MXPA96004023A - Heterociclic compounds, its preparation and its - Google Patents

Abstract

The present invention relates to therapeutically active heterocyclic compounds, to a method for preparing them and to pharmaceutical compositions comprising the compounds. The new compounds are useful for the treatment of diseases of the central nervous system related to the metabotropic glutamate receptor system

Description

HETEROCICOS COMPOUNDS. PREPARATION AND USE THEREOF DESCRIPTION OF THE INVENTION The present invention relates to thieno [2, 3-b] active therapeutic compounds, to a method for preparing them, to pharmaceutical compositions comprising the compounds and c. a method of treatment with them. Recent molecular biological studies have clearly established the existence of two main types of glutamate receptors in the nervous system. central. mainly the ionotropic receptors and metabotropic glutamate. The latter is characterized by being linked to the G protein for changes in the formation of the second messenger and the modulation of the ion channel (Meldrum, B (1991) Epilepsy Res. 10. 55-61 Chapman A. (1991) in Excitatory Amino Acids pp. 265-286, Blackwell scientific publ. Ltd .. Oxford). To date, 6 different subtypes of mbtabotropic glutamate receptors have been described (MGluR, MGluRo,) and. In addition, some spliced variants of the subtypes have been reported. Subtypes of glutamate receptors metabotropy MGluR ,. and MGluR- ,. are coupled to the hydrolysis of phosphoinositide (Johnson, G. and Bigge, C.F. (1991) Annu. Rep. Med. Chem. 26 ,. 11-22. Hansen, J.J. and KrogsgaardLarsen. P. Med. Res. Rßv. 10.55-94. Thomsen. C. REF: 23102 and Suzdak. P. (1993) Eur. J. Pharmacol. 245,299), while the others are coupled to cyclic AMP formation (Schoepp, DD Johnson, BG and Monn JA (1992) J. Neurochem 58. 11184-1186 Cartmell et al. (1992) J. Neurochem 58. 1964-1966, Manzoni, 0. et al. (1992) Eur. J. Pharmacol. 225. 357-358). It is known that compounds such as L-glutamate. quisqualate and ibotenate act as non-selective agonists on metabotropic glutamate receptors. whereas selective agonists of ionotropic glutamate receptors such as NMDA, AMPA and kainate have little effect on these receptors. Recently few compounds have been identified without activity in the ionotropic glutamate receptors. but with activity in metabotropic receptors. These comprise the trans-ACPD (trans acid 1S.3R-1-aminocyclopentane-1,3-dicarboxylic acid), the partial agonist L-AP3 (L-2-amino-3-phosphonopropionic acid) (Palmer. Monaghan, DT and Cotman, C. (1989) Eur. J. Pharmacol., 166, 585-587, Desai, MA and Conn. PJ (1990) Neurosci.Lett., 109.157-162, Schoepp, DD et al. (1991). ), J Neurochem 56. 1789-1796, Schoepp DD and Johnson BG (1989), J. Neurochem 53. 1865-1613). L-AP4 (L-2 amino-4-phosphonobutyrate) which is an agonist of the MGluR4 receptor (Thomsen C. et al. (1992), Eur. J. Pharmacol. 227, 361-362) and some of the CCG isomers (2- (carboxycyclopropyl) glycines) especially L-CCG-I and L-CCG-II (Hayashi, Y. et al., (1992) .Br. J. Pharmacol. 539-543). Very few selective agonists have been reported in metabotropic glutamate receptors; however, some derivatives of feni lgl icina S-CPG (S-4-carboxyphenylglycine). S-4C3HPG (S-4-carboxy-3-hydroxypheni-1 glycine) and S-MCPG (S-alpha-methyl-1-4-carboxyphenyl glycine) have been reported to antagonize phosphoinositide hydrolysis stimulated by ACPD and trans. in this way, they possibly act as antagonists of the metabotropic glutamate receptors on MGluR subtypes. and MGluRg (Thomsen, C. and Suzdak, P, (1993) Eur. J. Pharmacol, 245. 299). Evidence in scientific literature suggests that selective compounds for metabotropic glutamate receptors. either agonists or antagonists. They are useful in the treatment of different neurological diseases. The use of active compounds in the glutamate receptors mßtabotrópisos for the treatment of epilepsy, is corroborated by research on the influence of trans-ACPD in the formation of seizures (Sacaan and Schoepp, (1992) Neurosci. Lett. 139. 77) and that phosphoinositide hydrolysis mediated by MGluR is increased after induction experiments in rats (Akiyama et al. (1992), Brain Res. 569. 71). It has been shown that trans-ACPD increases the release of dopamine in the brain of rats. which indicates that the compounds that act on the metabotropic glutamate receptors. they can be used for the treatment of Parkinson's disease. and from Huntington's Korea (Sacaan et al. (1992), J. Neurochem 59. 245). The use of active compounds in metabotropic glutamate receptors for the treatment of neurological diseases such as senile dementia, has been indicated by the findings of Zheng and Gallagher ((1992), Neuron 9, 163) and Bashir et al. ((1993), Nature 363, 347), who demonstrated that the activation of metabotropic glutamate receptors is necessary for the induction of long-term potentiation (PLP) in nerve cells (sßptal nuclßus, hippocampus) and also that depression is induced long-term after the activation of metabotropic glutamate receptors in cerebrospinal granule cells (Linden et al. (1991), Neuron 7, 81).

Research also shows that the active compounds on metabotropic glutamate receptors can be useful in the treatment of mental and motor performance deficiencies observed after cerebral ischemia conditions. Trans-ACPD has been shown to be a neuroprotective agent in an MCAO model in mice (Chiamulera et al (1992), Eur. J. Pharmacol, 215, 353), and has been shown to inhibit NMDA-induced neurotoxicity. in nerve cell cultures (Koh et al. (1991), Proc. Nati Acad. Sei, USA 88. 9431). Also, in the treatment of pain. active compounds on metabotropic glutamate receptors appear to be of interest. This is confirmed by the fact that antagonists of metabotropic glutamate receptors antagonize the synaptic sensory response to noxious stimuli of thalamic neurons (Eaton, S. A. et al. (1993), Eur, J. Neurosci, 5. 186). The above results support the concept that the compounds acting on the metabotropic glutamate receptors are useful for the treatment of epilepsy, of neurological diseases such as senile dementia, Parkinson's disease, Huntington's disease. pain and impaired mental and motor performance observed after cerebral ischemia conditions. A number of new drugs have now been discovered [2.3-b] which are potent antagonists of metabotropic glutamate receptors. The present invention relates to compounds of formula I. wherein 1 R is H. an alkyl radical of 1 to 6 carbon atoms optionally substituted with halogen, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms. cycloalkyl of 3 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms, carboxy. -COR 9. -COOR9, alkyl of 1 to 4 carbon atoms substituted with dimethylamino, -R 9 -O-R110. -R9-O-R10-O-R11, phenylsulfonyl, bezoyl. benzyl or phenyl. each of the aromatic groups being optionally substituted with an alkyl radical of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms. halogen, carboxy or nitro, wherein R 9, R 10 and R 11, each independently, are an alkyl radical of 1 to 6 carbon atoms; 2 R is H, a carboxy radical, cyano. nitro, alkyl of 1 to 6 carbon atoms optionally substituted with hydroxy, -R 9 -O-R 10, -COOR 9, morpholcarbonyl lo. tiomorfol inocarboni lo. piperazine lcarboni optionally substituted with an alkyl radical of 1 to 4 carbon atoms, tetrazolyl. oxadiazolyl or thiadiazolyl optionally substituted with an alkyl radical of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, morpholinomethyl. unsubstituted or monosubstituted or disubstituted amino with an alkyl radical of 1 to 6 carbon atoms, unsubstituted or N-monosubstituted or disubstituted methylamino with an alkyl radical of 6 carbon atoms, sulfamoyl unsubstituted or monosubstituted or disubstituted with a radical C 1-6 alkyl or unsubstituted or monosubstituted carbamoyl or disubstituted carbamoyl with an alkyl radical of 1 to 6 carbon atoms, the alkyl group or groups being independently each. optionally substituted with dimethyl laminomethyl lo. halogen, phenyl or benzyl; 3 R is H, an alkyl radical of 1 to 6 carbon atoms, trifluoromethyl, trifluoroacetylo. C 1 -C 6 -alkoxy, halogen, nitro, cyano, -COOR or amino unsubstituted or monosubstituted or disubstituted with an alkyl radical of 1 to 6 carbon atoms; R, R, R and R, each independently, are H, a nitro, amino radical. halogen, tritium. trifluoromethyl. trif luoroaceti lo. sulfo carboxy, carbamoyl. sulfamoyl, -COR 9. -COOR9. alkoxy of 1 to 6 carbon atoms. alkyl of 1 to 6 carbon atoms optionally substituted with halogen; or a sai thereof with a pharmaceutically acceptable acid or base. The terms alkyl, alkenyl and alkynyl herein mean straight or branched chain alkyl, alkenyl or alkynyl radicals. These salts include pharmaceutically acceptable acid addition salts. pharmaceutically acceptable metal salts or optionally salts of alkylated ammonium; such as hydrochloric acid. Bromhydric, Yodhidric, Phosphoric, Sulfuric. luoroacetic trif. trichloroacetic, oxalic, maleic. pyruvic. malonic, succinic, citric, mandélico. benzoic, cinnamic, methanesulfonic, ethansulonic, plastic and the like, including acids related to the pharmaceutically acceptable salts listed in the journal 0f Pharmaceutica l Science, 66. 2 (1977). which is incorporated herein by reference; or lithium. sodium, potassium, magnesium, and the like. The present invention also relates to a method for preparing the aforementioned compounds. These methods comprise, a) reacting a compound of formula II prepared by known methods, wherein R. R. R. R and 7 R are as previously defined, with an N.N-dimethylamide, preferably formamide, and P0C1-. using the Vilsmeyer-Hack conditions, to form a compound to formula III (III) - 10 - wherein R is H or a methyl radical and R, R, R, R and R are as previously defined; and subsequently, b) reacting a compound of the formula 1 f? 7 ft III where R, R. R. R. R and R are as defined above, with methyl mercaptoacetate, to form a compound of formula IV where R 1. R4, R5, Rfi. R7 and R8 are as previously defined; and subsequently. c) reacting a compound of the formula 1? fi 7 ft IV where R. R, R, R, R and R are as previously defined, by means of known chemical reactions, transforming the methyl ester group to other functional groups such as acids, esters, amides, amines or reaction products thereof, such as 2 describes for the substituent R. to form a compound 1 7 * 5 fi 7 to the formula I wherein R, R. R. R. R and R are as 3 as defined above, and R is H or a methyl radical; or d) reacting a compound of the formula 1 7"4 *? Fi 7 where R is H and R" R, R, R and R are like the 1 1 previously defined, with R -Y where R is like the one defined above and Y is a group such as a halogen or sulfonate, using strong bases such as for example metal hydrides, to form a compound of the 1 n A c £ * 7 formula I wherein R.R.R.R.R.R and R are as those previously defined, as long as R is not H; e) reacting a compound of the formula III (III) wherein R1 is H and R4, R5, R6. R7 and R8 are as defined above, with a compound RY, where Y is a leaving group such as, for example, a halogen or sulfonate. using a strong base such as for example metal hydrides, to form a compound of formula III, wherein R 1, R 4, R 5. R6, R7 and R8 are like the 1 previously defined, provided that R is not H; or f) reacting a compound of the formula I wherein R 1. R2. and R3 are as previously defined, and at least one of R. R, R and R is H. with known reactive substrates leading to aromatic substitution, using reaction conditions known in the art, to form a compound of formula I wherein R, R. R. and R are as previously defined, as long as at least one of R. R. R or R is not H; or g) a compound of the formula I with different R groups could be prepared. R. R and R using conventional organic chemistry methods on functional groups already introduced as R, R groups. R, and R. The pharmacological properties of the compounds according to the present invention can be illustrated by determining their effects in different conventional radioligand binding assays or in functional tests n vi tro.

