HUP0800407A2 - Thieno [2,3-b] pyridine compounds as metalotropic glutamate receptor (mglur) ligands - Google Patents

Description

Subject matter of the invention

The invention relates to ligands of general formula (I) and/or salts and/or hydrates and/or solvates of the mGluR1 and mGluR5 receptor subtypes, processes for their preparation, pharmaceutical compositions containing the compounds, and the use of these compounds in the treatment and/or prevention of conditions requiring modification of the function of mGluR1 and/or mGluR5 receptors.

Description of the state of the art

International patent application WO 2007/072095 discloses ligands that preferentially target the mGluR1 and mGluR5 receptor subtypes, having the following formula:

r ₂ zf L / *

YR, where in the formula R _b R ₂ , X, Y and Z are as defined therein.

According to the description, these compounds may be useful for the prevention and/or treatment of pathological conditions requiring modulation of the function of mGluR1 and/or mGluR5 receptors, such as neurological, psychiatric disorders, acute and chronic pain, neuromuscular disorders of the lower urinary tract, and gastrointestinal disorders.

Patent application WO 2007 72095 does not disclose any further biological data on the compounds other than the binding affinity and functional activity for mGluR and mGluR5 receptors, and does not specify the specific value of binding to mGluR5 receptors for compounds with binding affinity less than 500 nM.

The binding affinity for the appropriate target receptors is a crucial and defining property of compounds. The higher the binding affinity for the target receptor, the lower the concentration of the active substance required to adequately modify the receptor functions during the treatment process. However, binding affinity alone does not ensure that the compound can be successfully used in therapy. In most diseases, the oral administrability of the drug compound is a basic requirement. Therefore, in vivo activity, especially oral activity, is a fundamental criterion for a future drug in terms of its medicinal properties and therapeutic applicability. Furthermore, in addition to oral efficacy and effectiveness, oral bioavailability is also an important property. Low oral bioavailability (<10%) can amplify individual differences in drug metabolism, which can lead to unwanted side effects and/or a decrease in efficacy.

In order to search for therapeutically useful drug molecules, the molecules described in international patent application WO 2007 72095 were screened for high mGluR5 binding affinity, in vivo efficacy following oral administration, and acceptable oral bioavailability.

Summary of the invention

The invention includes ligands of the general formula (I) that preferentially target the mGluR1 and mGluR5 receptor subtypes, wherein X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof (e.g. hydrates, solvates or pharmaceutically acceptable salts thereof or combinations thereof).

X

We have found that these compounds - surprisingly - have particularly advantageous properties for therapeutic use in the prevention and/or treatment of conditions requiring modification of the function of mGluR1 and mGluR5 receptors. For example, the compounds have favorable mGluR1 and mGluR5 receptor binding affinity (Ki value less than 10 nM), beneficial anxiolytic effects after oral administration in rats (minimum effective dose less than 10 mg/kg p.o.), and oral bioavailability in rodents exceeds 10.0%.

Other tested compounds (including close structural analogues) within the scope of patent application WO 2007 72095 do not satisfy these three criteria above.

The invention also provides processes for the preparation of the compound of formula (I).

The present invention also includes intermediate products formed during the production process.

The invention also provides pharmaceutical compositions comprising, as active ingredient, a therapeutically effective amount of at least one compound of formula (I) and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof (e.g. hydrates, solvates or pharmaceutically acceptable salts thereof or combinations thereof) together with a pharmaceutically acceptable diluent, excipient and/or inert carrier (or combinations thereof).

In the description, the term "at least one of a, b, or c" also includes combinations thereof, even if such combinations are not specifically mentioned.

The invention also relates to the use of compounds of general formula (I) for the prevention and/or treatment of mGluR5 receptor mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular disorders of the lower urinary tract and gastrointestinal disorders.

The invention also provides the use of compounds of formula (I) for the manufacture of a medicament for the prevention and/or treatment of mGluR5-mediated disorders, such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular disorders of the lower urinary tract and gastrointestinal disorders.

