SK16852001A3 - Thiazoloderivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula (I); processes to prepare such compounds; compositions containing such compounds and their use in the treatment of depression, anxiety, psychoses (for examples schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, cerebral ischaemia, obsessive-compulsive behaviour, panic attacks, social phobias, eating disorders such as bulimia, anorexia, snacking and binge eating, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidaemia, stress, and their use in the treatment and/or prophylaxis of seizures, neurological disorders such as epilepsy and/or conditions in which there is neurological damage such as stroke, brain trauma, cerebral ischaemia, head injuries and haemorrhage and as an aid to smoking cessation; are described.

Description

Technical field

The present invention relates to certain novel substituted dihydroimidazo [2,1-b] thiazoles and dihydro-5H-thiazolo [3,2-a] pyrimidines having affinity for the 5-ΗΤ receptor. _Ktoré and which inhibit neuronal reuptake of 5-hydroxytryptamine and / or noradrenaline, methods for their preparation, pharmaceutical compositions containing them and their use in the treatment of depression, anxiety, psychoses (e.g. schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, obsessive compulsive behaviors, panic attacks, social phobias, eating disorders such as bulimia, anorexia, excessive appetite and morbidity, insulin-independent diabetes, hyperglycemia, hyperlipidemia, stress relief, as well as stress relief and in the treatment and / or prevention of seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage occurs.

BACKGROUND OF THE INVENTION

WO 98/41528 discloses that compounds of formula A

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

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

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

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

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

are useful in the treatment of depression, anxiety, Parkinson's disease, obesity, cognitive diseases, seizures, neurological diseases such as epilepsy and as neuroprotective agents for the prevention of conditions such as stroke. The compounds of the present invention are not included in the above specification or are not intended to be used.

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

WO 97/02269 discloses compounds of formula B

including pharmaceutically acceptable salts thereof, wherein

A is S (O) _P or O;

p is 0, 1 or 2;

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

n is 2 or 3;

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

R 2, R 3 and R 4 each independently represent hydrogen or an alkyl group having 1 to carbon atoms optionally substituted by one or more halogen atoms; and

R 5 is selected from the group consisting of a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted by one or more halogen atoms; (e) hydroxy; (f) 1 to 3 carbon atoms; (g) (C1 -C3) hydroxyalkyl; (h) cyano; (i) alkanoyl j) C 2 -C 6 alkoxycarbonyl, k) carbamoyl or carbamoylmethyl each of which may optionally be N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) an amino group optionally e substituted by one or two alkyl groups each containing 1 to 3 carbon atoms, or n) H;

which have affinity for 5-HT _1A receptors and inhibit neuronal reuptake of 5-hydroxytryptamine and / or noradrenaline. These compounds are said to be useful in the treatment of CNS diseases. However, the compounds exhibit activity as monoamine oxidase inhibitors and / or have activity on other receptors, for example muscarinic receptors, and are likely to cause undesirable side effects.

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

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

SUMMARY OF THE INVENTION

The invention provides novel compounds of formula I

including pharmaceutically acceptable salts thereof, wherein

A is S or O;

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

n is 2 or 3;

R * is selected from the group consisting of a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, d) alkylthio , alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted by one or more halogen atoms; (e) hydroxy; (f) C1-C3 acyloxy; (g) C1-C3 hydroxyalkyl;) (h) cyano; (i) alkanoyl; J) C 2 -C 6 alkoxycarbonyl, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) or an amine a group optionally substituted with one or two allyl radicals each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings;

R 2 and R 3 each represent H;

R 4 represents a group consisting of hydroxyalkyl of 1 to 6 carbon atoms, α-hydroxy (2-C 1-3 alkoxyphenyl) methyl, hydroxyalkenyl of 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to one of the double bond carbons, hydroxyalkynyl of 3 up to 6 carbon atoms wherein the hydroxy group is not directly attached to any of the three-bonded carbons, hydroxycycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, arylalkenyl of 8 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, C 3-7 alkynyloxyC 1-3 alkyl, C 4-7 cycloalkylalkoxy C 1-3 alkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-3 alkylthioC 1-3 alkyl, C 1-3 alkyl. 3alkoxy, C _1-3 alkylthio, arylthio, C 1-6 alkanoyl, C 1-6 alkoxycarbonylalkyl, cyano, halogen, C 1-4 alkyliminomethyl, C 1-4 alkylaminoalkyl and hydroxyiminomethyl;

R 5 is H or halogen.

According to a preferred aspect of the invention, the invention includes compounds of formula I

- cl

Γ Γ * | - ,.

, "C C" including their pharmaceutically acceptable salts, where

A is S or O;

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

n is 2 or 3;

R ¹ is selected from the group consisting of (a) halogen, (b) alkyl of 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, (c) alkoxy of 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, (d) alkylthio , alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted by one or more halogen atoms; (e) hydroxy; (f) C1-C3 acyloxy; (g) C1-C3 hydroxyalkyl;) (h) cyano; (i) alkanoyl; J) C 2 -C 6 alkoxycarbonyl, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) or ami a group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings;

R 2 and R 3 each represent H;

R4 represents a hydroxyalkyl group having 1 to 6 carbon atoms, a hydroxyalkenyl group having 3 to 6 carbon atoms where a hydroxy group is not directly attached to one of the double bonded carbons, a hydroxyalkynyl group having 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to a C 3 -C 6 alkyl, C 3 -C 6 alkenyl, C 2 -C 8 alkenyl, C 3 -C 6 cycloalkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-6 alkylthioC 1-6 alkyl; C 3-6 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C 1-3 alkylthio ₆ alkanoyl, C 1-4 alkyliminomethyl, and hydroxyiminomethyl; and

R 5 is H or halogen.

The term halogen as used herein means fluoro, chloro, bromo and iodo. The terms alkyl groups, alkenyl groups, alkylthio groups and alkoxy groups are to be understood so that if they contain more than two carbon atoms, the alkyl group may be straight or branched. The term aryl as used herein means a phenyl group optionally substituted by one or more of the following groups: C 1-4 alkyl, C 1-3 alkoxy and halogen.

A first preferred group of compounds of the invention includes those wherein A is S.

A second preferred group of compounds of the invention includes those wherein A is O.

Preferably g is 0 or 1 and R 1 b) an alkyl group having 1 to 3 carbon atoms optionally substituted with one or more halogen atoms, or c) an alkoxy group having 1 to 3 carbon atoms optionally substituted with one or more halogen atoms. R 1 is preferably in the 5-position of the benzo [b] thiophene ring. Even more preferably, g is 0 or 1 and R 1 is halogen or C 1 -C 3 alkoxy. Most preferably, g is 0 and R 1 represents chlorine or methoxy.

Preferably n is 2.

Preferably R2 and R3 are each H.

R 4 is preferably a group selected from hydroxyalkyl of 1 to 6 carbon atoms, hydroxyalkenyl of 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to one of the double bonded carbons, hydroxyalkynyl of 3 to 6 carbon atoms where the hydroxy group is not directly attached to one of the three-bonded carbons, alkenyl of 2 carbon atoms optionally substituted with one or two C 1-2 alkyl groups, C 1-4 alkyliminomethyl, and hydroxyiminomethyl. Even more preferably, R 4 is C 1 -C 5 hydroxyalkyl, C 3 -C 5 hydroxyalkenyl wherein the hydroxy group is not directly attached to one of the double bonded carbons, C 3 -C 4 hydroxyalkynyl wherein the hydroxy group is not directly attached to any of the three-bonded carbons and alkenyl of 2 carbon atoms optionally substituted with one or two methyl groups. Most preferably, R 4 is a hydroxymethyl or vinyl group. R @ 4 is particularly preferably a hydroxymethyl group.

Preferably R4 is hydroxymethyl, 1-hydroxy-ethyl, 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-hydroxy-pent-4-enyl, 1-hydroxypropinyl,

1-hydroxybut-2-ynyl, methoxymethyl, ethoxymethyl, methylthio, bromo, chloro, vinyl, allyl, 1-methylvinyl, formyl, acetyl, N- (1-methylethyljiminomethyl, and hydroxyiminomethyl).

Even 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-hydroxy-pent-4-enyl, 1-hydroxypropinyl,

1-hydroxybut-2-ynyl, vinyl, 1-methylvinyl, acetyl, N- (1-methylethyl) iminomethyl, and hydroxyiminomethyl.

Most preferably, R 4 is a hydroxymethyl or vinyl group. It is particularly preferably a hydroxymethyl group.

Preferably R5 is H.

Preferably n is 2.

In a preferred group of compounds of formula I, A is S, g is 0 or 1; n is 2; R 1 represents halogen or C 1 -C 3 alkoxy; R 2 and R 3 each represent H; R4 represents a group selected from hydroxyalkyl of 1 to 5 carbon atoms, hydroxyalkyl of 3 to 5 carbon atoms wherein the hydroxy group is not directly attached to one of the double bonded carbons, hydroxyalkynyl of 3 to 4 carbon atoms where the hydroxy group is not directly attached to one of the three-bonded carbons and the alkenyl of 2 carbon atoms optionally substituted with one or two methyl groups, 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. Even more preferably, R 1 is in the 5-position of the benzo [b] thiophene ring.

According to another preferred aspect of the invention, the invention provides compounds of formula Ia

1a including their pharmaceutically acceptable salts, wherein

A is S or O;

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

n is 2 or 3;

R * is selected from the group consisting of a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted with one or more halogen atoms; (e) hydroxy; (f) 1 to 3 carbon atoms; (g) (C1-C3) hydroxyalkyl; (h) cyano; (i) alkanoyl j) C 2 -C 6 alkoxycarbonyl, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl, each of which may optionally be N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) or an amine a group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings; and

R 4 represents a group consisting of hydroxyalkyl of 1 to 6 carbon atoms, α-hydroxy (2-C 1-3 alkoxyphenyl) -methyl, hydroxyalkenyl of 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to one of the double bond carbons, hydroxyalkynyl of 3 to 6 carbon atoms Wherein the hydroxy group is not directly attached to any of the three-bonded carbons, alkenyl of 2 to 8 carbon atoms, arylalkenyl of 8 to 10 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, C3. 7alkynylalkoxyC1-3alkyl, C4-7cycloalkylalkoxyC1-3alkyl, C1-3alkoxyC1-3alkyl, C1-3alkylthioC1-3alkyl, C1-4alkoxy, C1-4alkylthio, arylthio, C1-6alkanoyl, C3-6alkoxycarbonylalkyl, cyano, halogeno

C 1-4 alkylaminoalkyl and hydroxyiminomethyl.

In a first preferred group of compounds of the invention, A is S. In this group of compounds, n is preferably 2. In said group of compounds, g is preferably 0 or 1. R 1 is a compound of formula (I). is preferably halogen, C1 -C3 alkoxy or C1 -C3 alkylthio.

In a second preferred group of compounds of the invention, A is O. In this group of compounds, n is preferably 2. In said group of compounds, g is preferably 0 or 1. R 1 is preferably halogen, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio. carbon atoms.

* «r · e-----r r r

In compounds of formulas I and Ia, R 1 preferably represents a group selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, isopropoxy, bromine, chlorine, fluorine, iodine, trifluoromethyl, 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. Even more preferably, R 1 is methoxy, chloro or methylthio.

In the compounds of formulas I and Ia, R4 preferably represents a group selected from the group consisting of cyclopropyl, methoxy, ethoxy, bromine, chlorine, fluorine, iodine, trifluoromethyl, trifluoromethoxy, 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-3enyl, 1-hydroxy-2-methylpropenyl, 1-hydroxy-2-methylbut-3-enyl,

1-hydroxypent-4-enyl, 3-hydroxybut-1-enyl, 1-hydroxypropinyl, 1-hydroxybut-2-ynyl, α-hydroxy-2-methoxybenzyl, methoxymethyl, ethoxymethyl, isopropoxymethyl, cyclopropylmethoxymethyl, cyclobutylmethoxymethyl, prop-2-ynyloxymethyl, methylthio, phenylthio, vinyl, allyl, prop-1-enyl, 2-methylprop-2-enyl, 1-methylvinyl, styryl, formyl, acetyl, cyano, ethoxycarbonylmethyl, N- (1-methylethyl) iminomethyl, N-methylaminomethyl and hydroxyiminomethyl . Even more preferably, R 4 is hydroxymethyl, 1-hydroxyethyl or vinyl. Most preferably, R 4 is a hydroxymethyl group or a vinyl group.

In particularly preferred compounds of formula (Ia), A is S or O; g is 0 or 1, n is 2; R 1 is halogen, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio, and R 4 is C 1 -C 4 hydroxyalkyl, α-hydroxy (2C 1-3 alkoxyphenyl) methyl, C 3 -C 4 hydroxyalkenyl carbon atoms wherein the hydroxy group is not directly attached to any of the double bond atoms, a (Ciny-C hydroxy) hydroxyalkynyl group wherein the hydroxy group is not directly attached to any of the atoms forming it. a triple bond, an alkenyl group having 2 to 3 carbon atoms,

C1-3alkylthio, C1-4alkonyl or hydroxyiminomethyl.

In the following, the term compound of formula I means compounds of formula I or formula Ia. Similarly, the term compound of formula I means a compound of formula I or formula Ia.

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

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

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

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

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

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

Specific compounds of formula I include:

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

- [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;

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

- [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;

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

- [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;

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

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

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

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

- [3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1] -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-en-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-phenyl-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-dihydro-imidazo [2, l-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-dihydro-imidazo [2, l-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-2-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-dihydro-imidazo [2, l-bjtiazol-2yljmetanol;

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

3- (benzo [b] thiophen-3-yl) -2-prop-2-yloxymethyl-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, including their pharmaceutically acceptable salts and their individual enantiomers.

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

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

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

Preferably, the compounds of the invention are administered orally in known dosage forms suitable for said administration. Dosage forms suitable for oral administration include tablets, pills, capsules, encapsulated forms, multiparticulate forms including: granules, grains, 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 invention with one or more of the following ingredients, or mixtures thereof, including:

inert diluents such as calcium carbonate, calcium sulfate, compressible sugar, confectionery sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, glylceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactose, magnesium carbonate, magnesium oxide, mannitol, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinized starch, sodium chloride, sorbitol, starch, sucrose, spherical sugar particles, talc and calcium phosphate;

disintegrants such as alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilininated cellulose, polacrilininate , sodium starch glycolate, starch including corn starch, and agar;

glidants such as calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, stearic acid and zinc stearate;

binders such as gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, guar, hydrogenated vegetable oil, hydroxyethylcellulose, hydroxypropylmethylcellulose, liquid glucose, methyl-magnesium aluminum silicate, polymethacrylate, malt, methacrylate; pregelatinized starch, sodium alginate, starches including corn starch, zein, sugars (such as sucrose, melase and lactose) and natural and synthetic gums (such as carrageenan, polyethylene glycol, waxes, microcrystalline cellulose and polyvinylpyrrolidone);

coloring agents such as the commonly used pharmaceutically acceptable colorants;

sweetening and flavoring agents;

preservatives;

one or more pharmaceutically acceptable dual compositions (such as those containing acid and carbonate or bicarbonate) which, upon addition of water to the dosage form, aid gas evolution upon dissolution; and optionally other ingredients known in the art to enable oral dosage forms to be prepared by known methods such as tableting.