The compounds according to the present invention were studied in an in vitro assay to measure the inhibition of PI hydrolysis in BHK570 cells expressing mGluR.a receptors. Background The metabotropic glutamate receptor (mGluR) is selectively activated by trans-aminocyclopentane dicarboxylic acid and is coupled to the hydrolysis of inositol phosphate via a GTP-binding protein. At the molecular level, DNAs encoding six subtypes of the mGluR family have been isolated. The first isolated subtype (Houamed et al .. 1991. Science 252. 1318), termed mGluRla. it has been shown to bind to the hydrolysis of inositol phosphate (Pl) when expressed in lactating hamster kidney (BHK) cells (Thomsen et al., Brain Res. (In press)). In these cells no stimulation was observed by 1 mM quisqualate or glutamate with control BHK cells, while a 6 to 8 fold increase was observed over the hydrolysis of basal Pl with BHK cells expressing mGluRla. Cell culture BHK570 cells expressing mGluRla are cultured in DMEM medium (4.5 g / l glucose, 2 mM glutamine) 5% fetal calf serum; 0.10 mg / ml of neo icine: 0.5 mg / ml of G418; 1 mM methotrexate; 50 ug / ml gentamicin. Cells are subcultured every 5 days using 0.05% trypsin / eti lendiaminotetraacetic acid (EDTA) in phosphate buffer (SRF). Formation of inoßitol phosphate The protocol for the hydrolysis of Pl was measured using a modification of a previously described method (Berridge et al., 1982, Biochem J. 206.587). Cells were cultured in 16 mm wells (24-well ultiplate, Costar) with 1 confluent 100-mm multiplak plate. The medium is replaced 24 h before the experiment with 500 ul of fresh growth medium 3 containing 4 uCi / ml of myo- [2 H] inositol (Activity specifies 18 ci / mmol, Amersham). The cells were washed twice with Krebs-Henseleit buffer (Sigma Catalog No. 3753: glucose 2.0 g / 1, MgSO 0.141 g / 1, KHPO4 0.16 g / 1, KC1 0.35 g / 1, NaCl 6.90 g / 1. and NaHC03 2.1 g / 1) supplemented with 10 mM LiCl and 2.5 mM CaCl. The buffer solution was equilibrated with 5% C02, 95% air at pH 7.5 at 37'C. After 5 min of preincubation in the above buffer, regulatory solution or test compounds were added and the cells were incubated for 30 min at 37 ° C. In antagonistic studies, the test compounds are added 5 min before the agonist stimulation. The formation of Pl was stopped by placing the cells on ice and rapidly sucking the medium. The wells were washed once with Krebs-Henseleit buffer solution cooled in ice and subsequently 1 ml of 10% perchloric acid cooled in ice was added to each well. The cells are placed on ice for 20 min. In Nunc minisorp test tubes (75 x 12 mm Catalog No. 443990): 250 ul of 10 mM EDTA is added. pH 7.0 + 5% universal indicator (Merck). The PCA extract is transferred to each tube containing the pH indicator. The samples are neutralized with 1.5 M KOH + 60 mM HEPES at pH 7.5 (approximately 1100-1200 ul). Centrifuge (6,000 rpm, 5 min, 0 * C). Samples can be stored by freezing at this stage. Phosphate fractions of inositol were separated using ion exchange columns (Amersham, RPN 1908) according to the method provided by Amersham. Separation of inositol phosphates in ion exchange columns Columns are prepared with 5 ml of 1 M KHC03 and washed with 15 ml of distilled water. A vacuum is adjusted so that the flow rate does not exceed 5 ml / min. 4 ml of distilled water and subsequently 1 ml of sample [H] InsP are added. It is washed with 5 ml of distilled water, fractions PI1 to PI4 can be collected with 5 ml of KHCO "0.05; 0.10; 0.17 and 0.25 M, respectively. Normally PI1 and PI2 fractions are collected simultaneously. Scintillation fluid: 12-15 ml of Ultima Gold (Packard) are used. Test procedure The test compounds are dissolved in dimethyl sulfoxide iDMSO), in DMSO and Pluronic F-127 or ethanol, and diluted in the assay buffer.

Glutamate (10 μM and 1000 μM) and buffer solution alone were included as control. Results Stimulation with 10mG glutamate should represent a submaximal stimulation. The response caused by 10 uM glutamate should exceed 3 times the basal level and should be below the maximum stimulation (1 mM glutamate). The results were calculated in relation to the stimulation caused by 10 uM glutamate and a dose-response curve was generated. Table 1 shows examples of the results obtained in the tests when testing some compounds of the present invention in the aforementioned test.

Table 1 Compound No. Cl 50 (tíM) 27 5.3 8 21.0 54 7.2 31 36.0 25 9.0 The compounds according to the present invention are effective in a wide range of doses. For example, in the treatment of human adults, doses of about 0.05 to about 100 mg, preferably about 0.1 to about 100 mg per day, may be used. A more preferable dose is from about 10 to about 70 mg per day. When selecting the regimen for patients suffering from a central nervous system disease related to the metabotropic glutamate receptor system. it may often be necessary to start with a dose of about 30 to about 70 mg per day and, when the condition is under control, the dose is reduced to an amount as low as about 1 to about 10 mg per day. The exact dose will depend on the route of administration, the way in which it is administered, the subject to be treated and the body weight of the subject to be treated., in addition to the preference and experience of the doctor or veterinarian in charge of the case. The route of administration can be any route that effectively transports the active compound to the appropriate or desired site of action, such as orally or parenterally, for example, rectal, transdermal, subcutaneous, intravenous, intraurethral. topical, intramuscular, intranasal, solution or ophthalmic ointment. the oral route being preferred. Typical compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable carrier. When preparing the compositions. conventional techniques can be used for the preparation of pharmaceutical compositions. For example. the active compound will normally be mixed with a vehicle or diluted with a vehicle, or enclosed within a vehicle, and may be in the form of a vial, capsule, pouch, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material that acts as a carrier, excipient or medium for the active compound. The active compound can be adsorbed in a solid granular container, for example in a pouch. Examples of suitable vehicles are water, saline solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatin, lactose, amylose. magnesium stearate, talcum. silicic acid, monoglycerides and diglycerides of fatty acids, fatty acid esters of pentaerythritol, hydroxymethylcellulose and poliniin 1pyrrolidone. The pharmaceutical preparations can also be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salts for influencing the osmotic pressure, regulatory solutions and / or colored substances and the like, which do not react adversely with the active compounds. For parenteral application, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions with the active compound dissolved in castor oil polyhydroxy side. The tablets, dragees or capsules having talc and / or a carbohydrate or binder vehicle or the like. they are particularly suitable for oral administration. Preferred vehicles for tablets, dragees or capsules include lactose, corn starch and / or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be used.

