JP2003500409A - Substituted imidazothiazoles as antidepressants - Google Patents

Abstract

  (57) [Summary] Embedded image Compounds of formula I, including pharmaceutically acceptable salts, wherein A is S or O; ₁Is H, halogen, C_1-3Alkyl group or C_1-3An alkylthio group; R₂Is H or fluorine; R₃Is methyl, ethyl or isopropyl), depression, anxiety, psychosis (eg, schizophrenia), tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-compulsive Treatment of sexual behavior, panic attacks, social phobias, bulimia, anorexia, eating disorders such as snacks and bulimia, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress, and even seizures It is useful in the treatment and / or prevention of neurological disorders such as epilepsy and / or nerve damage such as stroke, brain trauma, cerebral ischemia, head injuries and bleeding.

Description

DETAILED DESCRIPTION OF THE INVENTION       [0001]     (Technical field)   The present invention relates to 5-HT_1AHas affinity for the receptor,
Novel inhibits neuronal reuptake of thamin and / or noradrenaline
3- (benzo [b] thiophen-3-yl) imidazo [2,1-b] thiazolone
And their preparation methods, pharmaceutical compositions containing them, and depression, anxiety, and psychosis (
For example, schizophrenia), tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment
Harm, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic attack, social phobia, gluttony
Eating disorders such as dysbiosis, anorexia, snacks and bulimia, non-insulin dependent diabetes
As an adjunct to smoking cessation and in the treatment of hyperglycemia, hyperlipidemia, stress, and seizures
Neurological disorders and / or strokes such as epilepsy, brain trauma, cerebral ischemia, head injuries and
Its use in the treatment and / or prevention of conditions with nerve damage such as bleeding
It is about.       [0002]     (Background technology)   WO 98/41528 includes individual enantiomers, racemates or other enantiomers.
Compounds of Formula A below, including pharmaceutically acceptable salts, in the form of a mixture of enantiomers       [0003]     Embedded image       [0004]   (Where   Ar is phenyl, naphthyl or benzo [b] thiophenyl;
A) halogen, b) charcoal optionally substituted by one or more halogens
An alkyl group having 1 to 3 atoms, c) substituted by one or more halogens
Also alkoxy groups having 1 to 3 carbon atoms, d) substituted by one or more halogens
An alkylthio group having 1 to 3 carbon atoms which may be substituted, e) one or more halogens
A phenoxy group which may be substituted or f) one or more halogens.
Substituted by one or more substituents selected from phenyl groups which may be substituted
May be done;   R₁And R₂May be the same or different and independently a) H, b) carbon atom
An alkyl group having 1 to 6 carbon atoms, c) an alkenyl group having 3 to 6 carbon atoms, d) a carbon atom
E) a cycloalkyl group having 3 to 7 carbon atoms, e) a cycloalkyl having 3 to 7 carbon atoms in the ring.
Alkylmethyl group, f) i) halogen, ii) substituted by one or more halogens
An alkyl group having 1 to 3 carbon atoms, which may be iii) one or more halogen atoms
Therefore, an alkoxy group having 1 to 3 carbon atoms which may be substituted, iv) 1 or more
An alkylthio group having 1 to 3 carbon atoms which may be substituted by halogen
Aryl or hetero optionally substituted with one or more substituents selected from
An aryl group, g) an arylalkyl or heteroarylalkyl group
An alkyl chain having 1 to 3 carbon atoms, an aryl or heteroaryl group
Is i) a halogen, ii) a carbon atom optionally substituted by one or more halogens
An alkyl group having 1 to 3 atoms, iii) substituted by one or more halogens
An alkoxy group having 1 to 3 carbon atoms, iv) one or more halogen atoms
One or more selected from alkylthio groups having 1 to 3 carbon atoms which may be substituted
May be substituted with a substituent of the formula:₁And R₂And in it
Even if substituted by one or more alkyl groups each having 1 to 3 carbon atoms
Having a good alkylene chain, along with the atoms to which they are attached,
Forming a six-membered or six-membered ring;   R₃Is substituted by a) H, b) i) a halogen, ii) one or more halogens
An alkyl group having 1 to 3 carbon atoms, which may be iii) one or more halogen atoms
Therefore, an alkoxy group having 1 to 3 carbon atoms which may be substituted, iv) 1 or more
An alkylthio group having 1 to 3 carbon atoms which may be substituted by halogen
Aryl or hetero optionally substituted with one or more substituents selected from
An aryl group, c) an arylmethyl group, wherein the aryl group is i) halogen, ii
) Alkyl having 1 to 3 carbon atoms which may be substituted by one or more halogens
Iii) 1 to 1 carbon atoms which may be substituted by one or more halogens
Three alkoxy groups, iv) charcoal optionally substituted by one or more halogens
Substituted with one or more substituents selected from alkylthio groups having 1 to 3 atoms
Or d) an alkoxyalkyl group having 3 to 6 carbon atoms.
R;   R₄And R₅May be the same or different and independently have 1 to 3 carbon atoms
Is an alkyl group; or₄And R₅Together with the atoms to which they are attached
Forms a cycloalkyl ring of 3 to 6 carbon atoms), but is depressed, anxious,
-Treatment of neurological disorders such as Kinson's disease, obesity, cognitive impairment, seizures, epilepsy, and
It is disclosed that it is useful as a neuroprotective drug that protects against conditions such as inside
I have.       [0005]   Sharp et al. (Sharpe C. J and Shadbolt R. S., Journal of Medicinal Chemi
stry, 1971, Vol 14, No. 10, p. 977-982) describes a class of diuretics with antidepressant activity.
Disclosed are hydroimidazo [2,1-b] thiazole compounds. However
The document states, in general, that those compounds are also disclosed in the
It is also described that it has lower activity and higher toxicity than dazolines. In that document,
The compounds of the present invention are not disclosed or suggested.       [0006]   WO 97/02269 discloses compounds of the following formula B, including pharmaceutically acceptable salts:       [0007]     Embedded image       [0008]   (Where   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;   R₁May be substituted by a) a halogen, b) one or more halogens
An alkyl group having 1 to 3 carbon atoms, c) substituted by one or more halogens
An alkoxy group having 1 to 3 carbon atoms, d) each having at least one halogen
Accordingly, an alkylthio group having 1 to 3 carbon atoms which may be substituted, alkyls
A rufinyl group or an alkylsulfonyl group, e) a hydroxyl group, f) a carbon number of 1 to 3
Acyloxy groups, g) hydroxyalkyl groups having 1 to 3 carbon atoms, h)
An ano group, i) an alkanoyl group having 1 to 6 carbon atoms, j) a alkanoyl group having 2 to 6 carbon atoms
Alkoxycarbonyl group, k) 1 or 2 each having 1 to 3 carbon atoms
A carbamoyl group or a carbamoyl group which may be N-substituted by an alkyl group
Tyl group, l) 1 or 2 alkyl groups each having 1 to 3 carbon atoms and N
An optionally substituted sulfamoyl or sulfamoylmethyl group, or
M) is N-substituted by one or two alkyl groups having 1 to 3 carbon atoms.
An optionally substituted amino group; R₁Are the same or different when g is 2, 3 or 4.
May be;   R₂, R₃And R₄Is independently substituted with H or one or more halogen;
Are also alkyl groups having 1 to 3 carbon atoms;   R₅May be substituted by a) a halogen, b) one or more halogens
An alkyl group having 1 to 3 carbon atoms, c) substituted by one or more halogens
An alkoxy group having 1 to 3 carbon atoms, d) each having at least one halogen
Accordingly, an alkyl group having 1 to 3 carbon atoms which may be substituted, alkylsulfur
Ynyl or alkylsulfonyl, e) hydroxyl, f) C1 -C3
Acyloxy group, g) hydroxyalkyl group having 1 to 3 carbon atoms, h) cyano
A) an alkanoyl group having 1 to 6 carbon atoms; j) an alkanoyl group having 2 to 6 carbon atoms.
Koxycarbonyl group, k) 1 or 2 carbon atoms each having 1 to 3 carbon atoms.
A carbamoyl group or a carbamoylmethyl which may be N-substituted by
L) N-position with one or two alkyl groups each having 1 to 3 carbon atoms
Optionally substituted sulfamoyl or sulfamoylmethyl group, m) carbon atom
An amino which may be N-substituted by one or two alkyl groups having 1 to 3
And n) H. ) Is 5-HT_1AHas affinity for the receptor,
Neuronal retake of 5-hydroxytryptamine and / or noradrenaline
It is disclosed to inhibit entanglement. These compounds are useful in treating CNS disorders
Are described as being useful. However, these compounds are
Exhibits activity as a minoxidase inhibitor or e.g.
Has an affinity for other receptors, such as the body, causing undesirable side effects.
There is a possibility that it will break. Surprisingly, the present invention provides unexpectedly superior selectivity and potency
A compound having the formula: The compounds of the present invention are specifically described in WO 97/02269.
No disclosure or suggestion was made.       [0009]   U.S. Pat. No. 4,160,768 discloses 3- (2-benzofuranyl) -5,6-dihi.
Droimidazo [2,1-b] -thiazole has been shown to be useful as an anti-inflammatory drug.
It is shown. In this document, the compounds of the present invention are neither disclosed nor suggested.
No.       [0010]     (Disclosure of the Invention)   The present invention provides novel compounds of Formula I below, including pharmaceutically acceptable salts.       [0011]     Embedded image       [0012]   Where:   A is S or O;   R₁Is H, halogen, C_1-3Alkyl group or C_1-3An alkylthio group
R;   R₂Is H or fluorine;   R₃Is methyl, ethyl or isopropyl.       [0013]   Preferred substituent R₁Is H, fluorine, chlorine, bromine, methyl and methylthio
You.       [0014]   Preferably A is S.       [0015]   Preferably A is O.       [0016]   More preferably R₃Is methyl.       [0017]   A preferred group of compounds of Formula I is represented by Formula Ia, which includes pharmaceutically acceptable salts.
And R is H or chlorine.       [0018]     Embedded image       [0019]   In a preferred compound of the invention, A is S;₁Is H, fluorine or chlorine
Yes; R₂Is H or fluorine; R₃Is methyl.       [0020]   In a more preferred compound of the invention, A is S;₁Is H or fluorine
R;₂Is H or fluorine; R₃Is methyl.       [0021]   In the most preferred compounds of the invention, A is S;₁Is H; R₂Is H
And R₃Is methyl.       [0022]   The compounds of formula I can exist as salts with pharmaceutically acceptable acids.
The present invention includes all such salts. Examples of such salts include salt
Acid, hydrobromide, sulfate, methanesulfonate, nitrate, maleate,
Acid, acetate, citrate, fumarate, tartrate [e.g. (+)-tartrate, (
-)-Tartrate or mixtures thereof, including racemic mixtures], succinates, benzoates
Examples include citrates, oxalates and salts of glutamic acid with amino acids. Like that
Such salts can be produced by methods known to those skilled in the art.       [0023]   Certain compounds of formula I may be in various tautomeric forms or as various geometric isomers.
The present invention relates to each tautomer and / or geometrical compound of the formula I
It includes isomers and mixtures thereof.       [0024]   Certain compounds of formula I exist in various stable conformations that are separable.
Can be. For example, if bulky groups are present, one or more single bonds may be present due to steric hindrance.
Rotation around the joint may be restricted. For example due to steric hindrance or ring distortion
In addition, due to the twist asymmetry caused by the restriction of rotation around the asymmetric single bond, various
Separation of conformers may be possible. The present invention provides for each conformation of the compound of formula I
Includes isomers and mixtures thereof.       [0025]   Certain compounds of formula I and salts thereof may exist in multiple crystalline forms.
The present invention includes each crystalline form and mixtures thereof. Certain compounds of formula I and
Salts thereof can also exist in the form of solvates, for example hydrates,
Also includes each solvate and mixtures thereof.       [0026]   Certain compounds of formula I have one or more centers of chirality and exist in various optically active forms.
I do. Where a compound of Formula I has one chiral center, the compound may have two different chiral centers.
Present in enantiomeric form, the present invention relates to both enantiomers and enantiomers
It contains a mixture. Enantiomers can be separated, for example, by crystallization
Formation of diastereomeric isomer salts; eg crystallization, gas chromatography
Or diastereoisomeric derivatives that can be separated by liquid chromatography
Or complex formation; or, for example, silica with attached chiral ligands
Chromatography in Chiral Environments such as on a Chiral Carrier or in the Presence of Chiral Solvent
Separation by methods known to those skilled in the art, such as laffy or liquid chromatography.