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

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

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

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

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

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

The pharmaceutical compositions may also be administered parenterally (e.g., subcutaneously, intramuscularly, intradermally, and / or intravenously (as injection and / or infusion) in dosage forms known in the art for parenteral administration (such as sterile suspensions in aqueous and / or oily medium and / or or sterile solutions in suitable solvents, preferably being isotonic with the blood of the intended patient) Parenteral dosage forms may be sterilized (for example, by microfiltration and / or using suitable sterilizing agents [such as ethylene oxide]). acceptable adjuvant compositions suitable for parenteral administration; local anesthetics, preservative e.

compositions, buffers and / or mixtures thereof. The parenteral dosage forms are stored in suitable sterile well-sealed containers (e.g., ampoules and / or vials) until use. To increase storage stability, they can be prepared in the form obtained by freezing after filling into a container and removing the liquid (e.g. water) under reduced pressure.

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

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

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

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

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

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

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

Pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I can be used to treat depression, anxiety, psychoses (e.g. schizophrenia), tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, obsessive compulsive behavior, panic attacks, social phobias, eating disorders such as bulimia, anorexia, excessive killing and morbidity, non-insulin-dependent diabetes, hyperglycemia, hyperlipidemia and stress in mammals and especially humans, and also as aids to facilitate quitting smoking in humans. The compositions may also be used in the treatment and / or prevention of seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage occurs. Although the exact amount of active compound administered in the treatment depends on several factors such as the age of the patient, the severity of the condition, the medical history and, depending on the judgment of the attending physician, the daily dose of active compound ranges from 1 to 1000 mg, preferably 5 to 500 mg. in single or divided doses administered once or more daily.

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

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

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

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

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

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

In another aspect, the invention provides a method of reducing cardiovascular side effects of an anti-obesity drug comprising incorporating it into a compound having 5-HT2 agonist activity. Another aspect of the invention includes the use of a 5HT1A agonist compound which is a monoamine reuptake inhibitor, in particular is a norepinephrine reuptake inhibitor. for the treatment of obesity and related disease states without inducing cardiovascular side effects.

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

The agonism of 5-HT _1A particularly preferred compounds of the invention can be ascertained by electrophysiological assays known in the art.

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

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

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

wherein A, R 1, R 2, R 3, R 4, R 5, g and n are as defined above, optionally in the presence of an acid such as acetic acid or sulfuric acid at a temperature in the range of 0-200 ° C; preferably in the range of 20-150 ° C.

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

Wherein R2, R3 and n are as defined above, with a compound of formula IV < c

IV

wherein Z is a leaving group such as halogen such as bromine, and A, R 1, R 4 and R 5 and g are as defined above at a temperature in the range of 0-200 ° C in the presence of a solvent such as ethanol and optionally in the presence of an acid such as acetic acid; preferably with heating at a temperature between 20 ° C and the boiling point of the solvent used.

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

Compounds of formula I wherein R 4 is halogen may be prepared by reaction of a compound of formula V

3'n wherein A, R 1, R ₂ , R 3, R 5, nag are as defined above, with a halogenating agent such as bromine, phenyltriomethylammonium tribromide, iodine chloride or benzyltrimethylammonium tetrachloroiodate, at a temperature ranging from -50 to 200 ° C, optionally in the presence of a solvent such as dichloromethane, tetrahydrofuran or acetone.

Compounds of formula I wherein R 4 is -CH (OH) R _X wherein R _x is C 1-6 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, or (2- (C 1-3 alkoxyphenyl) may be prepared by reacting a compound of formula VI

wherein A, R 1, R ₂ , R 3, R 5, nag are as defined above and R _y is H, with an organometallic composition such as those of the formula R _x MgX or R _x Li, wherein R _x is as defined above and X is halogen e.g. bromine, in the presence of a solvent such as tetrahydrofuran or ether, at a temperature ranging from -50 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is -CH (OH) R _y wherein R _y is C 1-6 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, or (2- (C 1-3 alkoxyphenyl) may be prepared by reacting a compound of formula (VI) wherein A, R 1, R ₂ , R 3, R 5, nag are as defined above and R _y is C 1-5 alkyl, alkenyl of 2-5 or (2-C 1-3 alkoxyphenyl) with a reducing agent such as sodium borohydride, in the presence of a solvent such as ethanol, at a temperature ranging from 0 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is hydroxymethyl may be prepared by reacting a compound of formula VI wherein A, R 1, R 2, R 3, R 4, R 5, g are as defined above and R _y is H with a reducing agent such as borohydride sodium, in a solvent such as methanol, at a temperature ranging from -50 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is hydroxyiminomethyl. a group may be prepared by reacting 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 H with hydroxylamine or a salt thereof, optionally in a solvent e.g. in ethanol, at a temperature in the range of 0-250 ° C.

Compounds of formula I wherein R ₄ is cyano may be prepared by reacting 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 H, with hydroxylamine or a salt thereof in the presence formic acid at a temperature in the range of 0-250 ° C.

Compounds of formula I wherein R 4 is C 1-4 alkyliminomethylene can be prepared by reacting 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 H with an amine of R _and NH 2 wherein R _a is a C 1-4 alkyl group optionally in the presence of a solvent such as ethanol, optionally in the presence of an acid catalyst such as acetic acid at a temperature in the range of 0-250 ° C.

Compounds of formula I wherein R 4 is C 1-4 alkylaminomethylene can be prepared by reacting a compound of formula I wherein R ₄ is C 1-4 alkyliminomethylene and A, R 1, R 2, R 3, R 5, nag are as defined above with a reducing agent such as sodium borohydride, in the presence of a solvent such as ethanol, at a temperature ranging from 0 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is C 1-4 alkylaminomethylene can be prepared directly from 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 by reaction with an amine R _and NH 2, where R _a is C 1. And a reducing agent such as sodium triacetoxyborohydride in the presence of a solvent such as tetrahydrofuran at a temperature ranging from 0 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R ₄ is -C (OH) R _x R _y , where R _x and R _{y are} each independently C 1-6 alkyl, may be prepared by reacting a compound of formula VI wherein R _y is Cl alkyl, and A, R 1, R ₂ , R 3, R 5, g and n are as defined above with an organometallic composition, for example a compound of formula R _x MgX or R _x Li, wherein R _x is as defined above and X is halogen such as bromine in the presence of a solvent such as tetrahydrofuran or ether at a temperature ranging from -50 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R ₄ is -C (OH) R _x R _y , wherein R _x and R _y both represent the same C 1-6 alkyl group may be prepared by reacting a compound of formula VI as described above, except that: that R _y is OR _Z , where R _z is a C _1-6 alkyl group, with an organometallic composition, for example a compound of the formula R _x MgX or R _x Li, wherein R _x is as defined above and X is halogen such as bromine, in the presence of a solvent e.g. tetrahydrofuran or ether, at a temperature ranging from - 50 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is a C 2-6 alkenyl group whose double bond is attached to an alpha carbon relative to the thiazole ring or a styryl group can be prepared by reacting a compound of formula VI wherein R _y is hydrogen or C 1-4 alkyl and A, R 1, R 2, R 3, R 5, nag are as defined above, with a phosphonium salt of the general formula R ₂ Ph 3 P ⁺ Br ', where R _z is C 1-6 alkyl or benzyl, in the presence of a base such as butyllithium in a solvent such as for example an ether, e.g. tetrahydrofuran, at a temperature ranging from -78 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is a C 2-6 alkanoyl group may be prepared by reacting a compound of formula I wherein R 4 is halogen such as bromine or chlorine and A, R 1, R 2, R 3, R 5, nag are as defined above, or a compound of formula V with a compound of formula R _b MgX or R _b Li, wherein R _b is a C 1-6 alkyl group and X is a halogen such as bromine or chlorine, in the presence of a solvent such as an ether e.g. diethyl ether or tetrahydrofuran, at a temperature of from 78 ° C to the boiling point of the solvent, and then reacting the product with an acylating agent, for example a compound of formula R _c CON (CH 3) OCH _3, wherein R _c is a group Cj.salkylovú, in a solvent such as ethers such as tetrahydrofuran at a temperature ranging from 0 ° C to the boiling point of the solvent used. Compounds of formula (VI) may be prepared in a similar manner.

Compounds of formula I wherein R 4 is C 1-3 alkoxyC 1-3 alkyl may be prepared by reacting a compound of formula I wherein R 4 is hydroxyC 1-6 alkyl and A, R 1, R 2, R 3, R 5, g and n are as defined above with C 1-6 alkylation. by means of, for example, C1. _An alkyl halide, e.g. _An alkyl iodide, in the presence of a base such as sodium hydride, in a solvent such as napríklad, Ν-dimethylformamide, at a temperature ranging from -50 ° C to 150 ° C.

Compounds of formula I wherein R 4 is C 4-7 cycloalkylalkoxyC 1-3 alkyl may be prepared by reacting a compound of formula I wherein R 4 is hydroxyC 1. _The alkyl group and A, R 1, R 2, R 3, R 5, g and n are as defined above with a C 4-7 cycloalkylating agent such as a C 4-7 cycloalkyl halide such as a C 4-7 cycloalkyl iodide in the presence of a base such as sodium hydride in a solvent e.g. Dimethylformamide, at a temperature ranging from -50 ° C to 150 ° C.

Compounds of formula I wherein R ₄ is C 3-7 alkynyl alkoxyC 1. _{The 3} alkyl group can be prepared by reacting a compound of formula I wherein R 4 is hydroxyC 1-3 alkyl and A, R 1, R 2, R 3, R 5, g are as defined above with a C 3-7 alkynylalkyl halide such as a C 3-7 alkynylalkyl halide such as C 4-7 alkynyl alkyl iodide. , in the presence of a base such as sodium hydride, in a solvent such as Ν, Ν-dimethylformamide, at a temperature ranging from -50 ° C to 150 ° C.

Compounds of formula I wherein R 4 is a C 1-3 alkylthioC 1-3 alkyl group may be prepared by reacting a compound of formula I wherein R 4 is a mercaptoC 1-6 alkyl group and A, R 1, R 2, R 3, R 5, g and n are as defined above with by means of, for example, C1. A 3-alkyl halide, such as a C 1-3 alkyl iodide, in the presence of a base such as sodium hydride or sodium hydroxide, in a solvent such as Ν, im-dimethylformamide, at a temperature ranging from -50 ° C to 150 ° C.

Compounds of formula I wherein R ₄ is C 1-3 alkylthio or arylthio and A, R 1, R 2, R 3, R 5, nag are as defined above may be prepared by reacting a compound of formula I wherein R 4 is halogen or compounds of formula V with a metallating agent, for example a compound of formula RMgX or RLi, wherein R is a C 1-8 alkyl group and X is a halogen such as chlorine, bromine or iodine in a solvent such as ethers or a mixture of ethers such as tetrahydrofuran or diethyl ethers, at a temperature ranging from -100 ° C to the boiling point of the solvent used to prepare an intermediate complex, which is worked up by reaction with a disulfide of the formula R 15 -SR d, where R d represents a C 1-4 alkyl or aryl group, at a temperature in the range from -100 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is a C 1-3 alkoxy group and A, R 1, R 2, R 3, R 5, nag are as defined above may be prepared by reacting a compound of formula I wherein R 4 is halogen such as bromine or iodine with C 1 A -3alkoxide salt, for example a sodium or potassium salt, optionally in the presence of a solvent, for example a C 1-3 alcohol or dimethylformamide, optionally in the presence of a catalyst, for example a copper (I) salt, at a temperature in the range 0-350 ° C.

Compounds of formula I wherein R 4 is a C 3-6 alkenyl group whose double bond is not attached to the alpha carbon relative to the thiazole ring may be prepared by reacting a compound of formula I wherein R 4 is halogen such as bromine or chlorine and A, R 1, R2, R3, R5, nag are as defined above, or compounds of formula V with a compound of formula RbMgX or RbLi, wherein Rb is a C 1-6 alkyl group and X is a halogen such as bromine or chlorine in the presence of a solvent such as an ether e.g. diethyl ether or tetrahydrofuran, at a temperature ranging from -78 ° C to the boiling point of the solvent used, followed by reaction of the obtained product with an alkenylating agent, for example a C 3-6 alkenylmethyl halide, e.g. C3-6 alkenylmethyl iodide, in a solvent such as ethers, e.g. tetrahydrofuran, at a temperature ranging from 0 ° C to the boiling point of the solvent used.

Compounds of formula I wherein R 4 is C 3-6 alkoxycarbonylalkyl may be prepared by reacting compounds of formula VI wherein R _y is hydrogen and A, R 1, R 2, R 3, R 5, nag are as defined above with a phosphonate of formula Me 2 NH [ PO (OR _z ) 2h, wherein R _z represents a C 1-4 alkyl group, in the presence of a base such as sodium hydride, in a solvent such as an ether such as 1,4-dioxane, at a temperature ranging from -78 ° C to a temperature of boiling of the solvent used, and then subjecting the obtained product to partial hydrolysis in an acid medium such as hydrochloric acid.

Compounds of formula I wherein R 4 is a C 4-6 hydroxyalkenyl group wherein the double bond is attached to the alpha carbon relative to the thiazole ring may be prepared by reacting a compound of formula VI wherein R _y is hydrogen, and A, R 1, R 2, R 3, R 5, nag are as defined above, with a compound of formula (R _z O) ₂ POCH ₂ COR _c , wherein R _z is C 1-2 alkyl and R _c is C 1-4 alkyl, in the presence of a base such as sodium hydride, in a solvent such as an ether such as tetrahydrofuran at a temperature ranging from -78 ° C to the boiling point of the solvent used, and then subjecting the obtained intermediate to reaction with a reducing agent such as sodium borohydride, in a solvent such as ethanol at a temperature ranging from -20 ° C to the boiling point of the solvent used.

Compounds of formula III are commercially available or may be prepared by methods known in the art. Compounds of formula (IV) may be prepared by methods known in the art specified in the individual examples below.

The ability of the compounds of formula I to interact with 5-hydroxytryptamine (5-HT) receptors has been demonstrated for the products prepared according to Examples 1 to 56 by the assay below, which determines the ability of the compounds to inhibit tritiated ligand binding in vitro to 5-HT receptors. 5-HT | _And .

The brain hippocampus of male Sprague-Dawley rats (Charles River, weighing 150-250 g) is homogenized in ice-cold 50 mM Tris-HCl buffers (pH 7.7 at 25 ° C, 1:40 w / v) and then centrifuged at 40,000 g, 4 ° C and a spin time of 10 minutes. The pellet is rehomogenised in the same buffer, incubated for 10 minutes at 37 ° C and then centrifuged for 10 minutes at 40,000 g at 4 ° C. The final pellet is resuspended in 50 mM Tris-HCl buffers (pH 7.7) containing 4 mM CaCl 2, 0.1% L-ascorbic acid and 10 µΜ pargylin hydrochloride (equivalent to 6.25 mg wet tissue / ml) and the product is collected. used immediately prior to detention.

Membranes (400 μΐ; equivalent to 2.5 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] 8-hydroxy-2- (dipropylamino) tetralin - ([ ³ H] 8-OH-DPAT) at one concentration 1. nM and with 50 μΐ distilled water (total binding) or with 50 μΐ of the test compound (at a single concentration of 10 ' ⁶ M or at 10 concentrations in the range of 10' ^H -10 ' ³ M) or with 50 μΐ 5-HT (10 μΜ, non-specific binding) at 25 ° C for 30 minutes. The incubation is terminated by rapid filtration under vacuum through Skatron 1134 filters using a Skatron Cell Harvester. The filters are then washed with ice-cold 50 mM tris-HCl, pH 7.7 (at 25 ° C, and the wash values set at 9.9.0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and radioactivity is measured with a liquid scintillator.

The ability of the compounds of formula I to interact with 5-hydroxytryptamine (5-HT) reuptake sites has been demonstrated for the products prepared according to Examples 1 to 56 by the below assay, which determines the ability of the compounds to replace the standard ligand, [ ³ H] citalopram from uptake of 5-HT in vitro.