Generally, the compounds are assorted in unit forms comprising from about 1 to about 100 mg in a pharmaceutically acceptable carrier per unit dose. A typical tablet suitable for use in this method, can be prepared by conventional tableting techniques, and contains: Active Compound 5.0 mg Lactose 67.8 mg Ph. Eur. Avicel "31.4 mg Amberl ite * 1.0 mg Magnesium stearate 0.25 mg Ph Eur. * Ph. Eur. = European Pharmacopoeia The present invention will now be described in more detail with reference to the following examples: EXAMPLE 1 2-Cloroindol-3-carbaldehyde (1) POC13 (100 ml) was added dropwise to a mixture of anhydrous dimethylformamide (DMF) (100 ml) and dichloromethane (100 ml), maintained at 0 ° C. Indole (50 g) was dissolved in dichloromethane (200 ml) and pyridine (50 ml) was added dropwise to O C over a period of 1.5 hours, then stirred at O'C for 1 hour, the mixture was emptied in ice water (2000 ml), ralized with NaHCO-, after which the mixture was stirred for one hour. The aqueous phase was decanted and the organic phase evaporated, followed by an extraction with ethane l (in boiling). The ethanolic phase was evaporated and the crystalline residue was recrystallized from ethanol, yielding 70 g of the compound (1), m.p. 227 * C. 1-Benzyl-2-chloroindol-3-carbaldehyde (2) 10 g of compound (1) was added to a slurry of NaH (2.7 g) in anhydrous DMF (100 ml), subsequently benzyl bromide (9.52 g) was added. ) to the mixture and stirring was continued at room temperature overnight. Benzyl chloride (2.9 g) was added and stirring was continued for 4 hours. The mixture was poured into water (100 ml) and extracted 3 times with ether. The aqueous phase was extracted 2 times with ether, followed by filtration of the aqueous phase. The crystals isolated by filtration of the aqueous phase and the crystals isolated by evaporation of the two extractions with ether were mixed, obtaining compound (2) (9.2 g). p.f .136.5-137.5'C. In the same manner, the following 1-substituted 2-chloroindol-3-carbaldehydes were prepared. l-methyl-2-chloroindol-3-carbaldehyde (3) Prepared from 18 g of the compound (1). Methyl iodide (17.1 g) and NaH (2.88 g), obtaining 18.2 g of compound (3), m.p. 88-99'C. 1-cycloopropy Imethi 1-2-c 1oorindo1-3-carba 1dehyde (4) It was prepared from 18 g of the compound (1), cyclopromethyl bromide (16.2 g) and NaH (2.8 g), obtaining 23 g of the compound (4). p.f. 108-109 * C. In this reaction THF was used as the solvent instead of DMF and the reaction mixture was partially evaporated before the water treatment. EXAMPLE 2 8-benzylthienof 2, 3-b] indole-2-carboxylic acid methyl ester (5) 9.2 g of compound (2) was dissolved in methanol (100 ml) and mixed with 10.2 g of K, C 0 was added 2-mercapto methyl acetate (4.7 g) and the mixture was stirred overnight. Water (100 ml) was added and the mixture was stirred for an additional 2 h. After. the mixture was filtered and the precipitate rinsed well with water and dried under vacuum at 100 ° C. 10 g of the compound (5) are obtained in the form of slightly pink crystals, m.p. 158.3-158.8'C. The following thienof 2.3-b] indolecarboxylates were prepared in the following manner: methyl 8-methylthienof 2,3-b] indole-2-carboxylate (6) was prepared from 9.6 g of compound (3). K "C03 (15 g) and methyl 2-mercaptoacetate (10 ml). obtaining 9.3 g of compound (6), m.p. 133.5-133.8'C. 8-Cycloproate? methyl [2,3-b] indo1-2-carboxylate (7) was prepared from 6.5 g of compound (4), K2CO3 (10 g) and methyl 2-mercaptoacetate (3.2 ml) to obtain 6 g of the compound ( 7) pf 110-111"C. EXAMPLE 3 8-Benzyltin [2,3-b] indole-2-carboxylic acid (8) 3 g of KOH were dissolved in methanol-water (1/1) (50 ml). 3 g of the compound (5) were added and the mixture was refluxed until the compound dissolved and subsequently an additional 1 h. After cooling, the mixture was acidified with acetic acid to pH = 6 and the mixture was stirred overnight. The formed precipitate was filtered, washed with water and dried under vacuum at 50 * C. The crude product (3 g) was boiled in water once more. it was cooled, filtered and dried again, obtaining the analytically pure compound (8). p.f. 194-195'C. In the same manner the following tienof 2.3-b] indole-2-carboxylic acids were prepared: 8-Methylthieno [2,3-b] indole-2-carboxylic acid (9) was prepared from 2.1 g of the compound ( 6) after reflux for 3 h. obtaining compound (9) (1.9 g) after rinsing, m.p. 179-180'C. EXAMPLE 4 8-Benzyltin [2,3-b] indole-2-carbonyl chloride (10) 1 g of compound (8) was dissolved in S0C17 (20 mL) and the mixture was stirred overnight at room temperature. The mixture was subsequently evaporated to dryness. the residue was treated with acetone, obtaining a small amount of a colorless residue, which was filtered. The filtrate was evaporated to dryness, obtaining dark purple crystals, which were used for subsequent reactions without further purification. Yield of the compound (10). 0.95 g. 8-benzylthieno [2, 3-b] indole-2-carboxamide (11) 0.5 g of the compound (10) was dissolved in acetone. An aqueous solution of NH3 (25%, 3 mL) was added and the mixture was stirred at room temperature for 1 hour. It was added to? Fua, obtaining a precipitate.