Can be split. The desired enantiomer can be separated by another
In the case of conversion to a chemical substance, an additional step is required to release the desired enantiomer.
It will be clear that another step is needed. Alternatively, optically active reagents,
By asymmetric synthesis using a catalyst, a solvent or a solvent, or by asymmetric transformation
Synthesizing a specific enantiomer by converting one enantiomer to the other
Can be.       [0027]   Where a compound of Formula I has more than one chiral center, it may be a diastereomer.
May be present. Diastereomeric pairs are useful, for example, by chromatography and
Can be separated by methods known to those skilled in the art, such as crystallization and crystallization.
The individual enantiomers can be separated according to the methods described above. Departure
The description is intended to include each diastereomer of the compound of formula I and mixtures thereof.
You.       [0028]   Particular compounds of Formula I include pharmaceutically acceptable salts,   3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro
Imidazo [2,1-b] thiazole;   3- (5-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6
-Dihydroimidazo [2,1-b] thiazole;   3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,
6-dihydroimidazo [2,1-b] thiazole;   3- (benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydro
Imidazo [2,1-b] thiazole;   2-methyl-3- (5-methylbenzo [b] thiophen-3-yl) -5,6
-Dihydroimidazo [2,1-b] thiazole;   3- (benzo [b] thiophen-3-yl) -2-isopropyl-5,6-di
Hydroimidazo [2,1-b] thiazole;   2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-yl]
-5,6-dihydroimidazo [2,1-b] thiazole;   3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,
6-dihydroimidazo [2,1-b] thiazole;   3- (5-chlorobenzo [b] thiophen-3-yl) -2-ethyl-5,6
-Dihydroimidazo [2,1-b] thiazole;   3- (5-bromobenzo [b] thiophen-3-yl) -2-methyl-5,6
-Dihydroimidazo [2,1-b] thiazole; and   3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimimi
Dazo [2,1-b] thiazole and the like.       [0029]   The present invention further provides therapeutically effective compounds with a pharmaceutically acceptable diluent or carrier.
It is also intended to include a pharmaceutical composition comprising an amount of a compound of formula I or a salt thereof.       [0030]     (Best Mode for Carrying Out the Invention)   As used below, the term “active compound” refers to a compound of Formula I or
Refers to the salt of it. For therapeutic use, the active compound may be administered orally, rectally, or parenterally.
It can be administered or topically, preferably administered orally. Therefore, the cure of the present invention
Therapeutic compositions are known pharmaceutical compositions for oral, rectal, parenteral or topical administration.
Can take the form of an adult. Pharmaceutically acceptable suitable for use in such compositions
Such carriers are well-known in the pharmaceutical arts. 0.1 to 99% by weight of the composition of the present invention
% Active compound. The compositions of the invention are usually manufactured in unit dosage form.
It is. Preferably, the unit dose of the active ingredient is between 1 and 500 mg. These compositions
The excipients used in the manufacture of are the excipients known in the pharmaceutical industry.       [0031]   Compositions for oral administration are preferred compositions of the present invention, which include, for example, tablets,
Known for such administration, such as pexels, syrups and aqueous or oily suspensions
Is a pharmaceutical preparation of Excipients used in the manufacture of these compositions are known in the pharmaceutical industry.
Excipient. Tablets may be prepared by known methods, e.g., corn starch.
Phosphorus in the presence of any disintegrants and lubricants such as magnesium stearate
Manufactured by mixing an active compound with an inert diluent such as calcium acid
Can be. Tablets may be formulated in a manner known to those skilled in the art to provide a sustained release of a compound of the invention.
Can be done. Such tablets may optionally include, for example, phthalate
Applying an enteric coating by a known method such as using cellulose oxyacetate
Can be. Similarly, the active compounds may be added with or without excipients, e.g.
Or capsules such as soft gelatin capsules should be manufactured by conventional means
And an enteric coating can be applied by a known method, if desired. tablet
And the capsules each conveniently contain from 1 to 500 mg of the active compound
Can be. Other compositions for oral administration include carboxymethylcellulose sodium
Aqueous suspensions containing the active compounds in aqueous media in the presence of non-toxic suspending agents such as
Oil suspensions containing a compound of the present invention in a suitable vegetable oil such as, for example, peanut oil.
Liquid.       [0032]   Formulation of a solid oral preparation by a method known to those skilled in the art provides sustained release of the active compound.
I can. Enteric coating containing the composition according to the invention, depending on the nature of the active compound
Solid oral formulations with a coating may be advantageous. Eg shellac and
And / or whether various materials such as sugar can be present as a coating agent,
Alternatively, the physical form of the oral formulation can be altered separately. For example as desired
For example, cellulose acetate phthalate and / or hydroxypropyl phthalate
Tablets and pills can be coated with enteric coating by known methods such as using methylcellulose.
Can be applied.       [0033]   Capsules containing the active compound (with or without additional excipients such as fatty oils)
And / or small caplets (eg hard or soft gelatin capsules)
) Can be prepared by conventional means and, if desired, enteric coated by known methods.
A coating can be applied. Contents of capsule and / or small capsule
Can be formulated using known methods to achieve sustained release of the active compound.       [0034]   Liquid oral formulations containing the compositions of the present invention may include elixirs, suspensions and / or
It can be a syrup (eg, a non-toxic suspending agent [carboxymethylcell
Aqueous suspension containing the active compound in an aqueous medium in the presence of
And / or suitable vegetable oils (such as peanut oil and / or sunflower oil)
Oil-based suspension containing a water-soluble compound). One or more sweeteners and flavors for liquid oral preparations
, Preservatives and / or mixtures thereof.       [0035]   The active compound can be formulated as granules with or without additional excipients.
Can be. The granules can be taken directly by the patient, or
And a suitable liquid carrier (eg, water). Granules further contain disintegrants (
For example, pharmaceutically acceptable salts formed from acids and carbonates or bicarbonates.
Foaming admixture) can be included to facilitate dispersion in liquid media.       [0036]   Preferably, each of the above oral formulations contains from about 1 mg to about 1000 mg of the active compound, more
Preferably about 5 mg to about 500 mg (for example, 10 mg, 50 mg, 100 mg
, 200 mg or 400 mg).       [0037]   Compositions of the present invention suitable for rectal administration include, for example, hard fats, semi-synthetic glycerides, kaka
Such as suppositories containing an butter and / or polyethylene glycol base
It is a known pharmaceutical preparation for proper administration.       [0038]   Pharmaceutical compositions can also be administered parenterally (eg, known for parenteral administration).
Pharmaceutical preparations (e.g., aqueous and preferably isotonic with the blood of the intended patient)
Sterile suspensions in oily media and / or sterile solutions in suitable solvents)
Subcutaneous, intramuscular, intradermal and / or intravenous administration in the form of
Or injection etc.)). Parenteral preparations can be sterilized (eg, by microfiltration).
Therefore, or using a suitable sterilant [such as ethylene oxide]). As appropriate
Parenteral administration, such as local anesthetics, preservatives, buffers and / or mixtures thereof
Suitable pharmaceutically acceptable auxiliaries can be added to the parenteral preparation. Parenteral
The formulation may be placed in a suitable sterile, sealed container (e.g., ampoule and / or vial)
Le) can be saved. After filling the container to improve the stability of storage
The parenteral formulation can be frozen and the fluid (eg, water) removed under reduced pressure
it can.       [0039]   Pharmaceutical compositions can be prepared using known formulations for nasal administration (eg, sprays, aerosols, spray solutions).
And / or powder). Metered doses known to those skilled in the art
A system (eg, aerosol and / or inhaler) can be used.       [0040]   Pharmaceutical compositions can be prepared from known pharmaceutical preparations for oral administration (eg, delayed dissolution tablets, chewing tablets).
Gum gum, troches, lozenges, pastilles, gels, pastes, gargles, rinses and
And / or powder) for oral administration (eg sublingual).       [0041]   The composition for topical administration is obtained by dispersing the pharmacologically active compound of the present invention, and
A substrate that allows the compound to be administered transdermally by maintaining it in contact with the skin
Can be included. Preferred transdermal compositions are dimethyl sulfoxide or pro
Mineral oils, petrolatum and / or paraffin with a transdermal enhancer such as pyrene glycol
Pharmaceutically active compounds with topical vehicles such as waxes such as raffinic or beeswax
It can be manufactured by mixing with a product. Alternatively, the active compound can be administered
Or a cream or ointment base that is acceptable to the public. In topical formulations
The amount of active compound included should be adjusted over the period of time that the topical formulation is to remain on the skin.
A therapeutically effective amount of the compound must be reacted.       [0042]   The compounds of the present invention can be administered from an external source, for example, by intravenous infusion, or into the body.
Administration can also be by continuous infusion from a placed source of compound administration. Source for internal administration
Include an implant containing the compound to be injected which is continuously released, for example by permeation
The source of the drug, and (a) the derivative of a very poorly water-soluble derivative such as, for example, dodecanoate
Suspension or solution of the compound to be injected in pharmaceutically acceptable oil form.
Any liquid or (b) synthetic resin or wax material for the compound to be injected
By continuous injection from an implant, which can be solid in the form of an embedded support
It can also be administered. The support should be a single substance containing the whole amount of the compound or should be administered.
It can be a series of several, each containing part of a compound. Internal administration
The amount of active compound present in the source can be such that a therapeutically effective amount of the compound is administered over time.
Should be something like       [0043]   In some formulations, very high levels, such as those obtained by fluid energy milling,
It may be advantageous to use the compounds according to the invention in the form of small-particle granules.       [0044]   In the compositions of the present invention, the active compound may optionally be combined with other compatible pharmacologically active ingredients.
Can be combined.       [0045]   The present invention further includes compounds of formula I used as medicaments.       [0046]   Pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I are useful in mammals, especially humans.
Depression, anxiety, psychosis (eg, schizophrenia), tardive dyskinesia, obesity, drugs
Addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic
Eating disorders such as seizures, social phobia, bulimia, anorexia, snacking and bulimia,
For the treatment of insulin-dependent diabetes, hyperglycemia, hyperlipidemia and stress, and
It can be used to assist smoking cessation in humans. The composition also has seizures, epilepsy
Neurological disorders and / or stroke, brain trauma, cerebral ischemia, head injuries and bleeding
Can be used in the treatment and / or prevention of any nerve damage condition
You. The precise amount of active compound that will be administered in such treatment will, for example, be the patient's age,
Depends on many factors, including the severity of the condition and the medical history, and is always at the discretion of the attending physician.
The amount of active compound administered per day may vary more than once a day.
Range of 1 to 1000 mg, preferably 5 to 500 mg in single or divided dose
And       [0047]   In yet another aspect, the invention relates to depression, anxiety, psychosis (eg, schizophrenia).
), Tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's
Illness, cerebral ischemia, obsessive-compulsive behavior, panic attack, social phobia, bulimia, anorexia, snacking
And eating disorders such as binge eating, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia
As a treatment for stress, as an aid to smoking cessation, neurological disorders such as seizures, epilepsy and / or
Or nerve damage such as stroke, brain trauma, cerebral ischemia, head injuries and bleeding
There is provided the use of a compound of formula I in the manufacture of a medicament for use in therapy.       [0048]   The invention further relates to depression, anxiety, psychosis (eg, schizophrenia), late motor dyskinesia.
Common illness, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, compulsive
Sexual behavior, panic attacks, social phobia, bulimia, anorexia, snacking and bulimia, etc.
Eating disorders, non-insulin-dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress, seizures
Neurological disorders and / or strokes such as epilepsy, brain trauma, cerebral ischemia, head injuries and
A method of treating a condition having nerve damage, such as bleeding, comprising a therapeutically effective amount of a compound of formula I
Also provided is a method comprising administering an article to a patient in need of treatment. The present invention
In addition, it is a method of assisting humans to quit smoking in patients who need it.