Detailed description of the invention

The invention includes ligands of general formula (I) that preferentially target the mGluR1 and mGluR5 receptor subtypes.

Where X is Cl or F and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof (e.g. hydrates, solvates or pharmaceutically acceptable salts thereof or combinations thereof).

When X is F, the name of the compound is:

- Amino-2-(3-cyano-5-fluorobenzosulfonyl)-3-(3-fluorophenyl)thieno[2,3-b]pyridine (Compound 1)

When X is Cl, the name of the compound is:

5-Amino-2-(3-cyano-5-fluorobenzosulfonyl)-3-(3-chlorophenyl)thieno[2,3-b]pyridine (Compound 2)

In our experiments, we found that a specific subgroup of molecules protected by international patent application WO 2007 72095 surprisingly have an exceptionally high binding affinity for the GluR5 receptor (Ki value less than 10 nM) and have a significant anxiolytic effect in rats after oral administration (minimum effective dose less than 10 mg/kg p.o.). Furthermore, the bioavailability of these compounds in rodents exceeds 10.0%.

Meeting this triple criterion provides a distinct advantage in terms of drug properties and therapeutic or prophylactic utility in conditions where modulation of mGluR1 and mGluR5 receptors is required.

The compounds of formula (I) may form salts with acids. The scope of the invention extends to the salts of the compounds of formula (I) with acids, especially to the salts with pharmaceutically acceptable acids. Unless otherwise specified, the name of the compound of formula (I) may refer to both the free base and the salt.

Both organic and inorganic acids can be used to form acid addition salts. Suitable inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Suitable monovalent organic acids include formic acid, acetic acid, propionic acid, various butyric acids, valeric acids, and hexanoic acids. Suitable divalent organic acids include oxalic acid, malonic acid, maleic acid, fumaric acid, and succinic acid. Other organic acids, such as hydroxy acids, such as citric acid, tartaric acid, or aromatic carboxylic acids, such as benzoic acid or salicylic acid, and aliphatic and aromatic sulfonic acids, such as methanesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid, can also be used. A particularly valuable group of acid addition salts are those in which the acid component itself is physiologically acceptable, has no therapeutic effect at the dose used, or has no adverse effect on the action of the active ingredient. These are pharmaceutically acceptable acid addition salts. Other acid addition salts within the scope of the present invention - which are not included in the pharmaceutically acceptable acid addition salts - may be advantageous in the isolation and purification of the desired compounds, if desired.

Solvates and/or hydrates of the compounds of formula (I) are also within the scope of the invention.

Pharmaceutical preparations

The scope of the invention also includes pharmaceutical compositions which contain as active ingredient a compound of general formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates together with one or more pharmaceutically acceptable carriers.

The compounds of formula (I) and/or their pharmaceutically acceptable salts and/or hydrates and/or solvates and pharmaceutical compositions thereof may be administered by any conventional route, such as orally, parenterally (including subcutaneous, intramuscular and intravenous routes), buccally, sublingually, nasally, rectally or transdermally. The pharmaceutical compositions are prepared according to the routes of administration.

The orally active compounds of formula (I) and/or their pharmaceutically acceptable salts and/or hydrates and/or solvates can be formulated in liquid or solid form. For example, syrups, suspensions or emulsions, tablets, capsules or lozenges can be prepared.

The compounds of formula (I) and/or their pharmaceutically acceptable salts and/or their hydrates and/or their solvates in the form of a liquid preparation generally comprise the compound of formula (I) and/or its pharmaceutically acceptable salts and/or its hydrates and/or its solvates in the form of a suspension or solution in a suitable liquid carrier or carriers. The carrier may be an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent such as polyethylene glycol or an oil. The composition may also contain a suspending agent, a preservative, a flavoring agent and a coloring agent.

The composition may be prepared in the form of a solid tablet using any suitable carrier conventionally used in the preparation of solid pharmaceutical preparations. Examples of solid carriers include lactose, suitable silicates, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Optionally, the tablet may be coated by standard aqueous or non-aqueous techniques.