After an additional 0.5 h of stirring, the precipitate was filtered, washed with water and dried under vacuum. obtaining 0.47 g of the compound (11) p.f. 206.7-207.3 * C. 8-benzylthieno [2, 3-b] indol-2- (N-dimethylamino-propy1) carboxamide (12) 0.45 g of compound (10) was reacted with 3-dimethylaminopropanamine (0.17 g) in acetone. by stirring overnight at room temperature. By adding water to the reaction mixture, a brownish oil was separated. The oil was treated with pentane, obtaining hygroscopic brown crystals. The reprecipitation in methanol / acetone / pentane yielded 0.34 g of crystals, corresponding to the dihydrate of the compound (12) according to the elemental analysis, m.p. 212.2-214.0 * C. 8-Benzyl-2- (4-methyl-1-piperazine 1-carbonyl) thieno [2, 3-b] indole (13) 0.5 g of compound (10) and 4-ethylpiperazine (0.3 g) in acetone were stirred ( 50 mi) for one night. The treatment with water produced an oil. The mixture was extracted 3 times with ether, the ether phases were dried with MgSO 4, filtered and evaporated to dryness. The resulting crude product (13) (0.55 g) was recrystallized in acetone-pentane and subsequently precipitated as the hydrochloride in an acetone solution, m.p. 222-224'C. 8-benzyltin 2, 3-b] indol-2- (N-dimethylamino-propyl 1-N-methylcarcaramide) (14) 0.5 g of compound (10) and N-methyl-3-dimethylaminopropanamine (0.2 g) were stirred. ) in acetone at room temperature for 2 days. The mixture was evaporated and subsequently purified on a column of silica gel, using dichloromethane / methanol (4/1) as eluent. After evaporation of the solvent and precipitation as the hydrochloride in acetone / methanol / pentane, 0.4 g of the compound (14) was obtained. p.f. 172-174'C 8-benzyl 1-2-morphylcarbonyl lthienof 2.3-b] indole (15) 1.6 g of compound (10) were heated to 80 * C together with morpholine (2 ml) in anhydrous toluene. The mixture was cooled, obtaining a precipitate of 1.5 g of compound (15), m.p. 199-201 * C. 8-benzylthieno [2, 3-b] indol-2-N-ethylcarboxamide (16) One gram of the compound (10) was treated with ethylamine hydrochloride (3 g) in toluene (30 ml), triethylamine (4 g) was added. mi) and the mixture was heated at 80 * C for 0.5 h. After cooling and filtering, 0.85 g of the compound (16) was obtained. p.f. 175-176'C. 8-benzyl 1-2- (-3-cyclopropyl 1-1.2.4-oxadiazo1-5-i 1) thieno [2,3-b] indole (17) 2 g of compound (8) were treated with SOCl, (10 ml. ) by stirring at room temperature for 1 minute. The excess S0C1_ was evaporated and toluene (40 ml) was added followed by cyclopropylamide oxime (1.5 g) and triethylamine (2 ml). After stirring at room temperature for 0.5 h. followed by heating for 0.5 h at 80 ° C, a precipitate was obtained, which was filtered and treated with anhydrous xylene (30 ml) by heating at 130 ° C for 5 hours. After evaporation to dryness an oil was obtained, which was subsequently treated with methanol to obtain 1.5 g of the compound (17) as a crystalline compound, m.p. 140-141'C. 8-benzylthieno [2, 3-b] indol-2-carboxy isopropyl ester (18) 1 g of the compound (5) was mixed with titanium (IV) isopropoxide (4 ml) and isopropyla IPA (50 ml). After a 6 h reflux followed by evaporation of the IPA and a water treatment with subsequent filtration, a crystalline mass was obtained, which was dried. After trituration with dichloromethane, isolation of the organic phases, evaporation to dryness followed by trituration of the residue with petroleum ether, 0.9 g of compound (18), m.p. 88-89'C. EXAMPLE 5 Methyl thieno [2,3-b] indole-2-carboxylate (19) 4.5 g of compound (5) were dissolved in toluene (150 ml) and aluminum chloride (9.35 g) was added and the mixture was stirred at room temperature. environment during one night. Methanol (50 ml) was added cautiously and after completion of the development with heating, the reaction mixture was evaporated and extracted with water / ethyl acetate twice. The organic phases were dried with MgSO. and they evaporated. The residue was treated with methanol, filtered and the filtrate was evaporated. Addition of a small amount of methanol resulted in the precipitation of 2.6 g of the compound (19), m.p. 200-201'C. 8-Benzenesulfoni lthieno [2,3-b] indole-2-carboxylic acid methyl ester (20) 0.5 g of the compound (19) was added to a slurry of NaH (0.06 g) in anhydrous THF. Benzenesulfonyl chloride (0.39 g) was added by stirring and the mixture was stirred at room temperature overnight. The addition of water produced the formation of a precipitate, which was filtered and dried, obtaining 0.8 g of the compound (20), m.p. 195.1-197.2'C. 8-Benzoyl thieno [2,3-b] indol-2-carboxymethyl methacrylate (21) Prepared analogously to compound (20) from 0.5 g of compound (19). 0.06 g of NaH and 0.46 g of benzoyl chloride. 0.7 g of compound (21) p. F. 149.5-151.2"C. 8-acetylthieno [2,3-b] indol-2-carboxylic acid methyl ester (22) was prepared in the manner described for compound (21) from 0.5 g of the compound (19) acetyl (0.17 g) and NaH (0.06 g), obtaining 0.55 g of the compound (22) mp 179-181'C 2-morpholinecarbonyl ltiene [2, 3-b] indole (23) 0.5 g of the compound was treated ( 15) with A1C1 (1.5 g) in the manner described for the preparation of compound (19) The product obtained from extraction with ethyl acetate was purified on silica gel using ethyl acetate as eluent to obtain 0.2 g. of compound (23) mp 92-95'C EXAMPLE 6 8-benzylthienof 2, 3-b] indole-2-carbonitrile (24) 3 g of compound (8) were mixed with acetonitrile (100 ml) followed by The addition of chlorosulfone isocyanate (1.62 g) The mixture was stirred overnight at room temperature, after which triethyl (1.46 g) was added and the mixture was stirred overnight at room temperature. ra environment. The mixture was evaporated, extracted three times with NaOH / ether. the ether phases were combined, the combined was evaporated and purified on silica gel using pentane / triethyl sheet (15/1) as eluent. The residue after evaporation of the eluent was treated with ether, obtaining 1.15 g of the compound (24) p. F. 130-132'C. 8-benzyl-2- (5-tetrazolyl) thienof 2,3-b] indole (25) 0.3 g of compound (24) in chloroform (50 ml) was treated with NaNg (0.42 g) and NH.C1 (0.36 g) by stirring at reflux overnight. The mixture was evaporated, followed by the addition of water and acidification with acetic acid, obtaining 0.32 g of yellow crystals. The crystals were purified on silica gel using dichloromethane / methanol (4/1) as eluent, obtaining 0.07 g of pure compound (25), e.g. F. 277-280'C (with decomposition). EXAMPLE 7 8-methyliso [2,3-b] indole-2-carbonyl chloride (26) It was prepared in the manner described for compound (10) from 2.0 g of compound (9) and 20 ml of SOCl- , obtaining 2.1 g of the compound (26). which was used without further purification. 8-methi 1-2-morfo1 inocarboni ltieno [2.3-b] (27) 0.7 g of compound (26) was mixed with morpholine (0.29 g) in acetone (100 ml) and stirred overnight at room temperature. The reaction mixture was evaporated and treated with NaOH, after which it was subjected to extraction with ether and subsequently with dichloromethane. The organic phases were mixed and evaporated, obtaining an oil, which was purified on silica gel using dichloromethane / ether (1/1) as eluent. After evaporation of the eluent. 0.35 g of the compound (27) was isolated in the form of brownish crystals, e.g. F. 125-127'C. 8-meti ltienof 2.3-b] indo1-2- (N-methyl lcarboxamide) (28) Prepared in the manner described for compound (27) from 0.7 g of compound (26) and methylamine (gaseous), which was bubbled through the acetone solution until a clear solution was obtained. Purified on a column with dichloromethane / methanol (9/1) as eluent. After evaporating the eluent, the residue was reprecipitated in acetone-pentane, obtaining 0.36 g of the compound (28) p. F. 217-219'C. 8-methyltienof 2.3-b] indole-2- (N, N-dimeti-1 -carboxamide) (29) Prepared in the manner described for compound (28) from 0.7 g of compound (26) and dimethylamine ( soda). After concluding the addition of dimethylamine. The mixture was stirred at room temperature for 3 days. After purifying in a column and reprecipitating, 0.44 g of the compound (29) was obtained. p. F. 151.5-152. O'C. 8-methyltienof 2.3-b] indo1-2- (N-phenylenecarboxamide) (30) Prepared in the manner described for compound (27) from 0.96 g of compound (26) and aniline (0.43 g). stirring at room temperature during 14 days. Reprecipitation in acetone / pentane yielded 0. 45 g of the compound (30). p. F. 199.0-199.4'C. 8-methyl-2- (4-methyl-1-piperazinylcarboni 1) thieno [2,3-b] indole (31) Prepared in the manner described for compound (30) from 0.96 g of compound (26) and N - eti Ipiperazine (0.46 g). stirring for 14 days. purifying on a column of silica gel using dichloromethane / methanol (9/1) as eluent. The precipitation in the oxalate salt form yielded 0.78 g of the compound (31). p. F. 21 .1-219.5'C. 8-meti 1-2-morphol inometi ltieno [2.3-b] indole (32) 0.8 g of the compound (27) were dissolved in THF (anhydrous, 100 ml), LiAlH was added. (0.1 g) and the mixture was stirred at room temperature for 1 h, followed by reflux overnight. The reaction mixture was rinsed using the normal procedure (water / NaOH).

After filtration, the filtrate was purified on silica gel using ethyl acetate / toluene (1/1) as eluent. 0.05 g of the compound (32) was isolated after precipitation and an additional 0.18 g when the filtrate evaporated, p. F. 102.5-106. O'C. EXAMPLE 8 8-Benzyl 1-2-hydroxymethyl-lthieno [2, 3-b] indole (33) 0.9 g of compound (8) were subjected to a reduction reaction with LiAlH (1.2 g) in THF (50 ml) by stirring at room temperature overnight. After rinsing and filtering, the filtrate was evaporated and purified on silica gel using ether as eluent. After precipitating with ether / pentane. 0.22 g of the compound (33) were obtained. p. f.81-82'C. 8-methyl-l-5-methoxythieno [2,3-b] indole-2-carboxylic acid methyl ester (34) 0.87 g of 5-hydroxyindolone were dissolved in DMF (10 ml) and the solution was added to a solution of POC1 (20 ml), DMF (10 ml) and dichloromethane (10 ml) maintained at O'C. The reaction mixture was stirred at O'C for 1 h and subsequently at room temperature for 1 hour. Subsequently, the mixture was poured into water, neutralized with NaHCO3 and stirred overnight, subjected to extraction with dichloromethane, followed by purification on silica gel using CH2C12 / CH30H (9/1) as eluent. obtaining 0.4 g of crystals.

These were added slowly to a solution of NaH (0.12 g) in DMF (30 ml), followed by the addition of methyl iodide (0.64 g). The mixture was stirred at room temperature overnight, water (100 ml) was added and the resulting mixture was extracted with dichloromethane. The organic phases were combined, the combined was dried with MgSO. and evaporated to dryness, obtaining 0.27 g of yellow crystals. These crystals were dissolved in methanol (50 ml), K2CO3 (0.35 g) and methyl mercaptoacetate (0.15 g) were added, and the resulting mixture was stirred overnight at room temperature. Water (100 ml) was added and the mixture was stirred for 2 h, followed by filtration. The resulting crystals were dried in vacuo. obtaining 0.2 g of the compound (34) p. F. 124-125 'C. 8-benzyltin [2,3-b] indole (35) 1.0 g of compound (8) was heated for 2 h at 200 * C in quinoline (30 ml) by adding Cu (0.12 g). After cooling for one night. the mixture was filtered, dichloromethane was added and the mixture was subjected to extraction with dilute HCl and subsequently with water. The organic phase was dried (MgSo.) And evaporated, yielding c? which were recrystallized in ethanol / water (1/1). 0.3 g) of the compound (35) being obtained in the form of slightly gray crystals, e.g. F. 96-98'C.