And administering a therapeutically effective amount of a compound of Formula I.       [0049]   The present invention is further directed to a method of reducing the desire for smoking in a human, comprising:
Administering a therapeutically effective amount of a compound of Formula I to a patient in need thereof
It also provides the law. The invention further provides a method of reducing weight gain after smoking cessation in humans
Administering to a patient in need thereof a therapeutically effective amount of a compound of formula I
There is also provided a method comprising the steps of:       [0050]   In addition, the compounds of the present invention may be useful in metabolic disorders and conditions resulting therefrom, such as non-exercise
Active fever and increased metabolic rate, sexual dysfunction, sleep apnea, premenstrual syndrome, urine
Incontinence, hyperactivity disorder, hiatal hernia and reflux esophagitis, pain, especially neuropathic pain
Pain, medication related weight gain, chronic fatigue syndrome, osteoarthritis and gout, weight gain
Treatment of linked cancers, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension, or
May be useful in prevention.       [0051]   The compound of the present invention is useful for preventing cardiovascular disorders, reducing platelet adhesion, and reducing weight loss after pregnancy.
It may be helpful in assisting and assisting weight loss after smoking cessation.       [0052]   Compounds of the present invention may be useful in obesity and related co-morbid conditions, e.g.
For example, it is particularly useful in the treatment of diabetes, hyperglycemia and hyperlipidemia. Obesity treatment
Monoamine reuptake inhibitors are often used for cardiovascular side effects, such as
For example, it is known to be associated with increased heart rate and increased blood pressure. Compound of the present invention
Products are monoamine reuptake inhibitors, especially noradrenaline reuptake inhibitors
Reduces cardiovascular side effects expected to result from administration. Bound by theory
However, the compound of the present invention has 5-HT_1ABy combining actions,
Probably caused by inhibition of min reuptake, especially noradrenaline reuptake
Cardiovascular side effects are thought to be reduced.       [0053]   In another aspect, the invention is a method of reducing cardiovascular side effects of an antiobesity agent,
5-HT compound_1AA method is provided that includes incorporating an act.       [0054]   In another aspect, the invention relates to obesity and related syntheses without cardiovascular side effects.
5-HT in the treatment of co-morbid conditions_1AAgonist, monoamine retake
Provides the use of compounds that are nootropic inhibitors, especially noradrenaline reuptake inhibitors
I do.       [0055]   The advantageous properties of the particularly preferred compounds of the invention in reducing cardiovascular side effects are:
Rat telemetry test to continuously record the pulse rate, blood pressure, body temperature and locomotor activity over time
Indicated by A preferred method is the method of Brockway, BP, Mills,
 PA & Azar, SH (1991) A new method for continuous chronic measurement of
 blood pressure, heart rate and activity in the rat via radio-telemetry,
 Clinical and Experimental Hypertension-Theory and Practice A13 (5), 885-
895) and a report by Guiol et al. (Guiol, C., Ledoussal, C & Surge, J-M (199).
2) A radiotelemetry system for chronic measurement of blood pressure and
 heart rate in the unrestrained rat.Validation of method, Journal of Ph
armacological and Toxicological Methods 28, 99-105).       [0056]   5-HT of a particularly preferred compound of the present invention_1AOperation is in a manner known to those skilled in the art.
Can be measured by electrophysiology.       [0057]   The method for producing the compound of the formula I will be described. The method can be done individually
Or by multiple parallel synthesis, also referred to as high-speed analogization
Can be. The method is preferably performed at atmospheric pressure.       [0058]   Compounds of formula I can be prepared by the methods disclosed in WO 97/02269.
it can. Further, compounds of formula I can be prepared by the methods described below.
You.       [0059]   The compounds of the formula I have a temperature in the range from 0 to 200 ° C., preferably in the range from 20 to 150 ° C.
And optionally in the presence of an acid such as acetic acid or sulfuric acid, a compound of formula II       [0060]     Embedded image       [0061]   (Where A, R₁, R₂, R₃And g are as defined above)
Can be manufactured.       [0062]   The compound of formula II can optionally be, for example, acetic acid in the presence of a solvent, such as ethanol.
Which is used in the presence of any acid at a temperature in the range of 0 to 200 ° C., preferably
By heating at a temperature in the range up to the boiling point of the solvent       [0063]     Embedded image       [0064] And a compound of formula IV       [0065]     Embedded image       [0066]   Wherein Z is a leaving group such as a halogen such as bromine;₁, R₂And
And R₃Is as defined above).
You.       [0067]   Compounds of formula I can be used without acid intermediates, such as acetic acid, as appropriate, without isolation of intermediates of formula II.
In the presence and optionally in the presence of a solvent such as ethanol at a temperature in the range of 0 to 200 ° C.,
Heating at a temperature preferably in the range of 20 to 150 ° C. allows the compound of formula III
It can be prepared directly by reacting with a compound of formula IV.       [0068]   R₃Is a methyl or ethyl compound, the solvent used at −20 ° C.
In a solvent such as methylene chloride at a temperature in the range of the boiling point of
Compounds of formula V below in the presence of a catalyst such as any Lewis acid catalyst       [0069]     Embedded image       [0070]   (Where R₁, R₂And A are as defined above; R₄Is H or Met
And a reducing agent.       [0071]   Compounds of formula V can be obtained at temperatures ranging from -50 ° C to the boiling point of the solvent used.
Compounds of formula VI below in the presence of a solvent such as lahydrofuran       [0072]     Embedded image       [0073]   (Wherein X is a leaving group such as bromine) and ethyl magnesium chloride.
Reaction with any metallizing agent and then dimethylformamide or N-methoxy-N-
By reacting with a formylating or acylating agent such as methylacetamide
Can be manufactured.       [0074]   Compounds of the formula VI wherein X is bromine have a range from -50 ° C to the boiling point of the solvent used.
At ambient temperature, in the presence of a solvent such as methylene chloride or tetrahydrofuran,
Compound of Formula VII       [0075]     Embedded image       [0076] Reacts with bromine or a brominating agent such as phenyltrimethylammonium tribromide.
It can be manufactured by reacting.       [0077]   Compounds of formula VII can be prepared by the methods disclosed in WO 97/02269.
Can be.       [0078]   Compounds of formula I interact with 5-hydroxytryptamine (5-HT) receptor
Ability of the compound to bind to the 5-HT receptor in vitro, in particular 5-HT_1AReceptor
The following test, which measures the ability to inhibit tritiated ligand binding to
The products of Examples 1 to 17 are shown.       [0079]   Male Sprague-Dawley rat (Charles River, weight range 150-250g)
) Of hippocampal tissue from brain in ice-cold 50 mM Tris-HCl buffer (measured at 25 ° C.)
PH 7.7, 1:40 weight / volume) and 40000 at 4 ° C.
Centrifuged at g for 10 minutes. The pellet was re-homogenized with the same buffer and
And centrifuged at 40000g for 10 minutes at 4 ° C. Final peret
With 4 mM CaCl₂, 0.1% L-ascorbic acid and 10 μM pargi
Resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing phosphate hydrochloride
(Equivalent to a tissue wet weight of 6.25 mg / mL) and used immediately in the binding assay.       [0080]   Membrane (400 μL; equivalent to 2.5 mg tissue wet weight / tube) was applied to a single concentration of 1 nM.
[³H] 8-hydroxy-2- (dipropylamino) tetralin ([³H]
8-OH-DPAT) 50 μL and distilled water (total binding) 50 μL or tested
Compound (10^-6A single concentration of M or 10^-11-10^-310 types of M range
Concentration) 50 μL or 50 μL of 5-HT (10 μM, non-specific binding) and 25 μL
Incubated at 30 ° C for 30 minutes. Use Skatron cell harvester
Incubation is performed by rapid filtration under reduced pressure using a Skatron 11734 filter.
Stopped. Filter with ice-cold 50 mM Tris-HCl buffer (p
H7.7) (25 ° C., wash setting 9, 9, 0). Perforated filter paper circle
Drill the plate, place in a vial, add scintillation fluid and add liquid scintillation
Radioactivity was measured by counting.       [0081]   Compounds of Formula I are compatible with 5-hydroxytryptamine (5-HT) reuptake sites
The ability to interact is determined by the ability of the compound to react in vitro with a standard ligand from the 5-HT reuptake site.
Do [³H] The following test, which measures the ability to displace citalopram,
The results are shown for products 1 to 17.       [0082]   Procerebral cortex set from the brain of a male rat (Charles River) weighing 150-250 g
The tissue was ice-cold 50 mM containing 120 mM sodium chloride and 5 mM potassium chloride.
  Tris-HCl, pH 7.4 (measured at 25 ° C.) (Tris buffer,
(1:30 weight / volume) and centrifuged at 40,000 g for 10 minutes. Supernatant
And the pellet rehomogenized in Tris buffer 1:60 w / v, 4
Centrifuged at 0000 g for 10 minutes. This step was repeated one more time. Final pair
Lett is a 50 mM solution containing 120 mM sodium chloride and 5 mM potassium chloride.
  Resuspend in Tris-HCl, pH 7.4 (wet tissue weight 3.125 mg / m
L), immediately used for binding assays. All centrifugation was performed at 4 ° C.       [0083]   The membrane (400 μL; tissue wet weight 1.25 mg / tube) is called 1.3 nM
A single concentration of [³H] Citalopram 50 μL and distilled water (total binding) 50 μL
Or the test compound (10^-6A single concentration of M or 10^-11-10^-3In the range of M
10 concentrations) 50 μL or paroxetine (0.5 μM; non-specific binding)
Incubated with 50 μL for 1 hour at 27 ° C. Scatron cell harvester
Used, under reduced pressure with a Scatron 11734 filter pre-soaked in 0.5% PEI
The membrane-bound radioactivity was recovered by filtration. Filter the ice-cold 50 mM Tr
Washed with is-HCl buffer, pH 7.4 (at 25 ° C., wash setting 9, 9, 0)
. Drill a perforated filter paper disc into a vial and add scintillation fluid.
The radioactivity was measured by liquid scintillation counting.       [0084]   Ability of compounds of formula I to interact with noradrenaline (NA) reuptake sites
The compound can be converted from the noradrenaline reuptake site in vitro to a standard ligand [³ H] Nisoxetine Examples 1-1 were determined by the following test which measures the ability to displace.
7 are shown.       [0085]   Procerebral cortex set from the brain of a male rat (Charles River) weighing 150-250 g
Kinematic polytron (speed setting 6 for 10 seconds)
Ice-cold 50m containing 120 mM sodium chloride and 5 mM potassium chloride
M Tris-HCl, pH 7.4 (measured at 25 ° C.) (Tris buffer
, 1:60 weight / volume) and centrifuged at 40,000 g for 10 minutes. Up
Discard the supernatant and re-homogenize the pellet in Tris buffer 1:60 w / v,
Centrifuged at 40,000 g for 10 minutes. By repeating this step one more time,
In total, the brain tissue was homogenized and centrifuged four times. The final pellet is
50 mM Tris-HC with mM sodium chloride and 5 mM potassium chloride
l, pH 7.4 (equivalent to a tissue wet weight of 18.75 mg / mL) and immediately
Was used for the binding assay. All centrifugation was performed at 4 ° C.       [0086]   The membrane (400 μL; equivalent to a tissue wet weight of 7.5 mg / tube) was collected at a single volume of 0.6 nM.
One concentration of [³H] Nisoxetine 50 μL and distilled water (total binding) 50 μL or
Is the test compound (10^-6A single concentration of M or 10^-11-10^-31 in the range of M
0 types) 50 μL or mazindol (1 μM; non-specific binding) 50 μL
L and incubated at 4 ° C. for 4 hours. Using a skatron cell harvester,
Membrane-bound radioactivity is recovered by filtration under reduced pressure with a Katron 11734 filter
did. Filter containing 120 mM sodium chloride and 5 mM potassium chloride.
Ice-cold 50 mM Tris-HCl buffer, pH 7.4 (wash setting 9, 9, 0)
Washed quickly. Drill a perforated filter paper disc and place in a vial.
Radioactivity by liquid scintillation counting.
Specified.       [0087]   The ability of compounds of Formula I to interact with muscarinic receptors
Standard ligand from muscarinic receptor [³H] displaces N-methylscopolamine
The following tests to determine the performance demonstrated the products of Examples 1-17.       [0088]   Procerebral cortex set from the brain of a male rat (Charles River) weighing 150-250 g
The weave is Polytron PT3100 (speed 21700 rpm, 3 ×
100 mM sodium chloride and 10 mM magnesium chloride (5 seconds).
Ice-cold 20 mM HEPES buffer containing 1:10 weight / volume, pH 7.5 (2
(Measured at 5 ° C.) and centrifuged at 49500 g at 4 ° C. for 30 minutes. Supernatant
Discard and pellet with 100 mM sodium chloride and 10 mM magnesium chloride.