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

Membranes (400 μΐ; equivalent to 1.25 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] citalopram at a single concentration of 1.3 nM and 50 μΐ of distilled water (total binding) or 50 μΐ of test compound (at one concentration). a concentration of 10 * ⁶ M or at 10 concentrations in the range of 10 ^{l I} -10 ^{3 3} M) or with 50 μΐ of paroxetine (0,5 μΜ, non-specific binding) for 1 h at 27 ° C. Membrane-bound radioactivity was determined after filtration under vacuum through Skatron 11734 filters pre-saturated with 0.5% PEI, using a Skatron Cell Harvester. The filters are then washed with ice-cold 50 mM tris-HCl, pH 7.4 (at 25 ° C, and the wash values set at 9.9.0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and radioactivity is measured with a liquid scintillator.

The ability of the compounds of formula I to interact with noradrenaline reuptake sites (NA) has been demonstrated for the products prepared according to Examples 1 to 33 by the following assay, which determines the ability of the compounds to replace the standard ligand, [ ³ H] nizoxetine from noradrenaline reuptake sites. in vitro.

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

Membranes (400 μΐ; equivalent to 7.5 mg wet tissue / tube) are incubated with 50 μΐ [ ³ H] nisoxetine at a single concentration of 0.6 nM and with 50 μΐ of distilled water (total binding) or with 50 μΐ of the test compound (at one concentration). a concentration of 10 ⁶ M or 10 concentrations in the range of 10 ¹ '-10 ” ³ M) or with 50 μΐ of mazindole (1 μΜ, non-specific binding) for 4 h at 4 ° C. The membrane-bound radioactivity was determined after filtration under vacuum through Skatron 11734 filters using a Skatron Cell Harvester. The filters are then washed rapidly with ice-cold 50 mM tris-HCl, pH 7.4 containing 120 mM sodium chloride and 5 mM potassium chloride (at wash values of 9.9.0). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and radioactivity is measured with a liquid scintillator.

The ability of compounds of formula I to interact with muscarinic receptors was determined for the products prepared according to Examples 1 to 56 by the assay below, which determined the ability of the compounds to replace the standard ligand, [ ³ H] -N-methylscopolamine from muscarinic receptors in vitro.

Frontal cortical brain tissue of male Charles River rats, weighing 150-250 g, is homogenized in ice cold 20 mM HEPES buffers pH 7.5 (value determined at 25 ° C) containing 100 mM sodium chloride and 10 mM magnesium chloride (1). : 10 w / v) using a Polytron PT3100 (at a speed set at 21,700 rpm, 3x5 seconds) and then centrifuged at 49,500 g and a spin time of 30 minutes at 4 ° C. The superantant was removed and the pellet rehomogenized in 20 mM HEPES buffers, pH 7.5, containing 100 mM sodium chloride and 10 mM potassium chloride (equivalent to 12.5 mg wet tissue / ml). The membranes are stored at -80 ° C until use.

The membranes are thawed, diluted 1: 10 in ice-cold 20 mM HEPES buffers, pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride, homogenized using a Polytron 3110 as described above. Diluted membranes (200 μΐ; equivalent to 0.25 mg wet tissue / tube) are incubated with 200 μΐ 20 mM HEPES buffer pH 7.5 containing 100 mM sodium chloride and 10 mM magnesium chloride and 5 mM potassium chloride and 50 μΐ [ ³ H] N-methylscopolamine at a single concentration of 0.15 nM and with 50 μΐ of distilled water (total binding) or with 50 μΐ of the test compound (at a single concentration of 10 ' ⁶ M or at 10 concentrations in the range of 10' ^H -10 ' ³ M) or with 50 μΐ atropine sulphate (1 μΜ, non-specific binding) for 30 minutes at 30 ° C. Membrane-bound radioactivity was determined after filtration under vacuum through Skatron 1134 filters using a Skatron Cell Harvester. The filters are then rapidly washed with ice-cold 20 mM HEPES buffer, pH 7.5 (wash 1.2 at 5.5 setting). The filter discs thus treated are then introduced into vials, scintillation fluid is added, and radioactivity is measured with a liquid scintillator.

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

re Γ · · ^r rer

Π r r '

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

In the absence of compound:

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

In the presence of compound (10 ' ⁶ M):

B (dpm) = binding in the presence of 10 ' ⁶ M (dpm) - nonspecific binding (dpm)

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

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

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

% displacement at 10 ' ⁶ M = 100% special bond at 10' ⁶ M

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

ξ = [4 «-s

r. '= r

C F + K, and ab = k

c -L-on;

F ₂ = -ab + 1b + ² + K ₍ L

C ^«r i i ^F

Non-specific data ^K J ^{+ F} l ⁺

K., F d * 2

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

DPM

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

L is the concentration of the compound, [Ltot - the concentration of tritiated ligand used, calculated as:

(mean DPM for DPM of total samples added) x dilution [L] _Tot = -'---, (specific activity) x (volume per incubation)

K _D represents the equilibrium dissociation constant of the ligand

F 1 and F 2 are the concentrations of the corresponding free ligand and free compounds.

r 1 represents the total receptor concentration in the first experiment. This expression must be multiplied by Ck in subsequent attempts. (C 1 = 1).

f r

Nr means a non-specific binding constant.

The results obtained in the above assays for binding to 5-HT 1A and uptake of 5-HT 1A and binding to muscarinic receptors using the end products of Examples 1-56 below are shown in the table below.

1. K-, s values are in nM and are the mean of three independent determinations. Values in% represent% displacement at a concentration of 10 ^-6 in one assay.

Table 1

Example # 5-HT _1Ä capture the 5HT capture the ON THE muscarinic receptor 1 51% 1% 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%

Table 1 (continued)

Example # 5-ΗΤ, α capture the 5HT capture the ON THE muscarinic receptor 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%

Table 1 (continued)

Example # 5-ΗΤ, α capture the 5HT capture the ON THE muscarinic receptor 47 53% 65% 97% 39% 48 23 24.3 4.1 3.9 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%

If values for n = 1, mean n = 2 or mean n = 3,

NT = not rated

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

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

enzyme substrate incubation reaction product detection method MAO-A (h) Kynuramine (0.15 mM) 30 min / 30 ° C 4-OH quinoline spectrometer photometry

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

f '

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.

The combination of inhibition of monoamine oxidase activity and inhibition of 5-HT reuptake can induce serotonin syndrome (Sternbach H. Serotonin Syndrome. Am.J.Psychiatry 148,705-713,1991), which is highly undesirable.

Acute food intake studies

Test animals and environment

The experiments were performed on male Sprague-Dawley rats (300-450 g at the start of the experiment) obtained from Charles River (Margate). Animals are housed one by one in polypropylene cages with a metal grid floor at a temperature of 21 + 1 ° C and 55% humidity. Polypropylene trays are placed under each cage. Animals are housed in a reverse light-dark cycle. The light turns off from 9.30 to 17.30, during which time the red light is on. Animals have free access to powdered food for rats and have plenty of drinking water at all times. Food is placed in glass bowls (10 cm in diameter; 8 cm deep) with aluminum lids. Each lid has a cut hole (3 cm diameter) for access to food. Animals are housed under these conditions at least two weeks prior to the start of the experiment.

Test procedure

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

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

Analysis of results

Variations in body weight were included in the results by expressing the results in g / kg rat weight (mean rat group values ± mean standard deviation). ED50 values (drug dose needed to reduce food intake to 50% of control) were calculated from the logistic sigmoid curve using the appropriate computer program. Statistical comparisons of mean food intake values in each group were performed by dispersion analysis and Dunnett's two-tailed test.

Surprisingly, the compounds of the invention have a lower affinity for muscarinic receptors as compared to the compounds exemplified in WO97 / 02269, or have significantly reduced MAOa inhibitory activity compared to the compounds exemplified in WO97 / 02269. For example, the compound of Example 1 of WO97 / 02269 has a K i value for binding to the muscarinic receptor of 130 nM. Muscarinic affinity may cause undesirable side effects, such as dryness to the mouth, blue-red vision, sweating, palpitations, constipation, and narrow glaucoma with narrow ventricular vision (Blackwell, B. Adverse effects of antidepressant drugs.) Drugs 21,202. -219.1981). Obviously, it is desirable that the compounds have minimal affinity for muscarinic receptors.

• · *

Particularly preferred compounds of the invention show improved efficacy in acute food intake studies as compared to the compounds exemplified in WO97 / 02269.

The invention is further illustrated by the following examples, which are given by way of illustration only. The end products prepared by the method of the following examples were characterized by one or more of the following methods: high performance liquid chromatography, elemental analysis, nuclear magnetic resonance spectrometry, mass spectrometry, and infrared spectroscopy.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

To a stirred suspension of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (50 g; prepared by a method similar to that described in WO 97/02269) in dichloromethane (400 mL) triethylamine (75 mL) was added dropwise at <10 ° C, and then the mixture was stirred at room temperature for 1 hour. Then water (300 ml) was added, the organic phase was separated, washed with water (2 x 100 ml) and saturated aqueous sodium chloride solution (100 ml), dried (Na 2 SO 4) and the solvent removed in vacuo to give a pale yellow solid. (34 g) of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole, which was used without further purification.

Then butyllithium (2.5 mol solution) was added dropwise to a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (10.14 g) in tetrahydrofuran (260 mL). (1 in hexanes; 17.5 mL) and the mixture was stirred at -70 ° C for 20 minutes, then allowed to warm to 0 ° C and stirred at 0 ° C for 30 minutes. Dimethylformamide (2.86 mL) was then added and the mixture was stirred at room temperature for 20 minutes. Then, saturated aqueous sodium chloride solution (200 ml) and ether (400 ml) were added, the organic phase was separated, washed with water (100 ml) and saturated aqueous sodium chloride solution (100 ml), dried (Na 2 SO 2) and solvents. removed under vacuum. The residue was purified by flash chromatography on silica using a 10: 1 mixture of dichloromethane and methanol as eluent. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was refluxed with propan-2-ol (100 mL) for 5 minutes, then the mixture was filtered hot and allowed to cool to room temperature. The resulting solid was filtered and dried in vacuo at 60 ° C to give a yellow solid (1.4 g); 206 DEG C. gives 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde.

Example 2

A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.198 g), sodium borohydride (0.026 g) and methanol (20 mL) was stirred for 1 h. One hour under nitrogen at room temperature, water (2 ml) was added and the mixture was 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 evaporated in vacuo to give a residue. in the form of a yellow solid (0.077 g) s 1.1. 168-170 ° C to give [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol.

Example 3

A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.44 g), hydroxylamine hydrochloride (0.118 g) and ethanol (30 g). ml) was heated at reflux for 2.75 h and then cooled to room temperature. The precipitated solid was filtered off and suspended in dichloromethane (50 ml). Triethylamine (3 ml) was then added and the solution was washed with water (20 ml) and saturated aqueous sodium chloride solution (20 ml), dried (MgSO 4) and the solvent removed in vacuo as a white solid (0.07 g). ) s 1.1. 226-228 ° C gives 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde oxime.

Example 4

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (0.286 g) in tetrahydrofuran (30 mL) was added dropwise at 0 ° C methylmagnesium bromide (3M in ether, 1.2 mL), and the mixture was then stirred at room temperature for 15 minutes. Then water (5 ml) and ethyl acetate (70 ml) were added and 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 solvents removed in vacuo. . The residue was triturated with ether (30 mL), the solid was filtered off and dried in vacuo at 100 ° C to give an off-white solid (0.213 g) with m.p. 174-176 ° C gives 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] ethanol.

Example 5

A suspension of [3- (benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2,1-b] thiazol-2-yl] -methanol (0.5 g) in ethanol (25 mL) was heated to reflux until dissolution of all solids. A solution of hydrogen chloride in ether (1 mol / L, 2 ml) was then added and the mixture was then heated at reflux for 3 minutes and then allowed to cool to room temperature. The resulting solid was filtered off, washed with ether (20 ml) and dried in vacuo at 60 ° C as a white solid (0.32 g) with m.p. 240-250 ° C (dec.) Gave 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-methanol hydrochloride. After isolation of the solid product, a solution of hydrogen chloride in ether (1M; 2 ml) was added and the mixture was stirred at room temperature for 18 hours. The resulting solid was filtered, washed with ether (20 mL) and dried in vacuo at 60 ° C to give a second crop of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole. -2-yl] -methanol hydrochloride as a white solid (0.1 g), 1.1. Mp 240-250 ° C (dec.).

r r

Example 6

A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (200 g; prepared by a method similar to that described in WO 97/02269), saturated aqueous sodium carbonate solution (1000 mL) and dichloromethane (2000 mL) was stirred vigorously for 1.5 hours at room temperature, then the organic layer was separated, washed with water (500 mL), dried (MgSO 4) and the solvent removed in vacuo. The above procedure was repeated on the same scale and the two products combined to give a pale yellow solid (264.3).

g) 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole, which was used without further purification.

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (264.3 g) in dichloromethane was then added dropwise over 1.75 hours at 0-5 ° C. bromine (55.5 mL) and the mixture was then stirred at 0 ° C for 30 minutes and at room temperature for 1 hour. The resulting solid was then filtered, washed with dichloromethane (300 mL) and dried in vacuo at 70 ° C to give 3- (benzo [b] thiophen-3-yl) -2-bromo as a pale yellow product (431 g). -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide, which was used without further purification.

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

To an ice-cooled suspension of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (63 g) in methanol (1200 mL) was added over 10 minutes portionwise sodium borohydride (12.5 g), then stirred at 5 ° C for 30 minutes, then at room temperature for 4 hours and at reflux for 20 minutes. The mixture was then cooled to room temperature over one hour and stirred for an additional hour. The resulting solid was filtered, washed with water (200 mL), ethanol (200 mL) and ether (200 mL) and dried in vacuo at 60 ° C to give an off-white solid (52.1 g) [3 ( benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] -thiazol-2-yl] methanol, which was used without further purification.

A stirred suspension of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] methanol (52.1 g) in methanol (2200 mL) was heated at room temperature. reflux until substantially all of the solids are dissolved. The heat source was then removed and fumaric acid (21 g) in methanol (250 mL) was added over 1 minute. The mixture was then stirred for 10 minutes and then left at room temperature for 1 hour, then cooled in ice for 3 hours. The resulting solid was filtered, washed with ice-cold methanol (200 mL) and dried in vacuo for 3 hours at 60 ° C and for 2 hours at 80 ° C to give a white solid which was a 1 equivalent solvate according to NMR spectroscopy results. methanol. The solid product obtained is combined with a second sample of the product (5.2 g; also in the form of a solvate with methanol), prepared in the same manner as described above, and the combined product is comminuted using a pestle and mortar, and dried under vacuum after 15 hours at 90 ° C and 1 mm Hg as a white solid (53.4 g) with m.p. 258-262 ° C (dec.) Gave [3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl) methanol fumarate (solvated with 0.05 equivalents) methanol).

Example 7

To a stirred suspension of 3- (benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2,1-b] thiazole (2.0 g) in tetrahydrofuran (50 mL) was added at 0 ° C under nitrogen. Phenyltrimethylammonium tribromide (3.0 g) was added and the mixture was stirred at 0 ° C for 1 hour and then at room temperature for 18 hours. Then water (50 ml) and triethylamine (50 ml) were added, the organic phase was separated, washed with saturated aqueous sodium chloride solution (50 ml), dried (MgSO4) and then the solvent was removed in vacuo. The residue was 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 solvents removed in vacuo to give a yellow solid (1.0 g) with m.p. 196-200 ° C 3- (Benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole.