The solid preparation in the form of a capsule may be prepared by any routinely used encapsulation process. For example, the active ingredient may be pelletized with a standard excipient and then filled into a hard gelatin capsule. Alternatively, the active ingredient may be dispersed or suspended in a suitable pharmaceutical excipient and then filled into a soft gelatin capsule. Suitable pharmaceutical excipients include, for example, water-dispersible gums, cellulose, silicates or oils.

Typical forms of parenteral preparations are solutions or suspensions containing the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates in sterile aqueous vehicles or parenterally acceptable oily vehicles, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. Alternatively, the solution may be lyophilized and reconstituted with a suitable solvent immediately prior to administration.

The formulations of the invention suitable for nasal administration comprise the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates in aerosol, drop, gel or powder form. The aerosol formulations of the invention typically comprise the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates in solution or finely divided suspension in a physiologically acceptable aqueous or non-aqueous solvent. The sterile aerosol may be in a closed container containing a single dose or multiple doses, in which dispensing or refilling is provided and is usually provided with a nebulizer. Alternatively, the closed container may also be suitable for dispensing unit doses; such as, for example, a single dose inhaler or an aerosol dispenser with a metering valve, which is disposable after the container is empty. If the dosage is solved with an aerosol dispenser, a propellant gas, e.g. compressed gas (e.g. compressed air) or organic propellant (e.g. chlorofluorocarbon) is used. The dosage of the aerosol can also be solved with a nebulizer pump.

The compositions of the invention comprising the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates are also suitable for buccal or sublingual administration, e.g. in the form of tablets, lozenges and pastilles; these contain the active ingredient formulated with a carrier such as sugar and gum arabic, gum tragacanth, or gelatin, glycerin, etc.

The compositions of the invention comprising the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates are also suitable for rectal administration. For rectal administration, suppositories are usually prepared which contain the active ingredient in a suppository base, for example cocoa butter or other known excipients. Suppositories are prepared in a conventional manner by mixing the components, then softening or melting the mixture and pouring the melt into a mold and cooling it.

The composition comprising the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates is also suitable for transdermal administration, for example in the form of an ointment, gel or patch.

The compositions of the invention comprising the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates are preferably presented in dosage unit form, such as tablets, capsules or ampoules.

The unit dosage form of the present invention for oral administration preferably contains 0.1 to 500 mg of the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates per unit, calculated as the free base.

The unit dose formulation for parenteral administration according to the present invention preferably contains 0.1 to 500 mg of the compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates, calculated as the free base.

The compound of formula (I) and/or its pharmaceutically acceptable salts and/or hydrates and/or solvates are administered to the patient in a physiologically acceptable form on a daily dosage regimen. Disorders mediated by mGluR1 and mGluR5 receptors, such as schizophrenia, anxiety, depression, panic disorder, bipolar disorder, circadian rhythm disorder, chronic and acute pain, can be treated by administering a daily dose ranging from about 0.01 mg/kg body weight to about 140 mg/kg body weight, or alternatively, a daily dose ranging from about 0.5 mg to about 7 g/patient/day.

The amount of active ingredient that is admixed with the carrier to constitute a single dose will vary depending on the recipient to be treated and the particular route of administration. For example, for oral administration in humans, the composition will conveniently contain from about 0.5 mg to about 5 g of active ingredient in admixture with a suitably selected carrier, the amount of which will constitute from about 5% to about 95% of the composition. Dosage units will generally contain from about 1 mg to about 1000 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

It will be apparent to those skilled in the art that the desired dosage level for a given patient will depend on a number of factors, including the patient's age, weight, general health, sex and diet, time and route of administration, metabolic rate, concomitant medications, and the severity of the disease being treated.

Medical application

The compounds of general formula (I) and/or their pharmaceutically acceptable salts and/or hydrates and/or solvates exert biological activity at mGluR1 and mGluR5 receptors and are therefore expected to be useful in the treatment and/or prevention of diseases mediated by mGluR1 and mGluR5 receptors.