Again in 20 mM HEPES buffer, pH 7.5, containing
Amount 12.5 mg / mL). The membrane was stored at -80 C until needed.       [0089]   Thaw membranes containing 100 mM sodium chloride and 10 mM magnesium chloride.
Diluted 1:10 in 20 mM HEPES buffer, pH 7.5, and
Homogenization was performed using TRON PT3100. Dilution membrane (200 μL; tissue wet weight 0.
25 mg / tube) with 100 mM sodium chloride and 10 mM magnesium chloride.
20 mM HEPES buffer containing sodium, pH 7.5 (200 μL) and 0
. A single concentration of [³H] N-methylscopolamine 50 μL and steam
50 μL of distilled water (total binding) or test compound (10^-6A single concentration of M or 10 ^-11 -10^-310 concentrations in the range of M) 50 μL or atropine sulfate
(1 μM; non-specific binding) Incubated with 50 μL at 30 ° C. for 30 minutes.
Using a Skatron Cell Harvester under reduced pressure with a Skatron 11734 filter.
Filtration recovered the membrane-bound radioactivity. Filter the filter with ice-cold 20 mM HE
Washed rapidly with PES buffer, pH 7.5 (wash 1, 2 with settings 5,5). Misi
Drill a filter paper disc with a hole and place in a vial, add scintillation liquid,
Radioactivity was measured by body scintillation counting.       [0090]   Compounds of formula I can be used in vitro to produce 5-HT_1AReceptor and 5-hydroxytryp
Tamine (5-HT) and noradrenaline (NA) reuptake sites and mu
Each of these tests measures the ability to displace the standard ligand from the scalin receptor.
And 10^-6Displacement of specific binding of tritiated ligand by M test compound
Percent was calculated as follows:       [0091]   First, the tritiated reagents in the absence (A) and presence (B) of the test compound
The specific binding of Gand was determined.       [0092]   In the absence of compound:   A (dpm) = total binding (dpm)-non-specific binding (dpm).   In the presence of compound (10^-6M):   B (dpm) = 10^-6Binding at M (dpm)-Non-specific binding (dpm).       [0093]   Next, the specific binding of the tritiated ligand in the presence of the compound (B) was determined using the compound
Converted to percent specific binding of tritiated ligand in the absence (A)
.   10^-6% Specific binding at M = B (dpm) / A (dpm) × 100.       [0094]   Test compound (10^-6Displacement of specific binding of tritiated ligand by M)
Is the maximal binding and is therefore unique in the absence of compound equal to 100%
From the percent binding (equivalent to 100% from maximal binding)
Obtained by subtracting the percent specific binding below.   10^-6% Substitution at M = 100-10^-6% Specific binding at M.       [0095]   Then, in some cases, the concentration of the compound was^-6Tritiation in M
Displacement curves were obtained for compounds that displaced ≧ 50% of the specific binding of the ligand. Next
By robust non-linear regression on data from three experiments,
By simultaneously fitting the equations (derived from the Feldman equation), K
_iWas calculated.       [0096]     (Equation 1)       [0097]   Where B is the concentration of the bound ligand-receptor complex. It is about each observation
It is calculated as follows.       [0098]     (Equation 2)       [0099]   L is the compound concentration.   [L]_totOf the tritiated ligand used is calculated as
Concentration.       [0100]     (Equation 3)       [0101]   K_dIs the equilibrium dissociation constant for the ligand.   F₁And F₂Is the concentration of free ligand and free compound, respectively.   r₁Is the total concentration of the receptor in the first experiment. For subsequent experiments
And C_k(C₁= 1).   N_kIs the non-specific binding constant.       [0102]   5-HT for the final products of Examples 1 to 17 described below_1ABinding and 5
-Obtained in the above test for HT and NA incorporation, and for muscarinic binding
The results are shown in Table 1 below. K_iIs in nM and of three independent measurements
Average. % Figures are 10 per measurement^-6For the percent replacement with M
Things.       [0103]     [Table 1]       [0104]   The ability of the compounds of the present invention to inhibit monoamine oxidase A activity was determined by the following test.
Indicated by experimentation.       [0105]   The assay was performed using the following general procedure with the tissue source being human placenta.       [0106]     [Table 2]       [0107]   Compounds were tested in duplicate at 1 mM and 10 mM.       [0108]   References: Weyler, W. and Satach, J.I. (1985) Purification and propert
ies of mitochondrial monoamine oxidase type A from human placenta.J. Bi
ol. Chem., 260: 13199-13207.       [0109]   Acute dosing test Animals and the environment   Male Sprague obtained from Charles River, Margate
The experiment was performed on Dawley rats (300-450 g at the start of the experiment). animal
Is a polypropylene case with a metal grid floor at a temperature of 21 ± 1 ° C and a humidity of 55%.
The animals were reared individually. A polypropylene tray was placed under each cage. animal
Were maintained on a reversed light-dark cycle. Turn off the lights from 9:30 to 17:30
During that time, the room was illuminated with a red light. Animals should always have powdered rat feed and water
They were allowed to drink tap water freely. The feed is a glass feed jar with an aluminum lid (
(Diameter 10 cm, depth 8 cm). Make a hole in each lid (3cm in diameter)
The fee has been reached. Animals are allowed to acclimate to these conditions for at least two weeks before
The test was used.       [0110]   Procedure of test   On the day before the study, animals were randomly assigned to groups of 6-8 animals in each group, weighed,
Food intake over a period of 6 hours was measured. By taking this baseline reading,
No significant difference in body weight and food intake between different groups before drug administration
Caught. On the day of the study, animals are given either vehicle or three doses of study drug
Was. Rats consume most of the diet during the dark period, so all drugs are open during the dark period.
Oral administration at the beginning. At the time of drug administration and 1 hour, 2 hours, 4 hours after administration
After 6 hours and 24 hours, the feed jar was weighed (to the nearest 0.1 g unit).
Until). After each reading, examine the trays under the cage for spilled feed and
Returned to the jar. However, spillage of feed from feed jars is negligible
Was something.       [0111]   All drug doses are expressed as free base. Drugs are dissolved in deionized water
Or suspended in 0.4% cellosize using an ultrasonic bath
I let it.       [0112]   Data analysis   By expressing the results as g / kg rat body weight (administration group mean ± standard error mean),
Fluctuations in body weight were considered. ED₅₀Value (feed intake reduced to 50% of control value)
Using a special computer program to determine the
It was calculated from the S-shaped curve. Statistical comparisons between group intake means were analyzed by analysis of variance and
(Dunnett) test (two-sided).       [0113]   The compounds of the present invention are compared to the compounds exemplified in WO 97/02269 by 5HT _1A It has a surprisingly high affinity for the receptor.       [0114]   Preferred compounds of the invention are furthermore comparable to the compounds exemplified in WO 97/02269.
In comparison, the affinity for the muscarinic receptor is surprisingly low. For example, WO97 / 022
Example 1 of 69 has a K of 130 nM._iHaving. Muscarin affinity, for example,
Desirable, such as dry mouth, impaired vision, sweating, palpitations, constipation and exacerbation of narrow-angle glaucoma
Blackwell, B., Adverse effects of antidepres
sant drugs.Part 1 Monoamine oxidase inhibitors and tricyclics.Drugs 21
, 202-219, 1981). Compound has minimal affinity for muscarinic receptors
Clearly, it is desirable to do so.       [0115]   More preferred compounds of the invention are further compounds exemplified in WO 97/02269
MAO significantly lower than_AHas inhibitory activity.       [0116]   In the above test, the product of Example 1 of the present invention has an IC of 33 nM.₅₀Indicates
ing. These results indicate that the compounds of the present invention are compared to previously disclosed compounds.
And surprisingly improved selectivity. Monoamine oxidase
Highly undesirable due to the combination of inhibition of activity and inhibition of 5-HT reuptake
Serotonin syndrome may occur (Stembach, H. Serotonin syndrome, Am.
 J. Psychiatry 148, 705-713, 1991).       [0117]   The most preferred compounds of the present invention are further the compounds exemplified in WO 97/02269
Has improved activity in acute dosing studies. In the above acute administration test
The product of Example 1 of the present invention has an ED of 1.1 mg / kg in 2 hours.₅₀With
However, Example 1 of WO97 / 02269 has an ED of 4.5 mg / kg in 2 hours. ₅₀ Having.       [0118]   These results indicate that the compounds of the present invention are compared with the compounds disclosed in the prior art.
It shows a surprising increase in potency.       [0119]   The invention will now be described by way of example, which is for illustrative purposes only. Each of these practices
Examples of end products include high performance liquid chromatography, elemental analysis, and nuclear magnetic resonance.
Characterized by one or more of ringing spectrum measurements, mass spectrometry and infrared analysis
Was done.       [0120]   Example Example 1   a) Tetrahydrofuran of 3-acetyl-benzo [b] thiophene (10 g)
(250 mL) While stirring the solution, add lithium bismuth at -70 ° C under nitrogen.
(Trimethylsilyl) amide (1 M tetrahydrofuran solution 60 mL) was added dropwise.
The mixture was stirred at -70 ° C for 1 hour. Methyl iodide (3.54 mL) tetra
A solution of hydrofuran (20 mL) was added dropwise at -70 ° C over 15 minutes, and the mixture was stirred.
Was warmed to room temperature over 18 hours, and saturated ammonium chloride aqueous solution (3.
00 mL). The product was extracted into ethyl acetate (3 x 100 mL) and combined.
The extracted extract was combined with water (2 × 50 mL) and saturated aqueous sodium chloride solution (50 mL).
) And dried (Na₂SO₄), The solvent was removed under reduced pressure. About the residue
99% of petroleum ether (boiling point 40-60 ° C.) and ethyl acetate as eluents:
Biotage Flash 40i using one mixed solution (registered trademark)
) Purification by flash chromatography on silica on the instrument. Appropriate
The various fractions were combined and the solvent was removed under reduced pressure to give 3-propionylbenzo [b
] The thiophene was obtained as a colorless solid (2.7 g) which was used without further purification.
Was.       [0121]   b) 3-propionylbenzo [b] thiophene (6.75 g, as described above)
While stirring a tetrahydrofuran (100 mL) solution of
Over a period of 30 minutes under nitrogen at 0-5 ° C.
Ammonium (13.35 g) was added in small portions and the mixture was allowed to stand at 0 ° C. for 20 minutes at room temperature.
Stir for 4 hours. The obtained solid was filtered off and washed with tetrahydrofuran (30 mL).
After washing, the filtrate and the washing solution were combined, and the solvent was removed under reduced pressure. Methyl chloride residue
Dissolve in water (200 mL), and wash the solution with water (3 times with 30 mL) and saturated sodium chloride.
Washed with an aqueous solution of lithium (30 mL), dehydrated (Na₂SO₄), Remove solvent
Thus, 1- (benzo [b] thiophen-3-yl) -2-bromopropane-1
The -one was obtained as a brown oil (9.2 g). It gradually solidifies at room temperature, it
The above was used without purification.       [0122]   c) Crude 1- (benzo [b] thiophen-3-yl) -2-bromopropane-1
-One (9.2 g), 2-imidazolidinthione (3.5 g), ethanol (2 g)
00 mL) and acetic acid (100 mL) under nitrogen for 17 hours.
Heat at reflux and remove the solvent under reduced pressure. Residue with ether (100 mL)
Trituration, the solid obtained was filtered off and crystallized from ethanol to give 3- (benzo [
b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1
-B] Thiazole hydrobromide was obtained as a white solid (4.9 g). Melting point 277
~ 278 ° C.       [0123]   Separate manufacturing method A   a) Benzo [b] thiophene (50 g) and anhydrous sodium acetate (46 g)
The mixture in methylene chloride (500 mL) was stirred at about 5 ° C. with bromine (
20 mL) in methylene chloride (100 mL) was added dropwise and the mixture was allowed to stand at room temperature for 72 hours.
While stirring, it was filtered and the solvent was removed under reduced pressure. The residue is distilled to give
Lomobenzo [b] thiophene was obtained as a pale yellow oil (51.3 g). Boiling point 9
3-104 ° C / 53Pa.       [0124]   b) An aqueous solution of N, O-dimethylhydroxylamine hydrochloride (50 g) (water 50
0 mL) was cooled on ice with stirring, and potassium carbonate (125 g) was added for 10 minutes.
