formula (I) as claimed in any one of claims 1 to 19 for use in the treatment of obesity and related co-morbid conditions. a) the compound of formula II is dehydrated optionally at a temperature in the range of 0 to 200 ° C. in the presence of an acid, or b) reacting a compound of formula III with a compound of formula IV at a temperature ranging from 0 to 200 ° C., optionally in the presence of an acid, optionally in the presence of a solvent, without separation of the intermediate of formula II, or c) To obtain a compound of formula I wherein R ₄ is halo, the compound of formula V is optionally reacted with a halogenating agent at a temperature in the range of -50 to 200 ° C. in the presence of a solvent, d) R ₄ is a group of the formula -CH (OH) R _x wherein R _x is a C _1-5 alkyl group, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms or (2-C _1-3 alkoxyphenyl)] in order to obtain a compound of formula (I) wherein the compound of formula (VI) is in the presence of a solvent at an organic temperature of formula R _x MgX or R _x React with a metal reagent, where R _x is as defined above and X is halo, or e) R ₄ is a group of the formula -CH (OH) R _y wherein R _y is a C _1-5 alkyl group, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms or (2-C _1-3 alkoxyphenyl)], to obtain a compound of formula (I) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 , R _y is C _1-5 alkyl, an alkenyl group having 2 to 5 carbon atoms, an alkynyl group having 2 to 5 carbon atoms, or (2-C _1-3 alkoxyphenyl)] React with a reducing agent at a temperature in the boiling range of the solvent, f) In order to obtain a compound of formula I wherein R ₄ is hydroxymethyl, the compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 , R _y is H), in a solvent at a temperature ranging from -50 ° C. to the boiling point of the solvent used, or g) In order to obtain a compound of formula I wherein R ₄ is hydroxyiminomethyl, the compounds of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1; Wherein R _y is H) and optionally react with hydroxylamine or a salt thereof at a temperature in the range of 0 to 250 ° C., in the presence of a solvent, h) In order to obtain a compound of formula I, wherein R ₄ is cyano, a compound of formula VI wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 and R _y is H) and react with hydroxylamine or a salt thereof at a temperature ranging from 0 to 250 ° C. in the presence of formic acid, i) In order to obtain a compound of formula (I) wherein R ₄ is a C _1-4 alkyliminomethylene group, compounds of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are As defined in claim 1, wherein R _y is H, an amine of the formula R _a NH ₂ , wherein R _a is C _1- at a temperature ranging from 0 to 250 ° C., optionally in the presence of a solvent, optionally in the presence of an acid catalyst. ₄ alkyl group), or j) In order to obtain a compound of formula (I) wherein R ₄ is a C _1-4 alkylaminomethylene group, a compound of formula (I) wherein R ₄ is a C _1-4 alkyliminomethylene group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1) or reacted with a reducing agent in the presence of a solvent at a temperature ranging from 0 ° C. to the boiling point of the solvent used, k) In order to obtain a compound of formula (I) wherein R ₄ is a C _1-4 alkylaminomethylene group, compounds of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are the first are as defined in wherein, R _y is in the presence of a H) a solvent, of the formula R _a NH ₂ at a temperature of the boiling point range of 0 ℃ to the solvent to be used amines (wherein, R _a is a C _1-4 alkyl group ) And a reducing agent, l) In order to obtain a compound of formula (I) wherein R ₄ is a group of the formula -C (OH) R _x R _y , wherein R _x and R _y are each independently a C _1-5 alkyl group, To a compound wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 and R _y is a C _1-5 alkyl group in the presence of a solvent. To an organometallic reagent of formula R _x MgX or R _x Li, wherein R _x is a C _1-5 alkyl group and X is halo at a temperature in the boiling range of the solvent used, or m) In order to obtain a compound of formula (I), wherein R ₄ is a group of formula -C (OH) R _x R _y , wherein R _x and R _y are the same C _1-2 alkyl group, This gatdoe as to define, with the proviso that R _y are oR _z and, R _z is a C _1-6 alkyl group), the formula at a temperature of the boiling point range of the solvent to be used in the presence of a solvent to -50 ℃ _x R MgX or R react with an organometallic reagent of _x Li, wherein R _x is a C _1-2 alkyl group and X is halo, or n) In order to obtain a compound of formula (I) wherein R ₄ is a C _2-6 alkenyl group in which the double bond is bonded to the α carbon to the thiazole ring or styryl group, a compound of formula (VI) wherein R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 and R _y is hydrogen or a C _1-4 alkyl group) -78 ° C. to solvent in the presence of a base Or react with a phosphonium salt of the formula R _z Ph ₃ P ⁺ Br ^- where R _z is a C _1-5 alkyl group or benzyl group o) In order to obtain compounds of formula (I) wherein R ₄ is a C _2-5 alkanoyl group, compounds of formula (I) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 And R ₄ is halo) or a compound of formula R _b MgX or R _b Li at a temperature ranging from -78 ° C. to the boiling point of the solvent used in the presence of a solvent, wherein R _b is a c _1-6 alkyl group, X is a halo), and the reaction was then acylating agent of formula _{R c CON (CH 3) OCH} 3 and the resultant product at a temperature of the boiling point range of 0 ℃ to the solvent used in the solvent Or wherein R _c is a C _1-5 alkyl group p) In order to obtain a compound of formula (I) wherein R ₄ is a C _1-3 alkoxyC _1-3 alkyl group, a compound of formula (I) wherein R ₄ is a hydroxy C _1-3 alkyl group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1) or reacted with a C _1-3 alkylating agent at a temperature ranging from -50 to 150 ° C. in a solvent in the presence of a base, or q) In order to obtain a compound of formula (I) wherein R ₄ is a C _4-7 cycloalkoxyC _1-3 alkyl group, a compound of formula (I) wherein R ₄ is a hydroxy C _1-3 alkyl group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1) in a solvent in the presence of a base at a temperature ranging from -50 to 150 ° C. with a C _4-7 cycloalkylalkylating agent. Or r) To obtain a compound of formula (I) wherein R ₄ is a C _3-7 alkynylalkoxyC _1-3 alkyl group, a compound of formula (I) wherein R ₄ is a hydroxy C _1-3 alkyl group, A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1), reacting with a C _3-7 alkynylalkylating agent in a solvent in the presence of a base at a temperature ranging from -50 to 150 ° C. Or s) To obtain a compound of formula (I) wherein R ₄ is a C _1-3 alkylthioC _1-3 alkyl group, a compound of formula (I) wherein R ₄ is a mercapto C _1-3 alkyl group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1) or reacted with a C _1-3 alkylating agent at a temperature ranging from -50 to 150 ° C. in a solvent in the presence of a base, or t) obtaining a compound of formula (I) wherein R ₄ is a C _1-3 alkylthio group or an arylthio group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 In order to prepare a compound of formula (I) wherein R ₄ is halo or a compound of formula (V) at a temperature in the solvent ranging from -100 ° C. to the boiling point of the solvent used, _1-6 alkyl group, X is a halo) to give the to give the intermediate complex, and then this -100 ℃ to a disulfide of the formula R _d S-SR _d on the temperature of the boiling range of the solvent to be used (wherein, R _d Is a C _1-3 alkyl group or an aryl group), or u) R ₄ is a C _1-3 alkoxy group and A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are obtained in order to obtain a compound of formula I as defined in claim 1 The compound, wherein R ₄ is halo, is reacted with a C _1-3 alkoxide salt, optionally in the presence of a solvent, optionally in the presence of a catalyst, at a temperature ranging from 0 to 350 ° C, v) In order to obtain compounds of formula (I) wherein R ₄ is a C _3-6 alkenyl group in which the double bond is not bonded to the α carbon for the thiazole ring, compounds of formula (I) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 and R ₄ is halo, for example bromo or chloro) or a compound of formula V in the presence of a solvent at -78 ° C to Reacted with a compound of the formula R _b MgX or R _b Li, wherein R _b is a C _1-6 alkyl group and X is halo, for example bromo or chloro, at a temperature in the boiling range of the solvent used The product obtained is then reacted in an solvent with an alkenylating agent, for example C _3-5 alkenylmethyl halide, at a temperature ranging from 0 ° C. to the boiling point of the solvent used, w) In order to obtain a compound of formula (I) wherein R ₄ is a C _3-6 alkoxycarbonylalkyl group, compounds of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are selected from Phospho of formula Me ₂ NCH [PO (OR _z ) ₂ ] ₂ as defined in claim 1, wherein R _y is hydrogen) in the presence of a base at temperatures ranging from -78 ° C to the boiling point of the solvent used Reacted with a nate, wherein R _z is a C _1-4 alkyl group, then the resulting intermediate product is partially hydrolyzed in the presence of an acid, x) In order to obtain a compound of the formula (I) wherein R ₄ is a C _4-6 hydroxyalkenyl group in which the double bond is bonded to the α carbon for the thiazole ring, the compound of formula (VI) wherein A, R ₁ , R ₂ , R ₃ , R ₅ , g and n are as defined in claim 1 and R _y is hydrogen) in the solvent in the presence of a base at a temperature ranging from -78 ° C. to the boiling point of the solvent used. Reacted with a compound of (RzO) ₂ POCH ₂ COR _c where R _z is a C _1-2 alkyl group and R _c is a C _1-3 alkyl group, and then the resulting intermediate product is -20 in a solvent. A process for preparing a compound of formula (I) comprising the step of reacting with a reducing agent at a temperature in the boiling range of the solvent used. Formula II Formula III Formula IV Formula V Formula VI Where A, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , g and n are as defined in claim 1, Z is an exit group, R _y is H.