It has been found that the compounds of formula (I) and/or their salts bind with high potency and selectivity to the mGluR1 and mGluR5 receptors. In particular, the compounds of the invention are particularly potent ligands (Ki<10 nM) for the mGluR5 receptors. Consequently, the compounds are expected to be useful in the treatment and/or prevention of conditions associated with excitatory activation of the mGluR1 and mGluR5 receptors. The compounds are useful in the inhibition of the mGluR1 and mGluR5 receptors in mammals, including humans.

Furthermore, the compounds of the invention have shown favorable oral bioavailability (>10.0%) and effective in vivo activity (MED<10 mg/kg p.o.) in animal tests. Based on this, the compounds of the invention are particularly suitable for oral administration in conditions associated with modulation of mGluR1 and mGluR5 receptors.

Thus, the compounds of formula (I) and/or their salts according to the invention are expected to be very useful for the treatment and/or prevention of diseases mediated by mGluR1 and mGluR5 receptors, such as acute and chronic neurological and psychiatric diseases, chronic and acute pain, neuromuscular disorders of the lower urinary tract and gastrointestinal diseases.

The required dosage for therapeutic or prophylactic treatment will vary depending on the patient being treated and the route of administration.

The invention also relates to the therapeutic use of the compounds of general formula (I) as defined above.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of diseases mediated by mGluR1 and mGluR5 receptors.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of neurological diseases.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of psychiatric diseases.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of chronic and acute pain.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of neuromuscular disorders of the lower urinary tract and gastrointestinal diseases.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of migraine pain, inflammatory pain, neuropathic pain diseases such as diabetic neuropathy, arthritis and rheumatic diseases, low back pain, postoperative pain and pain associated with various other conditions (including angina), renal or biliary spasm, menstruation, migraine and gout.

The invention relates to the use of the compounds of general formula (I) as defined above for the treatment and/or prevention of Alzheimer's disease, senile dementia, AIDS-induced dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's chorea, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive-compulsive disorder, attention deficit hyperactivity disorder, drug abuse and drug addiction, ophthalmic diseases such as retinopathy, diabetic retinopathy, glaucoma, auditory neuropathic diseases such as tinnitus, chemotherapy-induced neuropathies, post-herpetic neuralgia and trigeminal neuralgia, fragile X syndrome, autism, mental retardation and Down's disease.

The invention relates to the use of compounds of general formula (I) as defined above for the treatment and/or prevention of stroke, traumatic brain injury, anoxia and ischemic injuries, hypoglycemia, cardiovascular diseases and epilepsy.

The compounds of general formula (I) defined above are suitable for the treatment and/or prevention of lower urinary tract dysfunctions, such as urgency, overactive bladder, frequent urination, reduced bladder capacity, cystitis, incontinence, bedwetting and painful urination.

Furthermore, one or all of the compounds of formula (I) may be useful for the treatment and/or prevention of gastrointestinal diseases such as transient lower esophageal sphincter dysfunction, gastrointestinal reflux disease and irritable bowel syndrome.

The invention also provides the use of the compounds of general formula (I) as defined above in the manufacture of pharmaceutical compositions for the treatment and/or prevention of diseases mediated by mGluR1 and mGluR5 receptors or any other disease listed above.

The invention relates to a method for the treatment and/or prevention of diseases mediated by mGluR1 and mGluR5 receptors or any of the other diseases listed above, comprising administering to patients suffering from or at risk of such diseases an effective amount of a pharmaceutical composition comprising a compound of formula (I) as defined above.

In the text of the description, the term "approximately" is intended to indicate the magnitude of the experimental error associated with the given measurement.

The term "disorder" - unless otherwise specified - refers to all conditions and diseases associated with metabotropic glutamate receptor activity.

Production processes

The invention also relates to a process for preparing compounds of general formula (I).

Where X is Cl or F and/or their hydrates and/or their solvates and/or their pharmaceutically acceptable salts. The preparation of compounds of general formula (I) is shown in the reaction scheme below.