And added in small portions. Toluene (500 mL) was added, and the stirred mixture was cooled to 0 ° C.
Then, propionyl chloride (43 mL) was added dropwise at 0 to 5 ° C. After addition is complete, mix
The thing was stirred at 0 ° C. for 5 minutes, the cooling bath was removed and stirring was continued for another hour. Minute aqueous phase
And triturated with toluene (2 x 100 mL) and the combined triene solution was washed with water (2
00 mL) and saturated aqueous sodium chloride solution (200 mL), and dried (
Na₂SO₄), The solvent is removed under reduced pressure and N-methoxy-N-methylpropio
Amide was obtained as a colorless oil. It was used without further purification. Combined
Extract the aqueous phase with ether (2 × 100 mL) and then with methylene chloride.
And (2 × 100 mL), additional product was isolated. Dehydrate the combined extracts
(Na₂SO₄), The solvent was removed under reduced pressure and N-methoxy-N-methylprop
The onamide was obtained as a colorless oil (14.2 g). Without further purification
Using.       [0125]   c) Several iodine crystals were mixed with magnesium chips (5.05 g) and tetrahydrofuran.
To a mixture of run (25 mL) was added, followed by 3-bromobenzo [b] thiophene (4
10 g of a solution of 2.1 g) in tetrahydrofuran (200 mL) was added. mixture
Is heated under nitrogen to initiate Grignard reagent formation, then remove the heat source and remove the remaining 3
-Bromobenzo [b] thiophene is stirred at such a rate that a gentle reflux is maintained.
It was added with stirring. After the addition is complete (about 35 minutes), the mixture is heated for another 35 minutes.
While it was heated at reflux for 10 minutes and allowed to cool to room temperature. N-methoxy-N
-Methylpropionamide (23.1 g) in tetrahydrofuran (100 mL)
The solution was added over 2 minutes and the mixture was stirred at room temperature for 20 minutes and at reflux for 5 hours,
Then, the mixture was cooled with ice and 2M hydrochloric acid (125 mL) was added dropwise. Heat the mixture for 30 minutes
, Filtered (Celite), and the filtrate was concentrated under reduced pressure to remove tetrahydrofuran.
. The product was extracted into ethyl acetate (2 x 300 mL) and the combined extracts were washed with water (2
(2 × 00 mL) and saturated aqueous sodium chloride solution (2 × 200 mL)
And dehydrated (Na₂SO₄), The solvent was removed under reduced pressure. Petroleum ether residue
(Boiling point 60-80 ° C.) (100 mL), and the resulting solid was collected by filtration and dried at 45 ° C.
And dried in vacuo for 6 hours to give 3-propionylbenzo [b] thiophene as a pale yellow solid
(23.3 g). 73-75 ° C.       [0126]   d) Tetrahydro of 3-propionylbenzo [b] thiophene (4.34 g)
While stirring the furan (80 mL) solution at 0-5 ° C. under nitrogen for 10 minutes
And phenyltrimethylammonium tribromide (8.6 g) was added in small portions.
The mixture was stirred at room temperature for 4 hours. The obtained solid is filtered off, and tetrahydrofuran (
30 mL), combine the filtrate and washings, remove the solvent under reduced pressure,
-(Benzo [b] thiophen-3-yl) -2-bromopropan-1-one was converted to brown
Obtained as a colored oil. It was used without further purification.       [0127]   e) Crude 1- (benzo [b] thiophen-3-yl) -2-bromopropane-1
-One, 2-imidazolidinthione (2.33 g) and ethanol (120 m
The mixture of L) was heated to reflux under nitrogen for 15 minutes, acetic acid (60 mL) was added and the mixture
Was heated under reflux for 24 hours and the solvent was removed under reduced pressure. Ethano residue
(125 mL) to give 3- (benzo [b] thiophen-3-yl
) -2-Methyl-5,6-dihydroimidazo [2,1-b] thiazole hydrogen bromide
The acid salt was obtained as a white solid (4.4 g). 272-274 ° C.       [0128]   Separate manufacturing method B   a) 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo
[2,1-b] thiazole hydrobromide (200 g, described in WO 97/02269)
Prepared in the same manner as described above), saturated aqueous sodium carbonate (1000 mL) and
And a mixture of methylene chloride (2000 mL) were stirred vigorously at room temperature for 1.5 hours.
Was separated, washed with water (500 mL), dried (MgSO 4)₄), Remove the solvent under reduced pressure
Removed. This process was repeated on the same scale and the two products were combined to give 3- (be
Nzo [b] thiophen-3-yl) -5,6-dihydroimidazo [2,1-b]
The thiazole was obtained as a pale yellow solid (264.3 g), which was used without further purification.
Used for       [0129]   b) 3- (benzo [b] thiophen-3-yl) -5,6-dihydroimidazo
While stirring a solution of [2,1-b] thiazole (264.3 g) in methylene chloride.
Then, bromine (55.5 mL) was added dropwise thereto over a period of 1.75 hours at 0 to 5 ° C.
Was stirred at 0 ° C. for 30 minutes and at room temperature for 1 hour. The obtained solid was collected by filtration and chlorided.
Wash with methylene (300 mL), dry under vacuum at 70 ° C., and give 3- (benzo [b]
Thiophen-3-yl) -2-bromo-5,6-dihydroimidazo [2,1-b
] Thiazole hydrobromide was obtained as a pale yellow solid (431 g). Any more
Used without purification.       [0130]   c) 3- (benzo [b] thiophen-3-yl) -2-bromo-5,6-dihi
Droimidazo [2,1-b] thiazole hydrobromic acid (170 g) was stirred under nitrogen.
Stirred ethyl magnesium chloride [2.0 M ether solution (620 mL)]
In tetrahydrofuran (1700 mL) solution over 1 hour at 0-8 ° C
And the mixture was stirred at 3 ° C. for 1.5 hours. Dimethylformamide (136m
L) is added over 30 minutes at 3-8 ° C. and the mixture is stirred for 2 hours at room temperature and cooled
8 ° C, saturated aqueous ammonium chloride solution (600 mL) and water (350 mL)
The reaction was quenched by careful addition of the solution. Add ethyl acetate (1500 mL)
The mixture was stirred at room temperature for 18 hours, and the obtained solid (fraction 1) was collected by filtration. Filtrate
The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (500 mL), and dried (
MgSO₄), The solvent was removed under reduced pressure. The residue was treated with hot propan-2-ol (1
000 mL), the solution was filtered while heating, and allowed to stand at room temperature for 20 hours.
The obtained solid was collected by filtration, washed with propan-2-ol (100 mL), and dried at 70 ° C.
And dried under vacuum with 3- (benzo [b] thiophen-3-yl) -5,6-dihydric
Loimidazo [2,1-b] thiazole-2-carboxaldehyde was converted to a yellow solid (
19.4 g). Melting point 206 [deg.] C. Solid fraction 1, methylene chloride (2100
mL), a mixture of dihedral acid (250 mL) and water (1000 mL) at room temperature for 15 minutes.
Stir for minutes and add triethylamine (80 mL). Separate the methylene chloride layer
Isolate more product from aqueous layer by extraction into methylene chloride (500 mL)
did. Dry the combined methylene chloride solution (MgSO 4₄), Solvent is removed under reduced pressure
To give additional 3- (benzo [b] thiophen-3-yl) -5,6-dihydroi
Midazo [2,1-b] thiazole-2-carboxaldehyde was converted to a yellow solid (63
. 0 g). Melting point 208 [deg.] C.       [0131]   d) Suspension of finely ground aluminum chloride (14 g) in methylene chloride (330 mL)
Was stirred under ice-cooling while adding borane / t-butylamine complex (18.3 g).
Was added in portions and the mixture was stirred at 0 ° C. for 55 minutes. 3- (benzo [b] thiof
Hen-3-yl) -5,6-dihydroimidazo [2,1-b] thiazol-2-
A solution of carboxaldehyde (10 g) in methylene chloride (70 mL) was added dropwise at 0 ° C.
The mixture was stirred at 0 ° C. for 15 minutes and at room temperature for 21 hours. Add water (1
000 mL) and then 2.5M hydrochloric acid (175 mL) by careful addition.
The reaction was stopped and made basic by adding a 5 M aqueous sodium hydroxide solution. water
The phases were separated, washed with methylene chloride (300 mL) and the combined methylene chloride solution
Is dehydrated (MgSO4₄), The solvent was removed under reduced pressure. Half of the residue (5 g)
Dissolved in ethanol (12 mL) and added 48% hydrobromic acid (3.5 mL). Mixed
The mixture was diluted with ether (100 mL) and the resulting solid was collected by filtration and filtered with ethanol.
(46 mL). The mixture is heated at reflux for 15 minutes, cooled on ice
The resulting solid was collected by filtration, washed with ether (40 mL), dried in vacuo,
(Benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimida
Zo [2,1-b] thiazole hydrobromide was obtained as a white solid (3.54 g).
. 273-276 ° C.       [0132]   Example 2   a) Ether of 3-bromo-5-chlorobenzo [b] thiophene (2 g) (2
0 mL) solution under nitrogen with n-butyllithium (2.5M hexane solution 4.14).
mL) in ether (46 mL) at −78 ° C. and the mixture is added at −70 ° C. for 3 hours.
Stirred for 0 minutes. 2-Bromopropionyl chloride (1.67 g) was added at one time.
The mixture was then stirred at -70 ° C for 4 hours and it was warmed to 0 ° C. The mixture
Stir at 0 ° C. for another 30 minutes, then add saturated aqueous ammonium chloride solution (50 mL)
Was added to stop the reaction. The aqueous layer was separated and washed with ether (2 in 30 mL).
Times), and the combined ether solution is washed with a saturated aqueous sodium chloride solution (30 mL).
Twice) and dehydrated (Na₂SO₄). The solvent was removed under reduced pressure and the residue was
Eluent is a 9: 1 mixture of oil ether (boiling point 60-80 ° C) and ethyl acetate
Flash chromatography on silica. Combine appropriate fractions
By removing the solvent under reduced pressure, 1- (5-chlorobenzo [b] thiophene-
3-yl) -2-bromopropan-1-one (0.32 g) was obtained as a white solid.
Was. It was used without further purification.       [0133]   b) 1- (5-chlorobenzo [b] thiophen-3-yl) -2-bromopro
Pan-1-one (0.3 g), 2-imidazolidinthione (0.12 g) and
A mixture of ethanol (10 mL) was heated at reflux under nitrogen for 15 minutes and acetic acid (4 mL)
) Was added and the mixture was heated under reflux for 24 hours and the solvent was removed under reduced pressure
. Dissolve the residue in a minimum amount of water and add 5M aqueous sodium hydroxide to dissolve the residue.
The solution was made basic to pH 12, and the product was extracted into methylene chloride (3 x 30 mL).
). The extract is dehydrated (Na₂SO₄), The solvent was removed under reduced pressure. About the residue
Methylene chloride and then 20: 1 methylene chloride and methanol as eluents
On silica in a Biotag Flash 40i® device using the mixture
Purification by flash chromatography was performed. Combine the appropriate fractions and
Is removed under reduced pressure to give 3- (5-chlorobenzo [b] thiophen-3-y.
L) -2-Methyl-5,6-dihydroimidazo [2,1-b] thiazole is converted to yellow
Obtained as a solid (0.1 g). 264-267 ° C.       [0134]   Example 3   a) Triethylamine (244.85 mL) in dimethylformamide (400
mL) while stirring the solution under nitrogen at 110 ° C.
(62.87 mL) was added dropwise, and the mixture was stirred at 110 ° C. for 30 minutes. 2,6
-Difluorobenzaldehyde (100 g) in dimethylformamide (100 m
L) The solution was added all at once, and the mixture was heated to reflux for 4 hours. Cool the mixture to room temperature
And it was added to an ice-water mixture (4000 mL). The product is filtered and dried under vacuum
Dry to give methyl 4-fluorobenzo [b] -thiophene-2-carboxylate as white
Obtained as a solid (110 g). It was used without further purification.       [0135]   b) 4-fluorobenzo [b] -thiophene-2-carboxylic acid at room temperature under nitrogen
To a suspension of methyl (110 g) in methanol (1500 mL) was added 2M
An aqueous solution of sodium chloride (1000 mL) was added. The mixture was stirred at room temperature for 4 hours,
The solution phase was placed in 2M hydrochloric acid (3000 mL) by a gradient method to unreact 4-F
Separated from methyl fluorobenzo [b] -thiophene-2-carboxylate. Obtained
The solids obtained are filtered from the acidic mixture and dried in vacuo at 60 ° C. to give 4-fluorobenzo [b
] -Thiophen-2-carboxylic acid was obtained as a white solid (77 g). It it
The above was used without purification. Remaining unreacted 4-fluorobenzo [b] -thiophene-
Dissolve methyl 2-carboxylate in hot methanol (500 mL) and add 2M sodium hydroxide
An aqueous solution of lithium (250 mL) was added at room temperature. The mixture was stirred at room temperature for 8 hours.