Ethyl 8-methyltiene [2, 3-b] indole-2-carboxylate (36) One gram of the compound (6). Sodium ethoxide (0.5 g) and acetamide oxime (1 g) were refluxed with ethanol (100 ml) to which crushed molecular sieves (0.5 g) were added. After refluxing for 2 h and stirring at room temperature overnight, the mixture was filtered and evaporated. Extraction with water / dichloromethane, followed by evaporation of the organic phases, produced a crystalline mass, which was purified on silica gel using dichloromethane as eluent. 0.5 g of compound (36) p. F. 99-100'C. 8-methyl-2- (3-methylated 1-1, 2,4-oxadiazole-5-y1) thieno [2,3-b] β-ddol (37) The procedure mentioned above is repeated for the compound (36) using, ethoxide of freshly prepared sodium (with Na (0.26 g) in ethanol (50 ml)) and refluxing for 3 days, which was followed by the same purification procedure mentioned above, obtaining 0.1 g of the compound (37) p. F. 199.8-200.7'C. Thieno [2,3-b] indole (38) 0.25 g of compound (23) were heated at 110 ° C in morpholine (3 ml) for 20 hours. The mixture was poured into water, filtered and dried, followed by purification on silica gel with dichloromethane as eluent, after evaporating the solvent, 0.05 g of the compound (38) was obtained. p. F. 210-211'C. EXAMPLE 9 8-benzyl-1-methyl-2-bromothieno [2, 3-b] indol-2-carboxylate (39) 0.5 g of compound (5) were dissolved in dichloromethane (30 ml), NBS (0.7 g) was added. ) and the mixture was stirred at room temperature for 0.5 hour. After adding water. Separate the organic phase and subsequently wash it with NaHCO3 > Dry it with MgSO. and evaporating it, 0.5 g of the compound (39) was obtained. p. F. 134-135'C. 8-bßnci 1-5, 6-dibromothieno [2,3-b] indole-2-carboxylic acid (40) 1 g of compound (5) was treated with NBS (1.4 g) by stirring overnight at room temperature in CH " C12 (50 ml), the reaction mixture was filtered and evaporated, yielding 2 g of the methyl ester of the compound (40) in the form of yellow crystals, which were washed with methanol, and 0.5 g of these crystals were hydrolysed with KOH in the manner described for compound (8), obtaining 0.4 g of compound (40) after drying, e.g. F. 269-273'C.

Methyl 5-bromothieno [2, 3-b] indol-2-carboxylate (41) was prepared from 1 g of the compound (39), by means of A1C1-. (2 g) in the manner described for the compound (19). obtaining 0.15 g of the compound (41), p. F. 216-218'C. Tieno [2,3-b] indole-2- (N-ethylcarboxamide) (42) It was prepared from 0.5 g of compound (16) and AlCl-j (1.5 g) in the manner described above. 0.2 g of the compound (42) being obtained. p. F. 253-254'C. EXAMPLE 10 1- methyl 1-4,6-dichloro-l, 3-dihydroindol-2-one (43) 4.0 g of 1-methi 1-4,6-dichloroisatin in anhydrous ethanol (40 ml) was suspended, hydrazine (9 ml) was added and the mixture was refluxed for 6 hours. Subsequently, the mixture was added slowly, at 70 ° C, to a solution of sodium (1.74 g) in anhydrous ethanol (80 ml) and refluxed overnight. The reaction mixture was cooled to room temperature, water (50 ml) was added and the volume reduced to about one third by evaporation.

The mixture was then poured into ice water (1000 ml) and acidified with 6 M HCl (pH-1). The precipitate was filtered, washed with water and dried to obtain 3.27 g (87%) of the compound (43). p. F. 144-145'C.

In the same manner, 1-methyl-1-7-chloro-1,3-dihydroindol-2-one (44) was prepared from 10 g of 1-methyl-1-7-chloroisatin, hydrazine (25 ml) and sodium (5.1 g). obtaining 8.1 g (88%) of the compound (44), p. F. 111-113 'C. EXAMPLE 11 1-methylo-2,5-dichloroindole-3-carbaldehyde (45) 6 ml of P0C13 was added dropwise to a mixture of anhydrous DMF (5.9 ml) and dichloromethane (5.9 ml) maintained at O'C. 4.0 g of 1-methyl-1-5-chloro-1,3-dihydroindol-2-one were dissolved in dichloromethane (20 ml) and pyridine (2.9 ml) was added dropwise to O'C in a period of 30 min. It was then stirred at room temperature for 3 h. The mixture was poured into ice water (500 ml). neutralized with NaHCO-, after which the mixture was stirred for 1 night. The precipitate was filtered, washed with water and dried. The crude material (4.45 g) was recrystallized in ethanol. obtaining 1.27 g (25.4%) of the compound (45), p. F. 165-167'C. In the same way the following were prepared Substituted 2-chloroindol-3-carbaldehydes: 1,5-dimethyl-2-chloroindol-3-carbaldehyde (46) Prepared from P0CL3 (1.7 ml), DMF (1.6 ml). 1,5-dimethyl-1,3-dihydroindol-2-one (1.0 g) obtaining 1.0 g (78%) of the compound (46), p. F. 120-121"C in the form of a crude product sufficiently pure for the next synthesis: 1-methyl 1-2,7-dichloroindole-3-carbaldehyde (47) was prepared from POClg (17 ml). ml), 7.5 g of the compound (44), obtaining 6.8 g of the compound (47) (72%), mp 185-187'C.In this reaction, the reaction time was 48 h instead of 3 hours. -meti 1-2.4.6-trichloroindol-3-carbaldehyde (48) It was prepared from P0C1- (11 ml). DMF (11 ml). 8.4 g of the compound (43). obtaining 6.5 g of the compound (48) in the form of a crude product i sufficiently pure for the next synthesis. H-NMR (DMSO-d6): 6 3.8 (3H), 7.43 (1H), 7.86 (1H), . 52 (s, 1H). In this reaction, the reaction time was 24 h instead of 3 hours. EXAMPLE 12 5-Chloro-8-methytienof 2, 3-b] indole-2-carboxylic acid (49) 1.0 g of the compound (45) and K2CO3 (1.71 g) in methanol (20 ml) were suspended. added methyl 2-mercaptoacetate (0.68 ml) and the reaction mixture was stirred for 2 h. Water (20 ml) was added and the mixture was stirred for 0. 5 additional hours The precipitate was filtered, washed with water and dried, to obtain 1.04 g (85%) of the compound (49). p. F. 188-19U'C (recrystallized in methanol).

In the same manner, the following substituted thieno [2, 3-b] indole-2-carboxylates were prepared: methyl 7-chloro-8-methyl-thieno [2,3-b] indole-2-carboxylate (50) It was prepared from 6.5 g of the compound (47), K_C03 (11.17 g) and methyl 2-mercaptoacetate (4.46 ml), obtaining 6.62 g (B3%) of the compound (50), p. F. 166-168'C. 8-phenylethien [2], 3-b] Methyl indole-2-carboxylate (51) It was prepared from 0.90 g of l-phenyl-2-chloroindol-3-carbaldehyde, K2C03 (1-38 g) and methyl 2-mercaptoacetate (0.55 g). ml), obtaining 0.86 g (79.6%) of the compound (51), p. F. 147-149'C. Methyl 5-methi 1-8-methyltieno [2, 3-b] indol-2-carboxylate (52) was prepared from 0.80 g of the compound (46). K2C03 (1.5 g) and methyl 2-mercaptoacetate (0.60 ml), obtaining 0.144 g (14.4%) of the compound (52). p. F. 152 -155'C. Methyl 4-6-dichloro-8-methyltieno [2,3-b] indole-2-carboxylate (53) was prepared from 6.5 g of the compound (48), K_C03 (9.59 g) and methyl 2-mßrcaptoacetate (3.82 ml) obtaining 2.5 g (32.5%) of the compound (53), p. F. 231-232'C. The product was purified by chromatography on silica gel using toluene as eluent. The compound was crylized by trituration with methanol. EXAMPLE 13 5-Chloro-8-methylthieno [2,3-b] indole-2-carboxylic acid (54) 0.57 g of KOH was dissolved in methanol / water (1/1) (10 ml). 0.50 g of the compound (49) was added and the mixture was refluxed for 1 3/4 h. After cooling, the mixture was acidified with 1 M HCl to pH-1. The precipitate was filtered, washed with water and dried, to obtain 0.44 g (93%) of the compound (54). p. F. 259-262 * C. In the same manner, the following substituted thiños [2, 3-b] indole-2-carboxy acids were prepared. except that the reaction mixture was acidified with acetic acid to pH-5. 5-Methyl-8-methylthißne [2,3-b] indo-1-carboxylic acid (55) It was also prepared from 0.40 g of KOH. 0.33 g of the compound (52). obtaining 0.312 g (100%) of the compound (55), p. F. 216-219'C. 4.6-Dichloro-8-methyltienof 2, 3-b] indole-2-carboxylic acid (56) Prepared from 2.23 g of KOH »2.20 g of the compound (56), refluxing for 4 1/3 h . obtaining 1.67 g (79.5%) of the compound (56). p. F. 278-281'C. 7-Chloro-8-methyloxy [2,3-b] indole-2-carboxylic acid (57) was prepared from 4.73 g of KOH, 5.9 g of the compound (50). refluxing for 1 night, obtaining 5.54 g (99.3%) of the compound (57), p. F. 233-234"C 8-Phenylthieno [2,3-b] indole-2-carboxylic acid (58) was prepared from 0.51 g of KOH, 0.70 g of the compound (51), refluxing during a overnight, yielding 0.63 g (94%) of the compound (58), mp 206-207'C EXAMPLE 14 5-chloro-8-methyl 1-2-morpholocarbonyltin [2,3-b] indole (59) 0.20 were dissolved g of compound (54) in S0C12 (5 ml), DMF (1 ul) was added and the mixture was stirred for 2 h at room temperature and 1 h at 50 ° C. The mixture was subsequently evaporated to dryness, the residue was collected with THF (10 ml) and dissolved in THF (5 ml), then morpholine (0.15 ml) was added.The mixture was stirred for 2 1/2 h at room temperature, evaporated to dryness and subjected to extraction with dichloromethane / water. .