Reaction scheme: Br CN i — ^s ° ² —\ / ^a II p o ^r (ID Br CN H ₂ N .---( Intermediate (II) Br CN /---( XXVyso ₂ -XX b X ^s X 0 ^F Intermediate (I) Xv X \ J CN ^N^^X .-( /—$θ ² —\ / F (I)

a.) aqueous HNOj-acetic acid, 100-130 °C, 4-6 h;

b.) Fe powder-acetic acid, 60-70 °C, 1 h;

c.) 3-C1 or 3-F -phenylboronic acid, toluene-ethanol / 2M NaCOa aqueous solution, boiling, lh.

In one embodiment of the invention, the compound of formula (I) can be prepared from the compound of formula (II) by nitration followed by reduction and Suzuki coupling.

In one embodiment of the invention, the salts and/or hydrates and/or solvates of the compound of general formula (I) can be prepared by selectively nitrating the intermediate (I) from the corresponding N-oxide of formula (II) (WO 2007 72095) in aqueous nitric acid-acetic acid.

The reaction takes place at a temperature between 100-130°C according to the method of Klemm, L.H. (J. Heterocycl. Chern., 7,1970, 81).

Intermediate (II) is selectively reduced in the presence of a combination of iron and an acid (HCl or preferably acetic acid) according to the method described in Org. Synth. Coll., 5, 346, 1973.

Compounds of formula (I) can be prepared by the well-known Suzuki coupling reaction using a suitable boronic acid and a palladium catalyst, as described, for example, in Suzuki & H.C. Brown: Organic Syntheses via Boranes Vol. 1-3.

Biological test methods

MGluRS receptor binding site affinity assay

Binding to the mGluR5 receptor was investigated using a modified version of the method of Gasparini et al. (Biorg. Med. Chem. Lett. 2000, 12: 407-409). Based on the high homology between human and rat mGluR5 receptors, rat cerebral cortex preparations were used to determine the binding properties of the reference compound and the new compounds. The binding of the compounds to the human mGluR5 receptor was examined using the A18 cell line, obtained from Euroscreen, expressing hmGluR5a, using [ ³ H]-M-MPEP (2 nM) as the radioligand. Non-specific binding was determined in the presence of 10 μΜ M-MPEP.

Measurement of anxiolytic activity (Vogel test)

The method described by Vogel et al. (Psychopharmacology (Berl.) 1971, 21:1-7) was used with some modifications.

On the day before the test, male Wistar rats (180-220 g) are placed in a measuring box with a metal grid at the bottom and a metal tube extending from the wall into the inside of the box. On the day before the measurement, the animals are placed in this measuring box for 5 minutes, so that they can drink freely (they do not receive an electric shock). After the adaptation period, the animals are deprived of water for 24 hours, so that they cannot access drinking water even when returned to their so-called living cages.

On the measurement day, the animals are returned to the measuring box and can only drink under this punishment condition after receiving an electric shock after every 10 licks. During the measurement time (270 sec), they can only drink under this punishment condition. The number of licks and the number of electric shocks endured are also registered by the measuring machine. The increased number of electric shocks endured can be used to conclude that the tested compound has an anxiolytic effect.

Determination of oral bioavailability

Oral bioavailability was measured in overnight fasted male Wistar rats (200220 g, n=4).

The compounds were freshly formulated as intravenous microemulsions and oral suspensions.

The compounds were administered intravenously at a dose of 3 mg/kg in a volume of 2.5 ml/kg via the tail vein. Blood samples (~1 ml) were collected from the retroorbital vein at 083, 0.333, 1.0, 5.0 hours after administration.

The compounds were administered orally to rats at a dose of 10 mg/kg in a volume of 5 ml/kg by gavage. Blood samples were collected from the retroorbital vein (~1 ml) at 04, 1.0, 2.0; 5.0 hours after administration.

Plasma samples were obtained by immediate centrifugation of blood samples, which were stored at -20°C until HPLC-UV analysis.

Plasma samples were extracted with chlorobutane and analyzed on a 150x4.6mm, 5pm, Zorbax Eclipse XDB-C18 column (Agilent) using a binary mobile phase gradient eluent consisting of 0.1 M ammonium acetate and acetonitrile. The analysis was performed at 40°C. The column eluent was monitored at 245nm (compound 2) and 250nm (compound 1).