Example 8

To a stirred suspension of 3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine (0.5 g; prepared by a method similar to that described in WO 97/02) Phenyltrimethylammonium tribromide (0.75 g) was added portionwise in a nitrogen atmosphere at 0 ° C in tetrahydrofuran (15 mL), then the mixture was stirred at 0 ° C for 4 hours and then allowed to warm to room temperature. Then water (50 ml) and triethylamine (50 ml) were added, the organic phase was separated, washed with saturated aqueous sodium chloride solution (50 ml), dried (MgSO4) and then the solvent was removed in vacuo. The residue was 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 solvents removed in vacuo to give a pale yellow solid (0.2 g) with m.p. 3- (benzo [b] thiophen-3-yl) -2-bromo-6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine.

Example 9

To a stirred solution of 3-acetylbenzo [b] thiophene (2.9 g) in diethyl carbonate (50 mL) was added portionwise under a nitrogen atmosphere at room temperature sodium hydride (60% dispersion in mineral oil; 1.35 g) then The mixture was stirred at 80 ° C for 1.5 hours and then poured into a mixture of water (300 mL) and acetic acid (5 mL). The product was extracted into ether (3 x 150 ml) then the extracts were combined and washed with water (2 x 50 ml) and saturated aqueous sodium chloride solution, dried (MgSO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica in a Biotage Flash 40i® eluting with hexane: ethyl acetate (9: 1). Appropriate fractions were combined and evaporated to give ethyl 3- (benzo [b] thiophen-3-yl) -3-oxopropanoate as a brown oil (1.5 g) which was used without further purification.

To a stirred solution of ethyl 3- (benzo [b] thiophen-3-yl) -3-oxo-propanoate (1.5 g) in tetrahydrofuran (30 mL) was added phenyltrimethylammonium tribromide portion wise at 0 ° C. (2.15 g) and the mixture was then stirred at 0 ° C for 30 min and then at room temperature for 1.5 h. The resulting solid was filtered off and washed with tetrahydrofuran (30 mL). The filtrate and washings were combined and the solvent removed in vacuo. The residue was purified by flash chromatography on silica in a Biotage Flash 40i® using a 9: 1 mixture of petroleum ether (b.p. 60-80 ° C) and ethyl acetate as eluent. Combine the appropriate fractions and evaporate the solvents in vacuo as a brown solid (1.7 g) with m.p. 81-83 ° C gives ethyl 3- (benzo [b] thiophen-3-yl) -2-bromo-3-oxopropanoate.

A mixture of ethyl 3- (benzo [b] thiophen-3-yl) -2-bromo-3-oxopropanoate (1.7 g), 2-imidazolidine thion (0.53 g) and ethanol (30 mL) was heated at room temperature for 10 min. at room temperature, then acetic acid (15 mL) was added and the mixture was heated at reflux for 18 hours. The solvents were then removed in vacuo and the residue triturated with ethanol (20 mL). The resulting solid is filtered off, washed with ethanol (10 ml) and ether (20 ml) dried in vacuo at 60 ° C as an off-white solid (1.15 g), m.p. 209-21 1 ° C gives 3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxylate.

A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxylate (0.4 g), triethylamine (2 mL) and dichloromethane (15 mL) The mixture was stirred at room temperature for 20 minutes, then diluted with dichloromethane (40 ml), washed with water (2 x 20 ml) and saturated aqueous sodium chloride solution (20 ml), dried (Na ₂ SO 4) and the solvents removed in vacuo. . The residue (0.22) was dissolved in tetrahydrofuran (7 mL) and methylmagnesium bromide solution (3M in ether; 0.66 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 hours, then an additional portion of methylmagnesium bromide (3 mol / L in ether; 0.42 mL) and toluene (5 mL) were added. The mixture was stirred at room temperature for 5 minutes and at 90-95 ° C for 5 hours, then cooled to room temperature and diluted with water (30 mL). The product was extracted into ethyl acetate (2 x 30 mL) and the combined extracts were washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), dried (MgSO 4) and the solvent removed in vacuo. A mixture of the residue, fumaric acid (0.037 g) and ethanol (5 ml) was heated at reflux for 5 minutes, then the hot solution was separated by decantation from a small amount of undissolved solids and allowed to cool to room temperature. The resulting solid was filtered and washed with ether (10 mL) and dried in vacuo at 60 ° C as an off-white solid (0.057 g) with m.p. 180-182 ° C gives 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] -1-methyl-ethanol-fumarate

Example 10

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (0.52 g) in tetrahydrofuran (30 mL) was added dropwise ethyl magnesium- chloride (2M in ether; 1.4 mL) and then stirred at room temperature for 1 hour. Then a further portion of ethylmagnesium 56 zium chloride (2M in ether; 0.5 ml) was added, the mixture was stirred at room temperature for 1 hour, and then quenched with water (30 ml). The product was extracted with ether (50 mL) followed by ethyl acetate (2 x 50 mL), then the combined extracts were washed with saturated aqueous sodium chloride solution (2 x 30 mL), dried (Na 2 SO 4) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica in a Biotage Flash 40i® eluting with dichloromethane / methanol 99: 1. Combine the appropriate fractions and evaporate the solvents in vacuo as an orange solid (0.24 g) with m.p. 92-94 ° C gives 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] propan-1-ol.

Example 11

To a stirred suspension of 3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole hydrobromide (1 g; prepared in a manner similar to that described in WO 97/02269) in triethylamine (50 mL) was added dropwise at room temperature and the mixture was stirred at room temperature for 10 minutes. Water (25 ml) was then added. The organic phase was separated, washed with water (25 ml), dried (Na 2 SO 4) and evaporated in vacuo to give 3- (5) as a brown solid (0.65 g). -methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole, which was used without further purification.

To a stirred solution of 3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (0.65 g) in tetrahydrofuran (25 mL) was added portionwise at 0 ° C. under a nitrogen atmosphere of phenyltrimethylammonium tribromide (1.5 g), stirred at 0 ° C for 16 hours and then allowed to warm to room temperature. Then triethylamine (50 ml) and water (50 ml) were added, the organic phase was separated, dried (Na 2 SO 4) and the solvent was removed in vacuo. The residue was purified by flash chromatography on silica eluting with ethyl acetate: methanol: triethylamine (99: 1: 0.1). Combine the appropriate fractions and evaporate the solvents in vacuo as an off-white solid (0.05 g) with m.p. 210 ° C (dec.) Gave 2-bromo-3- (5-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole.

r r r ··

Example 12

To a stirred solution of 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (0.8 g; prepared according to a method similar to that described in WO 97/02269) in tetrahydrofuran Phenyltrimethylammonium tribromide (1.0 g) was added portionwise at 0-5 ° C over a period of 15 minutes under a nitrogen atmosphere, and the mixture was stirred at room temperature for 18 hours. Water (30 ml) and triethylamine (5 ml) were then added and the product was extracted into dichloromethane (2 x 20 ml), the combined extracts were washed with water (4 x 20 ml), dried (MgSO4) and the solvents removed in vacuo. as a yellow solid (0.72 g) with 1.1. 205-208 ° C (dec.): 2-bromo-3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole.

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 heated at a temperature of 18 hours. and then allowed to cool to room temperature. The resulting solid is filtered off and dried in vacuo at room temperature to give 1.1 g as a pink solid (15.7 g). 169-171 ° C gives 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) propan-1-one hydrochloride. The solvent was removed in vacuo and the residue was triturated with ether (100 mL). The resulting solid was filtered and dried in vacuo to give a second solid of 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) -propan-1-one- as a pink solid (13.8 g). hydrochloride.

A mixture of 1- (benzo [b] thiophen-3-yl) -3- (dimethylamino) propan-1-one hydrochloride (29.4 g) and water (600 mL) was basified by addition of saturated aqueous sodium carbonate solution to pH 9 After stirring at room temperature for 1 hour, the free base was extracted into ether (3 x 100 mL). The combined extracts were dried (MgSO ₄ ) and the solvent removed in vacuo. The residue was dissolved in methanol (50 mL), then the solution was cooled in ice, and iodomethane (15.7 mL) was added dropwise. The mixture is stirred at room temperature for 1 hour and the resulting solid is filtered off, washed thoroughly with ether, and dried in vacuo at room temperature to give a pink solid (28.7 g) with m.p. 165-167 ° C gives [3- (benzo [b] -thiophen-3-yl) -3-oxopropyl] -trimethylammonium iodide.

A mixture of [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 was stirred at room temperature for 4 hours and then the product was extracted into ether (3 x 150 mL). The combined extracts were dried (MgSO 4) and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) propenone as a pink solid (2.1 g) which was 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 (100 mL) was added. 2 drops). The mixture was then stirred at 0 ° C for hours and then left at 4 ° C for 18 hours. Another portion of benzyl alcohol (0.82 mL) was added, the mixture was stirred at 0 ° C for 7 h, then diluted with dichloromethane (20 mL), washed with saturated aqueous sodium bicarbonate (2 x 10 mL) and water (10 mL). ) and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by preparative thin layer chromatography using a glass plate with silica gel and dichloromethane layer as the mobile phase. Appropriate zones were scraped from the developed plate and the product was extracted by trituration with dichloromethane (30 mL). The extract was filtered and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -3-benzyloxypropan-1-one as an orange oil (0.49 g) which was used without further purification.

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

A mixture of 1- (benzo [b] thiophen-3-yl) -3-benzyloxy-2-bromopropan-1-one (0.54 g), 2-imidazolidinedione (0.15 g), ethanol (3 mL), and acid of acetic acid (1 mL) was heated at reflux for 18 h and then the solvent was removed in vacuo

Γ r vacuum. The residue was triturated with ice-cold ethanol (5 ml) and the residual solid was filtered, washed with ethanol (5 ml) and dried under vacuum at 60 ° C as a cream solid (0.19 g) with mp <250 ° C to give 3 (benzo [b] thiophen-3-yl) -2-ethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide.

Example 14

To a stirred suspension of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (0.64 g) in tetrahydrofuran (30 mL) was added dropwise at 0 Vinylmagnesium chloride (1 mol / L in tetrahydrofuran; 6.7 mL) was added under nitrogen under nitrogen, and then the mixture was stirred at 0 ° C for 10 minutes and at room temperature for 30 minutes. Water (50 mL) was then added, the mixture was concentrated in vacuo to remove tetrahydrofuran, and the product was extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (2 x 25 mL), dried (MgSO 4) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica using a Biotage Flash 40i® system and 1-5% methanol in dichloromethane as the mobile phase. Combine the appropriate fractions and evaporate the solvents as a pale yellow foam (0.12 g) with m.p. 60-65 ° C gives 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] prop-2-en-1-ol

Example 1 5

I

To a stirred suspension of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (0.5 g) in tetrahydrofuran (30 mL) was added dropwise at 0 ° C under N 2 was added 1-propynylmagnesium bromide (0.5M in ether; 10.5 mL) and the mixture was stirred at 0 ° C for 10 min and then at room temperature for 30 min. Then water (60 ml) and ethyl acetate (100 ml) were added, the organic phases were separated, washed with saturated aqueous sodium chloride solution (2 x 25 ml), dried (MgSO 4) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica using a system

Biotage Flash 40i® and 1-5% methanol in dichloromethane as mobile phase. Combine the appropriate fractions and evaporate the solvents as a white solid (0.11 g) with m.p. 190-200 ° C (dec.): 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] but-2-yn-1-ol .

Example 16

To a stirred solution of methyltriphenylphosphonium bromide (4.2 g) in tetrahydrofuran (30 mL) was added butyllithium (2.5 mol / L in hexanes; 4.7 mL) dropwise at 0 ° C, followed by stirring Stir 5 min at 0 ° C and 30 min at room temperature. Then 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxaldehyde (3.05 g) was added portionwise, the mixture was heated at reflux for 3 hours and then allow to cool to room temperature. Ethyl acetate (75 ml) and water (50 ml) were then added, the organic phase was separated, washed with saturated aqueous sodium chloride solution (50 ml), dried (MgSO4) and the solvents removed in vacuo. The residue was diluted with 2.5 mol / L hydrochloric acid (75 mL), stirred at room temperature for 3 hours and then filtered to separate the gummy semi-solid. The filtrate was shaken with ethyl acetate (25 mL), the organic phase was separated, dried (MgSO 4) and evaporated in vacuo to give a slightly solid 3- (benzo [b] -thiophene) as a white solid (0.85 g). 3-yl) -2-vinyl-5,6-dihydroimidazo [2,1-bjtiazol hydrochloride. Further product was obtained by extraction with dichloromethane (2 x 50 mL), drying (MgSO ₄ ) and removal of the solvent in vacuo as 3- (benzo [b] thiophen-3-yl) -2-vinyl-5,6-dihydroimidazo [2]. 1,1'-thiazole hydrochloride as a white solid (0.49 g), 1.1. Mp 221-223 ° C.

Example 17

3- (Benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (2 g) was added portionwise under nitrogen for 10 minutes at 0-5 ° C to a stirred solution of ethylmagnesium chloride (2 mol / L solution in ethers;

t · r

7.2 ml) in tetrahydrofuran (20 ml) and the mixture was then stirred at 0-5 ° C for 30 minutes. Allyl bromide (0.87 ml) was then added dropwise, the mixture was stirred at room temperature for 18 hours and then quenched with saturated aqueous ammonium chloride solution (15 ml) and then water (10 ml). The product was extracted into ethyl acetate (50 mL), the extract was washed with water (25 mL) and saturated aqueous sodium chloride solution (25 mL), dried (MgSO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica using a 5-7% methanol in dichloromethane mixture as the mobile phase. Appropriate fractions were combined and the solvents evaporated in vacuo to give a brown gum (0.36 g). The gum was dissolved in ethanol (2 mL) and a solution of fumaric acid (0.13 g) in ethanol (2 mL) was added. The resulting solid is filtered off, washed with ethanol (10 ml) and dried under vacuum at 75 ° C as an off-white product with m.p. 163-164 ° C gives 2-allyl-3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole fumarate.

Example 18

To a stirred solution of 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (0.5 g; prepared according to a method similar to that described in WO 97/02269) in tetrahydrofuran (6 mL) butyllithium (2.5 mol / L in hexanes; 1 mL) was added dropwise under nitrogen at -70 ° C over 10 minutes and the mixture was stirred at -70 ° C for 30 minutes. Dimethylformamide (0.2 ml) was then added, the mixture was stirred at -70 ° C for 5 minutes and then allowed to warm to room temperature. Saturated aqueous ammonium chloride solution (30 mL) was added and the product was extracted with dichloromethane (3 x 30 mL). The combined extracts were washed with water (30 mL), dried (Na 2 SO 4) and the solvent removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (9: 1). Combine the appropriate fractions and remove the solvents in vacuo as a brown solid (0.24 g) with m.p. 192-195 ° C gives 3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde.

3- (Benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.17 g) was dissolved in methanol (6 mL) with gentle heating, then Sodium borohydride (0.035 g) was added and the mixture was stirred at room temperature for 30 minutes. Water (50 ml) was then added, the mixture was stirred at room temperature for 1 hour, the resulting solid was filtered off, washed with water (10 ml) and dried under vacuum at 60 ° C as a white solid (0.08 gs). Mp 184187 ° C gives [3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] methanol.

Example 19

A stirred mixture of 3- (benzo [b) thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g), isopropylamine (1 mL), ethanol (50 mL), and acid of acetic acid (1 drop) was heated at reflux for 4 hours and then the solvents were removed in vacuo. The residue was triturated with ether (30 mL) and the resulting solid was filtered, washed with ether and dried in vacuo at room temperature to give a pale brown solid (0.38 g) with m.p. 180-182 ° C gives N- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-ylmethylidene] -1-methylethylamine.