This was added to 2M hydrochloric acid (1000 mL). The solid obtained is filtered and dried in vacuo.
Thus, 4-fluorobenzo [b] -thiophene-2-carboxylic acid was converted to a white solid.
(33 g).       [0136]   c) 4-fluorobenzo [b] -thiophene-2-carboxylic acid (77 g)
While stirring the norin (500 mL) solution, copper powder (40 g) was added thereto and mixed.
The mixture was stirred and heated at 180-200 ° C. for 2 hours. Allow the mixture to cool
Room temperature was attained and it was added to 2M hydrochloric acid (1500 mL). Ethyl acetate (1000m
L) was added and the mixture was filtered through Celite®, which was then added to ethyl acetate (5.
00 mL) and the combined organic layers are dried (MgSO 4).₄), Remove the solvent under reduced pressure
Removed. For the residue, use petroleum ether (b.p.
And then a 25: 1 mixture of petroleum ether (boiling point 40-60 ° C.) and ethyl acetate
Chromatographic purification on silica was performed. Combine the appropriate fractions
And the solvent is removed under reduced pressure to give 4-fluorobenzo [b] thiophene.
Obtained as a colorless oil (50.46 g).       [0137]   d) 4-fluorobenzo [b] thiophene (50.46 g) and acetic anhydride
A mixture of thorium (40 g) in methylene chloride (400 mL) was stirred under nitrogen.
Then, a solution of bromine (18.7 mL) in methylene chloride (200 mL) was added dropwise at -25 ° C.
The mixture was stirred at room temperature for 18 hours, it was filtered and the solvent was removed under reduced pressure
. Dissolve the residue in methylene chloride (about 50 mL), then water (300 mL) and
Zinc powder (about 40 g) was added under nitrogen. The mixture is heated at reflux for 4 hours and left to stand
Room temperature was attained for 20 hours. Add ethyl acetate (300 mL) and add for 15 minutes.
Heat reflux was continued and the mixture was allowed to cool to room temperature. The mixture was filtered (celite
®), and the filter cake was washed with ethyl acetate (3 × 100 mL). Water phase
Separate, wash with ethyl acetate (200 mL) and dry the combined organic solution (Mg
SO₄), The solvent was removed under reduced pressure and 3-bromo-4-fluorobenzo [b] thi
Offen was obtained as a light brown solid (59.4 g), which was used without further purification.
Was.       [0138]   e) Tetra of 3-bromo-4-fluorobenzo [b] thiophene (59.4 g)
A solution of lahydrofuran (250 mL) was stirred under nitrogen with ethyl magnesium
Bromide [2.0 M ether solution (190 mL)] in tetrahydrofuran (8
00 mL) solution was added at 0 ° C. and the mixture was heated at reflux for 1.5 hours, allowed to cool to room temperature
did. Add N-methoxy-N-methylpropionamide (33.5 g) and mix
The material was heated at reflux for 2 hours. The mixture was allowed to cool to room temperature and it was saturated with ammonium chloride.
Solution (1000 mL). The product was extracted into ethyl acetate (500 m
L twice) and the combined extracts are dried (MgSO 4).₄), The solvent was removed under reduced pressure
. For the residue, petroleum ether (boiling point 40-60 ° C) as eluent and then chloride
Flash chromatography purification on silica using methylene was performed to give 4-
Fluoro-3-propionylbenzo [b] thiophene was obtained as a red-brown solid (
22g).       [0139]   f) 4-Fluoro-3-propionylbenzo [b] thiophene (22 g)
The solution of trihydrofuran (300 mL) was stirred at 0 ° C. under nitrogen while stirring.
Phenyltrimethylammonium bromide (39.5 g) was added and the mixture was added at room temperature for 3 hours.
Stirred for hours. The solid obtained is filtered off through silica, washed with methylene chloride,
The filtrate and washings were combined, the solvent was removed under reduced pressure and 2-bromo-1- (4-
Fluorobenzo [b] thiophen-3-yl) propan-1-one as a brown oil
(About 40 g). It was used without further purification.       [0140]   g) Crude 2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl)
Propan-1-one (about 40 g), 2-imidazolidinthione (10.71 g)
, A mixture of ethanol (150 mL) and acetic acid (75 mL) under nitrogen for 2 hours
Heat to reflux, add additional 2-imidazolidinthione (2.2 g) and heat to reflux.
Continued for 2 hours. The mixture was cooled to 0 ° C. and the solid obtained was filtered off and ethanol
(2 × 100 mL), and then wash it with a saturated aqueous sodium hydrogen carbonate solution (500 mL).
and a mixture of methylene chloride (500 mL) for 30 minutes.
To make it basic. Separate the organic layer and shake the aqueous layer with methylene chloride.
(2 × 250 mL), dehydrate the combined methylene chloride solution (MgSO 4)₄), Dissolved
The medium was removed under reduced pressure. The residue was dissolved in ethanol (200 mL) and concentrated hydrochloric acid (
6 mL) at 0 ° C. The solvent was removed under reduced pressure and the residue was ethanol (about 10
0 mL) to give 3- (4-fluorobenzo [b] thiophene.
-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazolone
Hydrochloride was obtained as a white solid (17.5 g). Melting point 259-262 [deg.] C.       [0141]   Example 4   3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro
Imidazo [2,1-b] thiazole (5 g, Example 1: separately described in Production Method B)
Of ethanol (10 mL) at 0 ° C. while stirring.
To this was added a solution of fumaric acid (2.13 g) in ethanol (40 mL). The mixture
Stir at 0 ° C. for 15 minutes, filter the resulting solid, dry in vacuo and obtain
b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1
-B] Thiazole fumarate was obtained as a white solid (4.71 g). Melting point 17
9-181 ° C.       [0142]   Example 5   3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro
Imidazo [2,1-b] thiazole (4.27 g, Example 1: separately described in Production Method B)
Concentrated hydrochloric acid (4 mL) was added to a solution of ethanol (45 mL) prepared in the same manner as described above.
) Was added and the mixture was added to ether (250 mL) and stirred for 15 minutes. Obtained
The solid which was collected by filtration, washed with ether (50 mL), dried in vacuo at 70 ° C.,
(Benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimida
Zo [2,1-b] thiazole hydrochloride was obtained as a white solid (3.50 g). Melting point
254-256 ° C.       [0143]   Example 6   3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydro
Imidazo [2,1-b] thiazole (2.66 g, Example 1: separately described in Production Method B)
D) into a solution of ethanol (28 mL) prepared in the same manner as described above) with stirring.
, L-tartaric acid (1.43 g) in ethanol (30 mL) was added. Got
The suspension was stirred for 5 minutes and ether (50 mL) was added. The solid is filtered off and
(50 mL), dried in vacuo at 70 ° C., and dried with 3- (benzo [b] thiophene
N-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazo
L.D, L-tartrate was obtained as a white solid (4.00 g). Melting point 204-2
05 ° C.       [0144]   Example 7   Example 1 First, benzo [b] thio was initially prepared in the same manner as described in Production Method A.
Fen is brominated, then reacted with magnesium, and then N-methoxy-
By reacting with N-methylbutyramide, 3- (benzo [b] thiophene-
3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole
Hydrobromide was produced as a colorless solid. 219-221 ° C.       [0145]   Example 8   a) 3-bromo-5-methylbenzo [b] thiophene (2.5 g, Example 1:
Separately, in the same manner as described in Production Method A, 5-methylbenzo [b] thiophene
A solution of the compound (prepared by bromination) in ether (5 mL) was added to n-butyllithium (1
. 6M hexane solution 7mL) in ether (20mL) solution under nitrogen at -70 ° C
And the mixture was stirred at -70 ° C for 30 minutes. N-methoxy-N-methyl
A solution of lopionamide (1.3 g) in ether (5 mL) was added dropwise over 20 minutes.
The mixture was stirred at -70 ° C for 3 hours and allowed to warm to room temperature over 20 hours.
The reaction was quenched by the addition of 2M hydrochloric acid (25 mL). Separate the ether layer and add water
(25 mL) and a saturated aqueous sodium chloride solution (25 mL), and dried (
MgSO₄), The solvent was removed under reduced pressure. For residue, use petroleum
Silica using a 40: 1 mixture of ether (boiling point 60-80 ° C.) and ethyl acetate
Was performed by flash chromatography. Combine appropriate fractions and remove solvent
Removal under reduced pressure gives 5-methyl-3-propionylbenzo [b] thiophene.
20: 1 mixture of butane and 5-methyl-2-propionylbenzo [b] thiophene
(1.2 g) was obtained as an off-white solid. Use it without further purification
Was.       [0146]   b) 5-methyl-3-propionylbenzo [b] thiophene (1.2 g, above
While stirring a solution of tetrahydrofuran (20 mL) prepared in
Phenyltrimethylammonium tribromide (2.25 g) at 0 ° C. in small portions
The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 20 hours. Filter the mixture and reduce the solvent
Removed under pressure. Dissolve the residue in methylene chloride (50 mL) and wash the solution with water
(2 × 50 mL), dehydrate (MgSO 4)₄), The solvent is removed under reduced pressure and dark brown
A solid was obtained. It was triturated with petroleum ether (boiling point 60-80 ° C.) (50 mL)
. The solvent was removed under reduced pressure to give 2-bromo-1- (5-methylbenzo [b] thiophene.
(N-3-yl) propan-1-one (0.75 g) was obtained. Put it under nitrogen, 2
-Imidazolidinethione (0.27 g), ethanol (30 mL) and acetic acid (
(15 mL) and heated to reflux under nitrogen for 24 hours. Remove the solvent under reduced pressure
The residue was triturated with ether (20 mL) and the resulting solid was collected by filtration and dried in vacuo.
After drying, 2-methyl-3- (5-methylbenzo [b] thiophen-3-yl)-
5,6-Dihydroimidazo [2,1-b] thiazole hydrobromide was converted to a white solid.
(0.52 g). 266-269 ° C.       [0147]   Example 9   Example 1 First, benzo [b] thio was initially prepared in the same manner as described in Production Method A.
Fen is brominated, then reacted with magnesium, and then N-methoxy-
By reacting with 3, N-dimethylbutyramide, 3- (benzo [b] thiof
Hen-3-yl) -2-isopropyl-5,6-dihydroimidazo [2,1-b
The thiazole hydrobromide was prepared as a light brown solid. 208-210 ° C
.       [0148]   Example 10   a) Tetrahydrofuran of 4-fluorophenylmethyl sulfide (22.0 g)
While stirring the run solution, sec-butyllithium (1.2
5M 92: 8 cyclohexane: hexane mixed solution (100 mL) was added dropwise and mixed.
The mixture was stirred at -70 ° C for 65 minutes. Dimethylformamide (13.2 mL)
Drop at -68 ° C to -70 ° C and allow the stirred mixture to warm slowly over 20 hours
Room temperature was attained and it was added to an aqueous solution of acetic acid (10 mL) (500 mL of water). Product
Was extracted into ether (3 × 150 mL), and the combined extracts were extracted with 2M hydrochloric acid (200 mL).
mL) and saturated aqueous sodium chloride (200 mL), dried (Na ₂ SO₄), The solvent was removed under reduced pressure. The residue used without further purification (2
5g) is mainly based on the nuclear magnetic resonance spectroscopy.
Phenylmethyl sulfide and 2-fluoro-5- (methylthio) benzalde
It was assumed to consist of a 2: 3 mixture of hides.       [0149]   b) Methyl thioglycolate (8.9 mL), crude 2-fluoro-5- (methyl
Thio) benzaldehyde (25 g, prepared above), dimethylacetamide (25
0 mL) and ethyldiisopropylamine (42 mL) with stirring.