The organic phase was subsequently washed with 1 M NaOH and 1 M HCl, dried with MgSO. and it evaporated. The residue was treated with ethanol and filtered to obtain 0.185 g (74%) of the compound (59), p. F. 178-182'C. 5.8-Dimeti 1-2-morpholine 1-incarbonyl [2, 3-b] indole (60) 0.295 g was dissolved in S0C12 (6 mL), DMF * (1 ul) was added and the mixture was stirred for 2.5 h at room temperature and 0.5 ha 50 * C. Subsequently, the mixture was evaporated to dryness, the residue was taken up in toluene (10 ml) and dissolved in THF (5 ml), then morpholine (0.21 ml) was added. The mixture was stirred for 1.5 h at room temperature, evaporated to dryness and subjected to extraction with dichloromethane / water. The organic phase was subsequently washed with 1 M NaOH and 1 M HCl, dried with MgSO. and it evaporated. The residue was purified by chromatography on silica gel using toluene / ethyl acetate 75/25 as eluent. The product was treated with methanol and filtered. to obtain 0.225 g (65%) of the compound (60). p. F. 158-160'C. 4,6-dichloro-β-methyl-2-morpholinecarboni Itieno [2,3-b] indole (61) 1.00 g in SOCl (20 ml) was suspended. DMF (1 drop) was added and the mixture was stirred for 2 h at room temperature, 1 h at 50 ° C and refluxed for 1 h. The mixture was evaporated to dryness and dissolved in THF (15 ml), then morpholine (0.60 ml) was added. After stirring overnight, the precipitate was filtered and recrylized from acetic acid / water to obtain 0.357 g (29%) of the compound (61). p. F. 224-226'C. 8-phenyi-1, 2-morpholine, incarbonyl, ltiene [2.3-b] indole (62) 0.44 g of compound (58) was dissolved in SOC1- (3.4 ml) and stirred for 72 h. The mixture was evaporated to dryness and the residue was taken up twice with acetone (5 ml) and dissolved in acetone (10 ml) *. Morpholine (0.28 ml) was added and the mixture was stirred for 72 h. it was evaporated to dryness and subjected to extraction with dichloro ethane / NaHCO solution. The organic phase was washed with 1 M NaOH and 1 M HCl, evaporated to dryness and purified by chromatography on silica gel., using dichloromethane / ether 1/1 as eluent. The product was recrystallized from acetic acid / water, to obtain 0.96 g (37.7%) of the compound (62), p. F. 162-167'C. 7-chloro-8-methyl 1-2-morphinocarboni lthienof 2.3-b] indole (63) 0.35 g of the compound (57) was suspended in SOC1- (3.0 ml) and stirred for 20 hours. The mixture was evaporated to dryness and the residue was taken up in toluene (10 ml) and dissolved in THF (8 ml). Morpholine (0.216 ml) was added and the mixture was stirred for 72 h, evaporated to dryness and extracted with dichloromethane / water. The organic phase was washed with 1 M NaOH and 1 M HCl, dried with Na_SO. and evaporated to dryness. The crude product was recrystallized from acetic acid / water to obtain 0.33 g (87%) of the compound (63), p. F. 140-143'C. EXAMPLE 15 5-acetyl-1-methyl-1-methyl-2-3-b-indole-2-carboxylate (64) To a slurry of 870 mg of A1C1? N 50 ml of 1, 2-anhydrous dichloroethane, 465 ul of acetyl chloride was added. The mixture was stirred for 30 min at room temperature, 800 mg of compound (6) was added and stirring was continued overnight. Another 870 mg of A1C13 and 465 ul of acetyl chloride were added and the stirring was continued overnight. Water was added and the organic phase was dried and evaporated to dryness, obtaining a brown powder, which was recrystallized in acetic acid and petroleum ether, obtaining compound (64). Yield, 210 mg, p. F. 196-198'C. EXAMPLE 16 2-chloro-5-nitroindo-3-3-carbaldehyde (65) 15 g of the compound (1) were added to a mixture of 150 ml of acetic acid and 150 ml of acetic anhydride. to O'C. 3.5 ml of HNO-, 100% were added slowly and after 1 h another 3.5 ml of 100% HNO was added. Stirring was continued for 1 h at O'C. Then, the mixture was emptied on ice, allowed to cool for 1 night and filtered, to obtain 10 g of the compound (65). which was used without further purification. 2-chloro-l-methyl-5-nitroindol-3-carbaldehyde (66) To 5 g of the compound (65) in 100 ml of THF. 550 mg of NaH and 2.5 ml of methyl iodide were added. The reaction was allowed to stir overnight. Much of the THF had evaporated, water was added and the aqueous part was extracted with EtOAc. The aqueous phase was subsequently acidified with acetic acid, which precipitated the pure product. After filtering and drying, 770 mg of the compound (66) were obtained. 8-methyl-l-5-nitrothieno [2,3-b] indole-2-carboxylic acid methyl ester (67) 1.4 g of the compound (66) was added to a slurry of an excess of K2CO3 in 100 ml of MeOH. 2 ml of methyl 2-mercaptoacetate were added and the mixture was allowed to stir overnight. After adding water, the product was precipitated and then washed with MeOH and water to obtain 640 mg of the compound (67). p. F. 269-271'C. EXAMPLE 17 8-Methyl-5-nitrothieno [2,3-b] indole-2-carboxylic acid (68) 480 mg of the compound (67) was hydrolyzed in a mixture of NaH in 25 ml of morpholine at 65 * C for 8 h . In an attempt to directly produce the morphine, Naloamide. After adding water and acidifying with acetic acid, the compound (68) precipitated »to obtain 280 mg, which were used without further purification. 8-meti 1-2-morfol inocarboni l-5-nitrothieno [2,3-b] indole (69) 280 mg of the compound (68) was added to 25 ml of THF, 0.5 ml of S0C12 was added and the reaction was left in stirring for 1 hour. 1 ml of morpholine was added in portions and stirring was continued. The precipitated morpholine hydrochloride was removed by filtration and the solvent was evaporated. The residue was purified by chromatography on a silica gel column, using MeOH in CH2C12, 1 + 9 as eluent. MeOH was added to the mixed fractions to precipitate the product, obtaining, after filtration and drying, 50 mg of the compound (69), p. F. 250-252 * C. EXAMPLE 18 5-Bromo-8-methyltienof 2,3] indo1-2-carboxymethyl methacrylate (70) 1.3 g of N-bromosuccinimide and 1.7 g of compound (6) were reacted in 25 ml of CH2C12 for 30 min . Water was added and the organic phase was washed with saturated NaHCO 3 solution and water. After drying and evaporation, 1.8 g of the product was obtained, which was dissolved in MeOH and precipitated by adding water. Yield, 1.6 g of the compound (70), which was used without further purification. 5-Bromo-8-methylthieno [2,3] indo-1-carboxylic acid (71) acid 2.5 g of compound (70) were hydrolyzed for 3 h at reflux in a mixture of 25 ml of 4 N NaOH and 100 ml of MeOH / water 1 + 1. After cooling to room temperature and acidifying with acetic acid, the product precipitated. After filtering and drying, 2.4 g of the compound (71) were obtained. p.f. 229-241 'C. 5-Bromo-8-methyl-2-morpholine, incarbonyl ltiene [2,3-b] indole (72) To 2 g of compound (71) in 50 ml of THF. 5 ml of S0C12 were added and the reaction was left stirring overnight, another 5 ml of S0C12 was added and the reaction was allowed to stir for 3 days. The solvent was evaporated, the residue was taken up in THF and 30 ml of morpholine was added. Then, the reaction was allowed to stir overnight. The precipitate was removed by filtration and the filtrate was evaporated, to obtain 1.7 g of the product, which was recrystallized from acetic acid-water, filtered and washed with MeOH, to obtain 1.1 g of the compound (72). p. F. 184'C. EXAMPLE 19 8-meti Itienof 2.3-b] indole (73) A slurry of 5 g of the compound (9) and 650 ml of copper powder in 50 ml of quinoline. it was heated at 200'C for 4 hours. To the cold reaction mixture was added 150 ml of CH2C1"and the mixture was washed with 1 N hydrochloric acid (3 x 100 ml). with water (100 ml), dried and evaporated. Recrystallization from EtOH / water yielded 500 mg of a by-product, which was discarded. Addition of EtOH gave 2 precipitates of the compound (73). which were combined. Performance. 1.5 g. p. F. 65.5-66.8'C. 8-meti 1-3-trif luoroacetylthiene [2.3-b] indoi (74) A mixture of 1 g of the compound (73) and 1.1 g of 2-trif luoromethylcarboni loxypyridine. prepared in accordance with the scientific literature (Keumi, T. et al., Chem. Lett 5 (1990) 783-6). in 25 ml of 1,2-dichloroethane, cooled to -10 ° C with stirring. 1.5 g of AlClg was added in a period of 15 min at this temperature, the reaction mixture was stirred at O'C for 4 h and at room temperature overnight. Water was added. 2 phases were separated and the organic phase was dried and evaporated to dryness. Purification by chromatography on a column of silica gel in toluene yielded the pure compound (74). Performance. 590 mg, p. F. 138-140'C. EXAMPLE 20 3-Acetyl-2-chloroindole (75) 13.7 ml POC-1 was added slowly to a mixture of dimeti-lacetamide (5.6 ml) in 25 ml of chloroform at 5 ° C. A solution of 6.66 g of oxy indol in 25 ml of chloroform was added slowly, and the reaction mixture was refluxed for 7 h and left overnight at room temperature with stirring. The reaction mixture was added to 250 ml of ice / water, 2 phases were separated and the organic phase was extracted with water (4 x 50 ml). The aqueous phases were mixed and the mixture was neutralized with sodium acetate and stirred for 4 h at room temperature. After filtering and drying, 4.8 g of the compound (75) were obtained. 3-acetyl-2-chloro-l-methylindole (76) To a slurry of 310 mg of NaH in 15 ml of THF, was added 1 g of the compound (75) and then 625 ul of methyl iodide. The reaction was allowed to stir for 3 days. Water was added, the product was extracted with diethyl ether and the ether phase was dried and evaporated to dryness to obtain the compound (76). Yield 870 mg. 3, 8-dimeti ltienof 2.3-b] indole-2-carboxylic acid methyl ester (77) 450 ul of methyl 2-mercaptoacetate were added to a slurry of 870 mg of the compound (76) and 1.2 g of K2C03 in 10 ml of MeOH. The reaction was stirred overnight, 30 ml of water was added, stirring was continued for 1 h and the product was filtered to obtain 160 mg of the product. Recrystallization from MeOH yielded 30 mg of compound (77), p. F. 165.5-166.8'C. EXAMPLE 21 2-chloro-l- (2-methoxyethoxy: imeti 1) indole-3-carbaldehyde (78) 1 g of the compound (1) was dissolved in 25 ml of THF, 268 mg of NaH and then 1.87 g of (2-eti loxyethyl) oxymethylchloride were added. The reaction was allowed to stir overnight, then it was added to a 2N K2C0 solution. The mixture was extracted with toluene, the organic phase was washed with water and with brine, dried and evaporated, get 1.5 g of an oil. Then, the oil was extracted 2 times with boiling heptane and the heptane solutions were allowed to stand for 2 h to separate a yellow oil phase. Finally, the heptane was removed by decantation, filtered and evaporated to obtain 1.21 g of the compound (78), p. F. 52.5-54'C. 8- ((2-Methyloxyeti-1) -oxymethyl) thieno [2,3-b] indol-2-carboxylic acid methyl ester (79). 400 μl of methyl 2-mercaptoacetate were added to a slurry of 1 g of the compound (78). and 1.1 g of K2C03 in 10 ml of MeOH. The reaction was allowed to stir overnight and then 20 ml of water was added.