Example 20

To a stirred solution of iodine chloride (10 g) in dichloromethane (120 mL) was added benzyltrimethylammonium chloride (8 g) portionwise at room temperature, and the mixture was stirred at room temperature for 2.5 hours. The resulting solid was filtered and dried in vacuo at room temperature to give benzyltrimethylammonium tetrachloroiodate as a yellow solid (16.2 g) which was used without further purification.

Benzyltrimethylammonium tetrachloroiodate (5 g) was then added portionwise at 0 ° C over 1 minute to a stirred solution of 3- (benzo [b] thiophen-3-yl) 5,6-dihydroimidazo [2,1-b] thiazole (3 g) in acetone (125 mL), and the mixture was then stirred at 0 ° C for 1 h. The resulting solid was filtered, triturated with hot propan-2-ol (150 mL) and crystallized from ethanol (150 mL) to give an off-white solid (0.74 g). Concentration of the mother liquor to 75 mL gave a second crop of product (0.41 g). The two portions were combined, triturated with hot ethanol (40 mL) and the solid was filtered, washed with ethanol (10 mL) and dried in vacuo at 60 ° C as an off-white solid (0.91 g). 1.1. 255-257 ° C gives 3- (benzo [b] thiophen-3-yl) -2-chloro-5,6-dihydroimidazo [2,1b] thiazole hydrochloride. 0,5hydrát.

Example 21

3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1b] thiazole hydrobromide (6 g) was added portionwise under nitrogen at 0-5 ° C for 10 minutes to a stirred solution of ethylmagnesium chloride (2 mol / L in ether; 21.6 mL) in tetrahydrofuran (100 mL) and the mixture was then stirred at 0-5 ° C for 1 hour. The resulting mixture was then added over 10 minutes at 50-70 ° C to a stirred solution of N-methoxy-N-methylacetamide (5 g) in tetrahydrofuran (50 mL), and then stirring was continued for another 2.5 hours at 70 ° C. . The mixture was then cooled with ice, and then saturated aqueous ammonium chloride solution (100 mL), water (100 mL) and ethyl acetate (150 mL) were added. The organic layer was separated, washed with a mixture of saturated aqueous sodium chloride solution (100 mL) and water (100 mL), dried (MgSO 4), and the solvents were removed in vacuo. The residue was triturated with ether (3 x 50 mL) and the residual solid was filtered, washed with ether (30 mL) and dried in vacuo to give a yellow solid (1.84 g). A sample of this product (0.25 g) was recrystallized from ethanol (5 ml), filtered, washed with ethanol (5 ml) and dried under vacuum at 75 ° C as a yellow solid (0.043 g) with m.p. 203-205 ° C gives 2-acetyl-3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole.

Example 22

To a stirred suspension of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] methanol (1 g) in dimethylformamide (20 mL) was added portionwise at temperature Sodium hydride (60% dispersion in mineral oil; 0.15 g) was added over 10 minutes at room temperature and the mixture was then stirred at room temperature for 45 minutes. Iodomethane (240 μΐ) is then added and stirring is continued for a further 2 hours. Then water (25 mL) and ethyl acetate (50 ml), the organic phase separated, washed with water (4 x 25 mL) and brine (25 mL), dried _(MgSO4) and the solvents removed under vacuum. The residue was purified by flash chromatography on silica using mixtures of 5-8% methanol in dichloromethane as the mobile phase. Appropriate phases are combined and the solvents are removed in vacuo. The residue was dissolved in hot ethanol, added to a solution of fumaric acid (0.085 g) in hot ethanol (2 mL) and then allowed to cool to room temperature. The resulting solid is filtered off, washed with ethanol (3 ml) and dried in vacuo at 75 ° C as a white solid (0.23 g) with m.p. 175-176 ° C gives 3- (benzo [b] thiophen-3-yl) -2- (methoxymethyl) -5,6-dihydroimidazo [2,1b] thiazole fumarate.

Example 23

3- (Benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (5 g) was added portionwise under nitrogen atmosphere at 0-5 ° C for 30 minutes to a stirred solution of ethylmagnesium chloride (2.0 M in ether (15 mL)) in tetrahydrofuran (75 mL) and then stirred at room temperature for 1 hour. The mixture was then cooled to 0 ° C, dimethyl disulfide (1.8 mL) was added, then the mixture was stirred at room temperature for 24 hours and then quenched by careful quenching with saturated aqueous ammonium chloride solution (50 mL). The product was then extracted into ethyl acetate (150 mL), then the extract was washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried (Na ₂ SO ₄ ) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica using a Biotage Flash 40i® system and a 19: 1 mixture of ethyl acetate and methanol as an eluting pros65 class. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was triturated with ether (20 ml) and the residual solid was filtered off and dried in vacuo as an off-white solid (1.9 g) with m.p. 129-131 ° C gives 3- (benzo [b] thiophen-3-yl) -2- (methylthio) -5,6-dihydroimidazo [2,1-b] thiazole.

Example 24

To an ice-cooled, stirred suspension of methyltriphenylphosphonium bromide (1.5 g) in tetrahydrofuran (25 mL) was added butyllithium (2.5 mol / L in hexanes; 1.7 mL), and the mixture was then stirred at room temperature for 30 minutes. . Then a 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 The mixture was heated at reflux for 4 hours, then left at room temperature for 18 hours, and finally quenched by the addition of water (50 mL). The product was then extracted with ethyl acetate (50 mL) and the extract was washed with saturated aqueous sodium chloride solution (50 mL), dried (MgSO 4) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica eluting with 5-6% methanol in dichloromethane. Combine the appropriate fractions and remove the solvents in vacuo as a brown solid (0.14 g) with m.p. 76 ° C gives 3- (benzo [b] thiophen-3-yl) -2- (1-methylvinyl) -5,6-dihydroimidazo [2,1-b] thiazole.

Examples 25-33

The compounds of Examples 25-33 were prepared as part of a High Speed Analogue library (EMC) system using the following general method.

The appropriate commercially available Grignard reagent (3 molar equivalents) was added to a solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (about 50 mg) in tetrahydrofuran (4 mL). The mixture was stirred at room temperature for 1 hour, then water (1 mL) was added and the mixture was left free in an atmosphere of 18 hours to remove the solvent. Then dichloromethane (4 ml) was added and the solution was pipetted onto a ChemElute column (CE 1103; pH9), left for 15 minutes and then eluted with dichloromethane (3 x 4 ml). The solvent was removed in vacuo to give the desired product, which was analyzed by high performance liquid chromatography on a Hypersil BDS C18 column (100 x 4.6 mm) using gradient elution with acetonitrile and ammonium acetate buffer mixtures as follows:

Time (minutes) Acetonitrile (%) Ammonium acetate (%) 0 10 90 8-9 100 0 11 10 90

All products according to the following examples have corresponding mass spectra. HPLC retention times and% purity are shown in each example.

Example 25 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] -2-methylpropan-1-ol (rt: 3.28) minutes, purity: 80%).

Example 26 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] butan-lol (rt: 3.29 min, purity: 100 %).

Example 27

- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-en-1-ol (rt: 3.42 minutes, purity: 100%).

f P »

Example 28 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -3-methylbutan-1-ol (rt: 3.51 minutes, purity: 90%).

Example 29 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pentan-1-ol (rt: 3.68 min, purity : 100%).

Example 30

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

Example 31

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

Example 32

- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-en-1-ol (rt: 3, 13 minutes, purity: 97%).

Example 25 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4en-1-ol (rt: 3, 44 minutes, purity: 85%).

c .68

Example 34

In a manner similar to that described in Example 4, 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (prepared as described in Example 6) was reacted with

2-methoxyphenylmagnesium bromide and crystallized from a mixture of methanol and propan-2-ol as a white solid, m.p. 195-197 ° C gives [3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] (2-methoxyphenyl) methanol.

Example 35

To a stirred mixture of methyltriphenylphosphonium bromide (65.7 g) and tetrahydrofuran (680 mL) was added butyllithium (2.5 mol / L in hexanes solution; 73.8 mL) at 0-4 ° C over 45 min. ml) and the mixture was then stirred at 4 ° C for 10 minutes and then at room temperature for 30 minutes. Then 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (48 g; prepared in a manner similar to that described in Example 6) was added portionwise, then The mixture was refluxed for 3 hours, then cooled to room temperature and water (500 mL) was added. The product was then extracted into ethyl acetate (3 x 400 mL) and the combined extracts were washed with water (400 mL), dried (MgSO 4) and the solvents removed in vacuo. The residue was triturated with ethyl acetate (300 mL), the residual solid was filtered and recrystallized from ethyl acetate to give an off-white solid. The liquid fractions from recrystallization and trituration were combined and concentrated to give a further crop of product. This process is repeated until no further product can be isolated. All the fractions were combined and recrystallized repeatedly from ethyl acetate until an off-white solid (43.5 g) was obtained with a purity of> 99% (HPLC) corresponding to 3- (benzo [b] thiophen-3-yl) -2-vinyl. -5,6dihydroimidazo [2-b] thiazole. Most of the solid product (41 g) was dissolved in hot methanol (500 mL) and combined with a saturated solution of filmaric acid (16.7 g) in methanol, then the solvent was removed in vacuo. The residue was stirred with ether for 3 hours, the residual solid was filtered and dried in vacuo at room temperature for 24 hours to give 3- (benzo [b] thiophen-3-yl) -2-vinyl-5,6-dihydroimidazo [2, m.p. 1-Bthiazole fumarate (56.8 g) as a white solid with m.p. Mp 161-162 ° C.

Example 36

In a similar manner to that described in Example 35, 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde was reacted with ethyltriphenylphosphonium bromide and butyllithium to give the crude product. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (19: 1). Combine the appropriate fractions and remove the solvents in vacuo as a yellow solid with m.p. 62-68 ° C gives a 3.7: 1 mixture of E- and Z-3 (benzo [b] thiophen-3-yl) -2-prop-1-phenyl-5,6-dihydroimidazo [2,1-b] thiazole.

Example 37

By a method similar to that described in Example 6, bromination of 3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidine is performed (prepared by a method similar to that described in WO 97/02269) followed by treatment with ethylmagnesium chloride and then dimethylformamide to give 3 (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidin-2 carboxaldehyde. The product obtained is reduced by sodium borohydride in a manner similar to that described in Example 2 and in the form of an off-white product with m.p. 174-176 ° C to prepare [3- (benzo [b] thiophen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-a] pyrimidin-2-yl] methanol.

Example 38

A mixture of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g; prepared in a manner similar to that described above)

ΊΟ in Example 6), hydroxylamine hydrochloride (0.16 g) and formic acid (1.3 ml) was heated at 90-95 ° C for 25 hours and then diluted with ether (50 ml). The resulting solid was filtered, washed with ether (30 mL) and purified by flash chromatography on silica eluting with dichloromethane: methanol (95: 5) then 85:15. Combine the appropriate fractions and remove the solvents in vacuo as a white solid (0.12 g) with m.p. 195-196 ° C gives 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carbonitrile. 0,3 formate.

Example 39

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.26 g) in tetrahydrofuran (15 mL) was added dropwise a solution of diethylbenzyl phosphonate (1.5 mL) in tetrahydrofuran (10 mL) dropwise at room temperature, and the mixture was Stir for 20 minutes at room temperature. Then 3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.83 g) was added in one portion, prepared in a manner similar to that described in Example 6), the mixture was stirred at room temperature for 72 hours and then quenched by the addition of water (30 mL). The product was then extracted into dichloromethane (3 x 30 mL) and the combined extracts were dried (MgSO 4 and solvents removed in vacuo. The residue was triturated with ether (20 mL)) and the remaining solids were filtered off. ether (10 mL) gave a second crop of solid product, and the combined solids were dried in vacuo to give 3- (benzo [b] thiophene-) as a yellow product (0.49g) with mp: 153-155 ° C. 3-yl) -2-styryl-5,6-dihydroimidazo [2, lb] thiazole.

Example 40

In a similar manner to that described in Example 6, bromination of 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (prepared by alkalizing the hydrobromide salt obtained by a method similar to that described in Example 6) is carried out. WO 97/02269), the product is then reacted with ethylmagnesium chloride and then with dimethylformamide to give a yellow solid with 1.1. 258-260 ° C 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde.

Example 41

To a stirred suspension of 3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.31 g) in ethanol (15 mL) was added sodium borohydride (0.06 g) was stirred at room temperature for 4 hours and then water (15 mL) was added. The solid present is filtered off, washed with ether (15 ml) and dried under vacuum at 60 ° C as a white solid (0.14 g) with m.p. 204-206 ° C gives [3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol.

Example 42

In a similar manner to Examples 40 and 41, [3- (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol was prepared. 6 g). In this case, however, the product obtained is contaminated. Therefore, it was purified by preparative HPLC using a mixture of acetonitrile and an aqueous solution of trimethylammonium format buffer as eluents. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was triturated with water (2 x 3 mL) and the residual solid was filtered and dried under vacuum at 60 ° C to give an off-white solid (0.19 g) with m.p. 171-173 ° C gives [3 (5-chlorobenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol-formate.

Example 43

In a manner similar to that described in Example 23, a

3- (Benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (5 g) was treated with ethylmagnesium chloride and then diphenyldisulfide to give 3- ( benzo [b] thiophen-3-yl) -2- (phenylthio) -5,6-dihydroimidazo [2,1-b] thiazole (0.6 g) as a yellow solid, m.p. Mp 123-125 ° C.

Example 44

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.5 g; prepared according to a method similar to that described in Example 6) in tetrahydrofuran (20 ml). methylamine (2M in tetrahydrofuran; 8.7 ml) and sodium triacetoxyborohydride (0.56 g) were added and the mixture was stirred at room temperature for 72 hours. Another portion of methylamine solution (4.3 mL) was added, the mixture was stirred at room temperature for 48 hours, and then quenched by the addition of saturated aqueous sodium bicarbonate solution (50 mL). The product was then extracted into ethyl acetate (3 x 30 mL), the combined extracts washed with water (30 mL) and saturated aqueous sodium chloride solution (30 mL), then dried (MgSO 4) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (9: 1). Combine the appropriate fractions and remove the solvents in vacuo as a waxy solid (0.19 g) with 1.1. 102-104 ° C gives [3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -N-methylmethylamine.

Example 45

To a stirred solution of cyclopropylacetic acid (5 g) and dimethylformamide (2 drops) in dichloromethane (20 mL) was added a solution of oxalyl chloride (13 mL) in dichloromethane (20 mL) under a nitrogen atmosphere at -10 to 0 ° C, stirred at room temperature for 24 hours and removal of the solvents under vacuum gave cyclopropylacetyl chloride as a brown oil which was used without further purification.

To a stirred solution of N, O-dimethylhydroxylamine hydrochloride (5.1 g) in a minimal volume of water was added potassium carbonate (9.2 g) in portions at 0-5 ° C followed by dichloromethane (30 mL). Then, the above-described cyclopropylacetyl chloride dissolved in dichloromethane (20 mL) was added dropwise to the dimethylhydroxylamine solution at -5 to 0 ° C. The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 2 hours, then the product was extracted into dichloromethane (3 x 50 mL). The combined extracts were dried (Na 2 SO 4) and the solvent removed in vacuo to give cyclopropyl-N-methoxy-N-methylacetamide (6.2 g) as a pale brown oil (6.2 g) which was used without further purification.

To a mixture of magnesium shavings (1.05 g), 2 iodine crystals and tetrahydrofuran (35 mL) was added a few drops of solution under a nitrogen atmosphere.