Pharmacokinetic parameters (AUC, Cmax, tmax) were calculated using non-compartmental analysis using Kinetica Version 4.4.1 Program.

Absolute oral bioavailability was calculated as AUC _ora i/AUC j _v · Dose _i / Dose _ora i .

Results

Test Compound 1 Compound 2 rat mGluR5 binding, Ki (nM) 1.9 7.2 human mGluR5a binding, Ki (nM) 3.2 8.7 Vogel test, MED (mg/kg) 3 5 Oral bioavailability (%) 10.2 13.4

Compounds 1 and 2 bind with high affinity to human and rat mGluR5 receptors.

After oral administration, the compounds showed significant anxiolytic activity and their oral bioavailability exceeded 10.0%. These pharmacological characteristics represent a distinct advantage in terms of the medicinal properties and therapeutic applicability of the molecules.

This makes compounds 1 and 2 particularly useful for orally treating conditions requiring modulation of mGluR1 and mGluR5 receptors.

The invention is illustrated by the following examples without limiting our claim thereto.

Examples

I. Intermediate

3-Bromo-2-(3-cyano-5-fluorobenzosulfonyl)-5-nitrothieno[2,3-b]pyridine-N-oxide

7.97 g, (19.3 mmol) of 3-bromo-2-(3-cyano-5-fluorobenzosulfonyl)-thieno[2,3-b]pyridine-Noxide (prepared according to the patent specification WO 2007 72095) was boiled in a mixture of 1.22 ml of 66% nitric acid with 25 ml of acetic acid at 120°C for 4 hours.

The reaction mixture was evaporated and the residue was purified by column chromatography (Kieselgel 60, chloroform:methanol = 5:0.1).

First the starting material was isolated (3.7 g, 47%), then the yellow product was treated with 5 ml of ether. After filtration, 0.72 g (8.3%) of the title compound was obtained LC-MS: (M+H) ⁺ 459.1.

2. Intermediary

5-Amino-3-bromo-2-(3-cyano-5-fluorobenzosulfonyl)-thieno[2,3-b]pyridine

1.0 g (2.18 mmol) of 3-bromo-2-(3-cyano-5-fluorobenzosulfonyl)-5-nitrothieno[2,3-b]pyridine-N-oxide is suspended in 12 ml of acetic acid and 0.73 g (13 mmol) of iron powder is added. The reaction mixture is stirred at 60-70 °C for 60 minutes. 45 ml of chloroform is added, filtered through celite, then the filtrate is evaporated, the crude residue is treated with 3 ml of methanol. The product is filtered and washed with methanol.

0.69 g (76.7%) of the title product was obtained as a yellow powder. LC-MS: (M+H) ⁺ 413.1

Example 1

5-Amino-2-(3-cyano-5-fluoro-benzosulfonyl)-3-(3-fluorophenyl)-thieno[2,3-b]-pyridine

1.2 g (29 mmol) of 5-amino-3-bromo-2-(3-cyano-5-fluorobenzosulfonyl)thieno[2,3b]pyridine was dissolved in a mixture of 16 ml of toluene and 18 ml of ethanol under an argon atmosphere.

To the solution were added 157 mg (0.15 mmol) of Pd(PPh3)4, 0.50 g (35.8 mmol) of 3-fluorophenylboronic acid and 14 ml of 2M Na ₂ COj solution.

The reaction mixture was boiled for 1 hour, filtered through celite and washed with toluene. The filtrate was concentrated in vacuo and 13 ml of water and 13 ml of ethyl acetate were added to the residue.

The phases were separated, the aqueous phase was extracted with 2x5 ml ethyl acetate. The organic phase was washed with 5.0 ml water, dried over Na ₂ SO 4 , filtered and evaporated in vacuo.

The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane=2:1) to give 0.94 g (76%) of the title product. The crude product was stirred with methanol to give a yellow powder.

LC-MS: (M+H) ⁺ 428.2.