The mixture was extracted with EtOAc and the organic phase was washed with water, dried and evaporated, to obtain the compound (79) in the form of a yellow oil. Yield, 880 mg. jH-NMR (ppm): 8.1 (s.1H); 7.8 (d.1 M); 7.3 (. 2 H); 5.6 (s, 2 H); 3.9 (s 3 H); 3.5 (, 4 H); 3.35 (s 3) H). EXAMPLE 22 3-acetyl-2-chloro-l- (2-methoxyethoxymethyl) 1) indole (80) 1 g of the compound (75) was dissolved in 25 ml of THF 250 mg of NaH and then 1.87 g of (2-methyloxyethyl) oxymethylchloride were added. The reaction was allowed to stir overnight, another 100 mg of NaH and the reaction continued for another 4 hours. The reaction mixture was added to a 2 N 2 C03 solution and subjected to extraction with toluene. The organic phase was washed with water and with brine, dried and evaporated. The resulting oil was extracted twice with boiling heptane, cooled, filtered and evaporated, yielding 1.23 g of the compound (80) as a yellow oil. H-NMR (ppm): 8.35 (m.h. H); 7.44 (m.h. H); 7.27 (m.2H); 5.62 (s, 2 H); 3.58 (m.2H); 3.47 (m. 2 H); 3.32 (s 3H); 2.65 (s, 3 H >. 8- ((2-methyloxiethyl J oxirneti l) -3-methyltieno [2,3-b] indole-2-carboxylic acid methyl ester (81). Methyl 2-mercaptoacetate to a slurry 1050 mg of the compound (80) and 1.1 g of CO in 10 ml of MeOH, and left stirring for 48 hours 20 ml of water were added and the precipitate was removed by filtration and This material was washed well with pentane, filtered, dried and recrystallized from EtOH to obtain 230 mg of the compound (81) as a white powder, mp 85.4-86 ° C. EXAMPLE 23 1-benzyl -2-chloro-3-acetyl 1 indole (82) To a 400 mg NaH slurry in 20 mg of THF was added 1 g of the compound (75) and then 770 ul of benzyl bromide. stirring for 3 days, water was added and the product was extracted with diethyl ether, dried and the solvent was evaporated to obtain 1.52 g of a reddish-brown powder, which was used without further purification. 1-benz 1-3-met? 1-methyl [2, 3-b] indole-2-carboxylic acid methyl ester (83) 550 ul of methyl 2-mercaptoacetate were added to a slurry of 1.45 g of compound (82) and 1.6 g of K_COg in 15 ml of MeOH and left in agitation overnight. 30 ml of water were added and the product was isolated in the form of a sticky lump. This lump was dissolved in EtOAc. it was washed with water, dried and evaporated, to obtain an oil, which solidified slowly. After crystallizing in MeOH, the compound was obtained (83). yield 330 mg. p. F. 132-134'C. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as an antecedent, what is contained in the following is claimed as property.

Claims (8)