3-Bromobenzo [b] thiophene (8.7 g) in tetrahydrofuran (35 mL) and warm the mixture gently to start the reaction. The remainder of the solution is then added at a rate allowing a slight reflux to be maintained. After the addition was complete, the mixture was heated at reflux for 1.5 hours and then allowed to cool to room temperature. A solution of cyclopropyl-N-methoxy-N-methylacetamide (6 g) in tetrahydrofuran (35 mL) was then added at room temperature, the mixture was stirred at reflux for 5 hours, allowed to stand at room temperature for 18 hours, and then quenched by quenching. 2M hydrochloric acid (50 ml) and stirred at room temperature for 1 hour. The product was then extracted into ethyl acetate (2 x 100 ml), the combined extracts washed with water (2 x 30 ml) and saturated aqueous sodium chloride solution (2 x 30 ml), dried (MgSO ₄ ) and the solvents removed in vacuo. The residue was purified by flash chromatography on silica using a mixture of dichloromethane and petroleum ether (t 60-80 ° C) as eluent. Appropriate fractions were combined and the solvent removed in vacuo to give 1- (benzo [b] thiophen-3-yl) -2-cyclopropyletan-1-one as an orange oil (4.15 g) which was used without further purification.

To a stirred solution of 1- (benzo [b] thiophen-3-yl) -2-cyclopropyletan-1-one (1 g) in tetrahydrofuran (15 mL) was added phenyltrimethylammonium tribromide (1.74 g) under nitrogen. After stirring at room temperature for 18 hours, it is filtered and the solvent is removed in vacuo. The residue was dissolved in ethanol (12 mL) and 2-imidazolidinethion (0.47 g) and acetic acid (4 mL) were added and the mixture was stirred under a nitrogen atmosphere for 18 h before the solvents were removed. The residue was purified by flash chromatography on silica eluting with dichloromethane / ether (1: 3). Combine the appropriate fractions and remove the solvents in vacuo as an off-white solid (0.72 g) with 1.1. 181-183 ° C gives 3- (benzo [b] thiophen-3-yl) -2-cyclopropyl-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide.

Example 46

To a stirred solution of 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole (3.8 g; prepared by a method similar to that described in Example 6) in dichloromethane (200 mL) was added dropwise at room temperature a solution of iodine chloride (1.83 g) in dichloromethane (5 mL) and the mixture was stirred at room temperature for 15 minutes. The resulting solid is filtered off, washed with dichloromethane (50 ml) and air-dried as a pale yellow solid (1.3 g) with m.p. 194.7-195.2 ° C gives 3- (benzo [b] thiophen-3-yl) -2-iodo-5,6-dihydroimidazo [2,1-b] thiazole hydrochloride.

Example 47

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.46 g) in tetrahydrofuran (15 mL) was added dropwise a solution of dimethyl 2-oxopropylphosphonate (1.28 g) in terahydrofuran (10 mL) at room temperature under nitrogen. ml) and the mixture was then stirred at room temperature for 20 minutes. Then 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (2 g; added in a similar manner to that described in Example 6) was added in portions and The mixture was stirred at room temperature for 18 hours, at reflux temperature for 7 hours, and then left at room temperature for 18 hours. The solvent was removed in vacuo, the residue was diluted with water (200 mL) and the product was extracted into dichloromethane (200 mL). The extract was dried (Na 2 SO 4), the solvent removed in vacuo, and the residue purified by flash chromatography on silica using a 19: 1 mixture of dichloromethane and methanol as eluent. Combine the appropriate fractions and remove the solvents in vacuo as a yellow solid (1.15 g) with m.p. 164-166 ° C gives 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] but-3-en-2-one.

To a stirred solution of 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] but-3-en-2-one (0.28 g) in ethanol (10 mL) was added sodium borohydride (36 mg), and the mixture was stirred at room temperature for 3 hours, then the solvent was removed in vacuo. The residue was diluted with water (100 mL) and the product was extracted into dichloromethane (100 mL), dried (Na 2 SO 4) and the solvent was removed in vacuo. The residue was triturated with ether (20 mL) and the residual solid filtered drying in vacuo to give 4- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1- g] as an off-white solid (0.16 g) having m.p. bjtiazol-2-yl] but-3-en-2-ol.

Example 48

In a manner similar to that described in Example 17, 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b] thiazole hydrobromide was reacted with ethylmagnesium chloride and then with 3-bromo- 2-methylpropene and fumaric acid to give an off-white solid, m.p. 54-56 ° C 3- (Benzo [b] thiophen-3-yl) -2- (2-methylprop-2-enyl) -5,6-dihydroimidazo [2,1-b] thiazole fumarate.

Example 49

To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 0.28 g) in 1,4-dioxane (5 mL) was added dropwise a solution of tetraethyl (dimethylamino) methylenediphosphonate (2.32 g) dropwise at room temperature under nitrogen. in 1,4-dioxane (5 mL) and the mixture was stirred at room temperature until the evolution of hydrogen ceased. Then 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-a] is added.

b] Thiazole-2-carboxaldehyde (2 g; prepared by a method similar to that described in Example 6) and the mixture was stirred at 60 ° C for 1.3 hours and at room temperature for 18 hours and then poured into water (50 ml). The product was extracted into ethyl acetate (3 x 30 mL), the combined extracts were dried (MgSO 4) and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica eluting with dichloromethane: methanol (93: 7). Appropriate fractions were combined and the solvents removed in vacuo to give diethyl 2- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] as a red oil (1.78 g). thiazol-2-yl] -1- (dimethylamino) ethenylphosphonate, which was used without further purification.

A mixture of 2- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1b] thiazol-2-yl] 1- (dimethylamino) ethenylphosphonate (1.7 g) and concentrated hydrochloric acid (12 mL) was heated at reflux for 1 h and then cooled with ice. The product was extracted into dichloromethane (3 x 30 mL) and the combined extracts were dried (MgSO 4) and the solvent removed in vacuo. The residue was dissolved in water (30 mL), the solution was neutralized by the addition of an excess of saturated aqueous sodium bicarbonate solution and the product was extracted into dichloromethane (3 x 30 mL). The combined extracts were dried (MgSO 4) and the solvent removed in vacuo. The residue was dissolved in ethanol (2 mL), oxalic acid was added, and the solvent was removed in vacuo. The residue was triturated with ether (10 mL) and the residual solid was filtered off and dried in vacuo as an off-white solid (40 mg) with m.p. 102-104 ° C gives ethyl [3- (benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2,1-b] thiazol-2-yl] -acetate oxalate.

Example 50

To a stirred solution of 4-fluorophenylmethylsulfide (22.0 g) in tetrahydrofuran was added dropwise at -78 ° C under a nitrogen atmosphere sec-butyllithium (1.25 M solution in cyclohexane / hexane 92: 8, 100 mL) and the mixture was stirred at -70 ° C for 65 minutes. Dimethylformamide (13.2 ml) was then added dropwise at -68 ° C to -70 ° C and the stirred mixture was allowed to warm slowly to room temperature over 20 hours and then a solution of acetic acid (10 ml) in water ( 500 ml). The product was extracted into ether (3 x 150 mL), the combined ether extracts were washed with 2M hydrochloric acid (200 mL) and saturated aqueous sodium chloride solution (200 mL), dried (Na 2 SO 4) and the solvents removed in vacuo. The residue (25 g), which was used without further purification, according to the results of nuclear magnetic resonance spectroscopy, contained predominantly 2: 3 2-fluoro-5- (methylthio) benzaldehyde 4-fluorophenylmethylsulfide.

A stirred mixture of methylthioglycolate (8.9 mL), crude 2-fluoro-5 (methylthio) benzaldehyde (25 g), dimethylacetamide (250 mL) and N, N-diisopropylethylamine (42 mL) was heated at 140-50 ° C for 3.5 hours. 150 ° C under a nitrogen atmosphere and then the solvent is removed in vacuo. Water (650 ml) was added to the residue and the product was extracted into dichloromethane (3 x 150 ml). The combined extracts were washed with water (3 x 150 mL), dried (Na 2 SO 4) and the solvent removed in vacuo. The residue was triturated with ether (250 mL) and the residual solid was filtered, washed with ether (2 x 50 mL) and dried in vacuo to give a pale yellow solid (13.3 g) with m.p. 89.7-90.4 ° C methyl 5 (methylthio) benzo [b] thiophene-2-carboxylate.

Sodium hydroxide (8 g) was dissolved in water (100 ml) and the resulting solution was added to a stirred solution of methyl 5- (methylthio) benzo [b] thiophene-2-carboxylate (23.8 g; prepared similarly as described above). supra) in methanol (300 mL). The resulting mixture was heated at reflux for 10 minutes and then left at room temperature for 3 days. Then, the suspension is concentrated to a total volume of about 250 ml by heating, water (100 ml) is added, and the mixture is filtered hot to remove insoluble components. A solution of concentrated hydrochloric acid (40 mL) in water (20 mL) was then added to the filtrate, and the resulting solid was filtered, washed with water and dried in vacuo at 80 ° C as a pale yellow solid (21 g). 1.1. 186-186.5 ° C gives 5 (methylthio) benzo [b] thiophene-2-carboxylic acid.

A mixture of copper powder (5.3 g), 5- (methylthio) benzo [b] -thiophene-2-carboxylic acid (20 g) and quinoline (100 ml) was stirred and refluxed under nitrogen for 30 minutes. and then filtered hot. The filtrate was added to a mixture of concentrated hydrochloric acid (100 mL), ice (500 g) and ether 78 (200 mL), the resulting solid was filtered and washed with ether (200 mL). The aqueous phase was separated and a further portion of the product was obtained by extraction into ether (2 x 150 mL). The combined ethereal solutions were washed with 2 mol / L hydrochloric acid (200 mL) and water (200 mL), dried (Na 2 SO 4) and evaporated to afford 5 (methylthio) benzo [b] as a pale brown solid (14.7 g). ] thiophene, which was used without further purification.

A solution of 5- (methylthio) benzo [b] thiophene (14.7 g) in dichloromethane (180 mL) was added at <0 ° C under nitrogen atmosphere to a stirred mixture of aluminum bromide (26.2 g), bromoacetyl bromide (7, 12 ml) and dichloromethane (120 ml), the resulting dark red-brown solution was stirred at <0 ° C for 30 minutes and 20 hours at room temperature and then added to a mixture of ice (600 g) and concentrated hydrochloric acid (50 ml). Dichloromethane (300 mL) was then added and the insolubles were filtered off (Celite®). The aqueous phase was separated and a further portion of the product was obtained by extraction into dichloromethane (300 mL), the combined dichloromethane solutions were dried (MgSO 4) and the solvent removed in vacuo. The residue was dissolved in a mixture of acetic acid (200 mL) and dichloromethane (200 mL), a solution of 2-imidazolidinethion (5.29 g) in acetic acid was added, and then dichloromethane was removed by distillation. The remaining mixture was heated at reflux for two hours and then reduced to about 200 mL by heating under vacuum. The hot solution is freed from undissolved components by decantation and then allowed to cool. Further precipitated fractions were removed in the same manner and the solvents were removed in vacuo at 50 ° C. The residue was treated with water (300 mL) and aqueous 5 M sodium hydroxide (300 mL) and the product was extracted into dichloromethane (300 mL). The extract was dried (Na 2 SO 4) and the solvent removed in vacuo. The residue was partially purified by flash chromatography on silica, eluting with ethyl acetate: methanol: triethylamine (8: 1: 1). The appropriate fractions were combined and the solvents removed in vacuo to give 3- [5- (methylthio) -benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2] as a yellow-brown gum (3.6 g). 1-bthiazole, which was used without further purification.

Then, to a stirred solution of 3- [5- (methylthio) benzo [b] -thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole (3.55 g) in dichloromethane (80 mL) was added a solution of tert-butadiene. of bromine (1.87 g) in dichloromethane (10 mL), stirred for 10 minutes at room temperature, then the dichloromethane solution was separated by decantation from the undissolved components and concentrated in vacuo. The residue was triturated with dichloromethane (10 mL) and the residual solid was filtered off and dried in vacuo as a yellow-brown solid (2.97 g) with m.p. 260-265 ° C gives 2-bromo-3- [5 (methylthio) -benzo [b] thiophen-3-yl] -5,6-dihydro-imidazo [2,1-b] thiazole hydrobromide.

Example 51

To a stirred suspension of 2-bromo-3- [5- (methylthio) -benzo [b] -thiophen-3-yl] -5,6-dihydro-imidazo [2,1-b] thiazole hydrobromide (2.9 g) in tetrahydrofuran (40 mL) Ethylmagnesium chloride (2.8 mol / L in tetrahydrofuran; 8.76 mL) was added at -10 ° C under a nitrogen atmosphere, the mixture was stirred at room temperature for 90 minutes and then cooled to -5 ° C. Dimethylformamide (5 ml) was added and the resulting suspension was stirred at room temperature for 2 hours, then ethyl acetate (200 ml) and saturated aqueous ammonium chloride solution (200 ml) were added. Separate the ethyl acetate layer, dry (Na 2 SO 4) and remove the solvents in vacuo as a solid (1.4 g) with 1.1. 157-158.5 ° C gives 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde, which is used without further purification.

To a stirred solution of 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b] thiazole-2-carboxaldehyde (0.664 g) in ethanol (40 mL) was added. sodium borohydride (0.114 g) was added, then the mixture was stirred at room temperature for 24 hours and then quenched with 5 M hydrochloric acid (10 mL). The mixture was then basified with excess 1 M aqueous sodium hydroxide and concentrated in vacuo to remove ethanol, and then the product was extracted into dichloromethane (3 x 30 mL). The combined extracts were dried (MgSO 4), the solvent was removed in vacuo and the residue purified by Biotage flash chromatography using silica and ethyl acetate / methanol / triethylamine (34: 3: 3) as eluent. Appropriate fractions were combined and the solvents were removed in vacuo and then the residue was triturated with ether (10 mL). The residual solid is filtered off and air-dried as a beige product (0.13 g) with m.p. 164-167 ° C gives {3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1b] thiazol-2-yl} methanol.

Example 52

In a manner similar to that described in Example 22, [3 (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (0.5 g) was treated with sodium hydride and bromomethylcyclopropane and then fumaric acid. In this case, the salt preparation is carried out in methanol, where no precipitate is formed. Therefore, the solvent was removed in vacuo and the residue was triturated with ether (10 mL). The residual solid is filtered and dried under vacuum to give a pale brown solid (40 mg) with m.p. 8298 ° C gives 3- (benzo [b] thiophen-3-yl) -2-cyclopropylmethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole fumarate.

Example 53

To a stirred suspension of [3- (benzo] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (1 g) in dimethylformamide (50 mL) was added at room temperature for 10 min. Sodium hydride (60% dispersion in mineral oil; 0.153 g) was added and the mixture was stirred at room temperature for 2 hours. 1-Chloroprop-2-η (276 μΐ) was then added and stirring was continued for a further 2 hours. Additional 1-chloroprop-2-yl (27 μΐ) was then added and the mixture was stirred at room temperature for 18 hours. Water (50 ml) was added, the product was extracted into ethyl acetate (x 50 ml), the combined extracts were washed with water (4 x 25 ml) and saturated aqueous sodium chloride solution (25 ml), dried (MgSO ₄ ) and the solvents were removed. removed under vacuum. The residue was purified by flash chromatography on silica eluting with 5-8% methanol in dichloromethane. Appropriate fractions were combined and the solvents were removed in vacuo. The residue was dissolved in methanol (15 mL), fumaric acid (0.185 g) was added, the mixture was stirred at room temperature for 5 hours, then warmed to dissolve the product and filtration to remove the insoluble material. Remove the solvent in vacuo as a brown solid (0.67 g) with m.p. 120 ° C (softens at 80-90 ° C) is obtained

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

Example 54

To a stirred solution of 2-methoxybenzenethiol (10.6 mL) in a mixture of ethanol (125 mL) and water (7.5 mL) was added, under a nitrogen atmosphere, in one portion a solution of potassium hydroxide (4.87 g) in a mixture of ethanol and water ( 35 ml) and the mixture was then stirred at room temperature for 3.5 hours. Then, 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, the mixture was stirred for 18 hours at at room temperature and the solvents are removed in vacuo. The residue was diluted with water (75 mL) and the product was extracted into ethyl acetate (2 x 115 mL), then the combined extracts were washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL), dried (MgSO 4) to remove of solvent in the form of a yellow oil (24.7 g) gave 1- (2-methoxyphenylthio) -4-phenoxybut-2-yne (24.7 g) which was used without further purification.