*H NMR (500 MHz, DMSO-17 ₆ , 25 °C): 5.67 (s, 2H); 6.81 (d, J= 2.6 Hz, 1H); 7.00-7.07 (m, 2H); 7.35-7.43 (m, 1H); 7.50-7.60 (m, 2H); 7.60-7.64 (m, 1H); 8.20-8.25 (m, 1H); 8.27 (d, J = 2.6 Hz, 1H).

Example 2

5-Amino-2-(3-cyano-5-fluoro-benzosulfonyl)-3-(3-chlorophenyl)-thieno[2,3-b]-pyridine

1.25 g (30 mmol) of 5-Amino-3-bromo-2-(3-cyano-5-fluorobenzosulfonyl)-thieno[2,3b]pyridine was dissolved in a mixture of 18 ml of toluene and 20 ml of ethanol under an argon atmosphere.

To the solution were added 157 mg (0.15 mmol) of Pd(PPh3)4, 0.58 g (37 mmol) of 3chlorophenylboronic acid and 15 ml of 2M Na ₂ CO 3 solution.

The reaction mixture was boiled for 1 hour, filtered through celite and washed with 2 x 5 ml of toluene. The filtrate was evaporated in vacuo and 13 ml of water and 13 ml of ethyl acetate were added to the residue.

The phases were separated, the aqueous phase was extracted with 2x5 ml ethyl acetate. The organic phase was washed with 5.0 ml water, dried over Na2SO4, filtered and evaporated in vacuo.

The crude product was purified by column chromatography (Kieselgel 60, ethyl acetate:hexane = 2:1) and then stirred with 5 ml of methanol to give 0.84 g (63%) of the title product as a yellow powder.

LC-MS: (M+H) ⁺ 444.2.

1H NMR (400 MHz, DMSO-1/ö, 25 °C): 5.68 (s, 2H); 6.80 (d, J= 2.6 Hz, 1H); 7.13-7.22 (m, 2H); 7.53 (t, J = 7.9 Hz, 1H); 7.56-7.65 (m, 3H); 8.24 (dm, J= 8.4 Hz, 1H); 8.27 (d, J = 2.6 Hz, 1H).

’H NMR spectra were obtained on a Varian V-500 or Varian V-400 spectrometer. Chemical shift values are given in ppm relative to TMS internal standard.

Example 3

Production of medicinal products

a) Tablets:

0.01-50% of the active ingredient of general formula (I), 15-50% lactose, 15-50% potato starch, 5-15% polyvinylpyrrolidone, 1-5% starch, 0.01-3% magnesium stearate, 1-3% colloidal silicon dioxide and 2-7% ultraamylopectin are mixed together, then granulated by wet granulation and compressed into tablets.

b) Dragees, film-coated tablets:

The tablets prepared by the method described above are coated with an enteric or gastro-soluble film, or a layer gel containing sugar and a dusting powder. The dragees are coated with a glaze consisting of a mixture of beeswax and camu wax.

c) Capsules:

0.01-50% of the active ingredient of general formula (I), 1-5% sodium lauryl sulfate, 15-50% starch, 15-50% lactose, 1-3% colloidal silicon dioxide and 0.01-3 magnesium stearate are thoroughly mixed, the resulting mixture is pressed through a sieve and filled into hard gelatin capsules.

d) Suspensions:

Ingredients: 0.01-15% active ingredient of general formula (I), 0.1-2% sodium hydroxide, 0.1-3% citric acid, 0.05-0.2% nipagin (sodium methyl-(4-hydroxybenzoate), 0.005-0.02% nipazole, 0.01-0.5% carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0.1-1% flavoring, 2070% sorbitol (70% aqueous solution) and 30-50% distilled water.