1. CLAIMS 1. A compound of the formula I characterized in that 1 R is H. an alkyl radical of 1 to 6 carbon atoms optionally substituted by halogen, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, alkyl from 1 to 4 carbon atoms substituted with cycloalkyl of 3 to 6 carbon atoms, carboxy. -COR 9, -COOR 9, alkyl of 1 to 4 carbon atoms substituted with dimethylamino, -R 9 -O-R 10. -R9-0-R10-O-R11, phenylsulfonyl, bezoyl, benzyl or phenyl. each of the aromatic groups being optionally substituted with an alkyl radical of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms. halogen, carboxy or nitro. where R 9. R10 and
2. , Each independently, are an alkyl radical of 1 to 6 carbon atoms; 2 R is H. a carboxy radical. cyano, nitro. alkyl of 1 to 6 carbon atoms optionally substituted with hydroxy, -R 9 -O-R 10. -COOR9. morfol inocarboni lo. tiamorfol inocarboni lo. piperazinylcarbonyl optionally substituted with an alkyl radical of 1 to 4 carbon atoms, tetrazolyl, oxadiazolyl or thiadiazolyl optionally substituted with an alkyl radical of 1 to 4 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, morphol ineethyl. unsubstituted or monosubstituted or disubstituted amino with an alkyl radical of 1 to 6 carbon atoms, unsubstituted or unsubstituted or unsubstituted methylamino with an alkyl radical of 1 to 6 carbon atoms. sulfamoyl unsubstituted or mono-substituted or disubstituted with an alkyl radical of 1 to 6 carbon atoms or carbamoyl unsubstituted or monosubstituted or disubstituted with an alkyl radical of 1 to 1 carbon atoms, the alkyl group or groups being, independently each, optionally substituted with dimethyl laminomethyl, halogen, phenyl or benzyl; 3 R is H, an alkyl radical of 1 to 6 carbon atoms, trifluoromethyl, trifluoroacetyl. alkoxy of 1 to 6 carbon atoms, halogen, nitro, cyano, -COOR or unsubstituted or monosubstituted or disubstituted amino with an alkyl radical of 1 to 6 carbon atoms, - R, R. R and R. each one independently. they are H, a nitro, amino, halogen, tritium, trifluoromethyl lo, trifluoroacetyl, sulfo, carboxy radical. carbamoyl sulfamoyl. -COR 9. -COOR9. C 1-6 alkoxy, C 1-6 alkyl optionally substituted with halogen; or a salt thereof with a pharmaceutically acceptable acid or base. 2. A compound according to claim 1, which is selected from the group consisting of: 8-benzyltin [2, 3-b] indol-2-carboxylic acid methyl ester, 8-methyltin 2, 3-b] indole-2-carboxylate methyl, 8-cyclopropylmethylthieno [2,3-b] indol-2-carboxylato-methyl, 8-benzylthieno [2,3-b] indole-2-carboxylic acid, 8- methytienof 2, 3-b] indole-2-carboxylic acid, 8-benzylthienof 2, 3-b] indole-2-carbonyl chloride, 8-benzylthieno [2,3-b] indol-2-sarboxamide, 8 β-benzylthieno [2, 3-b] indol-2- (N-dimethylamino-propyl) carboxamide, 8-benzyl-2- (4-methyl-1-piperazine 1carboni 1) thieno [2, 3-b] indole, 8-benzyltin [2, 3-b] indol-2- (N-dimethylamino-propi 1-N-methyl Icarboxamide), 8-benzyl 1-2-morphol incarboxyl ltienoi 2,3-bj indole, 8-benzyl ltieno [2, 3-b] indol-2-N-eti lcarboxamide, 8-benzyl-2- (3-scyclopropi 1-1,2,4-oxadiazol-5-yl) thieno [2,3-b] ] indole, 8-tencylthiene [2,3-b] indole -2-carboxy? The isopropyl ion, thienof 2, 3-b] indole-2-carboxylic acid methyl ester. 8-Benzenesulfoni ltienof 2,3-b] indole-2-carboxylic acid methyl ester, 8-benzoyl-1-thieno [2,3-b] indole-2-carboxylic acid methyl ester, 8-acetylthieno [2,3-b] indole-2-carboxy? lato de meti lo. 2-morpholinecarboni lthienof 2.3-b] indole, 8-benzylthieno [2,3-b] indole-2-carbonitriol, 8-benzyl-2- (5-tetrazolyl) thieno [2,3-b] indole, 8-methyl chloride ltieno [2,3-b] indole-2-carbonyl, 8-methyl-2-morpholinosarboni lthienof 2, 3-b] indole, 8-methyltieno [2,3-b] indole-2- (N -methylcarboxamide), 8-methyl ltienof 2.3-b] indole-2- (NN-dimet? 1 -carboxamide), 8-methytienof 2, 3-b] indole-2- (N-phenylcarboxamide). 8-methi 1-2- (4-raeti 1-1-piperazine 1carboni 1) thieno [2,3-b] indole. 8-methyl-2-morpholinomethyl thieno [2,3-b] indole. 8-benzyl-2-hydroxymethyl-triene [2,3-b] indole. 8-methyl-1-5-methoxythienof 2.3-b] indole-2-carboxylic acid methyl ester. 8-benzyltin [2, 3-b] indole. 8-methyltienof 2.3-b] indole-2-carboxylic acid ethyl ester. 8-methylo-2- (3-methi 1-1.2.4-oxadiazol-5-i 1) thieno [2.3-b] indole thieno [2,3-b] indole, 8-benzyl-1-methyl-2-bromothienof 2, 3-b] indole-2-carboxylate, acid 8-benzyl-1-5,6-dibromothiene [2,3-b] indole-2 -carboxyl ico, 5-bromothieno [2,3-b] indol-2-carboxylate methyloyl, Tienof 2.3-b] indol-2- (N-eti 1carboxamide). 5-Chloro-β-methyl-thieno [2,3-b] indole-2-carboxylic acid methyl, 7-chloro-β-methyl-thieno [2,3-b] indole-2-carboxylate, 8-phenylthieno [2 , 3-b] methyl indole-2-carboxylate, methyl 5-methyl-8-methylthieno [2,
3. 3-b] indole-2-carboxylate,
4. 4-6-dichloro-8-methylthieno [2,3- b] methyl indo1-2-carboxylate.
5. 5-Chloro-8-methyltiene [2.3-b] indo1-2-carboxylic acid. Acid 5-methi 1-8-meti 1tienof 2.3-b] indole-2-carboxy 1 ico. Acid 4, o-dichloro-8-methyltienof 2, 3-b] indole-2-carboxylic acid. 7-Chloro-8-methyltienof 2.3-b] indole-2-carboxylic acid. 8-Phenylthieno [2,3-b] indole-2-carboxylic acid. 5-Chloro-8-methyl 1-2-morphylcarbonyl 1-tieno [2,3-b] indole, 5,8-dimethyl-2-morphol-1-incarbonyl-lthieno [2,3-b] indole, 4,
6. 6-dichloro-8-methyl 1-2-morfolinocarboni 1-tieno [2, 3-b] indole. 8-phenyl 1-2-morpholcarboni Itienof 2, 3-b] indole.
7. 7-s parrot-8-methyl 1-2-morpholinecarbonyl lthienof 2, 3-b] indole, 5-acetyl-1-methyl-methyl-2,3-b] indole-2-carboxylate. 8-methyl-l-5-nitrothieno [2,3-b] indole-2-carboxylic acid methyl ester. 8-Methyl-5-Nitrotiene [2,3-b] indole-2-carboxylic acid.
8. 8-meti 1-2-morfol inocarboni l-5-nitrothieno [2,3-b] indole, 5-bromo-8-methyliso [2,3] indole-2-carboxymethyl methole, 5-bromo-8-acid -meti ltienof 2, 3] indole-2-carboxy 1 ico. 5-bromo-8-methyl 1-2-morphylcarbonyl lthieno [2, 3-b] indole, 8-met i 11 ieno [2.3-b] i ndo 1. 8-meti 1 -3-trif luoroaceti Itienof 2.3- b] indole. 3,8-dimethylthienof 2, 3-b] indo 1-2-carboxylate of met i 1 o. 8 - ((2-methyloxyethyl) -oxymethi 1) -thieno [2,3-b] indole-2-carboxylic acid methyl ester. 8 - ((2-methyloxieti-1) -oxymethyl) -3-methyl-thieno [2,3-b] indole-2-carboxylate. 1-Benzyl-3-methyl-2-methyl-2,3-b] indole-2-carboxylic acid ester, or a salt thereof with a pharmaceutically acceptable acid or base. 3. A method for preparing a compound according to claim 1, characterized in that a) a compound of the formula II is reacted prepared by known methods, wherein R. R. R. R and R are as previously defined, with an N, N-dimethylamide. preferably formamide, and P0C1 3 'using the conditions of Vi lsmeyßr-Hack. to form a compound of formula III 8 1 5 6 7 where R is H or a methyl radical and R. R, R. R and R are as previously defined; and subsequently, b) reacting a compound of the formula III wherein R R 7 and R 8 are as defined above, with methyl mercaptoacetate, to form a compound of formula IV R4 where R, R. R. R. R and R are as previously defined; and subsequently. c) reacting a compound of the formula IV wherein R 1, R 4. R5 R6 R7 and R8 are as defined above, by means of known chemical reactions, by transforming the methyl ester group to other functional groups such as acids, esters, amides, amines or reaction products thereof, as described for the R substituent to form a compound 1? ft 7 of the formula I where R. R. R. R. R and R are as 3 as defined above, and R is H or a methyl radical; or d) reacting a compound of the formula I 1 ri? K f. • and where R is H and R. R. R. R. R and R are as previously defined, with R 1 -V wherein R 1 is as previously defined and Y is a leaving group such as a halogen or sulfonate, using strong bases such as for example metal hydrides, to form a compound of the 1 ^? ? 7 formula I where R. R. R, R. R. R and R are like those previously defined, as long as R is not H; or e) reacting a compound of the formula III (III) 1 4 5 6 7 8 where R is Hy R. R. R. R and R ° are as previously defined, with a compound R -Y. wherein Y is a leaving group such as for example a halogen or sulfonate, using a strong base such as for example metal hydrides, to form a compound of the formula III, wherein R 1, R 4, R 5. R6, R7 and R8 are like the i previously defined, as long as R is not H; or f) reacting a compound of formula I wherein R 1, R 2, and R 3 are as previously defined, and at least one of R. R, R or R is H. with known reactive substrates that lead to aromatic substitution, using reaction conditions known in the art, to form a compound of formula I wherein R, R. R, and R are as previously defined, as long as at least one of R. R, R or R is not H. 4. A pharmaceutical composition characterized in that it comprises a compound according to claim 1. together with a pharmaceutically acceptable carrier or diluent. 5. A pharmaceutical composition for use in the treatment of a disease of the central nervous system, related to the system of metabotropic glutamate receptors. characterized in that it comprises an effective amount of a compound according to claim 1, together with a pharmaceutically acceptable carrier or diluent. 6. A pharmaceutical composition according to any of claims 4 or 5, in the form of an oral dose unit or a parenteral dosage unit. A pharmaceutical composition according to claim 6, characterized in that the dose unit comprises from about 1 to about 100 mg of a compound according to claim 1. 8. A method for treating a central nervous system disease related to the system of metabotropic glutamate receptors, characterized in that it comprises administering to a subject that needs it. an effective amount of a compound according to claim 1. 9. A method for treating a central nervous system disease related to the metabotropic glutamate receptor system. characterized in that it comprises administering, to a subject in need thereof, a pharmaceutical composition according to claim 5. 10. The use of a compound according to claim 1 for the preparation of a medicament for the treatment of a systemic disease. central nervous system related to the metabotropic glutamate receptor system.