To a stirred solution of 1- (2-methoxyphenylthio) -4-phenoxybut-2-yne (10.5 g) in chloroform (95 mL) was added dropwise a solution of 3-chloroperbenzoic acid over 1.5 h at 0-5 ° C. (70% purity; 9.1 g) in chloroform (210 mL), the mixture was stirred at room temperature for 18 hours and then washed with 5% aqueous sodium carbonate (3 x 120 mL) and water (3 x 80 mL), and dried (MgSO4). The chloroform solution was then heated with stirring at reflux for 7 hours, then left to stand for 18 hours at room temperature, washed with aqueous 5 M sodium hydroxide (115 mL) and water (4 x 110 mL) and saturated aqueous brine (100 mL) and dried (MgSO 4). The solvent was then 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 gum (10.7 g). g), which is used without further purification.

f r

A mixture of 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 drops) The mixture was heated at 90-95 ° C for 3 hours, then cooled to room temperature and poured into water (800 mL). The product was extracted into dichloromethane (2 x 250 ml), the combined extracts were washed with aqueous 2M sodium hydroxide solution (2 x 200 ml) and water (3 x 200 ml), then dried (MgSO 4) and the solvents were evaporated. removed under vacuum. The residue was purified by flash chromatography on silica using a 1: 1 mixture of dichloromethane and petroleum ether (b.p. 60-80 ° C) as eluent. Appropriate fractions were combined and the solvents removed in vacuo to give 1- (7-methoxybenzo [b] thiophen-3-yl) ethan-1-one as a brown oil (2 g) which was used without further purification.

To a stirred solution of 1- (7-methoxybenzo [b] thiophen-3-yl) -ethan-1-one (1.4 g) in tetrahydrofuran (40 mL) was added phenyltrimethylammonium in portions at room temperature under nitrogen. -tribromide (2.55 g), the mixture was stirred at room temperature for 1 hour and then filtered and the solvent was removed in vacuo. The residue was dissolved in ethanol (30 ml), 2-imidazolidinethion (0.69 g) and acetic acid (20 ml) were added, the mixture was heated at reflux for 18 hours and then cooled to room temperature. The resulting solid was filtered off, washed with ether (20 ml) and dried in vacuo at 60 ° C as a gray solid (1.48 g) with m.p. M.p. 277-279 ° C gives 3- (7-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide.

3- (7-Methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (1.48 g) was made basic by addition of aqueous 2 M sodium hydroxide solution (110 mL) and free the base was extracted into dichloromethane (150 mL). The extract was washed with water (2 x 70 mL), dried (MgSO 4) and the solvent removed in vacuo. The residue was dissolved in dichloromethane (23 mL), cooled to 0-5 ° C with stirring, and a solution of bromine (0.68 g) in dichloromethane (4.7 mL) was added dropwise over 45 minutes. The mixture was then stirred at 0-5 ° C for 30 minutes, then left at room temperature for 18 hours, the resulting solid was filtered off, washed with dichloromethane (20 ml) and dried in vacuo as a white solid (1.22 g). ) s 1.1. 240-242 ° C gives 2-bromo-3- (7-methoxybenzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide.

Example 55

To a stirred suspension of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (2.5 g) in dimethylformamide (50 mL) was added portionwise sodium hydride (60% dispersion in mineral oil; 0.38 g) was added over 10 minutes at room temperature, and the mixture was then stirred at room temperature for 2 hours. 2-Bromopropane (0.9 ml) was then added and the mixture stirred for a further 2 hours. Another portion of 2-bromopropane (0.4 mL) was added and the mixture was stirred at room temperature for 72 hours. Sodium hydride (60% dispersion in mineral oil; 0.07 g) was added, the mixture was stirred for 10 minutes, then 2-bromopropane (0.16 mL) was added and the mixture was stirred at room temperature for 18 hours. Water (100 ml) was added and the product was extracted into ethyl acetate (100 + 2 x 75 ml), the combined extracts were washed with water (3 x 100 ml) and saturated aqueous sodium chloride solution (100 ml), dried (MgSO 4) and the solvents are removed in vacuo. The residue was purified by flash chromatography on silica eluting with methanol / dichloromethane (1:19). Appropriate fractions were combined and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica eluting with ethyl acetate / methanol (9: 1). Combine the appropriate fractions and remove the solvents in vacuo as a yellow product (0.12 g) with m.p. 64-66 ° C 3- (Benzo [b] thiophen-3-yl) -2-isopropoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole.

Example 56

To a stirred suspension of [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] methanol (3 g) in dimethylformamide (80 mL) was added portionwise at sodium hydride (60% dispersion in mineral oil; 0.46 g) for 10 minutes and then stirred at room temperature for 2 hours. Bromomethylcyclobutane (1.7 g) was then added dropwise and the mixture was stirred at room temperature for 2.5 hours. Another portion of bromomethylcyclobutane (0.16 g) was then added dropwise and the mixture was stirred at room temperature for 1 hour. Another portion of bromomethylcyclobutane (0.16 g) was then added dropwise and the mixture was stirred at room temperature for 18 hours. TLC analysis showed that the starting material was still present, so additional bromomethylcyclobutane (0.32 g) was added and the mixture was stirred at room temperature for 2 hours and at 55 ° C for 1 hour. An additional portion of sodium hydride (0.042 g) and bromomethylcyclobutane (0.8 g) were added and the mixture was stirred at 55 ° C for 1 hour and at room temperature for 18 hours. Water (100 ml) was then added and the product was extracted into ethyl acetate (100 + 3 x 75 ml), the combined extracts were washed with water (4 x 75 ml) and saturated aqueous sodium chloride solution (75 ml), dried (MgSO4). and the solvents are removed in vacuo. The residue was purified by flash chromatography on silica eluting with methanol / dichloromethane (1:19). Appropriate fractions were combined and the solvents were removed in vacuo. The residue was purified by flash chromatography on silica using a 3: 1 mixture of petroleum ether (b.p. 60-80 ° C) and ethyl acetate followed by a 19: 1 mixture of dichloromethane and methanol as eluents. Appropriate fractions were combined and the solvents were removed in vacuo. A sample of the residue (30 mg of 70 mg) was further purified by preparative HPLC on a C8 column with symmetrically shaded groups using a 2: 3 mixture of acetonitrile and triethylammonium formate buffer as eluent. Appropriate fractions were collected and the solvents removed in vacuo to give 3- (benzo [b] thiophen-3-yl) -2-cyclobutylmethoxymethyl-5,6-dihydroimidazo [2,1-b] thiazole as a brown gum (12 mg);

1 H-NMR (DMSO-d 6): δ _Η 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, _CH2 N), 3,984,05 (2H, m, _CH2 O), 4.11-4.15 (2H, m, CH ₂ N), 7.45-7.49 (2H, m, 2 x ArH), 7.77-7.81 (1H, m, ArH), 8.01 (1H, s, ArH), 8.08-8.11 (1 H, m, ArH).

Example A

The use of the compounds of the invention in the preparation of pharmaceutical compositions is illustrated in the description below. As used herein, the term active compound means any compound of the invention, but especially any of the compounds that are the end products of any of the above examples.

(a) Capsules

To prepare the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are comminuted and mixed. The mixture is then dispensed into hard gelatin capsules, wherein each capsule then contains a single dose or a portion of a single dose amount of the active compound.

(b) Tablets

Tablets are prepared using the following ingredients:

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

The active compound, lactose and a portion of the starch are comminuted, mixed and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granules are mixed with magnesium stearate and the rest of the starch. The mixture is then compressed on a tablet press into tablets, each tablet containing a single dose or a portion of a single dose amount of the active compound.

c) Tablets with an enteric coating

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

d) Lace

In the preparation of suppositories, 100 parts by weight of the active compound are combined with 1300 parts by weight of the triglyceride lace base and the blend is processed into a lace mold, wherein one suppository contains a therapeutically effective amount of the active ingredient.

Claims (32)