And heated at 140-150 ° C. under nitrogen for 3.5 hours, and the solvent was removed under reduced pressure.
Water (650 mL) was added to the residue and the product was extracted into methylene chloride (150 m
L three times). The combined extracts were washed with water (3 x 150 mL), dried (Na ₂ SO₄), The solvent was removed under reduced pressure. Triturate the residue with ether (250 mL).
The solid obtained was collected by filtration, washed with ether (2 × 50 mL), and filtered.
After air-drying, methyl 5- (methylthio) benzo [b] thiophene-2-carboxylate
(13.3 g) as a pale yellow solid. 89.7-90.4 [deg.] C.       [0150]   c) Dissolve sodium hydroxide (8 g) in water (100 mL), and add
E) Methyl benzo [b] thiophene-2-carboxylate (23.8 g, as described above)
A solution of methanol (300 mL) prepared in the same manner as
The solution was added. The mixture was heated to dryness for 10 minutes and left at room temperature for 3 days. Suspension
Concentrate by heating to a total volume of about 250 mL, add water (100 mL), mix
Was filtered hot to remove insolubles. An aqueous solution of concentrated hydrochloric acid (40 mL) (water 20) was added to the filtrate.
mL) and the resulting solid was collected by filtration, washed with water, dried in vacuo, and treated with 5- (meth
Ruthio) benzo [b] thiophene-2-carboxylic acid as a pale yellow solid (21 g)
I got it. Melting point 185-186.5 [deg.] C.       [0151]   d) Copper powder (5.3 g), 5- (methylthio) benzo [b] thiophen-2-
A mixture of carboxylic acid (20 g) and quinoline (100 mL) was placed under nitrogen for 30 minutes.
The mixture was refluxed while heating, and filtered hot. The filtrate was concentrated (100 mL), ice (500 g) and
And a mixture of ether (200 mL), and the resulting solid was collected by filtration and washed with ether.
Washed. The aqueous phase was separated and additional product was then extracted into ether (150
mL twice). The combined ether layers were combined with 2M hydrochloric acid (200 mL) and water (200 mL).
mL) and dried (Na₂SO₄) And the solvent were removed under reduced pressure to give 5- (meth)
Tylthio) benzo [b] thiophene was obtained as a light brown solid (14.7 g). So
It was used without further purification.       [0152]   e) Aluminum bromide (26.2 g), bromoacetyl bromide (7.12)
and a mixture of methylene chloride (120 mL) was stirred at <0 ° C. under nitrogen.
Meanwhile, methyl chloride of 5- (methylthio) benzo [b] thiophene (14.7 g) was used.
A solution of ren (180 mL) was added and the resulting dark reddish brown solution was incubated at <0 ° C. for 30 minutes
Stirred at warm for 20 hours. Mix the solution with ice (600 g) and concentrated hydrochloric acid (50 mL)
Methylene chloride (300 mL) was added to the mixture, and insolubles were removed by filtration (Celite (
Registered trademark)). The aqueous phase was separated and the additional product was then separated from methylene chloride (300 m
L) and the combined methylene chloride solution was dried (MgSO 4).₄), Decompress the solvent
Removed below. Acetic acid (200 mL) and methylene chloride (200 mL) as residues
And a solution of 2-imidazolidinthione (5.29 g) in acetic acid (200 mL).
In addition, methylene chloride was removed by distillation. The remaining mixture was heated at reflux for 2 hours.
The total volume was reduced to about 200 mL by heating under reduced pressure. Hot solution by gradient method
Therefore, it was separated from insolubles and allowed to cool. Further, insoluble matter is removed by the method described above.
The solvent was removed at 50 ° C. under reduced pressure. The residue was washed with water (300 mL) and 5 M
The product was mixed with an aqueous solution of sodium chloride (300 mL) and the product was diluted with methylene chloride (300 mL).
L). The extract is dehydrated (Na₂SO₄), The solvent was removed under reduced pressure.
For the residue, ethyl acetate as eluent, then ethyl acetate, methanol and
Flash chromatography on silica using an 8: 1: 1 mixture of triethylamine
Partial purification by luffy was performed. Combine the appropriate fractions and remove the solvent under reduced pressure
To give 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5
, 6-Dihydroimidazo [2,1-b] thiazole was obtained as a tan gum.
(3.6 g). It was used without further purification.       [0153]   f) 3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6
-Dihydroimidazo [2,1-b] thiazole (3.55 g, prepared by the method described above)
) Of methylene chloride (80 mL) was stirred while the internal temperature was 20 ° C or lower.
A solution of bromine (1.87 g) in methylene chloride (10 mL) was added while maintaining underneath,
The methylene chloride phase was separated from the insolubles by a gradient method and concentrated under reduced pressure. Residue
Was triturated with methylene chloride (10 mL), and the resulting solid was collected by filtration to give 2-bromo-
3- [5- (methylthio) benzo [b] thiophen-3-yl] -5,6-dihi
Droimidazo [2,1-b] thiazole hydrobromide was obtained as a tan solid (
2.97 g). 260-265 ° C.       [0154]   g) 2-bromo-3- [5- (methylthio) benzo [b] thiophen-3-i
] -5,6-dihydroimidazo [2,1-b] thiazole hydrobromide (2.
90 g) in tetrahydrofuran (40 mL) was stirred at −10 ° C. under nitrogen.
While adding ethyl magnesium chloride [2.8 M in tetrahydrofuran
(8.76 mL)] and the mixture was stirred at room temperature for 90 minutes, cooled to -5 <0> C
And Dimethylformamide (5 mL) was added and the resulting suspension was allowed to stand at room temperature for 2 hours.
While stirring, ethyl acetate (200 mL) and saturated aqueous ammonium chloride (20 mL).
0 mL) was added. The ethyl acetate layer was separated and dried (Na₂SO₄), Reduce solvent
Removed under pressure to give 3- [5- (methylthio) benzo [b] thiophen-3-yl
] -5,6-Dihydroimidazo [2,1-b] thiazole-2-carboxyal
The aldehyde was obtained as a solid (1.4 g). Melting point 157-18.5 [deg.] C. This is it
The above was used without purification.       [0155]   h) Suspension of finely ground aluminum chloride (0.80 g) in methylene chloride (20 mL)
The solution was stirred at 0 ° C. under nitrogen while the borane / t-butylamine complex (1.
04 g) was added and the mixture was stirred at 0 ° C. for 1 hour. 3- [5- (methylthio) be
Nzo [b] thiophen-3-yl] -5,6-dihydroimidazo [2,1-b]
Thiazole-2-carboxaldehyde (0.66 g; prepared by the method described above) was added.
The mixture was stirred at 0 ° C. for 15 minutes and left at room temperature for 21 hours. Add water (2
The reaction was quenched by careful addition of 5 mL) and then 2M hydrochloric acid (25 mL),
The temperature was raised to decompose the borane complex. The suspension was filtered and the filtrate was washed with 5M sodium hydroxide.
The solution was made basic (pH 14) by adding an aqueous solution. Extract the product into methylene chloride
(50 mL x 2) and the combined extracts were dried (Na₂SO₄), Reduce solvent
Removed under pressure. The resulting orange-yellow residue (0.39 g) in methylene chloride (
Oxalic anhydride (0.1 mL) in a mixed solution of 25 mL) and ethyl acetate (50 mL).
2 g) in ethyl acetate (10 mL) was added and methylene chloride was removed by distillation.
did. The resulting solid was collected by filtration, washed with ethyl acetate (2 × 10 mL), and dried in vacuo.
After drying, 2-methyl-3- [5- (methylthio) benzo [b] thiophen-3-
Yl] -5,6-dihydroimidazo [2,1-b] thiazole oxalate
Obtained as a color solid (0.36 g), mp 197 ° C.       [0156]   Example 11   a) Aluminum chloride (7.34 g) and 2-bromopropionyl chloride
(4.73 g) in methylene chloride (70 mL) while stirring under nitrogen
, And 5-fluorobenzo [b] thiophene (2.8 g; Examples 3 and 10).
Prepared from 2,5-difluorobenzaldehyde) in the same manner as described in
A solution of methylene chloride (27 mL) was added dropwise and the mixture was stirred at room temperature for 2.5 hours.
Was added to ice-cold water (250 mL) and stirred for 1 hour. Separate the aqueous phase and add additional product
Was then extracted into methylene chloride (100 mL) and the combined methylene chloride solution was
Water (2x100mL) and saturated aqueous sodium chloride solution (2x100mL)
And dried (Na₂SO₄), The solvent was removed under reduced pressure. About residue
9: 1 mixture of petroleum ether (boiling point 60-80 ° C.) and ether as eluent
On silica in a Biotag Flash 40i® device using liquid
Purification by flash chromatography was performed twice. Combine the appropriate fractions and
Is removed under reduced pressure to give 2-bromo-1- (5-fluorobenzo [b] thio.
Phen-3-yl) propan-1-one and 2-bromo-1- (5-fluoro
9: 1 mixture of benzo [b] thiophen-2-yl) propan-1-one (2.
1 g). It was used without further purification.       [0157]   b) Crude 2-bromo-1- (5-fluorobenzo [b] thiophen-3-yl)
Propan-1-one (2.1 g; prepared by the above method), 2-imidazolidinthio
(0.75 g) and ethanol (60 mL) were heated to reflux for 10 minutes.
, Acetic acid (30 mL) was added. The mixture is heated at reflux for 20 hours and released at room temperature for 60 hours
And the solvent was removed under reduced pressure. Triturate the residue with ethanol (100 mL)
The obtained solid was dissolved in hot ethanol (100 mL). Total volume by distillation
The volume was reduced to about 60 mL and the mixture was allowed to cool to room temperature. The resulting solid is filtered and filtered.
Air dry and recrystallize from ethanol (75 mL) to give 3- (5-fluorobenzo
[B] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,
1-b] thiazole hydrobromide was obtained as a white solid (0.45 g). Melting point 2
68-271 ° C.       [0158]   Example 12   a) 3- (5-Fluorobenzo [b] thiophen-3-yl) -2-methyl-
5,6-dihydroimidazo [2,1-b] thiazole hydrobromide and 3- (
5-fluorobenzo [b] thiophen-2-yl) -2-methyl-5,6-dihi
Droimidazo [2,1-b] thiazole hydrobromide (method described in Example 11
The 58:42 mixture prepared in the same manner as in
Orobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimi
Dazo [2,1-b] thiazole was prepared. Methylene chloride and
A 9: 1 mixture of ethanol and then a 1: 1 mixture, or methylene chloride and
Biotag Fra using a 97: 3 mixture of methanol and then a 9: 1 mixture
For flash chromatography on silica on a Crush 40i® instrument
After purification by pure pure base was obtained.       [0159]   b) 3- (5-Fluorobenzo [b] thiophen-3-yl) -2-methyl-
5,6-dihydroimidazo [2,1-b] thiazole (4.6 g) in ethanol (250 mL) was added 5.5 M hydrochloric acid (4.3 mL) and mixed.
The mixture was added dropwise to ether (400 mL) with stirring and then ether (2000
mL) was added. The suspension was allowed to stand at room temperature for 3 hours, and the resulting solid was collected by filtration.
(200 mL), dried under vacuum at 40 ° C.,
[B] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,
1-b] thiazole hydrochloride was obtained as a white solid (3.6 g). Melting point 243-2
44 ° C.       [0160]   Example 13   5-chloro-3-propionylbenzo [b] thiophene (5.8 g, Example 2
Reaction with n-butyllithium followed by N-methoxy-
Reaction with N-methylpropionamide gives 3-bromo-5-chlorobenzo [
b] prepared from thiophene) in tetrahydrofuran (100 mL) under nitrogen
Phenyltrimethylammonium tribromide (9.7 g) at 0-5 ° C over 2 minutes
Was added in portions and the mixture was stirred at room temperature for 2.5 hours. The resulting solid is filtered off,
The solvent was removed from the filtrate under reduced pressure. The residue, 2-imidazolidinthione (2.6
A mixture of 5 g) and ethanol (120 mL) was heated to reflux for 15 minutes and acetic acid (
60 mL) was added. The mixture was heated at reflux for 24 hours and the solvent was removed under reduced pressure.
Ethanol (50 mL) was added to the residue and the solid was removed by removing the solvent under reduced pressure.