To a solution of nipagin and citric acid in 20 ml of distilled water, carbopol is added in small portions, while stirring vigorously, the resulting solution is set aside and left to stand for 10-12 hours. After that, sodium hydroxide in 1 ml of distilled water, an aqueous solution of sorbitol and finally the ethanolic raspberry flavoring are added while stirring vigorously. The active ingredient is added to this carrier in small portions and suspended using an immersion homogenizer. Finally, the suspension is made up to the desired final volume with distilled water and the suspension syrup is converted to its final distribution using a colloid mill.

e) Cones:

0.01-15% of the active ingredient of general formula (I) and 20% lactose are mixed vigorously, then this mixture is added to 50-95% of a fat suitable for making suppositories (e.g. Witepsol 4) melted and then cooled to 35 °C. The resulting mixture is homogenized and poured into cooled molds.

f) Lyophilized powder ampoule preparations:

A 5% solution of mannitol or lactose is prepared with double-distilled water for injection and the solution is filtered to obtain a sterile solution. A 0.01-5% sterile solution of the active ingredient of general formula (I) is prepared in the same way. The two solutions are mixed under aseptic conditions and filled into ampoules in 1 ml portions, the contents of the ampoules are lyophilized and the ampoules are sealed under nitrogen. The contents of the ampoules are dissolved in sterile water or sterile physiological saline (0.9% saline) immediately before administration.

Claims (16)

Requirements: 1. The compounds of general formula (I): where X is Cl or F or hydrates, solvates and salts thereof. 2. Compounds of general formula (I) selected from the following: 5-Amino-2-(3-cyano-5-fluorobenzosulfonyl)-3-(3-fluorophenyl)-thieno[2,3-b]-pyridine, 5-Amino-2-(3-cyano-5-fluorobenzosulfonyl)-3-(3-chlorophenyl)-thieno[2,3-b]-pyridine. 3. Process for the preparation of compounds of general formula (I): where X is Cl or F or their hydrates, solvates and salts, characterized in that the compound of general formula (II) is first nitrated and then is reduced, followed by Suzuki coupling, which gives compounds of general formula (I). If desired, salts, hydrates, and solvates of the compounds of formula (I) can be prepared. 4. The process according to claim 3, characterized in that the intermediate I is formed during the nitration: Intermediate I During the reduction, intermediate I is converted to intermediate II: Intermediate II During the Suzuki coupling, compounds of general formula (I) are formed from intermediate II. 5. Pharmaceutical compositions comprising a therapeutically effective amount of the compounds of general formula (I): X wherein X is Cl or F or hydrates, solvates thereof, combinations thereof with at least one pharmaceutically acceptable diluent, excipient or inert carrier. 6. Use of compounds of general formula (I) for the treatment and/or prevention of mGluR1 and mGluR5 receptor-mediated disorders, characterized in that a pharmaceutical composition according to claim 5 is administered to a mammal in need of treatment. 7. Use according to claim 6, characterized in that the disorder mediated by the mGluR1 and mGluR5 receptors is a psychiatric disease. 8. Use according to claim 6, characterized in that the disorder mediated by the mGluR1 and mGluR5 receptors is a neurological disease. 9. Use according to claim 6, characterized in that the disorder mediated by the mGluR1 and mGluR5 receptors is chronic or acute pain. 10. The use according to claim 6, characterized in that the disorder mediated by the mGluR1 and mGluR5 receptor is a neuromuscular disorder of the lower urinary tract or a gastrointestinal disease. 11. Use of compounds of general formula (I) for the prevention and/or treatment of disorders mediated by mGluR1 and mGluR5 receptors, characterized in that a therapeutically effective amount of the compound of general formula (I) is administered to a mammal in need of such prevention and/or treatment: X (I) wherein X is Cl or F or hydrates, solvates, pharmaceutically acceptable salts thereof or combinations thereof. 12. The use according to claim 11, wherein said mammal is a human. 13. The use according to claim 11, wherein the disorder mediated by mGluR1 and mGluR5 receptors is a psychiatric disease. 14. The use according to claim 11, wherein the disorder mediated by mGluR1 and mGluR5 receptors is a neurological disease. 15. The use according to claim 11, wherein the disorder mediated by mGluR1 and mGluR5 receptors is chronic or acute pain. 16. The use according to claim 11, wherein the disorder mediated by mGluR1 and mGluR5 receptors is a neuromuscular disorder of the lower urinary tract or a gastrointestinal disease.