PATENT CLAIMS A compound of formula I, including pharmaceutically acceptable salts thereof, wherein A is S or O; g is 0, 1, 2, 3 or 4; n is 2 or 3; R * is selected from the group consisting of a) halogen, b) alkyl of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, c) alkoxy of 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, d) alkylthio , alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted by one or more halogen atoms, (e) hydroxy, (f) acyloxy of 1 to 3 carbon atoms, (g) hydroxyalkyl of 1 to 3 carbon atoms h) cyano, (i) alkanoyl j) C 2 -C 6 alkoxycarbonyl, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, 1) sulfamoyl or sulfamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, m) or amino optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings; R 2 and R 3 each represent H; R 4 represents a group consisting of hydroxyalkyl of 1 to 6 carbon atoms, α-hydroxy (2-C 1-3 alkoxyphenyl) methyl, hydroxyalkenyl of 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to one of the carbon atoms forming the double bond, hydroxyalkynyl containing C 3-6 carbon atoms wherein the hydroxy group is not directly attached to any of the three-bonded carbon atoms, C 3 -C 6 hydroxycycloalkyl, C 2 -C 8 alkenyl, C 8 -C 10 arylalkenyl, C 3 -C 6 cycloalkyl carbon, C 3-7 alkynyl alkoxyC 1-3 alkyl, C 4-7 cycloalkylalkoxyCi. C 1-3 alkyl, C 1-3 alkoxyC 1-3 alkyl, C 1-3 alkylthioC 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, arylthio, C 1-6 alkanoyl, C 3-6 alkoxycarbonylalkyl, cyano, halogen, C 1-6 alkyliminomethyl, C 1-6 alkyl; ₄ alkylaminoalkyl and hydroxyiminomethyl; R 5 is H or halogen. A compound of formula I according to claim 1, including pharmaceutically acceptable salts thereof, wherein A is S or O; ¹ : · ·, · g represents 0, 1, 2, 3 or 4; n is 2 or 3; R ¹ represents a group selected from the group consisting of a) halogen; p r r f ť · r - ·.-r (b) alkyl of 1 to 3 carbon atoms, optionally substituted by one or more halogen atoms; (c) alkoxy having 1 to 3 carbon atoms, optionally substituted by one or more halogen atoms; d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms each optionally substituted by one or more halogen atoms, (e) hydroxy; f) acyloxy having 1 to 3 carbon atoms, g) hydroxyalkyl having 1 to 3 carbon atoms (h) cyano; (i) C 1 -C 6 alkanoyl; j) alkoxycarbonyl of 2 to 6 carbon atoms, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, l) sulfamoyl or sulfamoylmethyl, each of which may be optionally substituted with one or two alkyl groups each containing 1 to 3 carbon atoms; m) or an amino group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 is also it may have the same or different meanings; R 2 and R 3 each represent H; R 4 is a C 1 -C 6 hydroxyalkyl group, a C 3 -C 6 hydroxyalkenyl group wherein the hydroxy group is not directly attached to one of the double bond carbon atoms, the C 3 -C 6 hydroxyalkynyl group wherein the hydroxy group is not directly attached to one of the carbon atoms forming the triple bond, hydroxycycloalkyl of 3 to 6 carbon atoms, alkenyl of 2 to 8 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, C 1-3 alkoxyC 1-3 alkyl, C 1-3 alkylthioC 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C1-6alkanoyl, halogen, C1-4alkyliminomethyl, and hydroxyiminomethyl; and R 5 is H or halogen. A compound according to claim 1 or claim 2 wherein A is S. A compound according to claim 1 or claim 2 wherein A is O. A compound according to any one of the preceding claims wherein R 4 is C 1 -C 6 hydroxyalkyl, C 3 -C 6 hydroxyalkenyl wherein the hydroxy group is not directly attached to any of the double bond carbon atoms, C 3 -C 6 hydroxyalkynyl 6 carbon atoms wherein the hydroxy group is not directly attached to any of the carbon atoms forming the triple bond, alkenyl of 2 carbon atoms optionally substituted with one or two C 1-2 alkyl groups, C 1-4 alkyliminomethyl, and hydroxyiminomethyl. A compound according to any one of the preceding claims wherein R 4 is a C 1 -C 5 hydroxyalkyl group, a C 3 -C 5 hydroxyalkenyl group wherein the hydroxy group is not directly attached to any of the double bond carbon atoms, the C 3 hydroxyalkinyl group. wherein the hydroxy group is not directly attached to any of the carbon atoms forming the triple bond and the alkenyl of 2 carbon atoms optionally substituted by one or more methyl groups. A compound according to any one of the preceding claims, wherein R ₄ represents a hydroxymethyl or vinyl group. A compound according to any preceding claim, wherein n is. A compound according to any one of the preceding claims wherein g is 0 or 1 and R 1 is a) halogen, b) an alkyl group having 1 to 3 carbon atoms optionally substituted by one or more halogen atoms, or c) an alkoxy group having 1 to 3 atoms carbon optionally substituted by one or more halogen atoms. A compound according to any one of the preceding claims, wherein R 5 is H. A compound according to claim 1 of the general formula Ia N (CH ₂ ) _n including their pharmaceutically acceptable salts, wherein A is S or O; g is 0, 1, 2, 3 or 4; n is 2 or 3; R ¹ represents a group selected from the group consisting of a) halogen, (b) alkyl of 1 to 3 carbon atoms, optionally substituted by one or more halogen atoms; (c) alkoxy having 1 to 3 carbon atoms, optionally substituted by one or more halogen atoms; d) alkylthio, alkylsulfinyl or alkylsulfonyl of 1 to 3 carbon atoms, each optionally substituted with one or more halogen atoms, (e) hydroxy; f) acyloxy having 1 to 3 carbon atoms, (g) hydroxy (C 1 -C 3) alkyl; (h) cyano; (i) C 1 -C 6 alkanoyl; j) alkoxycarbonyl of 2 to 6 carbon atoms, k) carbamoyl or carbamoylmethyl, each of which may be optionally N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, l) sulfamoyl or sulfamoylmethyl, each of which may optionally be N-substituted with one or two alkyl groups each containing 1 to 3 carbon atoms, e β m) or an amino group optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms; when g is 2, 3 or 4, R 1 may have the same or different meanings; and R 4 represents a group consisting of hydroxyalkyl of 1 to 6 carbon atoms, α-hydroxy (2-C _1-3 alkoxyphenyl) -methyl, hydroxyalkenyl of 3 to 6 carbon atoms wherein the hydroxy group is not directly attached to one of the carbon atoms forming the double bond C 3 -C 6 hydroxyalkynyl wherein the hydroxy group is not directly attached to one of the triple bonded carbon atoms, C 2 -C 8 alkenyl, C 8 -C 10 arylalkenyl, C 3 -C 6 cycloalkyl, C ₃ - 7alkynylalkoxyC1-3alkyl, C4-7cycloalkylalkoxyC1. ₃ alkyl, C 1 _ ₃ alkoxy C ₃ alkyl, C ₃ alkyltioCi- ₃ alkyl, C. ₃ alkoxy; ₃ alkylthio, arylthio, C ôalkanoyl, C ₃ .6älkoxykarbonylalkyl, cyano, halo, C. ₄ alkyliminomethyl, C1-4 alkylaminoalkyl and hydroxyiminomethyl. A compound according to claim 11, wherein A is S. A compound according to claim 11 or 12, wherein n is 2. A compound according to any one of claims 11 to 13, wherein g is 0 or 1. A compound according to any one of claims 11 to 14, wherein R 1 is halogen, C 1 -C 3 alkoxy or C 1 -C 3 alkylthio. A compound according to any one of claims 11 to 15, wherein A is O. A compound according to any one of claims 11 to 16, wherein R ₄ is a C 1 -C 4 hydroxyalkyl group, an α-hydroxy (2-C 1-3 alkoxyphenyl) methyl group, a C 3 -C 4 hydroxyalkenyl group wherein the hydroxy group is not directly attached to any of the carbon atoms of the double bond, the hydroxyalkynyl group having from 3 to 4 carbon atoms wherein the hydroxy group is not directly attached to any of the carbon atoms of the triple bond, the alkenyl group of 2 to 3 carbon atoms, Ci. ₂ alkanoyl and hydroxyiminomethyl. 18. A compound selected from the group consisting of: 3- (benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2, l-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; l- [3- (benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2, l-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 [2,1b] 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-2en-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-methylethyl amine; 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-dihydro-imidazo [2, l-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2- (l-methylvinyl) -5,6-dihydro-imidazo [2, lb] thiazole; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methyl-propan-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] butan-10 °; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylbut-3-en-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-1ole; 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-3en-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-en-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4en-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-ene 1-5,6-dihydroimidazo [2,1-b] thiazole; [3- (benzo [bjtiofen-3-yl) -6,7-dihydro-5H-thiazolo [3,2-pyrimidin-and-2yljmetanol; 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-chloro-benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [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-5,6,6-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-3en-2-ol; 3- (benzo [b] thiophen-3-yl) -2- (2-methylprop-2-enyl) -5,6-dihydroimidazo [2,1b] thiazole; ethyl 1- [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 [2,1b] 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-5,6,6-diimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-prop-2-yloxymethyl-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; a p e r f 3- (benzo [b] thiophen-3-yl) -2-cyclobutylmethoxymethyl-5,6-dihydroimidazo [2,1b] thiazole, including their pharmaceutically acceptable salts of the individual enantiomers, racemates or other mixtures of enantiomers. 9. A compound selected from the group consisting of: 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-dihydro-imidazo [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-methoxy-benzo [b] thiophen-3-yl) -5,6-dihydro-imidazo [2, l-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-2en-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- (ethylthio) -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-en-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; 11- [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-3en-1-ol; 1- [3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] -2-methylprop-2-en-1-ol; and 1- [3- (Benzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-yl] pent-4en-1-ol; and pharmaceutically acceptable salts thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I according to any one of the preceding claims together with a pharmaceutically acceptable diluent or carrier. A compound of formula I according to any one of the preceding claims for use as a medicament. A compound of formula I according to any one of the preceding claims for use in the treatment of depression, anxiety, psychoses, schizophrenia, tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behaviors, panic and aticosis. , social phobias, eating disorders such as bulimia, anorexia, excessive stuttering and morbidity, insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia, and stress as well as supportive therapy to facilitate smoking cessation. • e 100 A compound of formula I according to any one of the preceding claims for use in the treatment and / or prevention of seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage. Use of a compound of formula I according to any one of claims 1 to 19 in the preparation of a medicament for use in the treatment of depression, anxiety, psychoses, schizophrenia, tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behaviors, panic attacks, social phobias, eating disorders such as bulimia, anorexia, excessive appetite and morbidity, non-insulin-dependent diabetes mellitus, hyperglycaemia, hyperlipidemia, and stress, as well as an aid to cure and cease smoking or preventing seizures, neurological diseases such as epilepsy, and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, head injury and hemorrhage occurs. 25. A method of treating depression, anxiety, psychoses, schizophrenia, tardive dyskinesia, obesity, drug addiction, drug abuse, cognitive diseases, Alzheimer's disease, cerebral ischemia, obsessive compulsive behavior, panic attacks, social phobias, eating disorders such as binge eating disorders anorexia, excessive stamina and morbidity, non-insulin dependent diabetes mellitus, hyperglycaemia, hyperlipidemia, stress and seizures, neurological diseases such as epilepsy and / or conditions in which neurological damage such as stroke, brain trauma, cerebral ischemia, and haemorrhage comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 19. 26. A method of reducing the appetite for smoking in a human comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 19. 27. A method of reducing weight gain in a human being then having quit smoking, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I according to any one of claims 1 to 19. A compound of formula I as claimed in any one of claims 1 to 19 for use in the treatment or prevention of metabolic diseases and conditions arising therefrom, such as non-muscular thermogenesis and increased metabolic rate, sexual dysfunction, sleep apnotic syndrome, premenstrual syndrome, urinary tract. incontinence, hyperactivity disorders, hiatal hernia and reflux esophagus, pain, especially neuropathic pain, weight gain associated with drug therapy, chronic fatal syndrome, osteoarthritis and gout, weight gain associated with weight gain, menstrual dysfunction, ileum hypotension, bile stone hypertension, bile stones . A compound of formula I according to any one of claims 1 to 19 for use in the prevention of cardiovascular disease, for reducing platelet cohesiveness, in post-pregnancy weight loss support therapy and in weight loss support therapy after the patient has stopped smoking. 102 Use of a 5-HT 1A agonist compound which is also a monoamine reuptake inhibitor, in particular a noradrenaline reuptake inhibitor, for the treatment of obesity and related disease states without causing cardiovascular side effects. 31. A method of treating obesity without inducing cardiovascular side effects, comprising administering a 5-HT1A agonist compound which is also a monoamine reuptake inhibitor, in particular a norepinephrine reuptake inhibitor to a patient in need of treatment. A compound of formula I according to any one of claims 1 to 19 for use in the treatment of obesity and related disease states. 33. A process for the preparation of compounds of formula (I), comprising: a) dehydrating the compound of formula II 103 wherein A, R 1, R ₂ , R 3, R 4, R 5, g and n are as defined above, optionally in the presence of an acid, at a temperature in the range of 0-200 ° C; or b) reaction of a compound of formula III) wherein R ₂ , R 3 and n are as defined above, with a compound of formula IV wherein Z is a leaving group and A, R 1, R 4, R 5 and g are as defined above, at a temperature in the range of 0-200 ° C, optionally in the presence an acid, and optionally in the presence of a solvent, without isolation of the intermediate of Formula II; or c) reacting a compound of formula V * e wherein A, R 1, R ₂ , R 3, R 5, nag are as defined above, with a halogenating agent at a temperature ranging from -50 to 200 ° C, optionally in the presence of a solvent to form a compound of formula I wherein R 4 is halogen; or e) reacting a compound of formula VI wherein A, R 1, R ₂ , R 3, R 5, nag are as defined above and R _y is H with an organometallic composition, for example a composition of formula R _x MgX or R _x Li, wherein R _x is C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl or (2-C 1-3 alkoxyphenyl) -alkyl and X is halogen, in the presence of a solvent, at a temperature in the range of -50 ° C to the boiling point of the solvent used to form compounds of formula I wherein R ₄ is -CH (OH) R _X wherein R _x is as defined above; or ee 105 e) reacting 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 1-6 alkyl, C 2-5 alkenyl, 2- Or a (2-C 1-3 alkoxyphenyl) group, with a reducing agent in the presence of a solvent at a temperature ranging from 0 ° C to the boiling point of the solvent, wherein said reaction produces compounds of formula I wherein R 4 is CH (OH) R _y , wherein R _y is C 1-6 alkyl, C 2-5 alkenyl, C 2-5 alkynyl or (2C 1-3 alkoxyphenyl); or f) reacting 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 H with a reducing agent in a solvent at a temperature ranging from -50 ° C to the boiling point of the solvent used; said reaction to prepare compounds of formula I wherein R 4 is hydroxymethyl; or g) reacting 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 H with hydroxylamine or a salt thereof, optionally in a solvent at a temperature of 0-250 ° C; the reaction produces compounds of formula I wherein R 4 is hydroxyiminomethyl; or h) reacting 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 H with hydroxylamine or a salt thereof, in the presence of formic acid, at a temperature of 0-250 ° C; wherein said reaction produces compounds of Formula I wherein R ₄ is cyano; or i) reacting 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 H with an amine of the formulas R _and NH 2 wherein R _a is C 1-4 alkyl optionally in the presence of a solvent , optionally in the presence of an acid catalyst, at a temperature in the range of 0-250 ° C, wherein said reaction produces: 106 of a compound of formula I wherein R 4 is C 1-6. A 4-alkyliminomethylene group; or j) reacting 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, nag are as defined above, 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; wherein said reaction produces compounds of Formula I wherein R 4 is C 1-4 alkylaminomethylene; or k) reacting 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 H with an amine of formula R _and NH 2 wherein R _a is C 1-4 alkyl; a composition, in the presence of a solvent at a temperature ranging from 0 ° C to the boiling point of the solvent used, wherein said reaction produces compounds of formula I wherein R 4 is C 1-4 alkylaminomethylene; or l) reacting a compound of formula VI wherein R _y is C 1-6 alkyl and A, R 1, R ₂ , R 3, R 5, nag are as defined above with an organometallic composition of formula R _x MgX or R _x Li, where R _x is C 1-6 alkyl and X is halogen, in the presence of a solvent at a temperature ranging from -50 ° C to the boiling point of the solvent used, wherein said reaction produces compounds of formula I wherein R 4 is -C (OH) R _x R _y , wherein R _x and R _y each independently represent a C 1-6 alkyl group; or m) reacting a compound of formula VI as described above except that R _y is OR _Z , where R _z is C 1-6 alkyl, with an organometallic composition of formula R _x MgX or R _x Li, where R _x is C 1-6 alkyl; X is halogen, in the presence of a solvent at a temperature ranging from -50 ° C to the boiling point of the solvent used, wherein said reaction produces compounds of formula I wherein R 4 is -C (OH) R _x R _y where R _x and R _y both represent the same C 1-2 alkyl group; or pe 107 n) reacting a compound of formula VI, wherein R _y is hydrogen or C ^ alkyl, and A, R, R 2, R 3, R 5, nag are as defined above, with a phosphonium salt of formula R _of Ph 3 P ⁺ Br, wherein R _z means a C 1-6 alkyl or benzyl group, in the presence of a base in a solvent at a temperature ranging from -78 ° C to the boiling point of the solvent used, said reaction to prepare compounds of formula I wherein R 4 is a C 2-6 alkenyl group from the alpha carbon position with respect to the thiazole ring or the styryl group; or o) reacting a compound of formula I wherein R 4 is halogen and A, R 1, R 2, R 3, R 5, nag are as defined above, or a compound of formula V with a compound of formula RbMgX or Rt, Li, where Rb is Cl. Oalkyl group and X is a halogen, in the presence of a solvent at a temperature of from 78 ° C to the boiling point of the solvent, and then reacting the product with an acylating agent of formula R _c CON (CH 3) OCH 3, wherein R _c is C |. an alkyl group, in a solvent, at a temperature ranging from 0 ° C to the boiling point of the solvent used, wherein said reaction produces compounds of Formula I wherein R 4 is a C 2-6 alkanoyl group; or p) reacting a compound of formula I wherein R 4 is hydroxy C ^ alkyl group, and A, R _t, R 2, R 3, R 5, g and are as defined above with a C ^ alkylating agent and a base in a solvent, for example at a temperature of from -50 ° C to 150 ° C, wherein said reaction produces compounds of Formula I wherein R 4 is C 1-3 alkoxyC 1-3 alkyl; or q) reacting a compound of formula I wherein R 4 is hydroxyC 1. The 3alkyl group and A, R 1, R 2, R 3, R 5, nag are as defined above with a C 4-7 cycloalkylating agent, in the presence of a base, in a solvent, at a temperature ranging from -50 ° C to 150 ° C. of formula I wherein R 4 is a C 4-7 cycloalkylalkoxyC 1-3 alkyl group; or 108 r) reacting a compound of formula I wherein R 4 is hydroxyC 1-3 alkyl and A, R 1, R 2, R 3, R 5, nag are as defined above with a C 3-7 alkynylalkylating agent, in the presence of a base, in a solvent at a temperature ranging from - 50 ° C to 150 ° C, wherein said reaction produces compounds of formula I wherein R 4 is C 3-7 alkynyl alkoxyC 1-3 alkyl; or s) reacting a compound of formula I wherein R 4 is mercaptoCl. 3alkyl and A, R1, R2, R3, R5, nag are as defined above with a C1-4 alkylating agent, in the presence of a base, in a solvent, at a temperature ranging from -50 ° C to 150 ° C, wherein said reaction is prepared compounds of formula I wherein R ₄ is C 1-4 alkylthioCi. 3alkyl; or t) reacting a compound of formula I wherein R 4 is halogen or a compound of formula V with a metallating agent of the formula RM 8 X or R 11, wherein R is C 1-6 alkyl and X is halogen, in a solvent at a temperature ranging from -100 ° C to the boiling point of the solvent used to prepare an intermediate complex which is treated by reaction with a disulfide of the formula R @ 15 -SRd where R @ 1 is a C1-4 alkyl or aryl group at a temperature ranging from -100 ° C to the boiling point of the solvent. solvents, and wherein the process is to prepare compounds of formula I wherein R 4 is C 1-3 alkylthio or arylthio and A, R 1, R 2, R 3, R 5, nag are as defined above; or u) reacting a compound of formula I wherein R 4 is halogen with C 1. 3alkoxide salt, in the presence of a solvent, optionally in the presence of a catalyst, at a temperature in the range of 0-350 ° C, wherein said reaction is to prepare compounds of formula I wherein R 4 is C 1-4 alkoxy and A, R1, R2, R3, R5, nag have the meaning given above; or v) reacting a compound of formula I wherein R 4 is halogen, and A, R 1, R 2, R 3, R 5, n and g are as defined above, or a compound of formula V with a compound of formula RbMgX or RbLi 109 C 1-6 alkyl and X is halogen, in the presence of a solvent, at a temperature ranging from -78 ° C to the boiling point of the solvent used, followed by reaction of the obtained product with an alkenylating agent, for example C 3-6 alkenylmethyl halide, in a solvent at a temperature from 0 ° C to the boiling point of the solvent used to prepare compounds of formula I wherein R 4 is a C 3-6 alkenyl group whose double bond is not attached to the alpha carbon relative to the thiazole ring; or w) reacting compounds of formula VI wherein R _y is hydrogen and A, R 1, R ₂ , R 3, R 5, nag are as defined above with a phosphonate of formula Me ₂ NCH [PO (OR _z ) ₂ ] ₂ , wherein R ₂ represents a C 1-4 alkyl group, in the presence of a base, in a solvent, at a temperature ranging from -78 ° C to the boiling point of the solvent used, followed by subjecting the obtained intermediate to partial hydrolysis in an acid medium to prepare compounds of formula I wherein R4 is C3-6alkoxycarbonylalkyl; or x) reacting a compound of formula VI wherein R _y is hydrogen, and A, R 1, R ₂ , R 3, R 5, nag are as defined above with a compound of formula (R _z O) ₂ POCH ₂ COR _c , wherein R _z means Cj. ₂ alkyl, and R _c is a C ^ alkyl group, and a base in a solvent at a temperature of from 78 ° C to the boiling point of the solvent, and then subjecting the resultant intermediate with a reducing agent in a solvent at a temperature from -20 ° C to the boiling point of the solvent used to prepare compounds of formula (I) wherein R 4 is a C 4-6 hydroxyalkenyl group whose double bond is attached to the alpha carbon relative to the thiazole ring.