Obtained. It is recrystallized from hot ethanol (250 mL) and dried under vacuum to obtain 3
-(5-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6-di
Hydroimidazo [2,1-b] thiazole hydrobromide was obtained as a pink solid
(6.25 g). Melting point 283-286 [deg.] C.       [0161]   Example 14   Analogously to the method described in Example 11, 5-chlorobenzo [b] thiophene [J.H.
eterocycl. Chem. (1988), 25 (4), 1271] and
Starting from 2-bromobutyryl chloride, 3- (5-chlorobenzo [b] thi
Offen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b]
Thiazole hydrobromide was prepared as an off-white solid. Melting point 285-28
9 ° C (shrink at 240 ° C).       [0162]   Example 15   Analogously to the method described in Example 11, 5-bromobenzo [b] thiophene
From 5-bromo-2-fluorobenzaldehyde in a manner analogous to that described in Example 3.
Production] and 2-bromopropionyl chloride as starting materials,
Mobenzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimida
Zo [2,1-b] thiazole hydrobromide was prepared as a brown solid. Melting point 27
2-275 ° C.       [0163]   Example 16   2-bromo-1- (4-fluorobenzo [b] thiophen-3-yl) propa
1-one (54 g; produced in the same manner as described in Example 3), 2-imida
Zolidinethione (19.4 g), ethanol (200 mL) and acetic acid (100
mL) of the mixture was heated to reflux under nitrogen for 2 hours and additional 2-imidazolidinthione was added.
(2 g) was added and heating to reflux was continued for 30 minutes. The mixture was cooled to 0 ° C.
The collected solid was collected by filtration, dried in vacuo, and dried with 3- (4-fluorobenzo [b] thiophene.
-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazolone
Hydrobromide was obtained as a yellow solid (52.1 g). 264-266 ° C.       [0164]   Example 17   3- (benzo [b] furan-3-yl) -5,6-dihydroimidazo [2,1
-B] thiazole (6.7 g; using the procedure of Example 3 of WO 97/02269)
N) in tetrahydrofuran (80 mL) suspension under nitrogen at -70 ° C.
Butyllithium (14 mL of a 2.5 M hexane solution) was added dropwise over 20 minutes.
The mixture was stirred at -70 ° C for 30 minutes. Add dimethylformamide (2.7 mL)
The mixture was then warmed to room temperature and saturated aqueous ammonium chloride (200 mL).
(mL) was added to stop the reaction. The product was extracted into methylene chloride (200 m
The extract was washed with a saturated aqueous sodium chloride solution (100 mL) and dehydrated.
(Na₂SO₄), The solvent was removed under reduced pressure. Residue as eluent
Flashing on silica using a 9: 1 mixture of methylene chloride and methanol
Chromatographic purification was performed. Combine appropriate fractions and remove solvent under reduced pressure
This gave a residue (4.3 g). About that, methylene chloride and eluent
Flash 40i using a 20: 1 mixture of methanol and methanol (registered)
Flash chromatographic purification on silica on a ™ device. Appropriate
The fractions were combined, and the solvent was removed under reduced pressure to give 3- (benzo [b] furan-3.
-Yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carboxy
The aldehyde was obtained as a brown solid (3.3 g). Use it without further purification
Was.       [0165]   Example 1 Separately, in the same manner as in the method described in Production Method B, 3- (benzo [b] furan
-3-yl) -5,6-dihydroimidazo [2,1b] thiazole-2-carbo
Xylaldehyde (3.0 g; prepared in the same manner as described above) and borane / t-
From the butylamine complex, 3- (benzo [b] furan-3-yl) -2-methyl-
5,6-Dihydroimidazo [2,1-b] thiazole (1.6 g) was prepared.
The crude product was dissolved in methylene chloride (50 mL) and ether (50 mL) was added
. The resulting solid was filtered off and the solvent was removed from the filtrate under reduced pressure. For the residue,
Use methylene chloride as the eluent and then a 9: 1 mixture of methylene chloride and methanol.
Jones Flashmaster II (R)
Flash chromatographic purification on silica was performed on the instrument. Appropriate fractionation
Combined and the solvent was removed under reduced pressure to give a residue (4.3 g). About it
Using a 19: 1 mixture of methylene chloride and methanol as eluent
Flash chromatography on silica with the Otag Flash 40i® instrument
Chromatographic purification was performed. Combine the appropriate fractions and remove the solvent under reduced pressure.
A residue (0.28 g) was obtained. It was dissolved in methanol (5 mL). Water (5
mL) and the mixture was acidified to pH 1 by adding 2M hydrochloric acid. Cloudy solution
Methanol was removed from the liquid under reduced pressure, and insolubles were removed by filtration. 2M sodium hydroxide
The filtrate was made basic to pH 12 by adding an aqueous solution, and the obtained solid was collected by filtration, and washed with water.
(10 mL), dried under vacuum and 3- (benzo [b] furan-3-yl)
-2-Methyl-5,6-dihydroimidazo [2,1b] thiazole as a white solid
(0.18 g). 119-122 ° C.       [0166]   Example A   The following description discusses the use of the compounds of the present invention in the manufacture of a pharmaceutical composition.
I will tell. In this description, the term "active compound" refers to any of the compounds of the invention.
Refers to compounds, but not to compounds which are the end products of the preceding examples.
No.       [0167]   a)capsule   In the manufacture of capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are added.
Crush and mix. The mixture is filled into hard gelatin capsules, each capsule having a unit
A dose or unit dose of a portion of the active compound is included.       [0168]   b)tablet   Tablets are manufactured from the following ingredients:       [0169]     [Table 3]       [0170]   The active compound, lactose and a portion of the starch are ground and mixed, and the resulting mixture is dried.
Granulate with polyvinylpyrrolidone in ethanol solution. Steari dry granules
Mix with magnesium phosphate and the remaining starch. Next, the mixture is compressed with a tableting machine.
Compress to give tablets containing the active compound in unit dose or unit dose, respectively
You.       [0171]   c)Enteric coated tablets   Tablets are produced by the method described in (b) above. The tablets are mixed with 20% acetate
Cellulose tantalate and 3% diethyl phthalate in ethanol: methylene chloride (1
1) Enteric coating with a conventional method using a solution.       [0172]   d)Suppository   In the manufacture of suppositories, 1300 parts by weight of the triglycerin suppository base was added to the active compound 100.
Parts by weight and the mixture is made up into suppositories, each containing a therapeutically effective amount of the active ingredient.
Shape.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 3/00 A61P 3/00 3/04 3/04 3/06 3/06 3/10 3/10 7 / 02 7/02 9/00 9/00 9/10 9/10 9/12 9/12 11/00 11/00 13/02 13/02 15/10 15/10 19/06 19/06 25/02 25/02 25/14 25/14 25/18 25/18 25/20 25/20 25/22 25/22 25/24 25/24 25/28 25/28 25/30 25/30 35/00 35 / 00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK , LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW・ F, Pennyhutt Street R ・ 5F term (reference 4C072 AA01 BB02 CC02 CC16 DD05 EE13 FF05 GG01 HH05 HH06 UU01 4C086 AA01 AA03 CB27 MA02 MA05 NA14 ZA01 ZA05 ZA08 ZA12 ZA15 ZA16 ZA18 ZA22 ZA36 ZA42 ZA43 ZA54 ZA66 ZA69 ZA70 ZA77 ZA81 ZA96 ZC11 ZC21 ZC33 ZC35 ZC39

Claims (1)

Claims: 1. A compound of formula I below comprising a pharmaceutically acceptable salt. Embedded image Wherein A is S or O; R ₁ is H, halogen, a C _1-3 alkyl group or a C _1-3 alkylthio group; R ₂ is H or fluorine; R ₃ is methyl, ethyl Or isopropyl. 2. The compound according to claim 1, wherein A is S. 3. The compound according to claim 1, wherein A is O. 4. The compound according to claim 1, wherein R ₁ is H, fluorine, chlorine, bromine, methyl and methylthio. 5. The compound according to claim 1, wherein R ₃ is methyl. 6. The compound according to claim 1, represented by formula Ia below, including a pharmaceutically acceptable salt. Embedded image Wherein R is H or chlorine. 7. A is S; R ₁ is H, fluorine or chlorine; R ₂ is H or fluorine; R ₃ is methyl. A compound according to claim 1. 8. The compound of claim 1, wherein A is S; R ₁ is H or fluorine; R ₂ is H or fluorine; R ₃ is methyl. 9. The compound according to claim 1, wherein A is S; R ₁ is H; R ₂ is H; and R ₃ is methyl. 10. (3- (benzo [b] thiophen-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole, including pharmaceutically acceptable salts; 3- ( 5-chlorobenzo [b] thiophen-3-yl) -2-methyl-5,6
-Dihydroimidazo [2,1-b] thiazole; 3- (4-fluorobenzo [b] thiophen-3-yl) -2-methyl-5,
6-dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-ethyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-methyl- 3- (5-methylbenzo [b] thiophen-3-yl) -5,6
-Dihydroimidazo [2,1-b] thiazole; 3- (benzo [b] thiophen-3-yl) -2-isopropyl-5,6-dihydroimidazo [2,1-b] thiazole; 2-methyl-3 -[5- (methylthio) benzo [b] thiophen-3-yl]
-5,6-dihydroimidazo [2,1-b] thiazole; 3- (5-fluorobenzo [b] thiophen-3-yl) -2-methyl-5
6-dihydroimidazo [2,1-b] thiazole; 3- (5-chlorobenzo [b] thiophen-3-yl) -2-ethyl-5,6
-Dihydroimidazo [2,1-b] thiazole; 3- (5-bromobenzo [b] thiophen-3-yl) -2-methyl-5,6
-Dihydroimidazo [2,1-b] thiazole; and 3- (benzo [b] furan-3-yl) -2-methyl-5,6-dihydroimidazo [2,1-b] thiazole. Item 7. The compound according to Item 1. 11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 together with a pharmaceutically acceptable diluent or carrier. 12. A compound of formula I for use as a medicament. 13. Depression, anxiety, psychosis (eg, schizophrenia), tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic attack, Eating disorders such as social phobia, bulimia, anorexia, snacks and bulimia, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia and stress; and neurological disorders such as seizures, epilepsy and / or stroke , Brain trauma, cerebral ischemia,
A compound of formula I used in the treatment of conditions with nerve damage, such as head injuries and bleeding; and as an aid to smoking cessation. 14. Depression, anxiety, psychosis (eg, schizophrenia), tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic attack, Eating disorders such as social phobia, binge eating, anorexia, snacks and bulimia, non-insulin dependent diabetes mellitus, hyperglycemia, hyperlipidemia, stress; and neurological disorders such as seizures, epilepsy and / or stroke Use of a compound of Formula I in the treatment of conditions having nerve damage such as cerebral trauma, cerebral ischemia, head injuries and bleeding; and in the manufacture of a medicament for use as a smoking cessation aid. 15. Depression, anxiety, psychosis (eg, schizophrenia), tardive dyskinesia, obesity, drug addiction, substance abuse, cognitive impairment, Alzheimer's disease, cerebral ischemia, obsessive-compulsive behavior, panic attack, In a method of treating eating disorders such as social phobia, bulimia, anorexia, snacking and bulimia, non-insulin dependent diabetes, hyperglycemia, hyperlipidemia and stress, a therapeutically effective amount of Formula I Administering a compound to a patient in need of treatment. 16. A method of reducing the desire for smoking in humans, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 10. A method comprising the step of administering. 17. A method for reducing body weight gain after smoking cessation in humans, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 10. A method comprising the step of administering. 14. Metabolic diseases and conditions resulting therefrom, in particular non-motor-active fever and increased metabolic rate, sexual dysfunction, sleep apnea, premenstrual syndrome, urinary incontinence, hyperactivity disorder, hiatal hernia and reflux Esophagitis, pain, especially neuropathic pain,
11. Use according to claims 1 to 10 for the treatment or prevention of pharmacotherapy related weight gain, chronic fatigue syndrome, osteoarthritis and gout, weight gain related cancer, menstrual dysfunction, gallstones, orthostatic hypotension and pulmonary hypertension. A compound of formula I according to any of the above. 15. The compound of formula I according to any one of claims 1 to 10, which is used for preventing cardiovascular disorders, reducing platelet adhesion, assisting weight loss after pregnancy, or assisting weight loss after smoking cessation. 16. A process for preparing a compound of Formula I as described herein.